A Study of Abemaciclib (LY2835219) in Combination With Another Anti-cancer Drug in Participants With Lung Cancer (NSCLC)
Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT02079636
Collaborator
Merck Sharp & Dohme LLC (Industry)
142
11
5
65.1
12.9
0.2
Study Details
Study Description
Brief Summary
The main purpose of this study is to evaluate the safety and tolerability of abemaciclib in combination with another anti-cancer drug in participants with NSCLC that is advanced or has spread to other parts of the body (stage IV). The study will also investigate how the body processes the combination treatment and how the study drug affects the body. The study will also collect disease-related symptoms and participant-reported pain related to NSCLC.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
142 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1b Study of LY2835219 in Combination With Multiple Single Agent Options for Patients With Stage IV NSCLC
Actual Study Start Date
:
Mar 28, 2014
Actual Primary Completion Date
:
May 2, 2018
Actual Study Completion Date
:
Aug 29, 2019
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Abemaciclib + Pemetrexed 150 milligram (mg) or 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 milligrams/square meter (mg/m^2) pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
Drug: Abemaciclib
Administered orally
Other Names:
Drug: Pemetrexed
Administered IV
Other Names:
|
| Experimental: Abemaciclib + Gemcitabine 150 mg or 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 milligram/square meter (mg/m^2) gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
Drug: Abemaciclib
Administered orally
Other Names:
Drug: Gemcitabine
Administered IV
Other Names:
|
| Experimental: Abemaciclib + Ramucirumab 150 mg or 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 or 8 to 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
Drug: Abemaciclib
Administered orally
Other Names:
Drug: Ramucirumab
Administered IV
Other Names:
|
| Experimental: Abemaciclib + LY3023414 100 mg or 150 mg or 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100, 150, or 200 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
Drug: Abemaciclib
Administered orally
Other Names:
Drug: LY3023414
Administered orally
|
| Experimental: Abemaciclib + Pembrolizumab 100 mg or 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
Drug: Abemaciclib
Administered orally
Other Names:
Drug: Pembrolizumab
Administered IV
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Dose-Limiting Toxicities (DLT) or DLT-equivalent in Part A, B, C, D and E [Baseline through study completion (Up To 15 Months)]
A DLT defined as adverse event(AE) occurring between Day 1 and Day 21 of Cycle 1 that was considered at least possibly related to either abemaciclib or the combination therapy and fulfilled a criteria selected (using the National Cancer Institute Common Terminology Criteria for Adverse Events,version 4.0 [NCI-CTCAE v 4.0] [NCI 2009]):Grade(Gr)≥3 nonhematological toxicity,Gr4 thrombocytopenia lasting at least 5 days and/or complicated with bleeding,Gr≥3 febrile neutropenia(ntr) and for Part D participants (pts): Gr3 hyperglycemia (fasting) of <5 days, Gr3 hypertriglyceridemia or hyperlipidemia without optimal treatment.A DLT-equivalent defined as AE that would have met the criteria for DLT if it had occurred during Cycle 1 for pts enrolled in dose-escalation phase,but that occurs between 1)Day 1 and Day 21 of Cycle 2 and beyond for a participant enrolled in dose-escalation phase 2) at any time for a participant in dose-expansion phase.
Secondary Outcome Measures
- Number of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) in Part A, B, C, D and E [Baseline through study completion (Up To 15 Months)]
ORR is the best response of CR or PR as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of not-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100.
- Progression Free Survival Time in Part A, B, C, D and E [Date of first dose until first documented progression or death (Up To 15 Months)]
Progression free survival (PFS) defined as the time from the date of randomization to the first evidence of disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of randomization, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. PFS time was summarized using Kaplan-Meier estimates.
- Change From Baseline in MD Anderson Symptom Inventory Scale-Lung Cancer (MDASI-LC) in Part A, B, C, D and E [Baseline, through study completion (Up To 15 Months)]
The MDASI-LC is a self-reported lung cancer instrument included 22 items covered by one of the following dimensions: Mean core symptom severity (Core items 1-13: pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sad, vomiting, numbness/tingling), Lung cancer symptoms (3 items: coughing, constipation, sore throat), Mean symptom severity (13 core items plus 3 lung items) and Interference with mood or functional status (6 items: general activity, mood, work, relations with other people, walking, enjoyment of life). The mean of all symptom subscale items was calculated where 0 equals "not present" and 10 equals "as bad as you can imagine." A change from baseline with negative values indicate improvement, positive values indicate worsening.
- Pharmacokinetics (PK): Maximum Concentration (Cmax) of Abemaciclib on Day 1 and at Steady State (Cycle 2 Day 1) in Part A , B, C, D and E [Cycle 1 Day 1 (C1D1) pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; Cycle 2 Day 1 (C2D1) pre-dose and 1, 2, 4, 6, 8, 10 h post-dose]
Cmax of Abemaciclib on day 1 and at steady State (Cycle 2 Day 1) Part A , B, C, D and E was evaluated.
- Pharmacokinetics: Maximum Concentration (Cmax) of Pemetrexed at Steady State in Part A [C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose]
Cmax of pemetrexed at steady state in Part A was evaluated.
- PK: Dose-normalized Maximum Concentration (Cmax) of Active Gemcitabine Metabolite: 2',2'-Difluorodeoxyuridine (dFdU) on Day 1 and at Steady State (Cycle 2 Day 1) in Part B [C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose]
Cmax of active gemcitabine metabolite (dFdU) on day 1 and at steady state (Cycle 2 Day 1) dose-normalized to 1250 mg/m^2 in Part B was evaluated.
- PK: Maximum Concentration (Cmax) of Ramucirumab at 1 Hour Post-End-of-Infusion in Part C [C1D1 and C2D1: 1 hour post-end-of-infusion]
Cmax of ramucirumab at 1 hour post-end-of-Infusion in Part C was evaluated.
- PK: Maximum Concentration (Cmax) of LY3023414 in Part D [C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose]
Cmax of LY3023414 in Part D was evaluated.
- PK: Area Under the Concentration Curve (AUC) of Abemaciclib in Part A, B, C, D and E [C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose]
Area under the concentration time curve from zero to 8 hours AUC(0-8h) of abemaciclib in Part A, B, C, D and E was evaluated.
- PK: Area Under the Concentration Curve (AUC) of Pemetrexed at Steady State in Part A [C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose]
Area under the plasma concentration versus time curve from time zero to infinity (AUC[0-∞]) of Pemetrexed in Part A was evaluated.
- PK: Area Under the Concentration Curve (AUC) of Active Gemcitabine Metabolite: 2',2'-Difluorodeoxyuridine (dFdU) on Day 1 and at Steady State (Cycle 2 Day 1) in Part B [C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose]
Area under the plasma concentration time curve from time zero to 12 hours (AUC[0-12h]) of active gemcitabine metabolite (dFdU) in Part B was evaluated
- PK: Area Under the Concentration Curve (AUC) of LY3023414 in Part D [C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose]
Area under the plasma concentration versus time curve from time zero to infinity (AUC) of LY3023414 in Part D was evaluated. For Day 1, AUC is defined as AUC from time zero to infinity (AUC[0-∞]), for steady state, AUC is defined as AUC from time zero to the end of the dosing interval, tau (AUC[0-tau ])
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
For all Parts: The participant must have stage IV non-small cell lung cancer (NSCLC).
-
For Part A (abemaciclib + pemetrexed): Non-squamous subtypes only. The participant must have received at least one but no more than three prior therapies for advanced/metastatic NSCLC.
-
For Part B (abemaciclib + gemcitabine): Any subtype. The participant must have received at least one but not more than three prior therapies for advanced/metastatic NSCLC.
-
For Part C (abemaciclib + ramucirumab): Any subtype. The participant must have received at least two but not more than three prior therapies for advanced/metastatic NSCLC.
-
For Part D (abemaciclib + LY3023414): Any subtype. The participant must have received at least two, but not more than three prior therapies for advanced/metastatic NSCLC. The participant must not have received prior treatment with any phosphoinositide 3-kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitor.
-
For Part E (abemaciclib + pembrolizumab): Any subtype. The participant must have received at least one but no more than three prior therapies for advanced/metastatic NSCLC.
-
Have either measureable or nonmeasurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
-
Have adequate organ function including:
-
Hematologic: Absolute neutrophil count (ANC) 1.5 x 109/liter (L), platelets 100 x 109/L, and hemoglobin 8 gram/deciliter (g/dL).
-
Hepatic: Bilirubin 1.5 times upper limits of normal (ULN), alanine aminotransferase (ALT) and aspartate transaminase (AST) 3.0 times ULN. For participants with tumor involvement of the liver, AST and ALT equaling ≤5.0 times ULN are acceptable. Alkaline phosphatase ≤5.0 times ULN for participants with tumor involvement of the bone is acceptable.
-
Renal: Serum creatinine 1.5 times ULN.
-
Have a performance status ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale.
-
Have discontinued all previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, and investigational therapy) for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving study drug, and recovered from the acute effects of therapy (treatment related toxicity resolved to baseline) except for residual alopecia.
-
Male and female participants of reproductive potential must agree to use medically approved contraceptive precautions during the trial and 3 to 4 months (as appropriate) following last dose of study drug.
-
Have an estimated life expectancy of ≥12 weeks.
