Study of MLN2480 in Participants With Relapsed or Refractory Solid Tumors Followed by a Dose Expansion in Participants With Metastatic Melanoma

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01425008
• Collaborator: (none)
• Enrollment: 149
• Locations: 16
• Arm: 1
• Actual Duration (Months): 85
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a phase 1, multicenter, nonrandomized, open-label, dose escalation study. The study will be conducted in 2 stages, Dose Escalation and Dose Expansion. The Dose Escalation phase will include participants with solid tumors (including melanoma) who have failed or are not candidates for standard therapies or for whom no approved therapy is available. The Dose Expansion phase will include participants with metastatic melanoma.

Condition or Disease	Intervention/Treatment	Phase
Melanoma; Metastatic Melanoma; Solid Tumor; Neoplasm	Drug: MLN2480	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 149 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Phase 1, Dose Escalation Study of MLN2480 in Patients With Relapsed or Refractory Solid Tumors Followed by a Dose Expansion Phase in Patients With Metastatic Melanoma
• Actual Study Start Date: Sep 15, 2011
• Actual Primary Completion Date: Apr 11, 2017
• Actual Study Completion Date: Oct 16, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: MLN2480

Drug: MLN2480; Dose Escalation Phase: participants will receive MLN2480 orally in escalating doses every other day or once weekly for three weeks of a 28-day cycle. Participants may continue treatment for additional cycles (up to 12 months) until disease progression, unacceptable toxicity, or the participant discontinues for any other reason. If it is determined that a participant would derive benefit from continued therapy beyond 12 months treatment may continue. Dose Expansion Phase: Participants will take MLN2480 at the maximum tolerated dose orally every other day or once weekly for three weeks of a 28-day cycle until disease progression, unacceptable toxicity, or the participant discontinues for any other reason. The maximum duration of treatment is 1 year unless determined that a participant would derive benefit from continued therapy beyond 12 months.; Other Names: TAK-580

Outcome Measures

Primary Outcome Measures

1. Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths [Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)]

2. Dose Escalation Phase: Number of Participants With Dose-limiting Adverse Events (AEs) [Cycle 1 (Cycle length= 22 days [Q2D] and 28 days [QW])]

   Dose limiting AEs were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Dose limiting AEs were defined as any of the following events: Grade 4 neutropenia for more than 7 days under maximum supportive therapy; febrile neutropenia; platelet counts decreased of Grade 3 requiring platelet transfusion or blood platelet decreased of Grade 4; if Course 2 was not initiated within 14 days due to AE related to the protocol treatment; Grade 3 or higher non-hematologic toxicity that was considered clinically significant, except the following cases, Grade 3 gastrointestinal symptoms that could be controlled with supportive therapy (example, appropriate use of antiemetics, antidiarrheals), and Grade 3 or higher electrolyte abnormalities that were not deemed clinically significant.

3. Number of Participants With TEAEs Related to Physical Examination Findings [Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)]

4. Clinically Significant Change From Baseline in Body Weight at End of Study Visit (EOSV) [Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)]

5. Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings [Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)]

6. Eastern Cooperative Oncology Group (ECOG) Performance Score [at EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)]

   ECOG performance score was measured on 6 point scale to assess participant's performance status, where: 0 (fully active, able to carry on all pre-disease activities without restriction); 1 (restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work); 2 (ambulatory greater than(>) 50 percent (%) of waking hours), capable of all self-care, unable to carry out any work activities); 3 (capable of only limited self-care, confined to bed or chair >50% of waking hours); 4(completely disabled, cannot carry on any self-care, totally confined to bed or chair); 5 (dead). A higher score indicated greater functional impairment.

7. Number of Participants With TEAEs Categorized Into Investigations Related to Laboratory Test of Chemistry, Hematology or Urinalysis [Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)]

Secondary Outcome Measures

1. Overall Response Rate (ORR) [Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)]

   ORR was defined as the percentage of participants with complete response (CR) or partial response (PR). The ORR assessment was based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (<) 10 millimeter (mm). PR: was at least a 30% decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD.

2. Progression-free Survival (PFS) [Baseline up to the date of first document PD, or death due to any cause, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase)]

   PFS was the time from first dose date of study drug to date of the first documentation of confirmed progressive disease (PD) or death, whichever occurred first. The PFS assessment was based on RECIST 1.1. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions. PFS was calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval. Participants with no response assessment were censored at the date of first dose.

3. Duration of Response (DOR) [From the first documented response (CR or PR) up to the date of first documented PD (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase)]

   DOR was assessed from the first documented response (CR or PR) to the date of first documented PD and was censored at the date of the last assessment for responders who died without documented PD and for responders who were still alive and had not progressed. DOR assessment was based on RECIST v1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR: at least 30% decrease in SOD of target lesions, taking as reference the baseline SOD persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. DOR was calculated using Kaplan-Meier estimate.

4. Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Cmax: Maximum Observed Plasma Concentration for TAK-580 [Escalation (Esc.) and Expansion (Exp.) Q2D: C1D1 and 21 pre-dose and at multiple time points (up to 48 hours [h]) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D1 and 22 at multiple time-points (up to168 h) post-dose (C=28 days)]

5. Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Ctrough: Trough Concentration for TAK-580 [Escalation and Expansion Q2D Cohorts: C1D21 pre-dose (C=22 days [Escalation Q2D] and 28 days [Expansion Q2D]); Escalation QW Cohorts: C1D22 pre-dose (C= 28 days)]

6. Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Tmax: Time to Reach the Cmax for TAK-580 [Escalation (Esc.) and Expansion (Exp.) Q2D: C1D1 and 21 pre-dose and at multiple time points (up to 48 h) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D1 and 22 at multiple time-points (up to168 h) post-dose (C=28 days)]

7. Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, t1/2z: Terminal Phase Disposition Half-life for TAK-580 [Escalation (Esc.) and Expansion (Exp.) Q2D: C1D21 pre-dose and at multiple time points (up to 48 h) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D22 at multiple time-points (up to168 h) post-dose (C=28 days)]

8. Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, CLr: Renal Clearance for TAK-580 [Q2D Cohorts: Cycle1 Days 1 and 21 up to 24 hours post-dose (Cycle1 length= 22 days); QW Cohorts: Cycle2 Days 1 and 22 up to 7 hours post-dose (Cycle 2 length= 28 days)]

9. Q2D Dose Escalation Phase and Q2D Dose Expansion Pharmacokinetic Cohort, AUC(0-48): Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Postdose for TAK-580 [Cycle 1 Days 1 and 21 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 22 days)]

10. QW Dose Escalation Phase, AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for TAK-580 [Cycle 1 Days 1 and 22 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)]

11. Dose Expansion Phase, Melanoma Cohorts: Percent Change From Baseline in RAF Inhibition Biomarkers at Specified Time Points [Baseline, Cycle 1 Day 21 (Q2D), and Cycle 1 Day 22 (QW) (Cycle length= 22 days [Q2D] and 28 days [QW])]

    The extent of phosphorylated extracellular signal-regulated kinase (pERK) staining was assessed in the melanoma expansion cohorts. The level of staining was assessed by a pathologist (semi-H scores) and by quantified image analysis (quant H-scores). The H-score scale used to interpret data from the pathologist rating was as follows: 0 to 99 =low staining; 100 to 199= medium staining; 200 to 300 =high staining. The H-score scale used to interpret data from the quantified image analysis was as followed: 0 to 100 =low staining; 100 to 150= medium staining; 150 to 235= high staining.

12. Dose Expansion Phase, Melanoma Cohorts: Percent Change From Baseline in Apoptotic Biomarkers at Specified Time Points [Baseline, Cycle 1 Day 21 (Q2D), and Cycle 1 Day 22 (QW) (Cycle length= 22 days [Q2D] and 28 days [QW])]

    The extent of cleaved poly ADP-ribose polymerase (cPARP) and BIM-1 was assessed in the melanoma expansion cohorts. The level of staining was assessed by quantified image analysis (quant H-scores) and by quantified image analysis (quant H-scores). The H-score scale used to interpret data from the pathologist rating was as follows: 0 to 99= low staining; 100 to 199 =medium staining; 200 to 300 =high staining. The H-score scale used to interpret data from the quantified image analysis was as followed in cPARP: 0 to 70= low staining; 70 to 175 =medium staining; 175 to 240 =high staining; BIM-1: 0 to 128= low staining; 128 to 155 =medium staining; 155 to 229 =high staining.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Informed consent.

2. Male or female participants 18 years or older.

3. Dose Escalation phase: Participants with solid tumors (including melanoma) who have failed or are not candidates for standard therapies of for whom no approved therapy is available.

4. Dose Expansion phase: Metastatic melanoma (locally advanced or metastatic melanoma).

5. Dose Expansion phase: At least 1 measurable lesion which has not been treated previously with radiotherapy. A newly arising lesion in a previously irradiated field is acceptable.

6. For participants undergoing biopsy procedures: Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be within the normal range.

7. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (<=) 1.

8. Adequate tissue sample from either archival formalin-fixed paraffin-embedded (FFPE) tumor tissue or new biopsy of tumor.

