Olaparib Tablets as a Treatment for Ovarian Cancer Subjects With Different HRD Tumor Status

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02983799
• Collaborator: (none)
• Enrollment: 272
• Locations: 47
• Arms: 4
• Actual Duration (Months): 47.4
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a non-randomized, open-label study to assess olaparib tablets as a treatment for subjects with different homologous recombination deficiency (HRD) tumor status and with platinum-sensitive, relapsed, high-grade serous or high-grade endometrioid ovarian cancer. Subjects should have received at least 1 prior line of platinum-based chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Relapsed Ovarian Cancer, BRCA Mutation, Platinum Sensitivity	Drug: OLAPARIB	Phase 2

Detailed Description

This is a Phase II, open-label, non-randomized, multi-center study assessing the efficacy and safety of olaparib tablets 300 mg (two 150 mg tablets) given orally twice daily (bid) in subjects with platinum-sensitive or partially platinum-sensitive, relapsed, high-grade serous or high-grade endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received at least 1 prior line of platinum-based chemotherapy.

The study will assess the effectiveness of olaparib tablets as measured by the objective response rate (ORR) as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, in subjects with germline BRCA mutations (gBRCAm), somatic BRCA mutations (sBRCAm), or potential aberrations in homologous recombination deficiency (HRD) as determined by myChoice® HRD, as well as in subjects without identifiable HRD. This study will utilize Myriad BRACAnalysis CDx® for germline BRCA analysis and a tumor test (myChoice® HRD) for tumor BRCA analysis and HRD status. Four cohorts will be identified based upon the genetic testing described above:

• Cohort 1: gBRCAm,

• Cohort 2: sBRCAm and germline BRCA wild type,

• Cohort 3: myChoice® HRD positive (genomic instability positive) and BRCA wild type (BRCAwt) (no BRCA mutation),

• Cohort 4: myChoice® HRD negative (genomic instability negative) and BRCAwt (no BRCA mutation).

Study Design

• Study Type: Interventional
• Actual Enrollment: 272 participants
• Allocation: N/A
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Non-Randomized, Open-Label Phase II Study to Assess Olaparib Tablets as a Treatment for Subjects With Different HRD Tumor Status and With Platinum-Sensitive, Relapsed, High-Grade Serous or High-Grade Endometrioid Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer That Have Received at Least 1 Prior Line of Chemotherapy
• Actual Study Start Date: Dec 22, 2016
• Actual Primary Completion Date: Dec 3, 2020
• Actual Study Completion Date: Dec 3, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: gBRCAm; germline BRCA mutant	Drug: OLAPARIB; 300 mg olaparib tablets taken orally twice daily
Experimental: sBRCAm and germline BRCA wild type; somatic BRCA mutant, germline BRCA wild type	Drug: OLAPARIB; 300 mg olaparib tablets taken orally twice daily
Experimental: myChoice® HRD positive and BRCAwt; genomic instability positive and no BRCA mutation	Drug: OLAPARIB; 300 mg olaparib tablets taken orally twice daily
Experimental: myChoice® HRD negative and BRCAwt genomic instability negative and no BRCA mutation	Drug: OLAPARIB; 300 mg olaparib tablets taken orally twice daily

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate, Defined as the Percentage of Subjects With a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) [From first dose up until progression, or last evaluable assessment in the absence of progression (up to 36 months)]

   To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using ORR according to RECIST v1.1 criteria (Investigator determined)

Secondary Outcome Measures

1. Duration of Response, for Those Subjects With a Confirmed Response of CR or PR [From the date of the measurement criteria for CR or PR are first met until the date of documented progression or death in the absence of disease progression (up to 36 months)]

   To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using duration of response

2. CA-125 Response Rate, Defined as the Percentage of Subjects With a CA-125 Response According to GCIG Criteria Divided by the Number of Subjects Evaluable for CA-125 Response [From baseline to Day 1 of each cycle and end of study treatment visit (up to 36 months)]

   To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using CA-125 response rate

3. Disease Control Rate Defined as the Percentage of Subjects Who Have a Best Overall Response of CR or PR or SD at Greater Than or Equal to 8 Weeks Divided by the Number of Subjects in the Efficacy Analysis Set, Prior to Any PD Event [From first dose up until progression, or last evaluable assessment in the absence of progression]

   To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using disease control rate (DCR). DCR is defined as the percentage of subjects with a best overall response of CR or PR (at any time up to and including the defined analysis cut-off point) or who have demonstrated stable disease (SD) for at least 8 weeks from first dose, divided by the number of subjects in the efficacy analysis set.

4. Progression Free Survival [From first dose to earlier date of assessment of objective progression or death by any cause in the absence of progression (up to 36 months)]

   To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using progression free survival

5. Time to Any Progression [From first dose to earlier date of CA-125 progression or RECIST v1.1 progression, or death by any cause in absence of progression (up to 36 months)]

   To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using time to any progression

6. Overall Survival [From date of first dose to date of death from any cause (up to 48 months)]

   To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using overall survival

7. HRD Status as Per HRRm Gene Panel Assessment Will be Correlated With Clinical Outcome (ORR) for Subjects Enrolled in the 2 Cohorts With BRCAwt (Cohorts 3 and 4) [At baseline]

   To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using HRRm gene panel status related to clinical outcome

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Provision of written signed informed consent prior to any study specific procedures;

• Female subjects with histologically diagnosed relapsed high-grade serous or high-grade endometrioid ovarian cancer;

• At least 1 lesion (measurable by RECIST v1.1) that can be accurately assessed at baseline by computed tomography (CT)/magnetic resonance imaging (MRI) and is suitable for repeated assessment;

• Subjects must have received at least 1 prior platinum-based line of chemotherapy for ovarian cancer. Note: There is no limit on the number of lines of chemotherapy;

• Subjects must be partially-platinum-sensitive (defined as progression 6 to 12 months after the end of the last platinum-based chemotherapy) or platinum sensitive (defined as progression > 12 months after the end of the last platinum-based chemotherapy);

• Subjects must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment;

• ECOG performance status 0 to 1;

• Subjects must have a life expectancy greater than or equal to 16 weeks;

• Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on Day 1;

• Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations; and

• Formalin fixed, paraffin embedded tumor sample (either archival or fresh sample) from the primary or recurrent cancer must be available for central testing. If there is not written confirmation of the availability of an archived or fresh tumor sample prior to enrollment, the subject is not eligible for the study.

