Trial Outcomes & Findings for A Study of Ramucirumab (LY3009806) or Necitumumab (LY3012211) Plus Osimertinib in Participants With Lung Cancer (NCT NCT02789345)

Last Updated: 2024-02-05

Results Overview

A Dose Limiting Toxicity (DLT) was defined as one of the following Adverse Events (AE) that is likely related to the study drug or combination, and fulfils any one of the following criteria, graded according to the NCI-CTCAE Version 4.0: 1. Any nonhematologic Grade ≥3 toxicity, except for toxicities such as liver or renal function abnormality, skin rash that resolves with appropriate therapy, transient hypersensitivity and injection site reactions, myalgia, fatigue, constipation, electrolyte imbalance, nausea, vomiting, diarrhea 2. Hematologic toxicity was considered a DLT as the following: 1. Grade 4 toxicity lasting ≥7 days, or 2. Grade 3 or 4 thrombocytopenia if associated with bleeding or requires platelet transfusion, or 3. Febrile neutropenia 3. Death if considered related to study treatment 4. Any other significant toxicity deemed by the primary investigator and Lilly clinical research personnel to be dose limiting

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

29 participants

Primary outcome timeframe

Arm A: Cycle 1 through Cycle 2 (14-day cycle); Arm B: Cycle 1 (21-day cycle)

Results posted on

2024-02-05

Participant Flow

The study consisted of the dose-finding portion (Phase 1a) and the dose-expansion portion (Phase 1b) * Phase 1a, Arm A = combination of ramucirumab and osimertinib; Arm B = combination of necitumumab and osimertinib * Phase 1b included one cohort, the expansion of Arm A with additional participants enrolled i.e., Cohort A, a combination of ramucirumab and osimertinib. Per Protocol, all outcomes for a combination of ramucirumab and osimertinib were analyzed under a single arm i.e., Arm A/Cohort A

Participants who did not "complete" study were those who discontinued study treatment by the time of study completion.

Participant milestones

Participant milestones
Measure	Arm A: Ramucirumab + Osimertinib Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Arm B: Necitumumab + Osimertinib Participants received Necitumumab 800 mg given IV on Days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Cohort A: Ramucirumab + Osimertinib Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.
Overall Study STARTED	3	4	22
Overall Study Received at Least One Dose of Study Drug	3	4	22
Overall Study COMPLETED	0	1	5
Overall Study NOT COMPLETED	3	3	17

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A: Ramucirumab + Osimertinib Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Arm B: Necitumumab + Osimertinib Participants received Necitumumab 800 mg given IV on Days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Cohort A: Ramucirumab + Osimertinib Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.
Overall Study Adverse Event	0	0	1
Overall Study Death	0	0	1
Overall Study Physician Decision	2	0	1
Overall Study Progressive Disease	1	3	14

Baseline Characteristics

A Study of Ramucirumab (LY3009806) or Necitumumab (LY3012211) Plus Osimertinib in Participants With Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A: Ramucirumab + Osimertinib n=3 Participants Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Arm B: Necitumumab + Osimertinib n=4 Participants Participants received Necitumumab 800 mg given IV on Days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Cohort A: Ramucirumab + Osimertinib n=22 Participants Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Total n=29 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	2 Participants n=5 Participants	2 Participants n=7 Participants	12 Participants n=5 Participants	16 Participants n=4 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	2 Participants n=7 Participants	10 Participants n=5 Participants	13 Participants n=4 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	3 Participants n=7 Participants	17 Participants n=5 Participants	21 Participants n=4 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants	8 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	4 Participants n=7 Participants	22 Participants n=5 Participants	29 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	13 Participants n=5 Participants	13 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants	16 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment South Korea	0 Participants n=5 Participants	0 Participants n=7 Participants	6 Participants n=5 Participants	6 Participants n=4 Participants
Region of Enrollment United States	1 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	5 Participants n=4 Participants
Region of Enrollment Taiwan	0 Participants n=5 Participants	0 Participants n=7 Participants	5 Participants n=5 Participants	5 Participants n=4 Participants
Region of Enrollment France	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Region of Enrollment Spain	2 Participants n=5 Participants	2 Participants n=7 Participants	8 Participants n=5 Participants	12 Participants n=4 Participants

PRIMARY outcome

Timeframe: Arm A: Cycle 1 through Cycle 2 (14-day cycle); Arm B: Cycle 1 (21-day cycle)