9. Previous chemotherapy, immunotherapy, and hormone therapy must be completed at least 4 weeks prior to the administration of MLN2480 and radiation must be completed at least 3 weeks prior to the administration of MLN2480; all associated toxicity must be resolved to <=Grade 1.

10. Expected survival time of at least 3 months in the opinion of the investigator.

11. Participants who do not have hypo- or hyperthyroidism.

12. Ability to swallow and retain oral medication.

13. Female participants who are postmenopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 3 months after the last dose of study drug or agree to practice true abstinence.

14. Male participants who, even if surgically sterilized, agree to practice effective barrier contraception through 3 months after the last dose of alisertib or agree to practice true abstinence.

Exclusion Criteria

1. History of any major disease that might interfere with safe protocol participation.

2. Dose Expansion phase: Previous treatment with RAF or MEK inhibitors.

3. Laboratory values as specified in study protocol.

4. Current enrollment in any other investigational treatment study.

5. Evidence of current uncontrolled cardiovascular conditions within the past 6 months.

6. Prior investigational agents for malignant or non-malignant disease within 4 weeks prior to Day 1.

7. Active hepatitis or human immunodeficiency virus (HIV) infection.

8. Active bacterial or viral infection.

9. Female participants who are pregnant or currently breastfeeding.

10. Major surgery within 28 days of Day 1.

11. Refractory nausea and vomiting, malabsorption, or significant bowel or stomach resection.

12. Inability to comply with study requirements.

13. Other unspecified reasons that, in the opinion of the investigator or Millennium, make the participant unsuitable for enrollment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		San Francisco	California	United States
2		Denver	Colorado	United States
3		Augusta	Georgia	United States
4		Indianapolis	Indiana	United States
5		New York	New York	United States
6		Easton	Pennsylvania	United States
7		Philadelphia	Pennsylvania	United States
8		San Antonio	Texas	United States
9		Lakewood	Washington	United States
10		Bristol	Avon	United Kingdom
11		Cambridge	Cambridgeshire	United Kingdom
12		Chelmsford	Essex	United Kingdom
13		London	Greater London	United Kingdom
14		Manchester	Greater Manchester	United Kingdom
15		Oxford	Oxfordshire	United Kingdom
16		Newcastle upon Tyne	Tyne & Wear	United Kingdom

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Statistical Analysis Plan - Jul 29, 2016
• Study Protocol - May 16, 2017

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01425008
• Other Study ID Numbers: C28001; 2012-003397-16; U1111-1164-7508; 13/SC/0007
• First Posted: Aug 29, 2011
• Last Update Posted: Aug 10, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millennium Pharmaceuticals, Inc.: Drug Therapy
• Additional relevant MeSH terms: Melanoma

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 16 investigative sites in the United States and United Kingdom from 13 September 2011 to 16 October 2018.
Pre-assignment Detail	Participants with relapsed and refractory solid tumors and metastatic melanoma were enrolled in Dose Escalation Phase and Dose Expansion Phase respectively to receive TAK-580 (MLN2480), once every other day (Q2D) or once weekly (QW). Q2D Dose Expansion Phase, TAK-580 (BRAF+) was discontinued due to sponsor's decision of strategic deprioritization.

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	Q2D Dose Expansion Phase: Pharmacokinetic Cohort	Q2D Dose Expansion Phase: TAK-580 (BRAF+)	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive
Arm/Group Description	TAK-580 20 milligram (mg), tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with rapidly accelerated fibrosarcoma (RAF) and mitogen-activated protein kinase (MEPK kinase) or extracellular signal-regulated kinase (ERK kinase) (MEK) inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (wild type [WT]), naive to any prior anticancer therapy except ipilimumab, anti-programmed cell death-1 (PD-1), and anti-PD ligand-1 (PDL-1) monoclonal antibodies.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.
Period Title: Dose Escalation Phase
STARTED	4	3	3	3	7	7	3	3	13	4	0	0	0	0	0	0	0	0	0
COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
NOT COMPLETED	4	3	3	3	7	7	3	3	13	4	0	0	0	0	0	0	0	0	0
Period Title: Dose Escalation Phase
STARTED	0	0	0	0	0	0	0	0	0	0	16	8	16	1	6	11	20	2	19
COMPLETED	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	15	8	16	1	6	11	20	2	19

Baseline Characteristics

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	Q2D Dose Expansion Phase: Pharmacokinetic Cohort	Q2D Dose Expansion Phase: TAK-580 (BRAF+)	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive	Total
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (WT), naive to any prior anticancer therapy except ipilimumab, PD-1, and PDL-1 monoclonal antibodies.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	Total of all reporting groups
Overall Participants	4	3	3	3	7	7	3	3	13	4	16	8	16	1	6	11	20	2	19	149
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	71.0 (10.10)	66.3 (8.33)	56.7 (10.26)	54.7 (13.65)	58.7 (14.77)	65.0 (4.40)	71.0 (6.24)	54.7 (13.58)	57.2 (9.34)	66.8 (7.50)	54.6 (12.44)	58.9 (16.39)	68.4 (7.86)	56.0 (NA)	56.7 (17.24)	67.5 (8.69)	65.1 (14.67)	50.5 (0.71)	66.1 (11.13)	62.5 (12.47)
Sex: Female, Male (Count of Participants)
Female	3 75%	2 66.7%	2 66.7%	2 66.7%	1 14.3%	4 57.1%	2 66.7%	1 33.3%	8 61.5%	2 50%	6 37.5%	5 62.5%	6 37.5%	1 100%	3 50%	6 54.5%	8 40%	2 100%	9 47.4%	73 49%
Male	1 25%	1 33.3%	1 33.3%	1 33.3%	6 85.7%	3 42.9%	1 33.3%	2 66.7%	5 38.5%	2 50%	10 62.5%	3 37.5%	10 62.5%	0 0%	3 50%	5 45.5%	12 60%	0 0%	10 52.6%	76 51%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 50%	1 33.3%	1 33.3%	0 0%	1 14.3%	2 28.6%	0 0%	2 66.7%	4 30.8%	1 25%	0 0%	1 12.5%	0 0%	0 0%	0 0%	0 0%	1 5%	0 0%	0 0%	16 10.7%
Not Hispanic or Latino	1 25%	1 33.3%	1 33.3%	1 33.3%	3 42.9%	2 28.6%	3 100%	1 33.3%	9 69.2%	3 75%	14 87.5%	7 87.5%	16 100%	1 100%	6 100%	11 100%	17 85%	2 100%	18 94.7%	117 78.5%
Unknown or Not Reported	1 25%	1 33.3%	1 33.3%	2 66.7%	3 42.9%	3 42.9%	0 0%	0 0%	0 0%	0 0%	2 12.5%	0 0%	0 0%	0 0%	0 0%	0 0%	2 10%	0 0%	1 5.3%	16 10.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 5%	0 0%	0 0%	1 0.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 25%	0 0%	0 0%	0 0%	1 14.3%	1 14.3%	0 0%	0 0%	1 7.7%	1 25%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	5 3.4%
White	3 75%	3 100%	3 100%	2 66.7%	6 85.7%	6 85.7%	3 100%	3 100%	12 92.3%	3 75%	15 93.8%	8 100%	16 100%	1 100%	6 100%	11 100%	19 95%	2 100%	19 100%	141 94.6%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 6.3%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 1.3%
Region of Enrollment (Count of Participants)
United States	4 100%	3 100%	3 100%	3 100%	7 100%	7 100%	3 100%	3 100%	13 100%	4 100%	6 37.5%	0 0%	10 62.5%	0 0%	1 16.7%	4 36.4%	20 100%	0 0%	11 57.9%	102 68.5%
United Kingdom	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	10 62.5%	8 100%	6 37.5%	1 100%	5 83.3%	7 63.6%	0 0%	2 100%	8 42.1%	47 31.5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths
Time Frame	Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least 1 dose of study drug (TAK-580).

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	Q2D Dose Expansion Phase: Pharmacokinetic Cohort	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive	Q2D Dose Expansion Phase: TAK-580 (BRAF+)
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (WT), naive to any prior anticancer therapy except ipilimumab, PD-1, and PDL-1 monoclonal antibodies.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.
Measure Participants	4	3	3	3	7	7	3	3	13	4	16	8	16	1	6	11	20	19	2
TEAEs	4 100%	3 100%	3 100%	3 100%	7 100%	7 100%	3 100%	3 100%	13 100%	4 100%	16 100%	8 100%	16 100%	1 100%	6 100%	11 100%	20 100%	19 950%	2 10.5%
SAEs	2 50%	0 0%	1 33.3%	0 0%	2 28.6%	4 57.1%	1 33.3%	2 66.7%	5 38.5%	3 75%	9 56.3%	6 75%	5 31.3%	1 100%	2 33.3%	4 36.4%	11 55%	8 400%	2 10.5%
Deaths	1 25%	0 0%	1 33.3%	0 0%	0 0%	1 14.3%	0 0%	0 0%	2 15.4%	1 25%	0 0%	2 25%	2 12.5%	0 0%	0 0%	0 0%	1 5%	0 0%	1 5.3%

2. Primary Outcome

Title	Dose Escalation Phase: Number of Participants With Dose-limiting Adverse Events (AEs)
Description	Dose limiting AEs were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Dose limiting AEs were defined as any of the following events: Grade 4 neutropenia for more than 7 days under maximum supportive therapy; febrile neutropenia; platelet counts decreased of Grade 3 requiring platelet transfusion or blood platelet decreased of Grade 4; if Course 2 was not initiated within 14 days due to AE related to the protocol treatment; Grade 3 or higher non-hematologic toxicity that was considered clinically significant, except the following cases, Grade 3 gastrointestinal symptoms that could be controlled with supportive therapy (example, appropriate use of antiemetics, antidiarrheals), and Grade 3 or higher electrolyte abnormalities that were not deemed clinically significant.
Time Frame	Cycle 1 (Cycle length= 22 days [Q2D] and 28 days [QW])

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least 1 dose of study drug (TAK-580).

