Trial Outcomes & Findings for A Study of Ramucirumab (IMC-1121B) and Paclitaxel in Participants With Solid Tumors (NCT NCT01515306)

Last Updated: 2022-03-08

Results Overview

Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose. Data presented are Geometric Least Squares (Geo LS) means. Geo LS means were adjusted for cycle, participant and random error.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

48 participants

Primary outcome timeframe

Cycle 1: 0, 1, 1.5, 2, 5, 7, 24, 48, 72 and 168 hours post paclitaxel infusion

Results posted on

2022-03-08

Participant Flow

Participant milestones

Participant milestones
Measure	Part A: Paclitaxel and Ramucirumab Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle. Cycle 2 and beyond: ramucirumab (IMC-1121B) 8 milligrams/kilogram (mg/kg) administered on Day 1 and Day 15, paclitaxel 80 mg/m² administered on Day 1, Day 8 and Day 15 of 4-week cycle.	Part B: Ramucirumab With or Without Paclitaxel Cycle 1: ramucirumab (IMC-1121B) 8 mg/kg administered as monotherapy on Day 1 of 3-week cycle. Cycle 2 and beyond: ramucirumab (IMC-1121B) 8 mg/kg administered on Day 1 and Day 15, paclitaxel 80 mg/m² administered on Day 1, Day 8 and Day 15 of 4-week cycle. \*After Cycle 1 (mandatory pharmacokinetic phase) is completed, participants may continue to receive ramucirumab (IMC-1121B) monotherapy or combination therapy with paclitaxel as described in Part A.
Overall Study STARTED	24	16
Overall Study Received at Least 1 Dose of Study Drug	24	16
Overall Study Cycle 1	24	16
Overall Study Cycle 2	21	15
Overall Study Drug-Drug Interaction Population	21	0
Overall Study COMPLETED	0	2
Overall Study NOT COMPLETED	24	14

Reasons for withdrawal

Reasons for withdrawal
Measure	Part A: Paclitaxel and Ramucirumab Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle. Cycle 2 and beyond: ramucirumab (IMC-1121B) 8 milligrams/kilogram (mg/kg) administered on Day 1 and Day 15, paclitaxel 80 mg/m² administered on Day 1, Day 8 and Day 15 of 4-week cycle.	Part B: Ramucirumab With or Without Paclitaxel Cycle 1: ramucirumab (IMC-1121B) 8 mg/kg administered as monotherapy on Day 1 of 3-week cycle. Cycle 2 and beyond: ramucirumab (IMC-1121B) 8 mg/kg administered on Day 1 and Day 15, paclitaxel 80 mg/m² administered on Day 1, Day 8 and Day 15 of 4-week cycle. \*After Cycle 1 (mandatory pharmacokinetic phase) is completed, participants may continue to receive ramucirumab (IMC-1121B) monotherapy or combination therapy with paclitaxel as described in Part A.
Overall Study Adverse Event	3	2
Overall Study Progressive Disease	19	9
Overall Study Withdrawal by Subject	1	2
Overall Study Physician Decision	1	1

Baseline Characteristics

A Study of Ramucirumab (IMC-1121B) and Paclitaxel in Participants With Solid Tumors

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part A: Paclitaxel and Ramucirumab n=24 Participants Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle. Cycle 2 and beyond: ramucirumab (IMC-1121B) 8 milligrams/kilogram (mg/kg) administered on Day 1 and Day 15, paclitaxel 80 mg/m² administered on Day 1, Day 8 and Day 15 of 4-week cycle.	Part B: Ramucirumab With or Without Paclitaxel n=16 Participants Cycle 1: ramucirumab (IMC-1121B) 8 mg/kg administered as monotherapy on Day 1 of 3-week cycle. Cycle 2 and beyond: ramucirumab (IMC-1121B) 8 mg/kg administered on Day 1 and Day 15, paclitaxel 80 mg/m² administered on Day 1, Day 8 and Day 15 of 4-week cycle. \*After Cycle 1 (mandatory pharmacokinetic phase) is completed, participants may continue to receive ramucirumab (IMC-1121B) monotherapy or combination therapy with paclitaxel as described in Part A.	Total n=40 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
Age, Categorical Between 18 and 65 years	14 Participants n=5 Participants	10 Participants n=7 Participants	24 Participants n=5 Participants
Age, Categorical >=65 years	10 Participants n=5 Participants	6 Participants n=7 Participants	16 Participants n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	9 Participants n=7 Participants	22 Participants n=5 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	7 Participants n=7 Participants	18 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	23 Participants n=5 Participants	16 Participants n=7 Participants	39 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 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
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	22 Participants n=5 Participants	15 Participants n=7 Participants	37 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	24 Participants n=5 Participants	16 Participants n=7 Participants	40 Participants n=5 Participants

PRIMARY outcome

Timeframe: Cycle 1: 0, 1, 1.5, 2, 5, 7, 24, 48, 72 and 168 hours post paclitaxel infusion

Population: All participants from Part A Cycle 1 and had sufficient concentration data to calculate paclitaxel AUC(0-∞).