Exclusion Criteria:

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca Representative staff and/or staff at the study site);

• Previous enrollment in the present study;

• Exposure to any investigational product (IP) within 30 days or 5 half-lives (whichever is longer) prior to start of study treatment;

• Any previous treatment with a PARP inhibitor, including olaparib;

• Subjects who have platinum-resistant or refractory disease defined as progression during or within 6 months of the last platinum-based chemotherapy;

• Other malignancy within the last 5 years (few exceptions apply);

• Resting ECG with clinically significant abnormal findings;

• Subjects receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment;

• Concomitant use of known strong CYP3A inhibitors or moderate CYP3A inhibitors;

• Concomitant use of known strong or moderate CYP3A inducers;

• Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE] grade

1. caused by previous cancer therapy, excluding alopecia;

• Subjects with MDS/AML or with features suggestive of MDS/AML;

• Subjects with pneumonitis or at risk of pneumonitis;

• Subjects with symptomatic uncontrolled brain metastases;

• Major surgery within 2 weeks of starting study treatment, and subjects must have recovered from any effects of any major surgery;

• Subjects considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active, uncontrolled infection;

• Breast feeding women;

• Immunocompromised subjects, e.g., subjects who are known to be serologically positive for human immunodeficiency virus;

• Subjects with known active hepatitis (i.e., Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Anchorage	Alaska	United States	99508
2	Research Site	La Jolla	California	United States	92093
3	Research Site	Los Angeles	California	United States	90017
4	Research Site	Aurora	Colorado	United States	80045
5	Research Site	Hartford	Connecticut	United States	06102
6	Research Site	New Haven	Connecticut	United States	06519
7	Research Site	Newark	Delaware	United States	19718
8	Research Site	South Miami	Florida	United States	33143
9	Research Site	Skokie	Illinois	United States	60077
10	Research Site	Shreveport	Louisiana	United States	71103
11	Research Site	Silver Spring	Maryland	United States	20910
12	Research Site	Springfield	Massachusetts	United States	01199
13	Research Site	Detroit	Michigan	United States	48201
14	Research Site	Detroit	Michigan	United States	48202
15	Research Site	Minneapolis	Minnesota	United States	55407
16	Research Site	Saint Paul	Minnesota	United States	55125
17	Research Site	Berkeley Heights	New Jersey	United States	07922
18	Research Site	Hackensack	New Jersey	United States	07601
19	Research Site	Newark	New Jersey	United States	07103
20	Research Site	Teaneck	New Jersey	United States	07666
21	Research Site	Bronx	New York	United States	10461
22	Research Site	New York	New York	United States	10021
23	Research Site	New York	New York	United States	10032
24	Research Site	New York	New York	United States	10065
25	Research Site	Winston-Salem	North Carolina	United States	27103
26	Research Site	Cincinnati	Ohio	United States	45219
27	Research Site	Portland	Oregon	United States	97227
28	Research Site	Abington	Pennsylvania	United States	19001
29	Research Site	Philadelphia	Pennsylvania	United States	19104
30	Research Site	Pittsburgh	Pennsylvania	United States	15224
31	Research Site	Providence	Rhode Island	United States	02905
32	Research Site	Germantown	Tennessee	United States	38138
33	Research Site	Houston	Texas	United States	77030
34	Research Site	Annandale	Virginia	United States	22003
35	Research Site	Milwaukee	Wisconsin	United States	53226
36	Research Site	Edmonton	Alberta	Canada	T6G 1Z2
37	Research Site	Vancouver	British Columbia	Canada	VSZ 4E6
38	Research Site	Winnipeg	Manitoba	Canada	R3E 0V9
39	Research Site	Halifax	Nova Scotia	Canada	B3H 1V7
40	Research Site	Hamilton	Ontario	Canada	L8V 5C2
41	Research Site	Kingston	Ontario	Canada	K7L 2V7
42	Research Site	Mississauga	Ontario	Canada	L5M 2N1
43	Research Site	Toronto	Ontario	Canada	M4N 3M5
44	Research Site	Montreal	Quebec	Canada	H1T 2M4
45	Research Site	Montreal	Quebec	Canada	H2X 0A9
46	Research Site	Montreal	Quebec	Canada	H4A 3J1
47	Research Site	Sherbrooke	Quebec	Canada	J1H 5N4

Sponsors and Collaborators

• AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Oct 10, 2017
• Statistical Analysis Plan - Oct 3, 2019

More Information

Additional Information:

• Cancer Study Locator 1-877-400-4656 [e-mail]
• Related Info
• Related Info

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02983799
• Other Study ID Numbers: D0816L00003
• First Posted: Dec 6, 2016
• Last Update Posted: Apr 13, 2022
• Last Verified: Mar 1, 2022

• 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 AstraZeneca: BRCA, ovarian, platinum, chemotherapy
• Additional relevant MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Olaparib

Study Results

Participant Flow

Pre-assignment Detail	A total of 272 subjects enrolled. One subject did not receive treatment and was excluded from analysis (Cohort 2 patient). All participants received a dose of 300mg BID of study drug

Arm/Group Title	COHORT 1	COHORT 2	COHORT 3	COHORT 4	Unassigned
Arm/Group Description	germline BRCA mutant	somatic BRCA mutant, germline BRCA wild type	HRD positive and no BRCA mutation	HRD negative and no BRCA mutation	Cohort unassigned
Period Title: Overall Study
STARTED	75	26	68	90	13
COMPLETED	25	8	18	14	3
NOT COMPLETED	50	18	50	76	10