-
Are able to swallow oral medications.
Exclusion Criteria:
-
Have a personal history of any of the following conditions: presyncope or syncope of either unexplained or cardiovascular etiology, ventricular arrhythmia (including but not limited to ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. Exception: Participants with controlled atrial fibrillation for >30 days prior to study treatment are eligible.
-
Parts A, B, D and E: Have central nervous system (CNS) metastasis with development of associated neurological changes 14 days prior to receiving study drug.
-
Have a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix or breast), unless in complete remission with no therapy for a minimum of 3 years.
-
Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 3 to 4 months after the last dose of trial treatment (as appropriate).
-
Have active bacterial, fungal, and/or known viral infection (for example, human immunodeficiency virus [HIV] antibodies, hepatitis B surface antigen [HBSAg], or hepatitis C antibodies). Screening is not required for enrollment.
-
Parts A, B, C, and E: Have QTc interval of > 470 millisecond (msec) on screening electrocardiogram (ECG). Part D participants have QTc interval of >450msec on screening ECG.
Additional Exclusion Criteria For Part C
-
History or evidence of cardiovascular risk including any of the following:
-
History of acute coronary syndromes (including myocardial infarction and angina), coronary angioplasty, or stenting within 6 months prior to enrollment.
-
History or evidence of current ≥Class II congestive heart failure as defined by New York Heart Association.
-
Treatment refractory hypertension defined as a blood pressure of systolic >140 millimeter of mercury (mmHg) and/or diastolic >90 mmHg which cannot be controlled by antihypertensive therapy.
-
Participants with intracardiac defibrillators.
-
History or evidence of CNS disease. Radiographic screening of all participants without history of CNS metastasis is required.
-
Radiographically documented evidence of major vessel invasion or encasement by cancer.
-
Uncontrolled thromboembolic or hemorrhagic disorders.
-
Participants receiving daily treatment with aspirin >325mg/day or other known inhibitors of platelet function.
-
History of gross hemoptysis within 2 months of study entry.
-
Evidence of nonhealing wounds, ulcers, or bone fractures within 28 days prior to study entry.
-
Undergone major surgery within 28 days prior to first dose of study drug or have subcutaneous venous access device placement within 7 days prior to first dose.
Additional Exclusion Criteria For Part D
-
Have insulin-dependent diabetes mellitus or a history of gestational diabetes mellitus.
-
Participants with a type 2 diabetes mellitus are eligible if adequate control of blood glucose level is obtained by oral anti-diabetic agents as documented by hemoglobin A1c (HbA1c) <7%.
-
History or evidence of cardiovascular risk including any of the following -- History of acute coronary syndromes (including myocardial infarction and angina), coronary angioplasty, or stenting within 6 months prior to enrollment.
Additional Exclusion Criteria for Part E
-
Received prior monoclonal antibody (mAb) within 4 weeks prior to study.
-
Has active autoimmune disease that has required treatment in the past 2 years.
-
Has history of interstitial lung disease or pneumonitis.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Highlands Oncology Group | Fayetteville | Arkansas | United States | 72703 |
| 2 | UCLA Department of Medicine-Hematology/Oncology | Los Angeles | California | United States | 90095 |
| 3 | University of California, Davis - Health Systems | Sacramento | California | United States | 95817 |
| 4 | Indiana Cancer Pavilion | Indianapolis | Indiana | United States | 46202 |
| 5 | Hackensack University Medical Center | Hackensack | New Jersey | United States | 07601 |
| 6 | University of New Mexico Cancer Center | Albuquerque | New Mexico | United States | 87102 |
| 7 | Carolinas Medical Center | Charlotte | North Carolina | United States | 28204 |
| 8 | The West Clinic | Germantown | Tennessee | United States | 38138 |
| 9 | Hospital Universitario Ramon y Cajal | Madrid | Spain | 28034 | |
| 10 | For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. | Majadahonda | Spain | 28222 | |
| 11 | For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. | Sevilla | Spain | 41013 |
Sponsors and Collaborators
- Eli Lilly and Company
- Merck Sharp & Dohme LLC
Investigators
- Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.Responsible Party:
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT02079636
Other Study ID Numbers:
- 15266
- I3Y-MC-JPBJ
- 2013-004648-41
- KEYNOTE-238
First Posted:
Mar 6, 2014
Last Update Posted:
Sep 11, 2020
Last Verified:
Nov 15, 2019
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | Completers include participants who had cycle 1 and had received greater than or equal to (>=) 75% of Abemaciclib drug in cycle 1. |
| Arm/Group Title | Part A: 150 Milligram(mg) Abemaciclib + 500 mg/m^2 Pemetrexed | Part A: 200 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part B: 150 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part C: 150 mg Abemaciclib + 10mg/kg Ramucirumab Day 1 | Part C: 200 mg Abemaciclib + 10mg/kg Ramucirumab Day1 | Part C: 150 mg Abemaciclib + 8 mg/kg Ramucirumab Days 1 and 8 | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Days 1 and 8 | Part D: 100 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 150 mg LY3023414 | Part D: 200 mg Abemaciclib + 150 mg LY3023414 | Part D: 150 mg Abemaciclib + 200 mg LY3023414 | Part E: 100 mg Abemaciclib + 200 mg Pembrolizumab | Part E: 150 mg Abemaciclib + 200 mg Pembrolizumab |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 150 mg abemaciclib given orally every 12 hours (Q12H) on Days 1 through 21 of a 21-day cycle in combination with 500 milligrams/square meter (mg/m^2) pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 8 mg/kg ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 mg/kg ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Period Title: Overall Study | |||||||||||||||
| STARTED | 8 | 15 | 3 | 21 | 4 | 19 | 12 | 4 | 3 | 9 | 10 | 6 | 8 | 3 | 17 |
| Received at Least One Dose of Study Drug | 8 | 15 | 3 | 21 | 4 | 19 | 12 | 4 | 3 | 9 | 10 | 6 | 8 | 3 | 17 |
| COMPLETED | 5 | 13 | 3 | 9 | 2 | 13 | 11 | 3 | 3 | 6 | 8 | 4 | 5 | 3 | 12 |
| NOT COMPLETED | 3 | 2 | 0 | 12 | 2 | 6 | 1 | 1 | 0 | 3 | 2 | 2 | 3 | 0 | 5 |
Baseline Characteristics
| Arm/Group Title | Part A:150 Milligram(mg) Abemaciclib + 500 mg/m^2 Pemetrexed | Part A: 200 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part B: 150 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part C:150 mg Abemaciclib+10mg/kg Ramucirumab Day1 | Part C: 200 mg Abemaciclib + 10mg/kg Ramucirumab Day1 | Part C: 150 mg Abemaciclib + 8 mg/kg Ramucirumab Days 1 and 8 | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Days 1 and 8 | Part D: 100 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 150 mg LY3023414 | Part D: 200 mg Abemaciclib + 150 mg LY3023414 | Part D: 150 mg Abemaciclib + 200 mg LY3023414 | Part E: 100 mg Abemaciclib + 200 mg Pembrolizumab | Part E: 150 mg Abemaciclib + 200 mg Pembrolizumab | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 milligrams/square meter (mg/m^2) pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 8 mg/kg ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 mg/kg ramucirumab given intravenously over approximately 60 minutes on on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | Total of all reporting groups |
| Overall Participants | 8 | 15 | 3 | 21 | 4 | 19 | 12 | 4 | 3 | 9 | 10 | 6 | 8 | 3 | 17 | 142 |
| Age (years) [Mean (Standard Deviation) ] | ||||||||||||||||
| Mean (Standard Deviation) [years] |
63.88
(7.61)
|
62.53
(11.19)
|
55.00
(8.66)
|
63.14
(10.07)
|
61.25
(14.24)
|
66.11
(9.31)
|
63.75
(6.77)
|
67.75
(4.92)
|
67.00
(9.54)
|
57.56
(8.26)
|
64.00
(8.41)
|
65.50
(7.48)
|
60.38
(10.20)
|
67.33
(3.51)
|
59.76
(9.94)
|
62.89
(9.30)
|
| Sex: Female, Male (Count of Participants) | ||||||||||||||||
| Female |
4
50%
|
5
33.3%
|
0
0%
|
11
52.4%
|
2
50%
|
10
52.6%
|
4
33.3%
|
0
0%
|
1
33.3%
|
5
55.6%
|
3
30%
|
2
33.3%
|
5
62.5%
|
1
33.3%
|
10
58.8%
|
63
44.4%
|
| Male |
4
50%
|
10
66.7%
|
3
100%
|
10
47.6%
|
2
50%
|
9
47.4%
|
8
66.7%
|
4
100%
|
2
66.7%
|
4
44.4%
|
7
70%
|
4
66.7%
|
3
37.5%
|
2
66.7%
|
7
41.2%
|
79
55.6%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||||||||||||||
| Hispanic or Latino |
0
0%
|
1
6.7%
|
1
33.3%
|
1
4.8%
|
0
0%
|
1
5.3%
|
1
8.3%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
16.7%
|
1
12.5%
|
0
0%
|
0
0%
|
7
4.9%
|
| Not Hispanic or Latino |
8
100%
|
13
86.7%
|
2
66.7%
|
20
95.2%
|
4
100%
|
17
89.5%
|
11
91.7%
|
4
100%
|
3
100%
|
9
100%
|
10
100%
|
5
83.3%
|
7
87.5%
|
3
100%
|
17
100%
|
133
93.7%
|
| Unknown or Not Reported |
0
0%
|
1
6.7%
|
0
0%
|
0
0%
|
0
0%
|
1
5.3%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
1.4%
|
| Race (NIH/OMB) (Count of Participants) | ||||||||||||||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
2
9.5%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
1.4%
|
| Asian |
0
0%
|
1
6.7%
|
0
0%
|
2
9.5%
|
0
0%
|
1
5.3%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
16.7%
|
1
12.5%
|
0
0%
|
1
5.9%
|
7
4.9%
|
| 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%
|
| Black or African American |
0
0%
|
1
6.7%
|
0
0%
|
1
4.8%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
33.3%
|
2
22.2%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
5
3.5%
|
| White |
8
100%
|
13
86.7%
|
3
100%
|
16
76.2%
|
4
100%
|
18
94.7%
|
12
100%
|
4
100%
|
2
66.7%
|
7
77.8%
|
10
100%
|
5
83.3%
|
7
87.5%
|
3
100%
|
16
94.1%
|
128
90.1%
|
| 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%
|
| Unknown or Not Reported |
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%
|
| Region of Enrollment (Count of Participants) | ||||||||||||||||
| United States |
6
75%
|
8
53.3%
|
2
66.7%
|
16
76.2%
|
4
100%
|
15
78.9%
|
6
50%
|
1
25%
|
3
100%
|
9
100%
|
10
100%
|
6
100%
|
8
100%
|
0
0%
|
3
17.6%
|
97
68.3%
|
| Spain |
2
25%
|
7
46.7%
|
1
33.3%
|
5
23.8%
|
0
0%
|
4
21.1%
|
6
50%
|
3
75%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
3
100%
|
14
82.4%
|
45
31.7%
|
Outcome Measures
| Title | Number of Participants With Dose-Limiting Toxicities (DLT) or DLT-equivalent in Part A, B, C, D and E |
|---|---|