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).
Measure Participants	4	3	3	3	7	7	3	3	13	4
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%	0 0%	2 28.6%	0 0%	0 0%	0 0%	2 50%

3. Primary Outcome

Title	Number of Participants With TEAEs Related to Physical Examination Findings
Time Frame	Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least 1 dose of study drug (TAK-580).

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	Q2D Dose Expansion Phase: Pharmacokinetic Cohort	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive	Q2D Dose Expansion Phase: TAK-580 (BRAF+)
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (WT), naive to any prior anticancer therapy except ipilimumab, PD-1, and PDL-1 monoclonal antibodies.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.
Measure Participants	4	3	3	3	7	7	3	3	13	4	16	8	16	1	6	11	20	19	2
Weight decreased	0 0%	0 0%	0 0%	0 0%	0 0%	1 14.3%	0 0%	0 0%	2 15.4%	0 0%	1 6.3%	1 12.5%	0 0%	0 0%	1 16.7%	2 18.2%	1 5%	2 100%	0 0%
Weight increased	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 6.3%	0 0%	0 0%	0 0%	3 15%	0 0%	0 0%
Breath sounds abnormal	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

4. Primary Outcome

Title	Clinically Significant Change From Baseline in Body Weight at End of Study Visit (EOSV)
Time Frame	Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least 1 dose of study drug (TAK-580). Participants who were evaluable for this measure at given time point were included for the assessment.

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	Q2D Dose Expansion Phase: Pharmacokinetic Cohort	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive	Q2D Dose Expansion Phase: TAK-580 (BRAF+)
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (WT), naive to any prior anticancer therapy except ipilimumab, PD-1, and PDL-1 monoclonal antibodies.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.
Measure Participants	4	3	3	3	7	7	3	3	13	4	16	8	16	1	6	11	20	19	2
Baseline	87.477 (15.7794)	72.077 (8.2162)	67.375 (17.3371)	77.717 (4.1695)	76.963 (21.9026)	77.695 (14.3247)	69.522 (17.6937)	73.589 (13.2534)	81.054 (23.6907)	80.503 (15.7401)	95.837 (30.2887)	71.288 (8.6570)	81.312 (17.4736)	57.100 (NA)	75.267 (15.3231)	72.847 (23.8439)	79.624 (16.6098)	83.298 (16.3695)	67.000 (NA)
Change at EOSV	7.167 (16.0315)	-1.693 (1.4468)	1.542 (1.1139)	-0.907 (1.3698)	0.065 (1.4543)	-0.544 (3.1033)	0.272 (1.6037)	-1.225 (4.5746)	-1.868 (4.8255)	-1.270 (0.0005)	-7.825 (20.1782)	-1.700 (6.2386)	-3.164 (3.7607)	-3.225 (2.9826)	0.201 (3.7358)	-4.292 (6.5671)	-3.189 (3.9690)

5. Primary Outcome

Title	Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings
Time Frame	Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least 1 dose of study drug (TAK-580).

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	Q2D Dose Expansion Phase: Pharmacokinetic Cohort	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive	Q2D Dose Expansion Phase: TAK-580 (BRAF+)
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (WT), naive to any prior anticancer therapy except ipilimumab, PD-1, and PDL-1 monoclonal antibodies.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.
Measure Participants	4	3	3	3	7	7	3	3	13	4	16	8	16	1	6	11	20	19	2
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

6. Primary Outcome

Title	Eastern Cooperative Oncology Group (ECOG) Performance Score
Description	ECOG performance score was measured on 6 point scale to assess participant's performance status, where: 0 (fully active, able to carry on all pre-disease activities without restriction); 1 (restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work); 2 (ambulatory greater than(>) 50 percent (%) of waking hours), capable of all self-care, unable to carry out any work activities); 3 (capable of only limited self-care, confined to bed or chair >50% of waking hours); 4(completely disabled, cannot carry on any self-care, totally confined to bed or chair); 5 (dead). A higher score indicated greater functional impairment.
Time Frame	at EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least 1 dose of study drug (TAK-580). Participants who were evaluable for this measure at given time point were included for the assessment.

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	Q2D Dose Expansion Phase: Pharmacokinetic Cohort	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive	Q2D Dose Expansion Phase: TAK-580 (BRAF+)
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (WT), naive to any prior anticancer therapy except ipilimumab, PD-1, and PDL-1 monoclonal antibodies.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.
Measure Participants	3	3	3	3	7	5	2	3	10	2	14	4	12	0	6	11	14	15	1
Mean (Standard Deviation) [score on a scale]	1.0 (0.00)	1.0 (1.00)	1.7 (1.53)	0.3 (0.58)	1.3 (0.49)	1.2 (0.45)	1.0 (0.00)	0.7 (0.58)	1.0 (0.47)	1.0 (0.00)	0.7 (0.73)	1.5 (0.58)	0.6 (0.90)	0.8 (0.41)	1.2 (0.98)	0.6 (0.74)	0.7 (0.80)	2.0 (NA)

7. Primary Outcome

Title	Number of Participants With TEAEs Categorized Into Investigations Related to Laboratory Test of Chemistry, Hematology or Urinalysis
Time Frame	Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least 1 dose of study drug (TAK-580).

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	Q2D Dose Expansion Phase: Pharmacokinetic Cohort	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive	Q2D Dose Expansion Phase: TAK-580 (BRAF+)
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (WT), naive to any prior anticancer therapy except ipilimumab, PD-1, and PDL-1 monoclonal antibodies.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.
Measure Participants	4	3	3	3	7	7	3	3	13	4	16	8	16	1	6	11	20	19	2
Liver function analyses	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	3 18.8%	2 25%	5 31.3%	0 0%	3 50%	3 27.3%	5 25%	2 100%	2 10.5%
Skeletal and cardiac muscle analyses	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	8 50%	1 12.5%	2 12.5%	0 0%	0 0%	5 45.5%	6 30%	1 50%	1 5.3%
Mineral and electrolyte analyses	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 12.5%	3 37.5%	0 0%	0 0%	0 0%	0 0%	2 10%	1 50%	1 5.3%
Tissue enzyme analyses NEC	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	3 18.8%	0 0%	1 16.7%	2 18.2%	1 5%	0 0%	1 5.3%
Renal function analyses	0 0%	0 0%	0 0%	0 0%	0 0%	1 14.3%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 6.3%	0 0%	0 0%	1 9.1%	4 20%	0 0%	0 0%
Platelet analyses	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%	0 0%	0 0%	0 0%	1 6.3%	0 0%	0 0%	0 0%	3 15%	0 0%	0 0%
White blood cell analyses	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 6.3%	0 0%	0 0%	0 0%	0 0%	0 0%	3 15%	0 0%	1 5.3%
Red blood cell analyses	0 0%	0 0%	0 0%	0 0%	1 14.3%	0 0%	0 0%	0 0%	0 0%	0 0%	1 6.3%	1 12.5%	0 0%	0 0%	1 16.7%	0 0%	0 0%	0 0%	0 0%
Pituitary analyses anterior	0 0%	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 6.3%	0 0%	0 0%	0 0%	1 16.7%	0 0%	0 0%	0 0%	0 0%
Carbohydrate tolerance analyses (incl diabetes)	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 5%	0 0%	0 0%
Cardiac function diagnostic procedures	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 6.3%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Coagulation and bleeding analyses	0 0%	0 0%	0 0%	0 0%	1 14.3%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Digestive enzymes	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

8. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	ORR was defined as the percentage of participants with complete response (CR) or partial response (PR). The ORR assessment was based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (<) 10 millimeter (mm). PR: was at least a 30% decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD.
Time Frame	Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)

Outcome Measure Data

Analysis Population Description

Response-evaluable population included all participants with measurable disease who received any amount of TAK-580 and had at least 1 postbaseline response assessment.