Baseline Characteristics

Arm/Group Title	COHORT 1	COHORT 2	COHORT 3	COHORT 4	Unassigned	Total
Arm/Group Description	germline BRCA mutant	somatic BRCA mutant, germline BRCA wild type	HRD positive and no BRCA mutation	HRD negative and no BRCA mutation	Cohort unassigned	Total of all reporting groups
Overall Participants	75	26	68	90	13	272
Age (Age Continuous) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Age Continuous]	60.7 (9.3)	69.7 (9.0)	63.2 (9.9)	67.8 (9.5)	69.8 (10.0)	64.9 (10.1)
Sex/Gender, Customized (Number) [Number]
Female	75 100%	26 100%	68 100%	90 100%	13 100%	272 100%
Race/Ethnicity, Customized (Number) [Number]
WHITE	58 77.3%	23 88.5%	50 73.5%	78 86.7%	11 84.6%	220 80.9%
BLACK OR AFRICAN AMERICAN	7 9.3%	0 0%	5 7.4%	5 5.6%	0 0%	17 6.3%
ASIAN	6 8%	3 11.5%	11 16.2%	6 6.7%	2 15.4%	28 10.3%
NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
AMERICAN INDIAN OR ALASKA NATIVE	0 0%	0 0%	1 1.5%	0 0%	0 0%	1 0.4%
OTHER	4 5.3%	0 0%	1 1.5%	1 1.1%	0 0%	6 2.2%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate, Defined as the Percentage of Subjects With a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR)
Description	To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using ORR according to RECIST v1.1 criteria (Investigator determined)
Time Frame	From first dose up until progression, or last evaluable assessment in the absence of progression (up to 36 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1	Cohort 2	COHORT 3	COHORT 4	Unassigned
Arm/Group Description	germline BRCA mutant	somatic BRCA mutant, germline BRCA wild type	HRD positive and no BRCA mutation	HRD negative and no BRCA mutation	Cohort unassigned
Measure Participants	75	25	68	89	13
Number (95% Confidence Interval) [Percent]	69.3	64.0	29.4	10.1	30.8

2. Secondary Outcome

Title	Duration of Response, for Those Subjects With a Confirmed Response of CR or PR
Description	To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using duration of response
Time Frame	From the date of the measurement criteria for CR or PR are first met until the date of documented progression or death in the absence of disease progression (up to 36 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1	Cohort 2	COHORT 3	COHORT 4	Unassigned
Arm/Group Description	germline BRCA mutant	somatic BRCA mutant, germline BRCA wild type	HRD positive and no BRCA mutation	HRD negative and no BRCA mutation	Cohort unassigned
Measure Participants	52	16	20	9	4
Median (95% Confidence Interval) [Months]	9.4	14.7	10.0	5.3	7.5

3. Secondary Outcome

Title	CA-125 Response Rate, Defined as the Percentage of Subjects With a CA-125 Response According to GCIG Criteria Divided by the Number of Subjects Evaluable for CA-125 Response
Description	To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using CA-125 response rate
Time Frame	From baseline to Day 1 of each cycle and end of study treatment visit (up to 36 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1	Cohort 2	COHORT 3	COHORT 4	Unassigned
Arm/Group Description	germline BRCA mutant	somatic BRCA mutant, germline BRCA wild type	HRD positive and no BRCA mutation	HRD negative and no BRCA mutation	Cohort unassigned
Measure Participants	44	20	48	64	12
Number (95% Confidence Interval) [Percent]	93.2	70.0	47.9	26.6	66.7

4. Secondary Outcome

Title	Disease Control Rate Defined as the Percentage of Subjects Who Have a Best Overall Response of CR or PR or SD at Greater Than or Equal to 8 Weeks Divided by the Number of Subjects in the Efficacy Analysis Set, Prior to Any PD Event
Description	To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using disease control rate (DCR). DCR is defined as the percentage of subjects with a best overall response of CR or PR (at any time up to and including the defined analysis cut-off point) or who have demonstrated stable disease (SD) for at least 8 weeks from first dose, divided by the number of subjects in the efficacy analysis set.
Time Frame	From first dose up until progression, or last evaluable assessment in the absence of progression

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1	Cohort 2	COHORT 3	COHORT 4	Unassigned
Arm/Group Description	germline BRCA mutant	somatic BRCA mutant, germline BRCA wild type	HRD positive and no BRCA mutation	HRD negative and no BRCA mutation	Cohort unassigned
Measure Participants	75	25	68	89	13
Number (95% Confidence Interval) [Percent]	96.0	100.0	79.4	75.3	92.3

5. Secondary Outcome

Title	Progression Free Survival
Description	To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using progression free survival
Time Frame	From first dose to earlier date of assessment of objective progression or death by any cause in the absence of progression (up to 36 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1	Cohort 2	COHORT 3	COHORT 4	Unassigned
Arm/Group Description	germline BRCA mutant	somatic BRCA mutant, germline BRCA wild type	HRD positive and no BRCA mutation	HRD negative and no BRCA mutation	Cohort unassigned
Measure Participants	75	25	68	89	13
Median (95% Confidence Interval) [Months]	11	10.8	7.2	5.4	9.2

6. Secondary Outcome

Title	Time to Any Progression
Description	To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using time to any progression
Time Frame	From first dose to earlier date of CA-125 progression or RECIST v1.1 progression, or death by any cause in absence of progression (up to 36 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1	Cohort 2	COHORT 3	COHORT 4	Unassigned
Arm/Group Description	germline BRCA mutant	somatic BRCA mutant, germline BRCA wild type	HRD positive and no BRCA mutation	HRD negative and no BRCA mutation	Cohort unassigned
Measure Participants	75	25	68	89	13
Median (95% Confidence Interval) [Months]	10.9	11.1	7.2	5.3	7.3

7. Secondary Outcome

Title	Overall Survival
Description	To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using overall survival
Time Frame	From date of first dose to date of death from any cause (up to 48 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1	Cohort 2	COHORT 3	COHORT 4	Unassigned
Arm/Group Description	germline BRCA mutant	somatic BRCA mutant, germline BRCA wild type	HRD positive and no BRCA mutation	HRD negative and no BRCA mutation	Cohort unassigned
Measure Participants	75	25	68	89	13
Median (95% Confidence Interval) [Months]	NA	NA	NA	23.8	18

8. Secondary Outcome

Title	HRD Status as Per HRRm Gene Panel Assessment Will be Correlated With Clinical Outcome (ORR) for Subjects Enrolled in the 2 Cohorts With BRCAwt (Cohorts 3 and 4)
Description	To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using HRRm gene panel status related to clinical outcome
Time Frame	At baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 3, HRRm Pos	Cohort 3, HRRm Neg	Cohort 4, HRRm Pos	Cohort 4, HRRm Neg
Arm/Group Description	HRD positive and no BRCA mutation, HRRm positive	HRD positive and no BRCA mutation, HRRm negative	HRD negative and no BRCA mutation, HRRm positive	HRD negative and no BRCA mutation, HRRm negative
Measure Participants	9	56	12	76
Number (95% Confidence Interval) [Percent]	11.1	32.1	8.3	10.5