Population: Arm A: participants who either completed the first 2 cycles of treatment or discontinued from study treatment or study participation Arm B: participants who either completed the first cycle of treatment or discontinued from study treatment or study participation

Outcome measures

Outcome measures
Measure	Arm A: Ramucirumab + Osimertinib n=3 Participants Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Arm B: Necitumumab + Osimertinib n=4 Participants Participants received Necitumumab 800 mg given IV on Days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.
Phase 1a: Number of Participants With Dose Limiting Toxicities (DLTs)	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Predose on Day (D) 1 of Cycle (C) 2, Predose on Day 1 of Cycle 4, Predose on Day 1 of Cycle 5, Predose on Day 1 of Cycle 7, Predose on Day 1 of Cycle 13

Population: All enrolled participants who received at least one dose of ramucirumab and had evaluable PK data.

Cmin was the concentration of study drug in the blood immediately before the next dose was administered.

Outcome measures

Outcome measures
Measure	Arm A: Ramucirumab + Osimertinib n=20 Participants Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Arm B: Necitumumab + Osimertinib Participants received Necitumumab 800 mg given IV on Days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab D1C2	41.3 microgram per milliliter (µg/mL) Geometric Coefficient of Variation 56.3	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab D1C4	66.7 microgram per milliliter (µg/mL) Geometric Coefficient of Variation 34.3	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab D1C5	76.7 microgram per milliliter (µg/mL) Geometric Coefficient of Variation 27	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab D1C7	90.7 microgram per milliliter (µg/mL) Geometric Coefficient of Variation 26.6	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab D1C13	103 microgram per milliliter (µg/mL) Geometric Coefficient of Variation 29.6	—

SECONDARY outcome

Timeframe: Predose on Day 1 of Cycle 3, Predose on Day 1 of Cycle 5

Population: All enrolled participants who received at least one dose of necitumumab and had evaluable PK data.

Cmin was the concentration of study drug in the blood immediately before the next dose was administered.

Outcome measures

Outcome measures
Measure	Arm A: Ramucirumab + Osimertinib n=2 Participants Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Arm B: Necitumumab + Osimertinib Participants received Necitumumab 800 mg given IV on Days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab D1C3	NA nanograms per milliliter (ng/mL) Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation couldn't be calculated as there were only two participants. Individual values reported: 575476.3 ng/mL and 150490.8 ng/mL	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab D1C5	NA nanograms per milliliter (ng/mL) Geometric Coefficient of Variation NA Geometric Mean and Geometric Coefficient of Variation couldn't be calculated as there was only one participant. Individual value reported: 225257.8 ng/mL	—

SECONDARY outcome

Timeframe: Baseline to Objective Disease Progression (up to 25 months)

Population: All enrolled participants from the ramucirumab + osimertinib arms who received at least one dose of study drug. Per Protocol, the outcomes for a combination of ramucirumab and osimertinib were analyzed under a single arm (Arm A/Cohort A), as Cohort A is an extension of Arm A.

ORR was the best overall response of complete response (CR) or partial response (PR) as classified by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). CR was a disappearance of all target and non-target lesions and normalization of tumor marker level. PR was an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions.

Outcome measures

Outcome measures
Measure	Arm A: Ramucirumab + Osimertinib n=25 Participants Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Arm B: Necitumumab + Osimertinib Participants received Necitumumab 800 mg given IV on Days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.
Objective Response Rate (ORR) for Ramucirumab in Combination With Osimertinib: Percentage of Participants With a Complete Response (CR) or Partial Response (PR)	76 Percentage of Participants Interval 58.1 to 89.0	—

SECONDARY outcome

Timeframe: Baseline to Objective Disease Progression (up to 25 months)

DCR was the best overall response of CR, PR, or SD as defined by RECIST v1.1. CR was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD was defined as 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 one or more new lesions.

Outcome measures

Outcome measures
Measure	Arm A: Ramucirumab + Osimertinib n=25 Participants Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Arm B: Necitumumab + Osimertinib Participants received Necitumumab 800 mg given IV on Days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.
Disease Control Rate (DCR) for Ramucirumab in Combination With Osimertinib: Percentage of Participants With CR, PR or Stable Disease (SD)	92 Percentage of Participants Interval 76.9 to 98.6	—

SECONDARY outcome

Timeframe: Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (up to 25 months)

Population: All enrolled participants from the ramucirumab + osimertinib arms who received at least one dose of study drug with a confirmed CR or PR (including censored). Number of participants censored = 7.