| Description | A DLT defined as adverse event(AE) occurring between Day 1 and Day 21 of Cycle 1 that was considered at least possibly related to either abemaciclib or the combination therapy and fulfilled a criteria selected (using the National Cancer Institute Common Terminology Criteria for Adverse Events,version 4.0 [NCI-CTCAE v 4.0] [NCI 2009]):Grade(Gr)≥3 nonhematological toxicity,Gr4 thrombocytopenia lasting at least 5 days and/or complicated with bleeding,Gr≥3 febrile neutropenia(ntr) and for Part D participants (pts): Gr3 hyperglycemia (fasting) of <5 days, Gr3 hypertriglyceridemia or hyperlipidemia without optimal treatment.A DLT-equivalent defined as AE that would have met the criteria for DLT if it had occurred during Cycle 1 for pts enrolled in dose-escalation phase,but that occurs between 1)Day 1 and Day 21 of Cycle 2 and beyond for a participant enrolled in dose-escalation phase 2) at any time for a participant in dose-expansion phase. |
| Time Frame | Baseline through study completion (Up To 15 Months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug in Part A, B, C, D and E. |
| Arm/Group Title | Part A:150 Milligram(mg) Abemaciclib + 500 mg/m^2 Pemetrexed | Part A: 200 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part B: 150 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part C:150 mg Abemaciclib+10 mg/kg Ramucirumab Day 1 | Part C: 200 mg Abemaciclib + 10 mg/kg Ramucirumab Day 1 | Part C: 150 mg Abemaciclib + 8 mg/kg Ramucirumab Days 1 and 8 | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Days 1 and 8 | Part D: 100 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 150 mg LY3023414 | Part D: 200 mg Abemaciclib + 150 mg LY3023414 | Part D: 150 mg Abemaciclib + 200 mg LY3023414 | Part E: 100 mg Abemaciclib + 200 mg Pembrolizumab | Part E: 150 mg Abemaciclib + 200 mg Pembrolizumab |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 milligrams/square meter (mg/m^2) pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 8 mg/kg ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 mg/kg ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Measure Participants | 8 | 15 | 3 | 21 | 4 | 19 | 12 | 4 | 3 | 9 | 10 | 6 | 8 | 3 | 17 |
| Count of Participants [Participants] |
1
12.5%
|
4
26.7%
|
0
0%
|
5
23.8%
|
1
25%
|
4
21.1%
|
1
8.3%
|
3
75%
|
1
33.3%
|
1
11.1%
|
1
10%
|
1
16.7%
|
2
25%
|
0
0%
|
0
0%
|
| Title | Number of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) in Part A, B, C, D and E |
|---|---|
| Description | ORR is the best response of CR or PR as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of not-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100. |
| Time Frame | Baseline through study completion (Up To 15 Months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug in Part A, B, C, D and E. |
| Arm/Group Title | Part A:150 Milligram(mg) Abemaciclib + 500 mg/m^2 Pemetrexed | Part A: 200 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part B: 150 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part C:150 mg Abemaciclib+10mg/kg Ramucirumab Day1 | Part C: 200 mg Abemaciclib + 10 mg/kg Ramucirumab Day 1 | Part C: 150 mg Abemaciclib + 8 mg/kg Ramucirumab Days 1 and 8 | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Days 1 and 8 | Part D: 100 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 150 mg LY3023414 | Part D: 200 mg Abemaciclib + 150 mg LY3023414 | Part D: 150 mg Abemaciclib + 200 mg LY3023414 | Part E: 100 mg Abemaciclib + 200 mg Pembrolizumab | Part E: 150 mg Abemaciclib + 200 mg Pembrolizumab |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 milligrams/square meter (mg/m^2) pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 or 8 to 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 8 mg/kg ramucirumab given intravenously over approximately 60 minutes on Day 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 mg/kg ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Measure Participants | 8 | 15 | 3 | 21 | 4 | 19 | 12 | 4 | 3 | 9 | 10 | 6 | 8 | 3 | 17 |
| Count of Participants [Participants] |
0
0%
|
1
6.7%
|
0
0%
|
1
4.8%
|
1
25%
|
1
5.3%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
10%
|
0
0%
|
0
0%
|
0
0%
|
2
11.8%
|
| Title | Progression Free Survival Time in Part A, B, C, D and E |
|---|---|
| Description | Progression free survival (PFS) defined as the time from the date of randomization to the first evidence of disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of randomization, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. PFS time was summarized using Kaplan-Meier estimates. |
| Time Frame | Date of first dose until first documented progression or death (Up To 15 Months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants in Part A, B, C, D and E. Censored participants: Part A= 13, Part B = 7, Part C = 17, Part D = 19, Part E = 10. |
| Arm/Group Title | Part A:Abemaciclib + 500 mg/m^2 Pemetrexed | Part B: Abemaciclib + 1250 mg/m^2 Gemcitabine | Part C:Abemaciclib+ 8/10mg/kg Ramucirumab Day1/8 | Part D: Abemaciclib + 100 mg/150 mg/ 200 mg LY3023414 | Part E: 100 mg/150 mg Abemaciclib + 200 mg Pembrolizumab |
|---|---|---|---|---|---|
| Arm/Group Description | 150/200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 milligrams/square meter (mg/m^2) pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150/200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 /200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 8 mg/kg /10 mg/kg ramucirumab / given intravenously over approximately 60 minutes on Day 1 or 8 to 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg/ 150 mg / 200 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg / 150 mg/ 200 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg / 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Measure Participants | 23 | 24 | 39 | 36 | 20 |
| Median (95% Confidence Interval) [Months] |
5.55
|
1.58
|
4.83
|
1.87
|
4.11
|
| Title | Change From Baseline in MD Anderson Symptom Inventory Scale-Lung Cancer (MDASI-LC) in Part A, B, C, D and E |
|---|---|
| Description | The MDASI-LC is a self-reported lung cancer instrument included 22 items covered by one of the following dimensions: Mean core symptom severity (Core items 1-13: pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sad, vomiting, numbness/tingling), Lung cancer symptoms (3 items: coughing, constipation, sore throat), Mean symptom severity (13 core items plus 3 lung items) and Interference with mood or functional status (6 items: general activity, mood, work, relations with other people, walking, enjoyment of life). The mean of all symptom subscale items was calculated where 0 equals "not present" and 10 equals "as bad as you can imagine." A change from baseline with negative values indicate improvement, positive values indicate worsening. |
| Time Frame | Baseline, through study completion (Up To 15 Months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants for cycles which at least 25% of participants in each arm have a score. MDASI-LC population included all randomized participants who completed at least 1 baseline assessment followed by at least 1 MDASI-LC result in Part A, B, C, D and E. |
| Arm/Group Title | Part A:150 Milligram(mg) Abemaciclib + 500 mg/m^2 Pemetrexed | Part A: 200 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part B: 150 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part C:150 mg Abemaciclib+10mg/kg Ramucirumab Day1 | Part C: 200 mg Abemaciclib + 10mg/kg Ramucirumab Day1 | Part C: 150 mg Abemaciclib + 8 mg/kg Ramucirumab Days 1 and 8 | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Days 1 and 8 | Part D: 100 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 150 mg LY3023414 | Part D: 200 mg Abemaciclib + 150 mg LY3023414 | Part D: 150 mg Abemaciclib + 200 mg LY3023414 | Part E: 100 mg Abemaciclib + 200 mg Pembrolizumab | Part E: 150 mg Abemaciclib + 200 mg Pembrolizumab |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 milligrams/square meter (mg/m^2) pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 or 8 to 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 or 8 to 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 8 mg/kg ramucirumab given intravenously over approximately 60 minutes on Day 1 or 8 to 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 mg/kg ramucirumab given intravenously over approximately 60 minutes on Day 1 or 8 to 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Measure Participants | 8 | 15 | 2 | 21 | 4 | 19 | 12 | 4 | 3 | 9 | 10 | 6 | 8 | 3 | 17 |
| Mean core symptom severity |
-0.16
|
0.89
|
-0.54
|
-0.08
|
-0.35
|
0.61
|
-0.64
|
-1.39
|
0.61
|
1.89
|
1.60
|
-0.80
|
0.28
|
0.91
|
0.88
|
| Mean symptom severity |
-0.05
|
0.83
|
-0.44
|
-0.03
|
-0.41
|
0.72
|
-0.61
|
-1.01
|
0.64
|
1.86
|
1.60
|
-0.73
|
0.19
|
0.99
|
0.75
|
| Mean lung cancer symptom |
1.22
|
0.71
|
1.67
|
0.19
|
-0.67
|
1.13
|
-0.78
|
3.01
|
0.78
|
1.40
|
2.19
|
-0.44
|
0.67
|
1.67
|
0.23
|
| Mean interference severity |
2.32
|
0.49
|
0.00
|
0.95
|
-1.33
|
0.15
|
-1.00
|
-3.08
|
0.72
|
1.47
|
1.81
|
-0.22
|
-0.38
|
1.44
|
1.00
|
| Title | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Abemaciclib on Day 1 and at Steady State (Cycle 2 Day 1) in Part A , B, C, D and E |
|---|---|
| Description | Cmax of Abemaciclib on day 1 and at steady State (Cycle 2 Day 1) Part A , B, C, D and E was evaluated. |
| Time Frame | Cycle 1 Day 1 (C1D1) pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; Cycle 2 Day 1 (C2D1) pre-dose and 1, 2, 4, 6, 8, 10 h post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug with evaluable PK data in Part A , B, C, D and E. |
| Arm/Group Title | Part A:150 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part A: 200 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part B: 150 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part C: 150 mg Abemaciclib + 8 mg/kg or 10 mg/kg Ramucirumab | Part C: 200 mg Abemaciclib + 10mg/kg Ramucirumab Day 1 | Part D: 100 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 100 or 150 or 200 mg LY3023414 | Part D: 200 mg Abemaciclib + 150 mg LY3023414 | Part E: 100 mg Abemaciclib + 200 mg Pembrolizumab | Part E: 150 mg Abemaciclib + 200 mg Pembrolizumab |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given IV over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1, or 8 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8, or 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 or 150 or 200 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Measure Participants | 8 | 15 | 3 | 20 | 20 | 19 | 3 | 27 | 6 | 3 | 17 |
| Day 1 |
114
(67.4)
|
212
(79.8)
|
80.6
(14.7)
|
201
(71.7)
|
140
(95.7)
|
195
(85.8)
|
86.2
(91.1)
|
159
(74.1)
|
225
(103)
|
125
(57.2)
|
114
(68.8)
|
| Steady State |
NA
(NA)
|
509
(40.5)
|
NA
(NA)
|
417
(77.7)
|
322
(112)
|
228
(152)
|
227
(85.1)
|
305
(55.8)
|
270
(47.7)