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	Q2D Dose Expansion Phase: Pharmacokinetic Cohort	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive	Q2D Dose Expansion Phase: TAK-580 (BRAF+)
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (WT), naive to any prior anticancer therapy except ipilimumab, PD-1, and PDL-1 monoclonal antibodies.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.
Measure Participants	3	3	2	3	6	4	1	3	8	3	16	6	14	1	6	9	14	17	2
Number [percentage of participants]	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	13 100%	33 825%	50 312.5%	17 212.5%	7 43.8%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

9. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS was the time from first dose date of study drug to date of the first documentation of confirmed progressive disease (PD) or death, whichever occurred first. The PFS assessment was based on RECIST 1.1. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions. PFS was calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval. Participants with no response assessment were censored at the date of first dose.
Time Frame	Baseline up to the date of first document PD, or death due to any cause, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least 1 dose of study drug (TAK-580).

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	Q2D Dose Expansion Phase: Pharmacokinetic Cohort	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive	Q2D Dose Expansion Phase: TAK-580 (BRAF+)
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (WT), naive to any prior anticancer therapy except ipilimumab, PD-1, and PDL-1 monoclonal antibodies.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.
Measure Participants	4	3	3	3	7	7	3	3	13	4	16	8	16	1	6	11	20	19	2
Median (95% Confidence Interval) [months]	1.4	1.4	1.4	1.4	1.5	1.2	NA	9.2	1.5	1.9	5.7	2.4	1.8	0.8	1.9	1.8	3.6	2.3	1.7

10. Secondary Outcome

Title	Duration of Response (DOR)
Description	DOR was assessed from the first documented response (CR or PR) to the date of first documented PD and was censored at the date of the last assessment for responders who died without documented PD and for responders who were still alive and had not progressed. DOR assessment was based on RECIST v1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR: at least 30% decrease in SOD of target lesions, taking as reference the baseline SOD persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. DOR was calculated using Kaplan-Meier estimate.
Time Frame	From the first documented response (CR or PR) up to the date of first documented PD (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase)

Outcome Measure Data

Analysis Population Description

Analysis population included only a subset of participants (all responders) with response.

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	Q2D Dose Expansion Phase: Pharmacokinetic Cohort	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive	Q2D Dose Expansion Phase: TAK-580 (BRAF+)
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (WT), naive to any prior anticancer therapy except ipilimumab, PD-1, and PDL-1 monoclonal antibodies.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.
Measure Participants	0	0	0	0	0	0	0	0	1	1	8	1	1	0	0	0	0	0	0
Median (95% Confidence Interval) [months]	NA	NA	6.0	NA	1.5

11. Secondary Outcome

Title	Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Cmax: Maximum Observed Plasma Concentration for TAK-580
Time Frame	Escalation (Esc.) and Expansion (Exp.) Q2D: C1D1 and 21 pre-dose and at multiple time points (up to 48 hours [h]) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D1 and 22 at multiple time-points (up to168 h) post-dose (C=28 days)

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who had sufficient dosing data and TAK-580 concentration-time data to permit calculation of any TAK-580 parameters. PK-evaluable population where data at specified time points was available.

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: Pharmacokinetic Cohort
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.
Measure Participants	4	3	3	3	7	7	3	3	13	4	20
Cycle 1 Day 1	140.0 (86.61)	393.1 (49.81)	921.7 (332.40)	1048.1 (290.91)	1933.6 (717.03)	2675.2 (1296.95)	2072.8 (287.29)	2934.0 (690.39)	4459.3 (1475.08)	6774.3 (1082.79)	1606.9 (670.48)
Cycle 1 Day 21	301.5 (61.83)	759.7 (138.59)	2038.8 (1076.99)	3321.5 (1275.83)	3809.1 (466.85)	4063.1 (782.33)	4588.4 (700.04)	3548.8 (1310.21)
Cycle 1 Day 22	3135.2 (485.70)	4739.8 (2902.53)	6460.2 (1632.31)

12. Secondary Outcome

Title	Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Ctrough: Trough Concentration for TAK-580
Time Frame	Escalation and Expansion Q2D Cohorts: C1D21 pre-dose (C=22 days [Escalation Q2D] and 28 days [Expansion Q2D]); Escalation QW Cohorts: C1D22 pre-dose (C= 28 days)

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who had sufficient dosing data and TAK-580 concentration-time data to permit calculation of any TAK-580 parameters. PK-evaluable population where data at specified time points was available.

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: Pharmacokinetic Cohort
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.
Measure Participants	4	3	3	3	7	7	3	3	13	4	20
Cycle 1 Day 21	178.3 (42.92)	265.5 (74.25)	1080.0 (797.75)	1720.0 (708.87)	1739.7 (746.88)	2135.0 (494.00)	2700.0 (1088.94)	2085.0 (672.26)
Cycle 1 Day 22	270.0 (108.00)	898.7 (618.68)	1216.7 (841.80)

13. Secondary Outcome

Title	Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Tmax: Time to Reach the Cmax for TAK-580
Time Frame	Escalation (Esc.) and Expansion (Exp.) Q2D: C1D1 and 21 pre-dose and at multiple time points (up to 48 h) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D1 and 22 at multiple time-points (up to168 h) post-dose (C=28 days)

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who had sufficient dosing data and TAK-580 concentration-time data to permit calculation of any TAK-580 parameters. PK-evaluable population where data at specified time points was available.

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: Pharmacokinetic Cohort
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.
Measure Participants	4	3	3	3	7	7	3	3	13	4	20
Cycle 1 Day 1	3.983	2.150	2.033	3.917	2.050	4.033	4.000	4.150	3.150	3.100	3.108
Cycle 1 Day 21	2.000	3.050	4.050	2.000	2.992	2.808	12.792	2.192
Cycle 1 Day 22	3.150	3.033	3.950

14. Secondary Outcome

Title	Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, t1/2z: Terminal Phase Disposition Half-life for TAK-580
Time Frame	Escalation (Esc.) and Expansion (Exp.) Q2D: C1D21 pre-dose and at multiple time points (up to 48 h) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D22 at multiple time-points (up to168 h) post-dose (C=28 days)

Outcome Measure Data

Analysis Population Description

PK-evaluable population. t1/2z of TAK-580 could not be determined in cancer participants who were on Q2D regimen with a 48-hour dose interval since the duration of plasma PK sample collection within the dose interval was shorter than the anticipated t1/2z of TAK-580. PK-evaluable population where data at specified time points was available.

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: Pharmacokinetic Cohort
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.
Measure Participants	0	0	0	0	0	0	0	3	6	3	0
Cycle 1 Day 22	50.22	59.06	69.65

15. Secondary Outcome

Title	Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, CLr: Renal Clearance for TAK-580
Time Frame	Q2D Cohorts: Cycle1 Days 1 and 21 up to 24 hours post-dose (Cycle1 length= 22 days); QW Cohorts: Cycle2 Days 1 and 22 up to 7 hours post-dose (Cycle 2 length= 28 days)

Outcome Measure Data

Analysis Population Description

CLr of TAK-580 could not be determined since urine samples were collected for a limited duration during a site visit.

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	Q2D Dose Expansion Phase: Pharmacokinetic Cohort
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.
Measure Participants	0	0	0	0	0	0	0	0	0	0	0

16. Secondary Outcome

Title	Q2D Dose Escalation Phase and Q2D Dose Expansion Pharmacokinetic Cohort, AUC(0-48): Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Postdose for TAK-580
Time Frame	Cycle 1 Days 1 and 21 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 22 days)

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who had sufficient dosing data and TAK-580 concentration-time data to permit calculation of any TAK-580 parameters. PK-evaluable population where data at specified time points was available.

Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	Q2D Dose Expansion Phase: Pharmacokinetic Cohort
Arm/Group Description	TAK-580 20 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 40 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 80 mg, tablet, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.
Measure Participants	4	3	3	3	7	7	3	20
Day 1	4799.7 (2570.95)	11019.7 (655.03)	30562.8 (16909.20)	36061.9 (8904.40)	50946.5 (10597.12)	78993.3 (23713.60)	66799.2 (7656.58)	53522.2 (17337.54)
Day 21	10679.2 (2571.83)	21007.9 (3501.86)	43294.2 (10403.72)	99626.7 (29090.62)	125540.2 (46299.79)	156439.3 (26263.33)	165002.1 (19899.97)	127026.4 (38244.03)

17. Secondary Outcome

Title	QW Dose Escalation Phase, AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for TAK-580
Time Frame	Cycle 1 Days 1 and 22 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)

Outcome Measure Data

Analysis Population Description

The PK-evaluable population included all participants who had sufficient dosing data and TAK-580 concentration-time data to permit calculation of any TAK-580 parameters. PK-evaluable population where data at specified time points was available.