Outcome measures

Outcome measures
Measure	Part A: Paclitaxel Alone (Cycle 1) n=19 Participants Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle.
Part A: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Paclitaxel From Time Zero to Infinity [AUC(0-∞)] in Cycle 1	29 nanograms*hour/milliliter/milligram Interval 24.5 to 34.34

PRIMARY outcome

Timeframe: Cycle 2: -1, 0, 1, 1.5, 2, 5, 7, 24, 48, 72, 96, 168, 264 and 336 hours post paclitaxel infusion

Population: All participants from Part A Cycle 2 and had sufficient concentration data to calculate paclitaxel AUC(0-∞).

Outcome measures

Outcome measures
Measure	Part A: Paclitaxel Alone (Cycle 1) n=17 Participants Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle.
Part A: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Paclitaxel From Time Zero to Infinity [AUC(0-∞)] in Cycle 2	31.67 nanograms*hour/milliliter/milligram Interval 26.58 to 37.73

PRIMARY outcome

Timeframe: Cycle 1: 0,1, 1.5, 2, 5, 7, 24, 48, 72 and 168 hours post paclitaxel infusion

Population: All participants from Part A Cycle 1 and had sufficient concentration data to calculate paclitaxel cmax.

Dose-normalized Cmax was calculated from Cmax divided by the dose. Data presented are Geometric Least Squares (Geo LS) means. Geo LS means were adjusted for cycle, participant and random error.

Outcome measures

Outcome measures
Measure	Part A: Paclitaxel Alone (Cycle 1) n=21 Participants Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle.
Part A: Pharmacokinetics - Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Paclitaxel in Cycle 1	18.84 nanograms/milliliter/milligram Interval 16.03 to 22.13

PRIMARY outcome

Timeframe: Cycle 2: -1, 0, 1, 1.5, 2, 5, 7, 24, 48, 72, 96, 168, 264 and 336 hours post paclitaxel infusion

Population: All participants from Part A Cycle 2 and had sufficient concentration data to calculate paclitaxel cmax.

Dose-normalized Cmax was calculated from Cmax divided by the dose. Data presented are Geometric Least Squares (Geo LS) means. Geo LS means were adjusted for cycle, participant and random error.

Outcome measures

Outcome measures
Measure	Part A: Paclitaxel Alone (Cycle 1) n=20 Participants Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle.
Part A: Pharmacokinetics - Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Paclitaxel in Cycle 2	18.30 nanograms/milliliter/milligram Interval 15.54 to 21.56

PRIMARY outcome

Timeframe: Cycle 1: 0,1, 1.5, 2, 5, 7, 24, 48, 72,168, 264, 336, 408, and 504 hours post ramucirumab infusion

Population: All participants who received ramucirumab and had sufficient concentration data to calculate ramucirumab AUC(0-∞) in Cycle 1 of Part B.

Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose.

Outcome measures

Outcome measures
Measure	Part A: Paclitaxel Alone (Cycle 1) n=15 Participants Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle.
Part B: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Ramucirumab From Time Zero to Infinity [AUC(0-∞)] as Monotherapy	55.3 micrograms*hour/milliliter/milligram Geometric Coefficient of Variation 27

SECONDARY outcome

Timeframe: Cycle 2: 0, 1, 2, 2.5, 3, 6, 8, 25, 49, 73, 97, 169, 265 and 337 hours post ramucirumab infusion

Population: All participants who received ramucirumab and paclitaxel and had sufficient concentration data to calculate ramucirumab AUC(0-∞) in Cycle 2 of Part A.

Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose.

Outcome measures

Outcome measures
Measure	Part A: Paclitaxel Alone (Cycle 1) n=13 Participants Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle.
Part A: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Ramucirumab From Time Zero to Infinity [AUC(0-∞)] in the Presence of Paclitaxel	55.4 micrograms*hour/milliliters/milligram Geometric Coefficient of Variation 27

SECONDARY outcome

Timeframe: Cycle 2: 0, 1, 2, 2.5, 3, 6, 8, 25, 49, 73, 97, 169, 265 and 337 hours post ramucirumab infusion

Population: All participants who received ramucirumab and paclitaxel and had sufficient concentration data to calculate ramucirumab Cmax in Cycle 2 of Part A.

Dose-normalized Cmax was calculated from Cmax divided by the dose.