|
240
(87.5)
|
| Title | Pharmacokinetics: Maximum Concentration (Cmax) of Pemetrexed at Steady State in Part A |
|---|---|
| Description | Cmax of pemetrexed at steady state in Part A was evaluated. |
| Time Frame | C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug with evaluable PK data in Part A. |
| Arm/Group Title | Part A:150 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part A: 200 mg Abemaciclib + 500 mg/m^2 Pemetrexed |
|---|---|---|
| Arm/Group Description | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given IV over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Measure Participants | 7 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [microgram per milliliter (μg/mL)] |
98.1
(29)
|
93.5
(30)
|
| Title | PK: Dose-normalized Maximum Concentration (Cmax) of Active Gemcitabine Metabolite: 2',2'-Difluorodeoxyuridine (dFdU) on Day 1 and at Steady State (Cycle 2 Day 1) in Part B |
|---|---|
| Description | Cmax of active gemcitabine metabolite (dFdU) on day 1 and at steady state (Cycle 2 Day 1) dose-normalized to 1250 mg/m^2 in Part B was evaluated. |
| Time Frame | C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug with evaluable PK data in Part B. |
| Arm/Group Title | Part B: 150 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg or MTD Abemaciclib + 1250 mg/m^2 Gemcitabine |
|---|---|---|---|
| Arm/Group Description | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib or maximum tolerated dose (MTD) under the combination treatment abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Measure Participants | 3 | 4 | 16 |
| Day 1 |
35600
(14)
|
49600
(12)
|
41900
(21)
|
| Steady State |
NA
(NA)
|
38700
(18)
|
35800
(17)
|
| Title | PK: Maximum Concentration (Cmax) of Ramucirumab at 1 Hour Post-End-of-Infusion in Part C |
|---|---|
| Description | Cmax of ramucirumab at 1 hour post-end-of-Infusion in Part C was evaluated. |
| Time Frame | C1D1 and C2D1: 1 hour post-end-of-infusion |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug with evaluable PK data in Part C. |
| Arm/Group Title | Part C: 150 mg Abemaciclib + 8 mg/kg Ramucirumab Days 1 and 8 | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Day 1 | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Days 1 and 8 | Part C: 200 mg Abemaciclib + 10mg/kg Ramucirumab Day1 |
|---|---|---|---|---|
| Arm/Group Description | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 8 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Measure Participants | 12 | 4 | 4 | 18 |
| C1D1 |
174
(19.6)
|
226
(10.0)
|
193
(27.0)
|
221
(30.6)
|
| C2D1 |
221
(15.0)
|
NA
(NA)
|
NA
(NA)
|
226
(32.3)
|
| Title | PK: Maximum Concentration (Cmax) of LY3023414 in Part D |
|---|---|
| Description | Cmax of LY3023414 in Part D was evaluated. |
| Time Frame | C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug with evaluable PK data in Part D. |
| Arm/Group Title | Part D: 100 or 150 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 or 200 mg Abemaciclib + 150 mg LY3023414 | Part D: 150 mg Abemaciclib + 200 mg LY3023414 |
|---|---|---|---|
| Arm/Group Description | 100 or 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 or 200 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Measure Participants | 12 | 15 | 8 |
| Day 1 |
298
(104)
|
454
(81)
|
578
(119)
|
| Steady State |
438
(63)
|
491
(52)
|
NA
(NA)
|
| Title | PK: Area Under the Concentration Curve (AUC) of Abemaciclib in Part A, B, C, D and E |
|---|---|
| Description | Area under the concentration time curve from zero to 8 hours AUC(0-8h) of abemaciclib in Part A, B, C, D and E was evaluated. |
| Time Frame | C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug with evaluable PK data in Part A, B, C, D and E. |
| Arm/Group Title | Part A:150 Milligram(mg) Abemaciclib + 500 mg/m^2 Pemetrexed | Part A: 200 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part B: 150 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part C: 150 mg Abemaciclib + 8 mg/kg or 10 mg/kg Ramucirumab | Part C: 200 mg Abemaciclib + 10mg/kg Ramucirumab Day1 | Part D: 100 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 100 or 150 or 200 mg LY3023414 | Part D: 200 mg Abemaciclib + 150 mg LY3023414 | Part E: 100 mg Abemaciclib + 200 mg Pembrolizumab | Part E: 150 mg Abemaciclib + 200 mg Pembrolizumab |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 milligrams/square meter (mg/m^2) pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1, or 8 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8, or 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 or 8 to 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 or 150 or 200 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Measure Participants | 8 | 15 | 3 | 20 | 20 | 19 | 3 | 27 | 6 | 3 | 17 |
| Day 1 |
533
(69.6)
|
979
(77.5)
|
393
(31.0)
|
886
(53.4)
|
797
(69.0)
|
1030
(127)
|
394
(71.7)
|
719
(77.3)
|
967
(139)
|
NA
(NA)
|
518
(21.6)
|
| Steady State |
NA
(NA)
|
3710
(41.1)
|
NA
(NA)
|
2690
(53.4)
|
1720
(119)
|
1840
(115)
|
NA
(NA)
|
1550
(83.7)
|
1400
(184)
|
| Title | PK: Area Under the Concentration Curve (AUC) of Pemetrexed at Steady State in Part A |
|---|---|
| Description | Area under the plasma concentration versus time curve from time zero to infinity (AUC[0-∞]) of Pemetrexed in Part A was evaluated. |
| Time Frame | C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug with evaluable PK data in Part A. |
| Arm/Group Title | Part A:150 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part A: 200 mg Abemaciclib + 500 mg/m^2 Pemetrexed |
|---|---|---|
| Arm/Group Description | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given IV over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Measure Participants | 7 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [microgram*hour per milliliter (μg*hr/mL)] |
201
(30)
|
198
(32)
|
| Title | PK: Area Under the Concentration Curve (AUC) of Active Gemcitabine Metabolite: 2',2'-Difluorodeoxyuridine (dFdU) on Day 1 and at Steady State (Cycle 2 Day 1) in Part B |
|---|---|
| Description | Area under the plasma concentration time curve from time zero to 12 hours (AUC[0-12h]) of active gemcitabine metabolite (dFdU) in Part B was evaluated |
| Time Frame | C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug with evaluable PK data in Part B. |
| Arm/Group Title | Part B: 150 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | 200 mg or MTD Abemaciclib + 1250 mg/m^2 Gemcitabine |
|---|---|---|---|
| Arm/Group Description | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib or maximum tolerated dose (MTD) under the combination treatment abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Measure Participants | 3 | 4 | 16 |
| Day 1 |
175000
(16)
|
246000
(29)
|
198000
(26)
|
| Steady State |
NA
(NA)
|
208000
(20)
|
210000
(23)
|
| Title | PK: Area Under the Concentration Curve (AUC) of LY3023414 in Part D |
|---|---|
| Description | Area under the plasma concentration versus time curve from time zero to infinity (AUC) of LY3023414 in Part D was evaluated. For Day 1, AUC is defined as AUC from time zero to infinity (AUC[0-∞]), for steady state, AUC is defined as AUC from time zero to the end of the dosing interval, tau (AUC[0-tau ]) |
| Time Frame | C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug with evaluable PK data in Part D. |
| Arm/Group Title | Part D: 100 or 150 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 or 200 mg Abemaciclib + 150 mg LY3023414 | Part D: 150 mg Abemaciclib + 200 mg LY3023414 |
|---|---|---|---|
| Arm/Group Description | 100 or 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 or 200 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg or 150 mg or 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Measure Participants | 12 | 15 | 8 |
| Day 1 |
1005
(63)
|
1751
(56)
|
3809
(95)
|
| Steady State |
1303
(64)
|
1293
(49)
|
NA
(NA)
|
Adverse Events
| Time Frame | Up to 4 years and 1 Month | |||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | All randomized participants who received at least one dose of study drug in Part A, B, C, D and E. Gender specific events only occurring in male or female participants have had the number of participants at risk adjusted accordingly. | |||||||||||||||||||||||||||||
| Arm/Group Title | Part A:150 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part A: 200 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part B:150 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Day1 | Part C: 200 mg Abemaciclib + 10 mg/kg Ramucirumab Day1 | Part C: 150 mg Abemaciclib + 8 mg/kg Ramucirumab Days 1 and 8 | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Days 1 and 8 | Part D: 100 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 150 mg LY3023414 | Part D: 200 mg Abemaciclib + 150 mg LY3023414 | Part D: 150 mg Abemaciclib + 200 mg LY3023414 | Part E: 100 mg Abemaciclib + 200 mg Pembrolizumab | Part E: 150 mg Abemaciclib + 200 mg Pembrolizumab | |||||||||||||||
| Arm/Group Description | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given IV over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 mg/m^2 pemetrexed given IV over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 mg/m^2 gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 mg/kg ramucirumab given intravenously over approximately 60 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 mg/kg ramucirumab given intravenously over approximately 60 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 8 mg/kg ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 mg/kg ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 150 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 100 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | |||||||||||||||
All Cause Mortality |
||||||||||||||||||||||||||||||
| Part A:150 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part A: 200 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part B:150 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Day1 | Part C: 200 mg Abemaciclib + 10 mg/kg Ramucirumab Day1 | Part C: 150 mg Abemaciclib + 8 mg/kg Ramucirumab Days 1 and 8 | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Days 1 and 8 | Part D: 100 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 150 mg LY3023414 | Part D: 200 mg Abemaciclib + 150 mg LY3023414 | Part D: 150 mg Abemaciclib + 200 mg LY3023414 | Part E: 100 mg Abemaciclib + 200 mg Pembrolizumab | Part E: 150 mg Abemaciclib + 200 mg Pembrolizumab | ||||||||||||||||
| 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 | 2/8 (25%) | 1/15 (6.7%) | 1/3 (33.3%) | 6/21 (28.6%) | 2/4 (50%) | 4/19 (21.1%) | 1/12 (8.3%) | 1/4 (25%) | 0/3 (0%) | 1/9 (11.1%) | 0/10 (0%) | 1/6 (16.7%) | 1/8 (12.5%) | 0/3 (0%) | 2/17 (11.8%) | |||||||||||||||