Arm/Group Title	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)
Arm/Group Description	TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).	TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).
Measure Participants	3	13	4
Day 1	184534.4 (50225.97)	278247.9 (128772.92)	431723.3 (106266.40)
Day 22	199210.4 (57957.62)	339244.8 (149201.72)	477700.2 (86620.19)

18. Secondary Outcome

Title	Dose Expansion Phase, Melanoma Cohorts: Percent Change From Baseline in RAF Inhibition Biomarkers at Specified Time Points
Description	The extent of phosphorylated extracellular signal-regulated kinase (pERK) staining was assessed in the melanoma expansion cohorts. The level of staining was assessed by a pathologist (semi-H scores) and by quantified image analysis (quant H-scores). The H-score scale used to interpret data from the pathologist rating was as follows: 0 to 99 =low staining; 100 to 199= medium staining; 200 to 300 =high staining. The H-score scale used to interpret data from the quantified image analysis was as followed: 0 to 100 =low staining; 100 to 150= medium staining; 150 to 235= high staining.
Time Frame	Baseline, Cycle 1 Day 21 (Q2D), and Cycle 1 Day 22 (QW) (Cycle length= 22 days [Q2D] and 28 days [QW])

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD)-evaluable: all participants who had sufficient dosing and PD data,collected within protocol-specified window of sampling time.Participants who were evaluable for this measure at given time point were included. Data for this measure was not planned to be collected and analyzed for Q2D Dose Expansion Phase:Pharmacokinetic Cohort.

Arm/Group Title	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive	Q2D Dose Expansion Phase: TAK-580 (BRAF+)
Arm/Group Description	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (wild type [WT]), naive to any prior anticancer therapy except ipilimumab, anti-programmed cell death-1 (PD-1), and anti-PD ligand-1 (PDL-1) monoclonal antibodies.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.
Measure Participants	3	4	6	0	2	5	3	1
Quant H-score	180.0	-93.5	-82.0	-51.0	-15.0	-8.0	-71.0
Semi H-score	-94.5	-80.5	-70.0	-24.5	-27.0	-12.0	-23.0

19. Secondary Outcome

Title	Dose Expansion Phase, Melanoma Cohorts: Percent Change From Baseline in Apoptotic Biomarkers at Specified Time Points
Description	The extent of cleaved poly ADP-ribose polymerase (cPARP) and BIM-1 was assessed in the melanoma expansion cohorts. The level of staining was assessed by quantified image analysis (quant H-scores) and by quantified image analysis (quant H-scores). The H-score scale used to interpret data from the pathologist rating was as follows: 0 to 99= low staining; 100 to 199 =medium staining; 200 to 300 =high staining. The H-score scale used to interpret data from the quantified image analysis was as followed in cPARP: 0 to 70= low staining; 70 to 175 =medium staining; 175 to 240 =high staining; BIM-1: 0 to 128= low staining; 128 to 155 =medium staining; 155 to 229 =high staining.
Time Frame	Baseline, Cycle 1 Day 21 (Q2D), and Cycle 1 Day 22 (QW) (Cycle length= 22 days [Q2D] and 28 days [QW])

Outcome Measure Data

Analysis Population Description

PD-evaluable: all participants who had sufficient dosing and PD data, collected within protocol-specified window of sampling time. Participants who were evaluable for this measure at given time point were included. Data for this measure was not planned to be collected and analyzed for Q2D Dose Expansion Phase: Pharmacokinetic Cohort.

Arm/Group Title	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive	Q2D Dose Expansion Phase: TAK-580 (BRAF+)
Arm/Group Description	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (wild type [WT]), naive to any prior anticancer therapy except ipilimumab, anti-programmed cell death-1 (PD-1), and anti-PD ligand-1 (PDL-1) monoclonal antibodies.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.	TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.	TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.
Measure Participants	3	4	6	0	2	5	3	1
cPARP Quant H-score	-100.0	317.5	-100.0	-33.5
cPARP Semi H-score	-96.0	-33.0	-11.0	-48.0
BIM-1 Quant H-score	265.0	136.0	158.0	-52.5	-23.5	35.5	960.0
BIM-1 Semi H-score	723.5	64.5	64.0	-41.0	-17.0	-3.5