Adverse Events

Time Frame	Adverse events (AEs), serious AEs, AEs of special interest (AESIs), and AEs leading to discontinuation were collected from signature of informed consent for study participation. Treatment emerging AEs were reported from date of first dose of study treatment and continued throughout the active treatment period and the follow-up period 30 days after the last dose of olaparib. After the primary analysis data cut-off till study completion, only deaths, SAEs, AESIs and DAEs were collected/reported.
Adverse Event Reporting Description	Adverse events and serious adverse events are reported in the safety analysis set including all patients who received at least one dose of study treatment. Between the primary analysis data cut-off and final data cut-off (12-month overall survival), only serious adverse events, adverse events of special interest, and adverse events leading to discontinuation were collected.
Arm/Group Title	COHORT 1		COHORT 2		COHORT 3		COHORT 4		UNASSIGNED
Arm/Group Description	germline BRCA mutant		somatic BRCA mutant, germline BRCA wild type		HRD positive and no BRCA mutation		HRD negative and no BRCA mutation		Cohort unassigned
All Cause Mortality
	COHORT 1		COHORT 2		COHORT 3		COHORT 4		UNASSIGNED
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/75 (26.7%)		5/25 (20%)		23/68 (33.8%)		47/90 (52.2%)		7/13 (53.8%)
Serious Adverse Events
	COHORT 1		COHORT 2		COHORT 3		COHORT 4		UNASSIGNED
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/75 (17.3%)		8/25 (32%)		7/68 (10.3%)		35/90 (38.9%)		6/13 (46.2%)
Blood and lymphatic system disorders
Anaemia	2/75 (2.7%)	2	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Anaemia macrocytic	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Thrombocytopenia	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Cardiac disorders
Acute myocardial infarction	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Atrial fibrillation	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Atrioventricular block	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Gastrointestinal disorders
Duodenal ulcer perforation	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Intestinal pseudo-obstruction	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Large intestinal obstruction	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Large intestine perforation	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Abdominal pain	1/75 (1.3%)	1	1/25 (4%)	1	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Diarrhoea	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	2/90 (2.2%)	3	0/13 (0%)	0
Gastrointestinal obstruction	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Ileus	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Intestinal obstruction	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	4/90 (4.4%)	4	0/13 (0%)	0
Nausea	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Small intestinal obstruction	4/75 (5.3%)	4	1/25 (4%)	1	0/68 (0%)	0	6/90 (6.7%)	7	4/13 (30.8%)	6
Small intestinal perforation	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Vomiting	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
General disorders
Asthenia	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Hepatobiliary disorders
Bile duct stenosis	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Cholangitis	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Infections and infestations
Bacteraemia	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	1/13 (7.7%)	1
Escherichia bacteraemia	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Folliculitis	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Pneumonia	1/75 (1.3%)	1	0/25 (0%)	0	2/68 (2.9%)	2	1/90 (1.1%)	1	0/13 (0%)	0
Sepsis	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Urinary tract infection	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Injury, poisoning and procedural complications
Gastrointestinal stoma complication	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Rib fracture	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Fall	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Hip fracture	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Incisional hernia, obstructive	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Sternal fracture	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Strangulated incisional hernia	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	1/13 (7.7%)	1
Investigations
Platelet count decreased	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Food intolerance	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Hypokalaemia	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Muscular weakness	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Nervous system disorders
Headache	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Dizziness	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Encephalopathy	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Syncope	0/75 (0%)	0	1/25 (4%)	2	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Psychiatric disorders
Confusional state	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Renal and urinary disorders
Chronic kidney disease	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Hydronephrosis	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Hydroureter	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Nephrolithiasis	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Urinary tract obstruction	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Pulmonary embolism	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	5/90 (5.6%)	5	0/13 (0%)	0
Dyspnoea	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	1/13 (7.7%)	1
Epistaxis	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Pleural effusion	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Pneumonitis	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	1/13 (7.7%)	2
Pulmonary fibrosis	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Skin and subcutaneous tissue disorders
Umbilical erythema	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Vascular disorders
Deep vein thrombosis	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Embolism	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	3/90 (3.3%)	3	0/13 (0%)	0
Hypertensive emergency	0/75 (0%)	0	1/25 (4%)	2	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Hypotension	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Vena cava thrombosis	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Other (Not Including Serious) Adverse Events
	COHORT 1		COHORT 2		COHORT 3		COHORT 4		UNASSIGNED
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	75/75 (100%)		25/25 (100%)		67/68 (98.5%)		88/90 (97.8%)		12/13 (92.3%)
Blood and lymphatic system disorders
Anaemia	18/75 (24%)	25	7/25 (28%)	13	14/68 (20.6%)	16	31/90 (34.4%)	38	5/13 (38.5%)	6
Leukopenia	1/75 (1.3%)	1	0/25 (0%)	0	2/68 (2.9%)	3	1/90 (1.1%)	2	1/13 (7.7%)	1