Serious Adverse Events |
||||||||||||||||||||||||||||||
| Part A:150 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part A: 200 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part B:150 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Day1 | Part C: 200 mg Abemaciclib + 10 mg/kg Ramucirumab Day1 | Part C: 150 mg Abemaciclib + 8 mg/kg Ramucirumab Days 1 and 8 | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Days 1 and 8 | Part D: 100 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 150 mg LY3023414 | Part D: 200 mg Abemaciclib + 150 mg LY3023414 | Part D: 150 mg Abemaciclib + 200 mg LY3023414 | Part E: 100 mg Abemaciclib + 200 mg Pembrolizumab | Part E: 150 mg Abemaciclib + 200 mg Pembrolizumab | ||||||||||||||||
| 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 | 4/8 (50%) | 8/15 (53.3%) | 1/3 (33.3%) | 10/21 (47.6%) | 3/4 (75%) | 12/19 (63.2%) | 3/12 (25%) | 3/4 (75%) | 1/3 (33.3%) | 2/9 (22.2%) | 3/10 (30%) | 0/6 (0%) | 4/8 (50%) | 0/3 (0%) | 9/17 (52.9%) | |||||||||||||||
| Blood and lymphatic system disorders | ||||||||||||||||||||||||||||||
| Anaemia | 1/8 (12.5%) | 1 | 2/15 (13.3%) | 2 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Febrile neutropenia | 0/8 (0%) | 0 | 3/15 (20%) | 3 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Leukopenia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Neutropenia | 0/8 (0%) | 0 | 3/15 (20%) | 3 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Thrombocytopenia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 2 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Cardiac disorders | ||||||||||||||||||||||||||||||
| Atrial fibrillation | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Atrial flutter | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Cardiac arrest | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Cardiac failure | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Cardiac failure congestive | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Cardiac tamponade | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 2 |
| Cardiogenic shock | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Coronary artery disease | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Myocardial infarction | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pericardial effusion | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Sinus tachycardia | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Stress cardiomyopathy | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Gastrointestinal disorders | ||||||||||||||||||||||||||||||
| Colitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Diarrhoea | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Duodenal ulcer haemorrhage | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 2 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Dysphagia | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Gastrointestinal haemorrhage | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Nausea | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pancreatitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Small intestinal obstruction | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| General disorders | ||||||||||||||||||||||||||||||
| Asthenia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Death | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 2/19 (10.5%) | 2 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hepatobiliary disorders | ||||||||||||||||||||||||||||||
| Hepatitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Hepatotoxicity | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Infections and infestations | ||||||||||||||||||||||||||||||
| Bronchitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Clostridium difficile colitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Device related infection | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Influenza | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pneumonia | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 3/21 (14.3%) | 3 | 1/4 (25%) | 1 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 1/4 (25%) | 1 | 1/3 (33.3%) | 3 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Respiratory tract infection | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Scrotal infection | 0/4 (0%) | 0 | 0/10 (0%) | 0 | 0/3 (0%) | 0 | 1/10 (10%) | 1 | 0/2 (0%) | 0 | 0/9 (0%) | 0 | 0/8 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/7 (0%) | 0 | 0/4 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/7 (0%) | 0 |
| Sepsis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Septic shock | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Upper respiratory tract infection | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Urinary tract infection | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||||||||||||||||||||||||
| Overdose | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Spinal fracture | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Investigations | ||||||||||||||||||||||||||||||
| Alanine aminotransferase increased | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Aspartate aminotransferase increased | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Blood creatinine increased | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Gamma-glutamyltransferase increased | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Myocardial strain | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Neutrophil count decreased | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||||||||||||||||||||||||||
| Dehydration | 0/8 (0%) | 0 | 2/15 (13.3%) | 2 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hypercalcaemia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hypokalaemia | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hyponatraemia | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Nervous system disorders | ||||||||||||||||||||||||||||||
| Cerebrovascular accident | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Dysarthria | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Ischaemic stroke | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Subarachnoid haemorrhage | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Syncope | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Renal and urinary disorders | ||||||||||||||||||||||||||||||
| Acute kidney injury | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Renal failure | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Ureterolithiasis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||||||||||||||||
| Acute respiratory failure | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Dyspnoea | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 1/3 (33.3%) | 1 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Epistaxis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pneumonia aspiration | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pneumonitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Pulmonary embolism | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Pulmonary haemorrhage | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Respiratory failure | 1/8 (12.5%) | 2 | 2/15 (13.3%) | 2 | 0/3 (0%) | 0 | 2/21 (9.5%) | 2 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Vascular disorders | ||||||||||||||||||||||||||||||
| Peripheral ischaemia | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Subclavian artery thrombosis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Venous thrombosis limb | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
Other (Not Including Serious) Adverse Events |
||||||||||||||||||||||||||||||
| Part A:150 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part A: 200 mg Abemaciclib + 500 mg/m^2 Pemetrexed | Part B:150 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part B: 200 mg Abemaciclib + 1250 mg/m^2 Gemcitabine | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Day1 | Part C: 200 mg Abemaciclib + 10 mg/kg Ramucirumab Day1 | Part C: 150 mg Abemaciclib + 8 mg/kg Ramucirumab Days 1 and 8 | Part C: 150 mg Abemaciclib + 10 mg/kg Ramucirumab Days 1 and 8 | Part D: 100 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 100 mg LY3023414 | Part D: 150 mg Abemaciclib + 150 mg LY3023414 | Part D: 200 mg Abemaciclib + 150 mg LY3023414 | Part D: 150 mg Abemaciclib + 200 mg LY3023414 | Part E: 100 mg Abemaciclib + 200 mg Pembrolizumab | Part E: 150 mg Abemaciclib + 200 mg Pembrolizumab | ||||||||||||||||
| 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 | 8/8 (100%) | 15/15 (100%) | 3/3 (100%) | 21/21 (100%) | 4/4 (100%) | 19/19 (100%) | 12/12 (100%) | 4/4 (100%) | 3/3 (100%) | 8/9 (88.9%) | 10/10 (100%) | 5/6 (83.3%) | 8/8 (100%) | 3/3 (100%) | 16/17 (94.1%) | |||||||||||||||
| Blood and lymphatic system disorders | ||||||||||||||||||||||||||||||
| Anaemia | 6/8 (75%) | 20 | 12/15 (80%) | 24 | 1/3 (33.3%) | 2 | 10/21 (47.6%) | 44 | 0/4 (0%) | 0 | 5/19 (26.3%) | 13 | 2/12 (16.7%) | 3 | 0/4 (0%) | 0 | 2/3 (66.7%) | 3 | 3/9 (33.3%) | 8 | 2/10 (20%) | 2 | 0/6 (0%) | 0 | 3/8 (37.5%) | 3 | 2/3 (66.7%) | 4 | 6/17 (35.3%) | 12 |
| Febrile neutropenia | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Leukopenia | 0/8 (0%) | 0 | 3/15 (20%) | 4 | 0/3 (0%) | 0 | 2/21 (9.5%) | 2 | 0/4 (0%) | 0 | 2/19 (10.5%) | 10 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 2/9 (22.2%) | 3 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Neutropenia | 1/8 (12.5%) | 6 | 4/15 (26.7%) | 12 | 0/3 (0%) | 0 | 3/21 (14.3%) | 4 | 0/4 (0%) | 0 | 3/19 (15.8%) | 14 | 1/12 (8.3%) | 14 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 2/9 (22.2%) | 2 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 5/17 (29.4%) | 7 |
| Thrombocytopenia | 1/8 (12.5%) | 1 | 2/15 (13.3%) | 5 | 0/3 (0%) | 0 | 2/21 (9.5%) | 2 | 1/4 (25%) | 2 | 2/19 (10.5%) | 6 | 0/12 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 1/17 (5.9%) | 3 |
| Cardiac disorders | ||||||||||||||||||||||||||||||
| Atrial fibrillation | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Atrial tachycardia | 1/8 (12.5%) | 2 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Atrioventricular block complete | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Cardiac failure | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Palpitations | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pericardial effusion | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pericarditis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Sinus bradycardia | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Sinus tachycardia | 2/8 (25%) | 2 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 2/21 (9.5%) | 2 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 4/10 (40%) | 4 | 0/6 (0%) | 0 | 1/8 (12.5%) | 2 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Tachycardia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Ventricular dysfunction | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Ear and labyrinth disorders | ||||||||||||||||||||||||||||||