Adverse Events

Time Frame	TEAEs are AEs that started after the first dose of study drug and no more than 30 days after the last dose of study drug (approximately Cycle 38 Days 52 [Q2D] and 58 [QW] in Escalation Phase; Cycle 49 Day 58 in Expansion Phase)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)		QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)		QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)		QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)		Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)		Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)		Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)		Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)		Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive		Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated		Q2D Dose Expansion Phase: Pharmacokinetic Cohort		Q2D Dose Expansion Phase: TAK-580 (BRAF+)		QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive
Arm/Group Description	TAK-580 20 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cy cle 38).		TAK-580 40 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).		TAK-580 80 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).		TAK-580 135 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).		TAK-580 200 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).		TAK-580 280 mg, tablets, orally, Q2D, in each 22-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).		TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).		TAK-580 400 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).		TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).		TAK-580 800 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 38).		TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.		TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF mutation-positive cutaneous melanoma, which in response to previous treatment with RAF inhibitors and/or MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.		TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.		TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with NRAS mutation-positive cutaneous melanoma, which in response to previous treatment with MEK inhibitors had relapsed following an objective response, failed to demonstrate an objective response and/or could not tolerate such a regimen due to unacceptable toxicity.		TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative cutaneous melanoma (WT), naive to any prior anticancer therapy except ipilimumab, PD-1, and PDL-1 monoclonal antibodies.		TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF/NRAS mutation-negative melanoma (WT), who had received at least 1 line of prior anticancer therapy.		TAK-580 200 mg, tablets, orally, on Days 1 through 21 in a 28-days treatment Cycle 1, followed by TAK-580 200 mg, tablets, orally, Q2D in each 28-days treatment cycle from Cycle 2 until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with any advanced solid tumor (excluding lymphoma, but including melanoma) who had failed or were not candidates for standard therapies or for whom no approved therapy was available.		TAK-580 200 mg, tablets, orally, Q2D, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49) in participants with BRAF-mutation positive cutaneous melanoma.		TAK-580 600 mg, tablets, orally, QW, in each 28-days treatment cycle until disease progression, unacceptable toxicity, or participant discontinuation for any other reason (up to Cycle 49), in participants with NRAS mutation-positive cutaneous melanoma, naive to prior therapy with RAF and MEK inhibitors.
All Cause Mortality
	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)		QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)		QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)		QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)		Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)		Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)		Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)		Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)		Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive		Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated		Q2D Dose Expansion Phase: Pharmacokinetic Cohort		Q2D Dose Expansion Phase: TAK-580 (BRAF+)		QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/4 (25%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)		1/7 (14.3%)		0/3 (0%)		0/3 (0%)		2/13 (15.4%)		1/4 (25%)		0/16 (0%)		2/8 (25%)		2/16 (12.5%)		0/1 (0%)		0/6 (0%)		0/11 (0%)		1/20 (5%)		1/2 (50%)		0/19 (0%)
Serious Adverse Events
	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)		QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)		QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)		QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)		Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)		Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)		Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)		Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)		Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive		Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated		Q2D Dose Expansion Phase: Pharmacokinetic Cohort		Q2D Dose Expansion Phase: TAK-580 (BRAF+)		QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/4 (50%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		2/7 (28.6%)		4/7 (57.1%)		1/3 (33.3%)		2/3 (66.7%)		5/13 (38.5%)		3/4 (75%)		9/16 (56.3%)		6/8 (75%)		5/16 (31.3%)		1/1 (100%)		2/6 (33.3%)		4/11 (36.4%)		11/20 (55%)		2/2 (100%)		8/19 (42.1%)
Blood and lymphatic system disorders
Anaemia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Cardiac disorders
Atrial fibrillation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	2/16 (12.5%)	2	0/1 (0%)	0	1/6 (16.7%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Cardiac failure	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Cardiac failure congestive	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Angina pectoris	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Cardio-respiratory arrest	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Gastrointestinal disorders
Constipation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	1/1 (100%)	11	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Gastrooesophageal reflux disease	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Abdominal pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Abdominal pain upper	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Rectal haemorrhage	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Nausea	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	2/19 (10.5%)	2
Melaena	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Upper gastrointestinal haemorrhage	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Crohn's disease	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Small intestinal obstruction	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Dysphagia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Diverticular perforation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Retroperitoneal haemorrhage	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Gastrointestinal haemorrhage	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
General disorders
Asthenia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	0
Peripheral swelling	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Oedema peripheral	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Adverse drug reaction	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Hepatobiliary disorders
Hyperbilirubinaemia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Cholangitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Infections and infestations
Lower respiratory tract infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Pneumonia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	1/19 (5.3%)	1
Sepsis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	1/16 (6.3%)	1	0/1 (0%)	0	1/6 (16.7%)	1	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Diverticulitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Clostridium difficile colitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Escherichia sepsis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	1/2 (50%)	1	0/19 (0%)	0
Urinary tract infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Injury, poisoning and procedural complications
Fall	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Investigations
Ejection fraction decreased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Alanine aminotransferase increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Metabolism and nutrition disorders
Diabetic ketoacidosis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Hypophosphataemia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Dehydration	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Musculoskeletal and connective tissue disorders
Flank pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Musculoskeletal chest pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic malignant melanoma	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	1/2 (50%)	1	0/19 (0%)	0
Malignant melanoma	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Colon cancer	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Colon cancer metastatic	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Tumour haemorrhage	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Pancreatic carcinoma	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Nervous system disorders
Guillain-Barre syndrome	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Haemorrhage intracranial	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Ataxia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	2/20 (10%)	0	0/2 (0%)	0	0/19 (0%)	0
Haematuria	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	0	0/3 (0%)	0	0/3 (0%)	0	3/13 (23.1%)	3	0/4 (0%)	0	2/16 (12.5%)	2	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	2/19 (10.5%)	2
Respiratory distress	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Pleural effusion	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	1/1 (100%)	1	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	1/2 (50%)	1	1/19 (5.3%)	1
Respiratory failure	1/4 (25%)	2	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Acute respiratory failure	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Haemoptysis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Pulmonary embolism	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Skin and subcutaneous tissue disorders
Rash macular	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	2/11 (18.2%)	2	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Rash maculo-papular	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Rash	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Erythema multiforme	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Psoriasis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Vascular disorders
Hypotension	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Other (Not Including Serious) Adverse Events
	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)		Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)		QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)		QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)		QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)		Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)		Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)		Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)		Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)		Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive		Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated		Q2D Dose Expansion Phase: Pharmacokinetic Cohort		Q2D Dose Expansion Phase: TAK-580 (BRAF+)		QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		7/7 (100%)		7/7 (100%)		3/3 (100%)		3/3 (100%)		12/13 (92.3%)		4/4 (100%)		16/16 (100%)		8/8 (100%)		16/16 (100%)		1/1 (100%)		6/6 (100%)		11/11 (100%)		19/20 (95%)		2/2 (100%)		19/19 (100%)
Blood and lymphatic system disorders
Anaemia	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/7 (28.6%)	2	2/7 (28.6%)	2	2/3 (66.7%)	2	1/3 (33.3%)	1	4/13 (30.8%)	4	3/4 (75%)	3	5/16 (31.3%)	7	2/8 (25%)	2	7/16 (43.8%)	9	1/1 (100%)	1	1/6 (16.7%)	1	5/11 (45.5%)	9	9/20 (45%)	13	2/2 (100%)	2	4/19 (21.1%)	5
Lymphopenia	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	2	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Leukopenia	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Neutropenia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	2	0/2 (0%)	0	0/19 (0%)	0
Thrombocytopenia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/7 (28.6%)	2	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Haemolytic anaemia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Leukocytosis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Reticulocytosis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Cardiac disorders
Tachycardia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	1/6 (16.7%)	1	1/11 (9.1%)	1	0/20 (0%)	0	1/2 (50%)	1	0/19 (0%)	0
Atrial fibrillation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	1/8 (12.5%)	1	0/16 (0%)	0	1/1 (100%)	1	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Atrial flutter	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	2/19 (10.5%)	2
Palpitations	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	4/19 (21.1%)	6
Angina pectoris	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Bradycardia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Pericardial effusion	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Sinus tachycardia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	3
Supraventricular extrasystoles	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Ear and labyrinth disorders
Vertigo	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Cerumen impaction	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Ear discomfort	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Ear disorder	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Ear pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Motion sickness	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Tinnitus	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Endocrine disorders
Hypothyroidism	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Eye disorders
Periorbital oedema	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/7 (14.3%)	1	2/7 (28.6%)	2	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	4/16 (25%)	4	2/8 (25%)	2	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	3/11 (27.3%)	4	3/20 (15%)	4	1/2 (50%)	1	2/19 (10.5%)	3
Eye swelling	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	2/16 (12.5%)	2	0/8 (0%)	0	3/16 (18.8%)	3	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Vision blurred	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	1/8 (12.5%)	1	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Eye pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Ocular hyperaemia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Conjunctival haemorrhage	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Dry eye	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	2	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Eye haemorrhage	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Eyelash discolouration	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Lacrimation increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Eye irritation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	7/16 (43.8%)	19	3/8 (37.5%)	4	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Eye pruritus	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Eyelid disorder	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Eyelid irritation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Eyelids pruritus	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Optic nerve disorder	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Photophobia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Scleral haemorrhage	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Vitreous floaters	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Gastrointestinal disorders