Lymphopenia	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	1/13 (7.7%)	1
Macrocytosis	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Neutropenia	5/75 (6.7%)	6	0/25 (0%)	0	2/68 (2.9%)	3	2/90 (2.2%)	3	0/13 (0%)	0
Thrombocytopenia	0/75 (0%)	0	0/25 (0%)	0	3/68 (4.4%)	3	2/90 (2.2%)	2	0/13 (0%)	0
Cardiac disorders
Angina pectoris	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Bradycardia	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Palpitations	1/75 (1.3%)	1	2/25 (8%)	2	0/68 (0%)	0	4/90 (4.4%)	4	0/13 (0%)	0
Pericardial effusion	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Sinus arrhythmia	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Sinus bradycardia	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Sinus tachycardia	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Tachycardia	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Tachycardia paroxysmal	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	2	0/13 (0%)	0
Ear and labyrinth disorders
Hypoacusis	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Tinnitus	2/75 (2.7%)	5	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	1/13 (7.7%)	1
Vertigo	0/75 (0%)	0	1/25 (4%)	1	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Endocrine disorders
Adrenal insufficiency	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Goitre	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Eye disorders
Conjunctival hyperaemia	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Dry eye	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Eye pain	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Eye pruritus	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Eye swelling	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Lacrimation increased	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	2/90 (2.2%)	2	0/13 (0%)	0
Ocular discomfort	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Papilloedema	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Photophobia	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Vision blurred	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	3/90 (3.3%)	3	0/13 (0%)	0
Vitreous floaters	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Abdominal distension	11/75 (14.7%)	12	2/25 (8%)	4	9/68 (13.2%)	10	8/90 (8.9%)	8	1/13 (7.7%)	3
Abdominal hernia	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Abdominal mass	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Abdominal pain	15/75 (20%)	20	4/25 (16%)	4	10/68 (14.7%)	10	13/90 (14.4%)	17	7/13 (53.8%)	9
Abdominal pain lower	0/75 (0%)	0	1/25 (4%)	1	3/68 (4.4%)	3	6/90 (6.7%)	7	0/13 (0%)	0
Abdominal pain upper	2/75 (2.7%)	2	0/25 (0%)	0	3/68 (4.4%)	3	6/90 (6.7%)	8	0/13 (0%)	0
Anal incontinence	2/75 (2.7%)	2	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Ascites	0/75 (0%)	0	1/25 (4%)	1	3/68 (4.4%)	3	6/90 (6.7%)	8	1/13 (7.7%)	2
Breath odour	2/75 (2.7%)	2	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Colitis	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Constipation	15/75 (20%)	19	7/25 (28%)	8	19/68 (27.9%)	19	24/90 (26.7%)	28	1/13 (7.7%)	1
Diarrhoea	17/75 (22.7%)	23	4/25 (16%)	4	15/68 (22.1%)	20	18/90 (20%)	25	5/13 (38.5%)	6
Dry mouth	3/75 (4%)	3	2/25 (8%)	2	8/68 (11.8%)	8	4/90 (4.4%)	4	1/13 (7.7%)	1
Dyspepsia	7/75 (9.3%)	8	3/25 (12%)	4	9/68 (13.2%)	10	11/90 (12.2%)	11	4/13 (30.8%)	5
Eructation	2/75 (2.7%)	2	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	1/13 (7.7%)	1
Flatulence	1/75 (1.3%)	1	0/25 (0%)	0	2/68 (2.9%)	2	5/90 (5.6%)	6	0/13 (0%)	0
Food poisoning	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Frequent bowel movements	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Gastrooesophageal reflux disease	11/75 (14.7%)	18	2/25 (8%)	2	5/68 (7.4%)	6	7/90 (7.8%)	8	0/13 (0%)	0
Haemorrhoidal haemorrhage	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Haemorrhoids	1/75 (1.3%)	1	1/25 (4%)	1	1/68 (1.5%)	1	2/90 (2.2%)	2	0/13 (0%)	0
Lip pain	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Nausea	50/75 (66.7%)	84	20/25 (80%)	38	42/68 (61.8%)	66	60/90 (66.7%)	76	8/13 (61.5%)	11
Oesophagitis	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Oral pain	2/75 (2.7%)	2	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Proctalgia	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Rectal haemorrhage	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	3/90 (3.3%)	5	0/13 (0%)	0
Small intestinal obstruction	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	2/13 (15.4%)	2
Stomatitis	3/75 (4%)	3	3/25 (12%)	3	1/68 (1.5%)	1	4/90 (4.4%)	4	0/13 (0%)	0
Tongue discolouration	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Toothache	2/75 (2.7%)	2	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Vomiting	21/75 (28%)	37	12/25 (48%)	17	15/68 (22.1%)	27	35/90 (38.9%)	56	6/13 (46.2%)	10
Dysphagia	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Haematochezia	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Intra-abdominal fluid collection	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Melaena	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Mouth ulceration	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	1/13 (7.7%)	1
Tongue ulceration	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
General disorders
Asthenia	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	4/90 (4.4%)	4	1/13 (7.7%)	1
Axillary pain	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	2	0/90 (0%)	0	1/13 (7.7%)	1
Chest discomfort	3/75 (4%)	3	0/25 (0%)	0	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Chest pain	3/75 (4%)	3	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	1/13 (7.7%)	1
Chills	1/75 (1.3%)	1	1/25 (4%)	1	2/68 (2.9%)	2	5/90 (5.6%)	6	0/13 (0%)	0
Early satiety	2/75 (2.7%)	3	1/25 (4%)	1	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Face oedema	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	2	1/90 (1.1%)	1	0/13 (0%)	0
Fatigue	50/75 (66.7%)	55	15/25 (60%)	16	43/68 (63.2%)	46	50/90 (55.6%)	56	9/13 (69.2%)	13
Feeling cold	0/75 (0%)	0	1/25 (4%)	2	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Feeling jittery	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Gait disturbance	0/75 (0%)	0	1/25 (4%)	1	1/68 (1.5%)	1	2/90 (2.2%)	2	0/13 (0%)	0
General physical health deterioration	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Generalised oedema	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Influenza like illness	3/75 (4%)	4	1/25 (4%)	1	5/68 (7.4%)	5	1/90 (1.1%)	1	1/13 (7.7%)	1
Localised oedema	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Malaise	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Mucosal inflammation	1/75 (1.3%)	1	1/25 (4%)	1	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Non-cardiac chest pain	1/75 (1.3%)	1	1/25 (4%)	1	2/68 (2.9%)	3	1/90 (1.1%)	1	0/13 (0%)	0
Oedema peripheral	10/75 (13.3%)	11	4/25 (16%)	4	3/68 (4.4%)	3	14/90 (15.6%)	24	0/13 (0%)	0
Pain	2/75 (2.7%)	2	2/25 (8%)	2	1/68 (1.5%)	1	2/90 (2.2%)	2	0/13 (0%)	0