| Ear pain | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hypoacusis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Endocrine disorders | ||||||||||||||||||||||||||||||
| Hyperthyroidism | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Hypothyroidism | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Eye disorders | ||||||||||||||||||||||||||||||
| Cataract | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Eye swelling | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 1/3 (33.3%) | 1 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Lacrimation increased | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Vision blurred | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Gastrointestinal disorders | ||||||||||||||||||||||||||||||
| Abdominal distension | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 2 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Abdominal pain | 2/8 (25%) | 2 | 5/15 (33.3%) | 19 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 3/12 (25%) | 3 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 3/10 (30%) | 3 | 0/6 (0%) | 0 | 3/8 (37.5%) | 3 | 0/3 (0%) | 0 | 2/17 (11.8%) | 2 |
| Abdominal pain upper | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 3/21 (14.3%) | 3 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Abdominal tenderness | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Anal fissure | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Anal fistula | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Ascites | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Colitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 2/19 (10.5%) | 2 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Constipation | 3/8 (37.5%) | 4 | 2/15 (13.3%) | 2 | 0/3 (0%) | 0 | 5/21 (23.8%) | 5 | 0/4 (0%) | 0 | 2/19 (10.5%) | 3 | 3/12 (25%) | 3 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 3/10 (30%) | 3 | 1/6 (16.7%) | 1 | 0/8 (0%) | 0 | 1/3 (33.3%) | 1 | 2/17 (11.8%) | 2 |
| Dental caries | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Diarrhoea | 4/8 (50%) | 7 | 14/15 (93.3%) | 31 | 1/3 (33.3%) | 1 | 13/21 (61.9%) | 28 | 2/4 (50%) | 2 | 14/19 (73.7%) | 32 | 10/12 (83.3%) | 27 | 2/4 (50%) | 3 | 2/3 (66.7%) | 4 | 6/9 (66.7%) | 6 | 9/10 (90%) | 17 | 1/6 (16.7%) | 1 | 6/8 (75%) | 8 | 1/3 (33.3%) | 1 | 10/17 (58.8%) | 30 |
| Dry mouth | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 1/19 (5.3%) | 1 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 2/9 (22.2%) | 2 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Duodenitis | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Dyspepsia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 2 | 3/10 (30%) | 3 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Dysphagia | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 1/3 (33.3%) | 2 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 1/19 (5.3%) | 3 | 2/12 (16.7%) | 2 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Enteritis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Faeces discoloured | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Flatulence | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Gastric ulcer | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Gastrointestinal haemorrhage | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Gastrooesophageal reflux disease | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 1/19 (5.3%) | 2 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Gingival pain | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Haematochezia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Haemorrhoidal haemorrhage | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Haemorrhoids | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 2 |
| Hypoaesthesia oral | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 1/6 (16.7%) | 1 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Impaired gastric emptying | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Nausea | 5/8 (62.5%) | 6 | 6/15 (40%) | 13 | 3/3 (100%) | 3 | 13/21 (61.9%) | 17 | 1/4 (25%) | 2 | 12/19 (63.2%) | 22 | 6/12 (50%) | 11 | 2/4 (50%) | 3 | 2/3 (66.7%) | 2 | 5/9 (55.6%) | 5 | 6/10 (60%) | 16 | 3/6 (50%) | 6 | 4/8 (50%) | 6 | 0/3 (0%) | 0 | 7/17 (41.2%) | 7 |
| Odynophagia | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Oesophagitis | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Oral mucosal discolouration | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Oral pain | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Proctalgia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Retching | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Stomatitis | 1/8 (12.5%) | 1 | 2/15 (13.3%) | 2 | 0/3 (0%) | 0 | 2/21 (9.5%) | 2 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 2/12 (16.7%) | 3 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 2/8 (25%) | 2 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Tooth disorder | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Toothache | 1/8 (12.5%) | 2 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Vomiting | 3/8 (37.5%) | 4 | 4/15 (26.7%) | 18 | 0/3 (0%) | 0 | 8/21 (38.1%) | 10 | 1/4 (25%) | 2 | 11/19 (57.9%) | 17 | 3/12 (25%) | 3 | 1/4 (25%) | 2 | 2/3 (66.7%) | 3 | 4/9 (44.4%) | 5 | 7/10 (70%) | 7 | 2/6 (33.3%) | 4 | 6/8 (75%) | 6 | 0/3 (0%) | 0 | 4/17 (23.5%) | 4 |
| General disorders | ||||||||||||||||||||||||||||||
| Asthenia | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 2/21 (9.5%) | 2 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 4/12 (33.3%) | 12 | 3/4 (75%) | 9 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 1/6 (16.7%) | 1 | 2/8 (25%) | 2 | 0/3 (0%) | 0 | 3/17 (17.6%) | 6 |
| Chills | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 3/9 (33.3%) | 3 | 3/10 (30%) | 5 | 1/6 (16.7%) | 1 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Face oedema | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Fatigue | 5/8 (62.5%) | 14 | 12/15 (80%) | 32 | 2/3 (66.7%) | 4 | 17/21 (81%) | 30 | 2/4 (50%) | 2 | 12/19 (63.2%) | 23 | 5/12 (41.7%) | 9 | 0/4 (0%) | 0 | 2/3 (66.7%) | 2 | 4/9 (44.4%) | 7 | 4/10 (40%) | 5 | 2/6 (33.3%) | 2 | 2/8 (25%) | 2 | 3/3 (100%) | 4 | 12/17 (70.6%) | 20 |
| Gait disturbance | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| General physical health deterioration | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Generalised oedema | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Influenza like illness | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 2/17 (11.8%) | 2 |
| Malaise | 0/8 (0%) | 0 | 1/15 (6.7%) | 2 | 0/3 (0%) | 0 | 3/21 (14.3%) | 3 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 1/6 (16.7%) | 1 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Mucosal inflammation | 1/8 (12.5%) | 1 | 4/15 (26.7%) | 4 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 4/12 (33.3%) | 5 | 1/4 (25%) | 2 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 2/17 (11.8%) | 2 |
| Non-cardiac chest pain | 2/8 (25%) | 2 | 0/15 (0%) | 0 | 1/3 (33.3%) | 1 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 2 |
| Oedema peripheral | 3/8 (37.5%) | 3 | 2/15 (13.3%) | 2 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 1/4 (25%) | 1 | 4/19 (21.1%) | 8 | 2/12 (16.7%) | 7 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 3/10 (30%) | 3 | 0/6 (0%) | 0 | 2/8 (25%) | 2 | 0/3 (0%) | 0 | 2/17 (11.8%) | 3 |
| Pain | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Peripheral swelling | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pyrexia | 3/8 (37.5%) | 3 | 2/15 (13.3%) | 3 | 0/3 (0%) | 0 | 2/21 (9.5%) | 3 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 1/12 (8.3%) | 1 | 2/4 (50%) | 2 | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 2/10 (20%) | 2 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Temperature intolerance | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hepatobiliary disorders | ||||||||||||||||||||||||||||||
| Cholangitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Infections and infestations | ||||||||||||||||||||||||||||||
| Acute sinusitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Bacteraemia | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Bronchitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Clostridium difficile colitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Conjunctivitis | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Cystitis | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Fungal infection | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Fungal skin infection | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Furuncle | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Gastroenteritis | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Gingivitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Herpes zoster | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Lower respiratory tract infection | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Lung infection | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 2/3 (66.7%) | 2 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Nasal vestibulitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Nasopharyngitis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Oesophageal candidiasis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Oral candidiasis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pharyngitis | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pneumonia | 3/8 (37.5%) | 3 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Pyoderma | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Respiratory tract infection | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 2/17 (11.8%) | 2 |
| Respiratory tract infection viral | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Scrotal infection | 0/4 (0%) | 0 | 0/10 (0%) | 0 | 0/3 (0%) | 0 | 1/10 (10%) | 1 | 0/2 (0%) | 0 | 0/9 (0%) | 0 | 0/8 (0%) | 0 | 0/4 (0%) | 0 | 0/2 (0%) | 0 | 0/4 (0%) | 0 | 0/7 (0%) | 0 | 0/4 (0%) | 0 | 0/5 (0%) | 0 | 0/2 (0%) | 0 | 0/7 (0%) | 0 |