Constipation	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	3/3 (100%)	3	3/7 (42.9%)	3	2/7 (28.6%)	2	0/3 (0%)	0	0/3 (0%)	0	4/13 (30.8%)	4	0/4 (0%)	0	12/16 (75%)	42	7/8 (87.5%)	23	9/16 (56.3%)	11	0/1 (0%)	0	3/6 (50%)	3	1/11 (9.1%)	1	6/20 (30%)	10	0/2 (0%)	0	4/19 (21.1%)	5
Nausea	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	2/7 (28.6%)	2	1/7 (14.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	5/13 (38.5%)	5	1/4 (25%)	1	5/16 (31.3%)	5	1/8 (12.5%)	1	5/16 (31.3%)	5	0/1 (0%)	0	1/6 (16.7%)	1	1/11 (9.1%)	2	11/20 (55%)	15	2/2 (100%)	2	5/19 (26.3%)	6
Vomiting	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	2/13 (15.4%)	4	2/4 (50%)	3	0/16 (0%)	0	0/8 (0%)	0	2/16 (12.5%)	5	1/1 (100%)	1	2/6 (33.3%)	5	3/11 (27.3%)	3	4/20 (20%)	9	1/2 (50%)	2	3/19 (15.8%)	4
Diarrhoea	1/4 (25%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	2/7 (28.6%)	2	1/3 (33.3%)	1	0/3 (0%)	0	2/13 (15.4%)	3	1/4 (25%)	1	3/16 (18.8%)	4	0/8 (0%)	0	3/16 (18.8%)	3	0/1 (0%)	0	1/6 (16.7%)	1	1/11 (9.1%)	1	5/20 (25%)	6	0/2 (0%)	0	1/19 (5.3%)	4
Abdominal pain	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	1/7 (14.3%)	2	0/7 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	2/13 (15.4%)	2	2/4 (50%)	2	2/16 (12.5%)	3	1/8 (12.5%)	1	1/16 (6.3%)	1	1/1 (100%)	1	0/6 (0%)	0	1/11 (9.1%)	1	3/20 (15%)	3	0/2 (0%)	0	0/19 (0%)	0
Gastrooesophageal reflux disease	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	3/16 (18.8%)	4	0/8 (0%)	0	3/16 (18.8%)	5	0/1 (0%)	0	1/6 (16.7%)	1	1/11 (9.1%)	1	4/20 (20%)	4	0/2 (0%)	0	1/19 (5.3%)	1
Dry mouth	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	3/8 (37.5%)	3	1/16 (6.3%)	1	0/1 (0%)	0	1/6 (16.7%)	1	2/11 (18.2%)	2	2/20 (10%)	2	0/2 (0%)	0	0/19 (0%)	0
Dyspepsia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	2/16 (12.5%)	3	0/1 (0%)	0	0/6 (0%)	0	2/11 (18.2%)	2	0/20 (0%)	0	0/2 (0%)	0	3/19 (15.8%)	3
Stomatitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	2/7 (28.6%)	2	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Abdominal distension	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	2/20 (10%)	2	0/2 (0%)	0	0/19 (0%)	0
Abdominal discomfort	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	2/16 (12.5%)	3	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	1/19 (5.3%)	1
Abdominal pain upper	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Rectal haemorrhage	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	4/13 (30.8%)	4	4/4 (100%)	5	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Ascites	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	2	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Haematochezia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	2/16 (12.5%)	2	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Retching	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Anal haemorrhage	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Dysphagia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Lip swelling	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Abdominal pain lower	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Chapped lips	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Cheilitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Colitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	2
Eructation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Flatulence	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Gastritis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Gastrointestinal haemorrhage	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Gastrointestinal pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Gingival bleeding	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Gingival pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Glossodynia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Hiatus hernia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	1/2 (50%)	1	0/19 (0%)	0
Hypoaesthesia oral	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Lip dry	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Mouth ulceration	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Oral pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Proctalgia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	2	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Salivary gland pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
General disorders
Fatigue	3/4 (75%)	3	1/3 (33.3%)	1	1/3 (33.3%)	1	2/3 (66.7%)	2	6/7 (85.7%)	8	6/7 (85.7%)	7	1/3 (33.3%)	1	3/3 (100%)	3	6/13 (46.2%)	7	2/4 (50%)	2	5/16 (31.3%)	5	3/8 (37.5%)	4	7/16 (43.8%)	8	0/1 (0%)	0	3/6 (50%)	4	3/11 (27.3%)	3	12/20 (60%)	13	1/2 (50%)	1	9/19 (47.4%)	12
Oedema peripheral	1/4 (25%)	1	0/3 (0%)	0	2/3 (66.7%)	3	0/3 (0%)	0	2/7 (28.6%)	2	2/7 (28.6%)	2	0/3 (0%)	0	0/3 (0%)	0	3/13 (23.1%)	3	0/4 (0%)	0	3/16 (18.8%)	5	2/8 (25%)	2	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	7/20 (35%)	9	0/2 (0%)	0	0/19 (0%)	0
Pyrexia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	2/13 (15.4%)	5	0/4 (0%)	0	7/16 (43.8%)	9	1/8 (12.5%)	1	1/16 (6.3%)	1	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	2/20 (10%)	2	2/2 (100%)	2	3/19 (15.8%)	4
Face oedema	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	3/7 (42.9%)	4	3/7 (42.9%)	3	0/3 (0%)	0	1/3 (33.3%)	1	1/13 (7.7%)	1	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	4/20 (20%)	4	0/2 (0%)	0	0/19 (0%)	0
Chills	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/7 (28.6%)	2	3/7 (42.9%)	3	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	1/4 (25%)	1	2/16 (12.5%)	2	1/8 (12.5%)	1	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	3/20 (15%)	3	0/2 (0%)	0	0/19 (0%)	0
Chest pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	3/16 (18.8%)	3	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Mucosal inflammation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	2/11 (18.2%)	3	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Influenza like illness	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Pain	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Non-cardiac chest pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	2	0/2 (0%)	0	0/19 (0%)	0
Peripheral swelling	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	2/16 (12.5%)	2	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Chest discomfort	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Localised oedema	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Oedema	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Asthenia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Axillary pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Catheter site pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Facial pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Feeling cold	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Gait disturbance	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Injection site bruising	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Malaise	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	2/11 (18.2%)	2	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Hepatobiliary disorders
Hyperbilirubinaemia	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Hepatotoxicity	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Infections and infestations
Urinary tract infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	3/16 (18.8%)	3	2/8 (25%)	3	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	2/11 (18.2%)	2	2/20 (10%)	2	0/2 (0%)	0	1/19 (5.3%)	1
Nasopharyngitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	2/16 (12.5%)	2	1/8 (12.5%)	1	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	1/2 (50%)	1	0/19 (0%)	0
Oral candidiasis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	1/1 (100%)	1	1/6 (16.7%)	1	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Upper respiratory tract infection	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	2	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Cellulitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	2/16 (12.5%)	4	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Pneumonia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1	0/2 (0%)	0	1/19 (5.3%)	1
Sepsis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	1/1 (100%)	1	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Conjunctivitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	2	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Lower respiratory tract infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	1/8 (12.5%)	1	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Lung infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/13 (0%)	0	1/4 (25%)	1	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	2	0/2 (0%)	0	0/19 (0%)	0
Oral herpes	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	2/16 (12.5%)	2	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Candida infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Escherichia urinary tract infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Rash pustular	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	2/8 (25%)	2	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Rhinitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Sinusitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	1/19 (5.3%)	1
Tinea infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Biliary tract infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Bronchitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Ear lobe infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	2	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Folliculitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Fungal skin infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Genital infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Klebsiella bacteraemia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Laryngitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Paronychia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Peritonitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Post procedural infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Skin infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	2	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Fall	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	1/8 (12.5%)	2	0/16 (0%)	0	1/1 (100%)	1	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Procedural pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Conjunctival abrasion	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Joint dislocation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Limb injury	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Stoma site pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Transfusion reaction	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Investigations
Blood creatine phosphokinase increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	8/16 (50%)	13	1/8 (12.5%)	1	2/16 (12.5%)	2	0/1 (0%)	0	0/6 (0%)	0	5/11 (45.5%)	7	6/20 (30%)	10	1/2 (50%)	1	1/19 (5.3%)	1
Aspartate aminotransferase increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	2/16 (12.5%)	3	0/8 (0%)	0	4/16 (25%)	4	0/1 (0%)	0	1/6 (16.7%)	2	2/11 (18.2%)	3	5/20 (25%)	8	2/2 (100%)	2	0/19 (0%)	0
Blood bilirubin increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	2/8 (25%)	2	1/16 (6.3%)	1	0/1 (0%)	0	1/6 (16.7%)	2	3/11 (27.3%)	3	2/20 (10%)	2	0/2 (0%)	0	2/19 (10.5%)	2
Weight decreased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/13 (15.4%)	2	0/4 (0%)	0	1/16 (6.3%)	1	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	2/11 (18.2%)	2	1/20 (5%)	1	0/2 (0%)	0	2/19 (10.5%)	6
Blood creatinine increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	4/20 (20%)	7	0/2 (0%)	0	0/19 (0%)	0
Alanine aminotransferase increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	2/16 (12.5%)	2	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Blood alkaline phosphatase increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	2/16 (12.5%)	2	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1	1/2 (50%)	1	0/19 (0%)	0
Platelet count decreased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	3/20 (15%)	4	0/2 (0%)	0	0/19 (0%)	0
Blood calcium decreased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	2/20 (10%)	2	0/2 (0%)	0	1/19 (5.3%)	1
Haemoglobin decreased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Lymphocyte count decreased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	3/20 (15%)	3	0/2 (0%)	0	0/19 (0%)	0
Weight increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	3/20 (15%)	3	0/2 (0%)	0	0/19 (0%)	0
Blood lactate dehydrogenase increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Blood phosphorus decreased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	2/16 (12.5%)	2	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Blood thyroid stimulating hormone increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
White blood cell count decreased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	3/20 (15%)	3	0/2 (0%)	0	0/19 (0%)	0
Blood sodium decreased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	1/2 (50%)	1	0/19 (0%)	0
Neutrophil count decreased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	2/20 (10%)	3	0/2 (0%)	0	0/19 (0%)	0
Blood folate decreased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Blood potassium increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	2	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Breath sounds abnormal	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Electrocardiogram QT prolonged	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Electrocardiogram T wave inversion	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
International normalised ratio increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Lipase increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Neutrophil count increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	1/2 (50%)	1	0/19 (0%)	0
White blood cell count increased	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	1/2 (50%)	1	0/19 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	1/4 (25%)	1	0/3 (0%)	0	2/3 (66.7%)	3	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	1/4 (25%)	1	3/16 (18.8%)	3	2/8 (25%)	2	4/16 (25%)	5	0/1 (0%)	0	2/6 (33.3%)	2	1/11 (9.1%)	1	2/20 (10%)	2	0/2 (0%)	0	4/19 (21.1%)	5
Hypocalcaemia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	2/7 (28.6%)	2	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	2	0/1 (0%)	0	2/6 (33.3%)	2	1/11 (9.1%)	1	1/20 (5%)	1	0/2 (0%)	0	1/19 (5.3%)	1
Hypokalaemia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	3/13 (23.1%)	3	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	2/20 (10%)	2	0/2 (0%)	0	0/19 (0%)	0
Hyponatraemia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	1/8 (12.5%)	1	2/16 (12.5%)	2	0/1 (0%)	0	0/6 (0%)	0	3/11 (27.3%)	4	2/20 (10%)	2	0/2 (0%)	0	0/19 (0%)	0
Dehydration	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	3	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	1/4 (25%)	1	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	1/1 (100%)	1	0/6 (0%)	0	0/11 (0%)	0	2/20 (10%)	2	0/2 (0%)	0	0/19 (0%)	0