Performance status decreased	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Peripheral swelling	0/75 (0%)	0	0/25 (0%)	0	4/68 (5.9%)	4	1/90 (1.1%)	1	0/13 (0%)	0
Physical deconditioning	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Pyrexia	0/75 (0%)	0	0/25 (0%)	0	3/68 (4.4%)	3	7/90 (7.8%)	7	1/13 (7.7%)	1
Suprapubic pain	1/75 (1.3%)	1	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Temperature intolerance	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Hepatobiliary disorders
Jaundice	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Immune system disorders
Food allergy	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Seasonal allergy	2/75 (2.7%)	2	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Contrast media allergy	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	1/13 (7.7%)	1
Drug hypersensitivity	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	2	0/90 (0%)	0	0/13 (0%)	0
Infections and infestations
Arthritis infective	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Bacteraemia	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	1/13 (7.7%)	1
Bronchitis	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	3/90 (3.3%)	3	1/13 (7.7%)	1
Candida infection	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Cellulitis	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Cellulitis orbital	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Cystitis	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Ear infection	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Eye infection	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Fungal infection	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Furuncle	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Genital herpes	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Herpes zoster	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Hordeolum	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Impetigo	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Influenza	1/75 (1.3%)	1	2/25 (8%)	2	1/68 (1.5%)	1	3/90 (3.3%)	3	0/13 (0%)	0
Laryngitis	1/75 (1.3%)	2	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Lung infection	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Nasopharyngitis	10/75 (13.3%)	12	1/25 (4%)	2	3/68 (4.4%)	3	6/90 (6.7%)	6	1/13 (7.7%)	2
Oral candidiasis	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	2/90 (2.2%)	3	0/13 (0%)	0
Oral herpes	3/75 (4%)	3	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Paronychia	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Pharyngitis	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Pneumonia	0/75 (0%)	0	3/25 (12%)	3	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Rhinitis	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Sinusitis	3/75 (4%)	4	0/25 (0%)	0	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Skin candida	2/75 (2.7%)	2	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Skin infection	2/75 (2.7%)	3	0/25 (0%)	0	2/68 (2.9%)	2	0/90 (0%)	0	0/13 (0%)	0
Staphylococcal infection	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Tooth infection	1/75 (1.3%)	1	0/25 (0%)	0	2/68 (2.9%)	2	2/90 (2.2%)	2	0/13 (0%)	0
Urinary tract infection	10/75 (13.3%)	15	3/25 (12%)	4	5/68 (7.4%)	5	11/90 (12.2%)	12	1/13 (7.7%)	1
Vaginal infection	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Vulvovaginal mycotic infection	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Catheter site infection	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Gastroenteritis	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Herpes simplex	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Upper respiratory tract infection	4/75 (5.3%)	5	2/25 (8%)	2	2/68 (2.9%)	2	3/90 (3.3%)	4	0/13 (0%)	0
Injury, poisoning and procedural complications
Ankle fracture	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Contusion	2/75 (2.7%)	2	0/25 (0%)	0	3/68 (4.4%)	3	1/90 (1.1%)	1	0/13 (0%)	0
Fall	1/75 (1.3%)	1	3/25 (12%)	3	3/68 (4.4%)	6	1/90 (1.1%)	1	0/13 (0%)	0
Humerus fracture	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Incisional hernia	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Limb injury	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Muscle strain	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Skin laceration	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Subdural haematoma	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Thermal burn	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Tibia fracture	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Procedural pain	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Rib fracture	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Stoma site erythema	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Investigations
Alanine aminotransferase increased	2/75 (2.7%)	2	0/25 (0%)	0	3/68 (4.4%)	4	3/90 (3.3%)	3	0/13 (0%)	0
Aspartate aminotransferase increased	0/75 (0%)	0	0/25 (0%)	0	2/68 (2.9%)	2	3/90 (3.3%)	3	0/13 (0%)	0
Blood alkaline phosphatase increased	0/75 (0%)	0	1/25 (4%)	3	2/68 (2.9%)	3	2/90 (2.2%)	2	0/13 (0%)	0
Blood bilirubin increased	1/75 (1.3%)	1	1/25 (4%)	2	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Blood chloride decreased	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Blood creatinine increased	10/75 (13.3%)	10	9/25 (36%)	18	13/68 (19.1%)	14	13/90 (14.4%)	16	0/13 (0%)	0
Blood glucose increased	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Blood magnesium decreased	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Blood urea decreased	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Blood urea increased	0/75 (0%)	0	2/25 (8%)	2	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Carbohydrate antigen 125 increased	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Creatinine renal clearance decreased	1/75 (1.3%)	1	1/25 (4%)	2	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Electrocardiogram qt prolonged	0/75 (0%)	0	0/25 (0%)	0	2/68 (2.9%)	2	0/90 (0%)	0	0/13 (0%)	0
Electrocardiogram abnormal	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Gamma-glutamyltransferase increased	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Glomerular filtration rate decreased	1/75 (1.3%)	1	4/25 (16%)	5	2/68 (2.9%)	2	4/90 (4.4%)	4	0/13 (0%)	0
Haematocrit decreased	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Haemoglobin decreased	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Lipase increased	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Lymphocyte count decreased	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	3/90 (3.3%)	4	0/13 (0%)	0
Neutrophil count decreased	4/75 (5.3%)	4	0/25 (0%)	0	4/68 (5.9%)	5	1/90 (1.1%)	1	1/13 (7.7%)	2
Platelet count decreased	3/75 (4%)	5	1/25 (4%)	1	3/68 (4.4%)	5	2/90 (2.2%)	2	1/13 (7.7%)	1