| Sepsis | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Septic shock | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Tongue fungal infection | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Tooth infection | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Upper respiratory tract infection | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 1/3 (33.3%) | 1 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 2/3 (66.7%) | 3 | 5/17 (29.4%) | 7 |
| Urinary tract infection | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 1/4 (25%) | 1 | 2/19 (10.5%) | 3 | 2/12 (16.7%) | 2 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 1/3 (33.3%) | 1 | 2/17 (11.8%) | 2 |
| Viral rash | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||||||||||||||||||||||||
| Arthropod bite | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Contusion | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Fall | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 2/10 (20%) | 2 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Head injury | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 1/6 (16.7%) | 1 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Limb injury | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Overdose | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Procedural anxiety | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Skin abrasion | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Spinal column injury | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Spinal fracture | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Toxicity to various agents | 1/8 (12.5%) | 2 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Investigations | ||||||||||||||||||||||||||||||
| Alanine aminotransferase increased | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 1/19 (5.3%) | 2 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 4 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 1/3 (33.3%) | 4 | 3/17 (17.6%) | 7 |
| Aspartate aminotransferase increased | 0/8 (0%) | 0 | 2/15 (13.3%) | 2 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 3 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 4 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 1/3 (33.3%) | 1 | 2/17 (11.8%) | 2 |
| Blood alkaline phosphatase increased | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Blood bilirubin increased | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Blood creatine increased | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 2 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Blood creatine phosphokinase increased | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Blood creatinine increased | 5/8 (62.5%) | 13 | 3/15 (20%) | 5 | 1/3 (33.3%) | 2 | 4/21 (19%) | 13 | 0/4 (0%) | 0 | 4/19 (21.1%) | 10 | 3/12 (25%) | 4 | 0/4 (0%) | 0 | 1/3 (33.3%) | 2 | 1/9 (11.1%) | 1 | 1/10 (10%) | 2 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 1/3 (33.3%) | 1 | 2/17 (11.8%) | 3 |
| Electrocardiogram qt prolonged | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 1/17 (5.9%) | 3 |
| Electrocardiogram t wave abnormal | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Gamma-glutamyltransferase increased | 0/8 (0%) | 0 | 3/15 (20%) | 4 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 0/19 (0%) | 0 | 1/12 (8.3%) | 2 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 1/3 (33.3%) | 2 | 2/17 (11.8%) | 3 |
| Heart rate increased | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Lymphocyte count decreased | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 1/4 (25%) | 2 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 1/6 (16.7%) | 1 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Neutrophil count decreased | 5/8 (62.5%) | 9 | 4/15 (26.7%) | 17 | 2/3 (66.7%) | 9 | 9/21 (42.9%) | 36 | 0/4 (0%) | 0 | 3/19 (15.8%) | 7 | 1/12 (8.3%) | 1 | 1/4 (25%) | 1 | 2/3 (66.7%) | 5 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Neutrophil count increased | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Platelet count decreased | 3/8 (37.5%) | 9 | 4/15 (26.7%) | 7 | 1/3 (33.3%) | 1 | 10/21 (47.6%) | 24 | 0/4 (0%) | 0 | 5/19 (26.3%) | 13 | 2/12 (16.7%) | 2 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 2/9 (22.2%) | 3 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 2/8 (25%) | 3 | 1/3 (33.3%) | 1 | 1/17 (5.9%) | 1 |
| Weight decreased | 2/8 (25%) | 2 | 4/15 (26.7%) | 4 | 0/3 (0%) | 0 | 2/21 (9.5%) | 2 | 1/4 (25%) | 3 | 3/19 (15.8%) | 3 | 3/12 (25%) | 3 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 1/9 (11.1%) | 1 | 2/10 (20%) | 2 | 1/6 (16.7%) | 1 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| White blood cell count decreased | 3/8 (37.5%) | 9 | 1/15 (6.7%) | 3 | 0/3 (0%) | 0 | 4/21 (19%) | 12 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||||||||||||||||||||||||||
| Decreased appetite | 4/8 (50%) | 4 | 9/15 (60%) | 17 | 0/3 (0%) | 0 | 9/21 (42.9%) | 12 | 1/4 (25%) | 2 | 6/19 (31.6%) | 7 | 6/12 (50%) | 19 | 3/4 (75%) | 8 | 1/3 (33.3%) | 2 | 2/9 (22.2%) | 2 | 3/10 (30%) | 5 | 2/6 (33.3%) | 2 | 5/8 (62.5%) | 5 | 1/3 (33.3%) | 1 | 9/17 (52.9%) | 20 |
| Dehydration | 2/8 (25%) | 2 | 2/15 (13.3%) | 6 | 1/3 (33.3%) | 2 | 7/21 (33.3%) | 8 | 0/4 (0%) | 0 | 6/19 (31.6%) | 6 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 1/9 (11.1%) | 1 | 4/10 (40%) | 4 | 1/6 (16.7%) | 3 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Failure to thrive | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Fluid intake reduced | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hypercalcaemia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 2 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hyperglycaemia | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 1/6 (16.7%) | 1 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hyperkalaemia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 2 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hyperphosphataemia | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 1/3 (33.3%) | 1 | 0/17 (0%) | 0 |
| Hyperuricaemia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 2 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hypoalbuminaemia | 1/8 (12.5%) | 1 | 2/15 (13.3%) | 5 | 0/3 (0%) | 0 | 4/21 (19%) | 6 | 0/4 (0%) | 0 | 1/19 (5.3%) | 2 | 1/12 (8.3%) | 8 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 2 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 1/3 (33.3%) | 1 | 5/17 (29.4%) | 12 |
| Hypocalcaemia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 2/21 (9.5%) | 2 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Hypoglycaemia | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hypokalaemia | 1/8 (12.5%) | 1 | 3/15 (20%) | 3 | 0/3 (0%) | 0 | 3/21 (14.3%) | 4 | 0/4 (0%) | 0 | 3/19 (15.8%) | 5 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 3/9 (33.3%) | 3 | 2/10 (20%) | 5 | 0/6 (0%) | 0 | 4/8 (50%) | 5 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hypomagnesaemia | 2/8 (25%) | 2 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 2/21 (9.5%) | 2 | 0/4 (0%) | 0 | 2/19 (10.5%) | 4 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hyponatraemia | 0/8 (0%) | 0 | 2/15 (13.3%) | 3 | 0/3 (0%) | 0 | 2/21 (9.5%) | 2 | 1/4 (25%) | 3 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 1/10 (10%) | 2 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hypophosphataemia | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 5 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 3/17 (17.6%) | 4 |
| Musculoskeletal and connective tissue disorders | ||||||||||||||||||||||||||||||
| Arthralgia | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 1/3 (33.3%) | 1 | 1/17 (5.9%) | 1 |
| Back pain | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 1/21 (4.8%) | 2 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 1/10 (10%) | 2 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 1/3 (33.3%) | 1 | 1/17 (5.9%) | 1 |
| Bone pain | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 2 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Flank pain | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Muscle spasms | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 1/4 (25%) | 2 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Muscle twitching | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Muscular weakness | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 2/21 (9.5%) | 3 | 0/4 (0%) | 0 | 1/19 (5.3%) | 3 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 2 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Musculoskeletal chest pain | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Musculoskeletal pain | 2/8 (25%) | 5 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 2/21 (9.5%) | 2 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 3 | 1/4 (25%) | 5 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Myalgia | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Neck pain | 1/8 (12.5%) | 4 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pain in extremity | 1/8 (12.5%) | 1 | 2/15 (13.3%) | 2 | 0/3 (0%) | 0 | 1/21 (4.8%) | 2 | 1/4 (25%) | 1 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Spinal pain | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Trigger finger | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||||||||||||||||||
| Cancer pain | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Nervous system disorders | ||||||||||||||||||||||||||||||
| Aphasia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Cerebral ischaemia | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Dizziness | 2/8 (25%) | 2 | 2/15 (13.3%) | 3 | 0/3 (0%) | 0 | 2/21 (9.5%) | 2 | 1/4 (25%) | 1 | 1/19 (5.3%) | 1 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 2/10 (20%) | 2 | 1/6 (16.7%) | 1 | 2/8 (25%) | 2 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Dizziness postural | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Dysarthria | 0/8 (0%) | 0 | 2/15 (13.3%) | 2 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Dysgeusia | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 2/12 (16.7%) | 2 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 2/10 (20%) | 2 | 1/6 (16.7%) | 1 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 2 |
| Encephalopathy | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Facial spasm | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 1/3 (33.3%) | 1 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Headache | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 4/21 (19%) | 4 | 0/4 (0%) | 0 | 4/19 (21.1%) | 4 | 2/12 (16.7%) | 2 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 2/9 (22.2%) | 2 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Hypoaesthesia | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Lethargy | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Neuralgia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Neurological decompensation | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 1/3 (33.3%) | 1 | 0/17 (0%) | 0 |