Hypoalbuminaemia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	2	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Hypophosphataemia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	3	1/11 (9.1%)	1	0/20 (0%)	0	1/2 (50%)	2	0/19 (0%)	0
Hyperglycaemia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	2	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Hyperkalaemia	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	2/20 (10%)	2	0/2 (0%)	0	0/19 (0%)	0
Fluid retention	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Musculoskeletal and connective tissue disorders
Myalgia	1/4 (25%)	1	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	1/7 (14.3%)	1	2/3 (66.7%)	2	2/3 (66.7%)	2	2/13 (15.4%)	2	1/4 (25%)	1	2/16 (12.5%)	2	1/8 (12.5%)	3	3/16 (18.8%)	3	0/1 (0%)	0	2/6 (33.3%)	2	2/11 (18.2%)	2	9/20 (45%)	9	1/2 (50%)	1	3/19 (15.8%)	3
Arthralgia	2/4 (50%)	3	2/3 (66.7%)	2	0/3 (0%)	0	2/3 (66.7%)	2	1/7 (14.3%)	1	2/7 (28.6%)	2	0/3 (0%)	0	0/3 (0%)	0	3/13 (23.1%)	3	1/4 (25%)	1	3/16 (18.8%)	4	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	2/11 (18.2%)	2	4/20 (20%)	4	0/2 (0%)	0	4/19 (21.1%)	4
Pain in extremity	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	1/4 (25%)	1	2/16 (12.5%)	4	2/8 (25%)	3	3/16 (18.8%)	3	1/1 (100%)	1	2/6 (33.3%)	3	3/11 (27.3%)	5	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Back pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	2/13 (15.4%)	2	0/4 (0%)	0	3/16 (18.8%)	3	0/8 (0%)	0	1/16 (6.3%)	1	1/1 (100%)	1	1/6 (16.7%)	3	3/11 (27.3%)	4	3/20 (15%)	3	0/2 (0%)	0	1/19 (5.3%)	1
Muscle spasms	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	2/16 (12.5%)	2	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	2/20 (10%)	2	0/2 (0%)	0	1/19 (5.3%)	1
Musculoskeletal chest pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	2/7 (28.6%)	2	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	3/16 (18.8%)	3	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Flank pain	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/7 (0%)	0	2/7 (28.6%)	2	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Musculoskeletal pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	3	1/8 (12.5%)	1	1/16 (6.3%)	2	0/1 (0%)	0	2/6 (33.3%)	2	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Joint swelling	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Muscular weakness	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	1/19 (5.3%)	1
Bone pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Groin pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Intervertebral disc protrusion	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Joint stiffness	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Limb discomfort	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Muscle tightness	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus	2/4 (50%)	3	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Seborrhoeic keratosis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	1/19 (5.3%)	1
Metastases to chest wall	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Tumour pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	2	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Nervous system disorders
Headache	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	5/13 (38.5%)	5	0/4 (0%)	0	4/16 (25%)	5	2/8 (25%)	2	1/16 (6.3%)	2	0/1 (0%)	0	2/6 (33.3%)	5	0/11 (0%)	0	2/20 (10%)	2	0/2 (0%)	0	2/19 (10.5%)	3
Dysgeusia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	5/16 (31.3%)	5	3/8 (37.5%)	3	1/16 (6.3%)	1	0/1 (0%)	0	1/6 (16.7%)	1	3/11 (27.3%)	4	3/20 (15%)	3	0/2 (0%)	0	1/19 (5.3%)	1
Dizziness	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	1/6 (16.7%)	2	0/11 (0%)	0	3/20 (15%)	3	0/2 (0%)	0	1/19 (5.3%)	1
Peripheral motor neuropathy	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	1/13 (7.7%)	2	1/4 (25%)	1	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Neuropathy peripheral	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	2/8 (25%)	2	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Paraesthesia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	2	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Peripheral sensory neuropathy	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	1/19 (5.3%)	1
Ageusia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Hypoaesthesia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	4	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Presyncope	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Aphasia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Ataxia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Balance disorder	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Dysarthria	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Facial paralysis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Hyperaesthesia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Lethargy	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Memory impairment	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Nervous system disorder	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Poor quality sleep	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	1/1 (100%)	1	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Restless legs syndrome	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Somnolence	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Tremor	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Psychiatric disorders
Insomnia	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	2	1/20 (5%)	1	1/2 (50%)	1	0/19 (0%)	0
Anxiety	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/13 (15.4%)	2	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Depression	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	2	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Confusional state	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Hallucination	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Mood altered	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Sleep disorder	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Renal and urinary disorders
Pollakiuria	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	3/20 (15%)	3	0/2 (0%)	0	0/19 (0%)	0
Dysuria	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	2/20 (10%)	2	0/2 (0%)	0	0/19 (0%)	0
Haematuria	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Proteinuria	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	2	0/20 (0%)	0	1/2 (50%)	1	1/19 (5.3%)	1
Urinary retention	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Acute kidney injury	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Hydronephrosis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Ureteric obstruction	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Urinary bladder haemorrhage	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Reproductive system and breast disorders
Atrophic vulvovaginitis	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Breast oedema	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Scrotal oedema	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Vaginal haemorrhage	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/7 (28.6%)	2	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	6/16 (37.5%)	8	1/8 (12.5%)	1	3/16 (18.8%)	3	0/1 (0%)	0	1/6 (16.7%)	1	2/11 (18.2%)	2	9/20 (45%)	10	1/2 (50%)	1	2/19 (10.5%)	2
Cough	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	3/16 (18.8%)	4	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	5/20 (25%)	5	0/2 (0%)	0	2/19 (10.5%)	2
Dyspnoea exertional	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	2/11 (18.2%)	2	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Epistaxis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/13 (15.4%)	2	0/4 (0%)	0	2/16 (12.5%)	2	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	5	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Pleural effusion	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	1/1 (100%)	1	1/6 (16.7%)	1	1/11 (9.1%)	1	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Oropharyngeal pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	1	2/16 (12.5%)	3	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Productive cough	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	2	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Pulmonary haemorrhage	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	1/4 (25%)	2	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	2/2 (100%)	2	0/19 (0%)	0
Haemoptysis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	2
Dysphonia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Nasal inflammation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Pleuritic pain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Pneumonitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	2	0/2 (0%)	0	1/19 (5.3%)	1
Rhinitis allergic	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	1/19 (5.3%)	1
Sinus congestion	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	2/20 (10%)	2	0/2 (0%)	0	0/19 (0%)	0
Upper-airway cough syndrome	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Wheezing	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Hiccups	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	2	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Hypoxia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Interstitial lung disease	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Nasal congestion	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Nasal dryness	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Nasal ulcer	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Pulmonary oedema	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Restrictive pulmonary disease	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Rhinorrhoea	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Throat tightness	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Skin and subcutaneous tissue disorders
Rash maculo-papular	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/3 (66.7%)	2	2/7 (28.6%)	2	4/7 (57.1%)	5	2/3 (66.7%)	3	0/3 (0%)	0	2/13 (15.4%)	2	0/4 (0%)	0	7/16 (43.8%)	11	3/8 (37.5%)	5	9/16 (56.3%)	18	0/1 (0%)	0	1/6 (16.7%)	1	2/11 (18.2%)	2	7/20 (35%)	9	0/2 (0%)	0	2/19 (10.5%)	3
Pruritus	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	1/7 (14.3%)	1	2/3 (66.7%)	2	0/3 (0%)	0	3/13 (23.1%)	3	0/4 (0%)	0	2/16 (12.5%)	2	3/8 (37.5%)	4	4/16 (25%)	4	0/1 (0%)	0	2/6 (33.3%)	3	1/11 (9.1%)	1	4/20 (20%)	5	0/2 (0%)	0	1/19 (5.3%)	1
Dermatitis acneiform	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	4/16 (25%)	8	0/8 (0%)	0	2/16 (12.5%)	3	0/1 (0%)	0	1/6 (16.7%)	1	2/11 (18.2%)	3	3/20 (15%)	3	0/2 (0%)	0	2/19 (10.5%)	2
Hair colour changes	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	6/16 (37.5%)	7	1/8 (12.5%)	1	3/16 (18.8%)	3	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	2/20 (10%)	2	0/2 (0%)	0	1/19 (5.3%)	1
Dry skin	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	2/16 (12.5%)	2	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	3/20 (15%)	4	0/2 (0%)	0	2/19 (10.5%)	2
Photosensitivity reaction	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	4/16 (25%)	4	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	2/20 (10%)	4	0/2 (0%)	0	2/19 (10.5%)	2
Rash	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	3/16 (18.8%)	8	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	2/20 (10%)	2	0/2 (0%)	0	2/19 (10.5%)	2
Alopecia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/13 (0%)	0	0/4 (0%)	0	2/16 (12.5%)	2	0/8 (0%)	0	2/16 (12.5%)	2	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	2/20 (10%)	2	0/2 (0%)	0	0/19 (0%)	0
Rash macular	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	3	0/4 (0%)	0	2/16 (12.5%)	3	1/8 (12.5%)	4	1/16 (6.3%)	1	0/1 (0%)	0	1/6 (16.7%)	2	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	3
Hyperhidrosis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	3/20 (15%)	3	0/2 (0%)	0	0/19 (0%)	0
Rash erythematous	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	2/16 (12.5%)	2	0/1 (0%)	0	0/6 (0%)	0	2/11 (18.2%)	2	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Rash papular	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	2/16 (12.5%)	2	1/8 (12.5%)	2	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Rash pruritic	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	2/16 (12.5%)	2	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Rash generalised	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	2	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	1/2 (50%)	1	0/19 (0%)	0
Night sweats	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/13 (15.4%)	3	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Pain of skin	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/7 (14.3%)	1	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Swelling face	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	2	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Eczema	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Madarosis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Purpura	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Skin exfoliation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	2	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Skin mass	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Vitiligo	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	2/20 (10%)	2	0/2 (0%)	0	0/19 (0%)	0
Acne	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	1/19 (5.3%)	1
Butterfly rash	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Ecchymosis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Erythema	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Hyperkeratosis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Hypertrichosis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Lichenoid keratosis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Livedo reticularis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Nail disorder	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Palmar-plantar erythrodysaesthesia syndrome	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Psoriasis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	2	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Skin hypopigmentation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Skin plaque	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Skin ulcer	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Vascular disorders
Flushing	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/7 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	1/6 (16.7%)	1	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	2/19 (10.5%)	2
Hypotension	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	2	0/2 (0%)	0	0/19 (0%)	0
Hot flush	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	1/20 (5%)	1	0/2 (0%)	0	0/19 (0%)	0
Hypertension	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	1/16 (6.3%)	1	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Haematoma	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/13 (7.7%)	1	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Lymphoedema	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	1/8 (12.5%)	1	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Peripheral coldness	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	1/16 (6.3%)	1	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Raynaud's phenomenon	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	0/11 (0%)	0	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0
Vena cava thrombosis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/13 (0%)	0	0/4 (0%)	0	0/16 (0%)	0	0/8 (0%)	0	0/16 (0%)	0	0/1 (0%)	0	0/6 (0%)	0	1/11 (9.1%)	1	0/20 (0%)	0	0/2 (0%)	0	0/19 (0%)	0

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.