Red blood cell count decreased	1/75 (1.3%)	1	1/25 (4%)	1	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Urine leukocyte esterase positive	0/75 (0%)	0	1/25 (4%)	1	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Weight decreased	3/75 (4%)	3	0/25 (0%)	0	4/68 (5.9%)	4	6/90 (6.7%)	8	0/13 (0%)	0
Weight increased	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
White blood cell count decreased	3/75 (4%)	4	0/25 (0%)	0	2/68 (2.9%)	5	2/90 (2.2%)	2	1/13 (7.7%)	2
White blood cell count increased	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
White blood cells urine positive	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Amylase increased	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Blood alkaline phosphatase decreased	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Metabolism and nutrition disorders
Cachexia	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Cardiometabolic syndrome	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Decreased appetite	11/75 (14.7%)	14	6/25 (24%)	6	16/68 (23.5%)	16	21/90 (23.3%)	25	5/13 (38.5%)	6
Dehydration	2/75 (2.7%)	2	0/25 (0%)	0	1/68 (1.5%)	1	2/90 (2.2%)	2	1/13 (7.7%)	1
Hypercalcaemia	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	2	0/90 (0%)	0	0/13 (0%)	0
Hyperglycaemia	1/75 (1.3%)	1	0/25 (0%)	0	3/68 (4.4%)	8	3/90 (3.3%)	3	0/13 (0%)	0
Hyperkalaemia	2/75 (2.7%)	2	0/25 (0%)	0	1/68 (1.5%)	2	2/90 (2.2%)	2	0/13 (0%)	0
Hypernatraemia	0/75 (0%)	0	1/25 (4%)	1	2/68 (2.9%)	3	0/90 (0%)	0	0/13 (0%)	0
Hyperuricaemia	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Hypoalbuminaemia	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Hypocalcaemia	1/75 (1.3%)	1	1/25 (4%)	1	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Hypoglycaemia	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	2	0/90 (0%)	0	0/13 (0%)	0
Hypokalaemia	4/75 (5.3%)	4	1/25 (4%)	1	4/68 (5.9%)	6	4/90 (4.4%)	5	0/13 (0%)	0
Hyponatraemia	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	2	5/90 (5.6%)	5	0/13 (0%)	0
Hypophosphataemia	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Increased appetite	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Iron deficiency	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Malnutrition	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Type 2 diabetes mellitus	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Hypomagnesaemia	5/75 (6.7%)	5	0/25 (0%)	0	0/68 (0%)	0	8/90 (8.9%)	8	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	6/75 (8%)	6	2/25 (8%)	2	2/68 (2.9%)	2	5/90 (5.6%)	6	0/13 (0%)	0
Arthritis	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	1/13 (7.7%)	1
Back pain	8/75 (10.7%)	9	2/25 (8%)	2	5/68 (7.4%)	5	8/90 (8.9%)	9	3/13 (23.1%)	3
Bone pain	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Fibromyalgia	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Flank pain	0/75 (0%)	0	1/25 (4%)	1	4/68 (5.9%)	4	1/90 (1.1%)	1	0/13 (0%)	0
Groin pain	1/75 (1.3%)	1	1/25 (4%)	1	2/68 (2.9%)	4	1/90 (1.1%)	1	0/13 (0%)	0
Joint swelling	0/75 (0%)	0	1/25 (4%)	1	1/68 (1.5%)	1	0/90 (0%)	0	1/13 (7.7%)	1
Limb discomfort	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Muscle spasms	4/75 (5.3%)	4	1/25 (4%)	1	4/68 (5.9%)	6	4/90 (4.4%)	4	0/13 (0%)	0
Muscle tightness	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Muscular weakness	2/75 (2.7%)	2	0/25 (0%)	0	4/68 (5.9%)	4	3/90 (3.3%)	4	0/13 (0%)	0
Musculoskeletal chest pain	2/75 (2.7%)	2	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Musculoskeletal discomfort	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Musculoskeletal pain	2/75 (2.7%)	3	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Musculoskeletal stiffness	0/75 (0%)	0	1/25 (4%)	1	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Myalgia	5/75 (6.7%)	5	3/25 (12%)	4	4/68 (5.9%)	5	2/90 (2.2%)	2	0/13 (0%)	0
Neck pain	1/75 (1.3%)	1	0/25 (0%)	0	3/68 (4.4%)	3	2/90 (2.2%)	2	0/13 (0%)	0
Osteoarthritis	2/75 (2.7%)	3	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Osteopenia	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Pain in extremity	6/75 (8%)	6	1/25 (4%)	1	3/68 (4.4%)	3	7/90 (7.8%)	8	0/13 (0%)	0
Pain in jaw	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Plantar fasciitis	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Temporomandibular joint syndrome	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Tendonitis	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Torticollis	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acrochordon	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Benign neoplasm	0/75 (0%)	0	0/25 (0%)	0	2/68 (2.9%)	2	0/90 (0%)	0	0/13 (0%)	0
Melanocytic naevus	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Seborrhoeic keratosis	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Nervous system disorders
Amnesia	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Burning sensation	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Dementia	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Dizziness	10/75 (13.3%)	10	7/25 (28%)	10	11/68 (16.2%)	14	12/90 (13.3%)	14	1/13 (7.7%)	2
Dysarthria	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Dysgeusia	7/75 (9.3%)	7	5/25 (20%)	5	13/68 (19.1%)	15	14/90 (15.6%)	14	2/13 (15.4%)	2
Hypoaesthesia	1/75 (1.3%)	1	1/25 (4%)	1	0/68 (0%)	0	2/90 (2.2%)	3	0/13 (0%)	0
Memory impairment	1/75 (1.3%)	1	1/25 (4%)	1	1/68 (1.5%)	1	2/90 (2.2%)	2	0/13 (0%)	0
Neuralgia	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Neuropathy peripheral	2/75 (2.7%)	2	0/25 (0%)	0	4/68 (5.9%)	4	0/90 (0%)	0	0/13 (0%)	0
Paraesthesia	2/75 (2.7%)	3	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Peripheral sensory neuropathy	4/75 (5.3%)	4	0/25 (0%)	0	1/68 (1.5%)	1	4/90 (4.4%)	4	0/13 (0%)	0
Poor quality sleep	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Presyncope	1/75 (1.3%)	2	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Restless legs syndrome	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Sciatica	2/75 (2.7%)	3	0/25 (0%)	0	3/68 (4.4%)	4	0/90 (0%)	0	0/13 (0%)	0
Somnolence	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Syncope	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Taste disorder	3/75 (4%)	4	0/25 (0%)	0	2/68 (2.9%)	2	3/90 (3.3%)	4	1/13 (7.7%)	2
Transient ischaemic attack	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Tremor	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	3/90 (3.3%)	3	0/13 (0%)	0
Headache	19/75 (25.3%)	28	8/25 (32%)	10	13/68 (19.1%)	17	11/90 (12.2%)	13	1/13 (7.7%)	1
Sinus headache	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Psychiatric disorders
Anxiety	4/75 (5.3%)	4	1/25 (4%)	1	1/68 (1.5%)	1	6/90 (6.7%)	7	0/13 (0%)	0
Depressed mood	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Depression	5/75 (6.7%)	5	1/25 (4%)	1	2/68 (2.9%)	2	4/90 (4.4%)	5	0/13 (0%)	0
Insomnia	8/75 (10.7%)	8	0/25 (0%)	0	4/68 (5.9%)	4	3/90 (3.3%)	3	0/13 (0%)	0