Outcome measures

Outcome measures
Measure	Part A: Paclitaxel Alone (Cycle 1) n=21 Participants Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle.
Part A: Pharmacokinetics - Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Ramucirumab in the Presence of Paclitaxel	0.384 micrograms/milliliter/milligram Geometric Coefficient of Variation 31

SECONDARY outcome

Timeframe: -1 hour on Day 1 of Cycle 2, and 30 days after last dose of study drug

Population: All participants from Part A Cycle 2, who received ramucirumab and paclitaxel and had data for anti-ramucirumab antibodies.

Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. A treatment-emergent anti-drug antibodies (TEADA) sample was defined as: a post treatment sample with at least a 4-fold increase in titer from pre treatment sample; or 1:20 post treatment titer for participants that had no detectable ADA titer at baseline.

Outcome measures

Outcome measures
Measure	Part A: Paclitaxel Alone (Cycle 1) n=10 Participants Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle.
Part A: Immunogenicity of Ramucirumab in Combination With Paclitaxel - Number of Participants With Anti-Ramucirumab Antibodies	0 Participants

SECONDARY outcome

Timeframe: 0 hour on Day 1 of Cycle 1, and 30 days after last dose of study drug

Population: All participants from Part B cycle 1, who received ramucirumab and had data for anti-ramucirumab antibodies.

Outcome measures

Outcome measures
Measure	Part A: Paclitaxel Alone (Cycle 1) n=1 Participants Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle.
Part B: Immunogenicity of Ramucirumab as Monotherapy - Number of Participants With Anti-Ramucirumab Antibodies	0 Participants

Adverse Events

Part A: Paclitaxel Alone (Cycle 1)

Serious events: 1 serious events

Other events: 18 other events

Deaths: 0 deaths

Part A: Paclitaxel + Ramucirumab (Cycle 2)

Serious events: 6 serious events

Other events: 21 other events

Deaths: 0 deaths

Part B: Ramucirumab Alone (Cycle 1)

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Part B: Ramucirumab + Paclitaxel (Cycle 2)

Serious events: 6 serious events

Other events: 14 other events

Deaths: 0 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 Investigators agreed to delay independently publishing or disclosing data, findings or conclusions from the study except as part of a multi-center publication. Upon study publication or if the draft publication is not produced within approximately 6 months of the final report of the study results, investigators may independently publish, subject to confidential information review/redaction by sponsor. The sponsor may request publication delay up to 90 days to seek patent protection.
Publication restrictions are in place

Restriction type: OTHER

Measure	Part A: Paclitaxel Alone (Cycle 1) n=24 participants at risk Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle.	Part A: Paclitaxel + Ramucirumab (Cycle 2) n=21 participants at risk Cycle 2: ramucirumab (IMC-1121B) 8 milligrams/kilogram (mg/kg) administered on Day 1 and Day 15, paclitaxel 80 mg/m² administered on Day 1, Day 8 and Day 15 of 4-week cycle.	Part B: Ramucirumab Alone (Cycle 1) n=16 participants at risk Cycle 1: ramucirumab (IMC-1121B) 8 mg/kg administered as monotherapy on Day 1 of 3-week cycle.	Part B: Ramucirumab + Paclitaxel (Cycle 2) n=15 participants at risk Cycle 2 and beyond: ramucirumab (IMC-1121B) 8 mg/kg administered on Day 1 and Day 15, paclitaxel 80 mg/m² administered on Day 1, Day 8 and Day 15 of 4-week cycle.
Gastrointestinal disorders Abdominal pain	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	4.8% 1/21 • Number of events 2 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Gastrointestinal disorders Colitis	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Gastrointestinal disorders Constipation	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Gastrointestinal disorders Large intestinal obstruction	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	4.8% 1/21 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
General disorders Non-cardiac chest pain	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	4.8% 1/21 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
General disorders Pain	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	4.8% 1/21 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
General disorders Pyrexia	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	4.8% 1/21 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Hepatobiliary disorders Acute hepatic failure	4.2% 1/24 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Infections and infestations Device related infection	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Infections and infestations Influenza	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	4.8% 1/21 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Infections and infestations Pneumonia	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Infections and infestations Sepsis	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Fall	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	4.8% 1/21 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Investigations Hepatic enzyme increased	4.2% 1/24 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 2 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Nervous system disorders Depressed level of consciousness	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	4.8% 1/21 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Nervous system disorders Hypoaesthesia	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	4.8% 1/21 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Renal and urinary disorders Renal failure acute	4.2% 1/24 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	4.8% 1/21 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	4.8% 1/21 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 2 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/21 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/24 • Baseline, up to 8 years All participants who received at least one dose of study drug.	4.8% 1/21 • Number of events 1 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/16 • Baseline, up to 8 years All participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 8 years All participants who received at least one dose of study drug.