Duration of Response (DoR) was defined only for participants with a confirmed CR or PR. It was measured from the date of first evidence of a confirmed CR or PR to the date of objective progression or the date of death due to any cause, whichever is earlier. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date, DOR was censored at the date of the last complete objective progression-free disease assessment.

Outcome measures

Outcome measures
Measure	Arm A: Ramucirumab + Osimertinib n=19 Participants Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Arm B: Necitumumab + Osimertinib Participants received Necitumumab 800 mg given IV on Days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.
Duration of Response (DoR) for Ramucirumab in Combination With Osimertinib	13.37 Months Interval 9.63 to 21.19	—

SECONDARY outcome

Timeframe: Baseline to Measured Progressive Disease or Death from Any Cause (up to 26 months)

Population: All enrolled participants from the ramucirumab + osimertinib arms who received at least one dose of study drug (including censored). Number of participants censored = 7.

Progression-free survival (PFS) was the time from the date of first study treatment until the date of radiographic documentation of progression (as defined by RECIST v. 1.1) based on investigator assessment or the date of death due to any cause, whichever was earlier. If a participant did not have a complete baseline disease assessment, then the PFS time was censored at the enrollment date, regardless of whether or not objectively determined disease progression or death was observed for the participant; otherwise, 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 complete objective progression-free disease assessment date.

Outcome measures

Outcome measures
Measure	Arm A: Ramucirumab + Osimertinib n=25 Participants Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Arm B: Necitumumab + Osimertinib Participants received Necitumumab 800 mg given IV on Days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.
Progression Free Survival (PFS) for Ramucirumab in Combination With Osimertinib	11.04 Months Interval 5.49 to 19.29	—

SECONDARY outcome

Timeframe: Baseline to Death from Any Cause (up to 29 months)

Population: All enrolled participants from the ramucirumab + osimertinib arms who received at least one dose of study drug (including censored). Number of participants censored = 13.

OS was date of first study treatment until death due to any cause. If the participant was alive at the data inclusion cutoff date for the analysis (or was lost to follow-up), OS was censored on the last date the participant was known to be alive.

Outcome measures

Outcome measures
Measure	Arm A: Ramucirumab + Osimertinib n=25 Participants Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Arm B: Necitumumab + Osimertinib Participants received Necitumumab 800 mg given IV on Days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.
Overall Survival (OS) for Ramucirumab in Combination With Osimertinib	NA Months Interval 16.03 to There were not enough events to estimate the median, upper confidence limit.	—

Adverse Events

Arm A: Ramucirumab + Osimertinib

Serious events: 1 serious events

Other events: 3 other events

Deaths: 2 deaths

Arm B: Necitumumab + Osimertinib

Serious events: 1 serious events

Other events: 4 other events

Deaths: 1 deaths

Cohort A: Ramucirumab + Osimertinib

Serious events: 8 serious events

Other events: 22 other events

Deaths: 11 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	Arm A: Ramucirumab + Osimertinib n=3 participants at risk Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Arm B: Necitumumab + Osimertinib n=4 participants at risk Participants received Necitumumab 800 mg given IV on Days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.	Cohort A: Ramucirumab + Osimertinib n=22 participants at risk Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.5% 1/22 • Number of events 3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Cardiac disorders Atrioventricular block second degree	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.5% 1/22 • Number of events 1 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Cardiac disorders Cardiac failure congestive	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.5% 1/22 • Number of events 1 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	25.0% 1/4 • Number of events 1 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/22 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.5% 1/22 • Number of events 1 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.5% 1/22 • Number of events 1 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
General disorders Pyrexia	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	13.6% 3/22 • Number of events 3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Infections and infestations Cystitis klebsiella	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.5% 1/22 • Number of events 1 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Infections and infestations Device related infection	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.5% 1/22 • Number of events 1 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Infections and infestations Diverticulitis	33.3% 1/3 • Number of events 1 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/22 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Infections and infestations Pneumonia	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	9.1% 2/22 • Number of events 2 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Injury, poisoning and procedural complications Subdural haemorrhage	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.5% 1/22 • Number of events 2 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.5% 1/22 • Number of events 1 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Renal and urinary disorders Acute kidney injury	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.5% 1/22 • Number of events 1 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.5% 1/22 • Number of events 1 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.5% 1/22 • Number of events 1 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/3 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	0.00% 0/4 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.5% 1/22 • Number of events 2 • Baseline to follow up (5.38 years) All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.