Restlessness	1/75 (1.3%)	2	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Sleep disorder	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Bladder discomfort	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Bladder spasm	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Chronic kidney disease	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Cystitis interstitial	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Dysuria	1/75 (1.3%)	1	1/25 (4%)	1	1/68 (1.5%)	1	2/90 (2.2%)	2	0/13 (0%)	0
Hydronephrosis	1/75 (1.3%)	1	1/25 (4%)	1	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Micturition urgency	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Nocturia	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Pollakiuria	4/75 (5.3%)	4	1/25 (4%)	1	3/68 (4.4%)	3	1/90 (1.1%)	1	0/13 (0%)	0
Renal failure	0/75 (0%)	0	0/25 (0%)	0	2/68 (2.9%)	2	0/90 (0%)	0	0/13 (0%)	0
Urinary incontinence	1/75 (1.3%)	1	0/25 (0%)	0	2/68 (2.9%)	2	3/90 (3.3%)	3	0/13 (0%)	0
Urinary retention	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	2/90 (2.2%)	2	0/13 (0%)	0
Urinary tract obstruction	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Urinary tract pain	2/75 (2.7%)	2	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Haematuria	1/75 (1.3%)	1	2/25 (8%)	2	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Reproductive system and breast disorders
Breast pain	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Dyspareunia	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Pruritus genital	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Vaginal haemorrhage	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	3/90 (3.3%)	3	0/13 (0%)	0
Vaginal lesion	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Vulvovaginal discomfort	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Vulvovaginal dryness	1/75 (1.3%)	1	1/25 (4%)	1	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Vulvovaginal rash	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Pelvic pain	0/75 (0%)	0	0/25 (0%)	0	2/68 (2.9%)	2	0/90 (0%)	0	0/13 (0%)	0
Vaginal discharge	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	2/90 (2.2%)	3	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Choking	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Cough	11/75 (14.7%)	11	4/25 (16%)	4	12/68 (17.6%)	14	14/90 (15.6%)	14	3/13 (23.1%)	3
Dry throat	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	2	0/90 (0%)	0	0/13 (0%)	0
Dysphonia	0/75 (0%)	0	0/25 (0%)	0	2/68 (2.9%)	2	2/90 (2.2%)	4	0/13 (0%)	0
Dyspnoea	10/75 (13.3%)	11	4/25 (16%)	5	8/68 (11.8%)	9	20/90 (22.2%)	22	1/13 (7.7%)	1
Dyspnoea exertional	1/75 (1.3%)	1	1/25 (4%)	1	0/68 (0%)	0	1/90 (1.1%)	1	1/13 (7.7%)	1
Epistaxis	2/75 (2.7%)	2	0/25 (0%)	0	1/68 (1.5%)	1	2/90 (2.2%)	2	0/13 (0%)	0
Hiccups	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Nasal congestion	0/75 (0%)	0	0/25 (0%)	0	3/68 (4.4%)	3	1/90 (1.1%)	1	0/13 (0%)	0
Nasal dryness	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Oropharyngeal pain	4/75 (5.3%)	4	2/25 (8%)	2	3/68 (4.4%)	3	2/90 (2.2%)	2	0/13 (0%)	0
Pharyngeal swelling	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Pleural effusion	0/75 (0%)	0	1/25 (4%)	1	3/68 (4.4%)	3	0/90 (0%)	0	0/13 (0%)	0
Pleuritic pain	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Pneumothorax	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Productive cough	1/75 (1.3%)	1	1/25 (4%)	1	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Pulmonary embolism	2/75 (2.7%)	2	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	1/13 (7.7%)	1
Rhinitis allergic	2/75 (2.7%)	3	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Rhinorrhoea	1/75 (1.3%)	1	2/25 (8%)	2	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Sinus congestion	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Upper-airway cough syndrome	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Pneumonia aspiration	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Skin and subcutaneous tissue disorders
Actinic keratosis	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Alopecia	9/75 (12%)	9	1/25 (4%)	1	3/68 (4.4%)	3	3/90 (3.3%)	3	1/13 (7.7%)	1
Dermal cyst	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	1/13 (7.7%)	1
Dry skin	2/75 (2.7%)	2	0/25 (0%)	0	1/68 (1.5%)	2	1/90 (1.1%)	1	0/13 (0%)	0
Erythema	2/75 (2.7%)	2	1/25 (4%)	1	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Lichen sclerosus	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Lipohypertrophy	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Nail discolouration	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Neurodermatitis	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Night sweats	2/75 (2.7%)	2	1/25 (4%)	1	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Onychoclasis	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Pruritus	0/75 (0%)	0	0/25 (0%)	0	2/68 (2.9%)	2	4/90 (4.4%)	5	0/13 (0%)	0
Purpura	0/75 (0%)	0	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Rash	4/75 (5.3%)	4	1/25 (4%)	1	2/68 (2.9%)	2	5/90 (5.6%)	5	2/13 (15.4%)	2
Rash maculo-papular	2/75 (2.7%)	2	1/25 (4%)	1	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Rash pruritic	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Scar pain	1/75 (1.3%)	1	0/25 (0%)	0	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Skin discolouration	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Skin hyperpigmentation	2/75 (2.7%)	2	1/25 (4%)	1	0/68 (0%)	0	0/90 (0%)	0	0/13 (0%)	0
Skin lesion	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Skin ulcer	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Swelling face	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	2	0/90 (0%)	0	0/13 (0%)	0
Urticaria	1/75 (1.3%)	1	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Hyperhidrosis	1/75 (1.3%)	1	1/25 (4%)	1	0/68 (0%)	0	2/90 (2.2%)	2	0/13 (0%)	0
Nail disorder	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Vascular disorders
Collateral circulation	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Deep vein thrombosis	1/75 (1.3%)	1	1/25 (4%)	1	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Embolism	0/75 (0%)	0	1/25 (4%)	1	2/68 (2.9%)	3	1/90 (1.1%)	1	0/13 (0%)	0
Flushing	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	2/90 (2.2%)	2	0/13 (0%)	0
Haematoma	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Haemorrhage	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Hot flush	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Hypertension	4/75 (5.3%)	4	1/25 (4%)	1	0/68 (0%)	0	8/90 (8.9%)	8	0/13 (0%)	0
Hypotension	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0
Intermittent claudication	0/75 (0%)	0	0/25 (0%)	0	0/68 (0%)	0	1/90 (1.1%)	1	0/13 (0%)	0
Lymphoedema	4/75 (5.3%)	4	0/25 (0%)	0	1/68 (1.5%)	1	1/90 (1.1%)	1	0/13 (0%)	0
Pallor	0/75 (0%)	0	0/25 (0%)	0	1/68 (1.5%)	1	0/90 (0%)	0	0/13 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Institution and PI shall be entitled to publish the results of, or make presentations related to, the Study, provided that any publications or presentations to be made within two (2) years of completion of the Study shall require the Sponsor's prior written consent. Sponsor to be consulted prior to presentation or publication.