| Neuropathy peripheral | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Neurotoxicity | 0/8 (0%) | 0 | 2/15 (13.3%) | 3 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Paraesthesia | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Peripheral sensory neuropathy | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Presyncope | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Sciatica | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Seizure | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Somnolence | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 2/12 (16.7%) | 2 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Syncope | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Tremor | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 2 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Vocal cord paralysis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Psychiatric disorders | ||||||||||||||||||||||||||||||
| Agitation | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Anxiety | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 2/3 (66.7%) | 3 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 2/19 (10.5%) | 2 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Confusional state | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Depressed mood | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Depression | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 1/6 (16.7%) | 1 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Disorientation | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Insomnia | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 1/3 (33.3%) | 1 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 4/19 (21.1%) | 4 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 2/6 (33.3%) | 2 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Mental status changes | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Stress | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Renal and urinary disorders | ||||||||||||||||||||||||||||||
| Acute kidney injury | 2/8 (25%) | 3 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 2/10 (20%) | 3 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Azotaemia | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Micturition urgency | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Oliguria | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Polyuria | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Proteinuria | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 4 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 2/3 (66.7%) | 2 | 2/17 (11.8%) | 2 |
| Renal failure | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Renal vein thrombosis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Urinary retention | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Reproductive system and breast disorders | ||||||||||||||||||||||||||||||
| Menorrhagia | 0/4 (0%) | 0 | 0/5 (0%) | 0 | 0/0 (NaN) | 0 | 0/11 (0%) | 0 | 0/2 (0%) | 0 | 0/10 (0%) | 0 | 1/4 (25%) | 1 | 0/0 (NaN) | 0 | 0/1 (0%) | 0 | 0/5 (0%) | 0 | 0/3 (0%) | 0 | 0/2 (0%) | 0 | 0/3 (0%) | 0 | 0/1 (0%) | 0 | 0/10 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||||||||||||||||
| Acute respiratory distress syndrome | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Chronic obstructive pulmonary disease | 2/8 (25%) | 2 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Cough | 2/8 (25%) | 2 | 4/15 (26.7%) | 8 | 1/3 (33.3%) | 1 | 5/21 (23.8%) | 9 | 0/4 (0%) | 0 | 5/19 (26.3%) | 5 | 3/12 (25%) | 5 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 1/10 (10%) | 1 | 1/6 (16.7%) | 1 | 1/8 (12.5%) | 1 | 1/3 (33.3%) | 1 | 3/17 (17.6%) | 4 |
| Dry throat | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Dysphonia | 0/8 (0%) | 0 | 2/15 (13.3%) | 2 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Dyspnoea | 1/8 (12.5%) | 1 | 6/15 (40%) | 10 | 1/3 (33.3%) | 1 | 3/21 (14.3%) | 3 | 1/4 (25%) | 2 | 2/19 (10.5%) | 4 | 3/12 (25%) | 3 | 2/4 (50%) | 3 | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 1/6 (16.7%) | 3 | 3/8 (37.5%) | 5 | 0/3 (0%) | 0 | 4/17 (23.5%) | 6 |
| Dyspnoea exertional | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Epistaxis | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 1/4 (25%) | 1 | 2/19 (10.5%) | 2 | 2/12 (16.7%) | 2 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 2/8 (25%) | 2 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Haemoptysis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 1/4 (25%) | 1 | 2/19 (10.5%) | 2 | 1/12 (8.3%) | 1 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hypercapnia | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hypoxia | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 1/3 (33.3%) | 1 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Nasal congestion | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Nasal dryness | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Oropharyngeal pain | 0/8 (0%) | 0 | 2/15 (13.3%) | 15 | 0/3 (0%) | 0 | 3/21 (14.3%) | 4 | 1/4 (25%) | 1 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Pleural effusion | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pleuritic pain | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pneumonitis | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 2 |
| Pneumothorax | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Productive cough | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 1/4 (25%) | 1 | 0/19 (0%) | 0 | 1/12 (8.3%) | 2 | 2/4 (50%) | 3 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pulmonary oedema | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 1/3 (33.3%) | 1 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Respiratory failure | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Respiratory tract congestion | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Rhinalgia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Rhinitis allergic | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Rhinorrhoea | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Sinus pain | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Wheezing | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 2 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||||||||||||||||||||||||||
| Alopecia | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Dermatitis acneiform | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 1/3 (33.3%) | 1 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Drug eruption | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Dry skin | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 2/3 (66.7%) | 2 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 3/12 (25%) | 6 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 1/3 (33.3%) | 1 | 3/17 (17.6%) | 3 |
| Eczema | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Hyperhidrosis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Night sweats | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 1/6 (16.7%) | 1 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Petechiae | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Pruritus | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 2/17 (11.8%) | 3 |
| Psoriasis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 2 |
| Rash | 1/8 (12.5%) | 1 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 2/21 (9.5%) | 2 | 1/4 (25%) | 1 | 2/19 (10.5%) | 2 | 1/12 (8.3%) | 3 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 2/10 (20%) | 10 | 0/6 (0%) | 0 | 1/8 (12.5%) | 3 | 1/3 (33.3%) | 1 | 1/17 (5.9%) | 1 |
| Rash generalised | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Rash macular | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 1/8 (12.5%) | 1 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Rash maculo-papular | 0/8 (0%) | 0 | 2/15 (13.3%) | 2 | 1/3 (33.3%) | 3 | 1/21 (4.8%) | 2 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 2/9 (22.2%) | 2 | 2/10 (20%) | 3 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Rash pruritic | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Skin disorder | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Skin irritation | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 1 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Skin mass | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Skin ulcer | 1/8 (12.5%) | 1 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Vitiligo | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Vascular disorders | ||||||||||||||||||||||||||||||
| Deep vein thrombosis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Embolism | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Flushing | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/10 (10%) | 3 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Haematoma | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 1/12 (8.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Hypertension | 0/8 (0%) | 0 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 2/12 (16.7%) | 3 | 2/4 (50%) | 2 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Hypotension | 3/8 (37.5%) | 3 | 1/15 (6.7%) | 1 | 0/3 (0%) | 0 | 1/21 (4.8%) | 1 | 1/4 (25%) | 2 | 1/19 (5.3%) | 1 | 1/12 (8.3%) | 1 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 5/10 (50%) | 5 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Thrombophlebitis superficial | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 1/3 (33.3%) | 1 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Thrombosis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 1/19 (5.3%) | 1 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
| Vena cava thrombosis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 0/3 (0%) | 0 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 1/17 (5.9%) | 1 |
| Venous thrombosis | 0/8 (0%) | 0 | 0/15 (0%) | 0 | 1/3 (33.3%) | 1 | 0/21 (0%) | 0 | 0/4 (0%) | 0 | 0/19 (0%) | 0 | 0/12 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/10 (0%) | 0 | 0/6 (0%) | 0 | 0/8 (0%) | 0 | 0/3 (0%) | 0 | 0/17 (0%) | 0 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Chief Medical Officer |
|---|---|
| Organization | Eli Lilly and Company |
| Phone | 800-545-5979 |
| ClinicalTrials.gov@lilly.com |
Responsible Party:
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT02079636
Other Study ID Numbers:
- 15266
- I3Y-MC-JPBJ
- 2013-004648-41
- KEYNOTE-238
First Posted:
Mar 6, 2014
Last Update Posted:
Sep 11, 2020
Last Verified:
Nov 15, 2019