Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal Cell Carcinoma (CLEAR)

• ClinicalTrials.gov Identifier: NCT02811861
• Recruitment Status: Active, not recruiting
• First Posted: June 23, 2016
• Results First Posted: September 24, 2021
• Last Update Posted: July 10, 2023
• Sponsor: Eisai Inc.
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Eisai Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Renal Cell Carcinoma
• Interventions: Drug: Lenvatinib; Drug: Everolimus; Drug: Pembrolizumab; Drug: Sunitinib
• Enrollment: 1069

Participant Flow

Recruitment Details

Participants took part in the study at 181 investigative sites in Austria, Belgium, Canada, France, Germany, Greece, Ireland, Italy, Netherlands, Poland, Spain, Switzerland, United Kingdom of Great Britain and Northern Ireland, the United States of America, Australia, Czechia, Israel, Japan, Korea, Russian Federation, from 13 October 2016 to 28 August 2020 (date of data cutoff for the primary analysis of PFS and second interim analysis of Overall Survival).

Pre-assignment Details

A total of 1417 participants were screened, of which, 1069 were randomized. Of the 1069 randomized, 1047 participants were treated in the study.

Arm/Group Title	Lenvatinib 18 mg Plus Everolimus 5 mg	Lenvatinib 20 mg Plus Pembrolizumab 200 mg	Sunitinib 50 mg
Arm/Group Description	Participants received lenvatinib 18 milligrams (mg) administered orally, once daily in each 21-day cycle, plus everolimus 5 mg administered orally, once daily in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent.	Participants received lenvatinib 20 mg administered orally, once daily in each 21-day cycle, plus pembrolizumab 200 mg administered intravenously, every 3 weeks in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent, completion of 35 treatments (approximately 2 years) with pembrolizumab, or sponsor termination of the study.	Participants received sunitinib 50 mg administered orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off treatment until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent.
Period Title: Overall Study
Started	357	355	357
Treated	355	352	340
Completed	0	0	0
Not Completed	357	355	357
Reason Not Completed
Radiological Disease Progression	123	97	174
Clinical Disease Progression	20	19	22
Adverse Event	63	60	41
Lost to Follow-up	0	0	1
Subject Choice	29	17	23
Withdrawal by Subject	4	4	9
Other	4	13	3
Treatment Ongoing at Cutoff Date	112	142	67
Randomized but not treated	2	3	17

Baseline Characteristics

Arm/Group Title		Lenvatinib 18 mg Plus Everolimus 5 mg	Lenvatinib 20 mg Plus Pembrolizumab 200 mg	Sunitinib 50 mg	Total
Arm/Group Description		Participants received lenvatinib 18 milligrams (mg) administered orally, once daily in each 21-day cycle, plus everolimus 5 mg administered orally, once daily in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent.	Participants received lenvatinib 20 mg administered orally, once daily in each 21-day cycle, plus pembrolizumab 200 mg administered intravenously, every 3 weeks in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent, completion of 35 treatments (approximately 2 years) with pembrolizumab, or sponsor termination of the study.	Participants received sunitinib 50 mg administered orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off treatment until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent.	Total of all reporting groups
Overall Number of Baseline Participants		357	355	357	1069
Baseline Analysis Population Description		The full analysis set (FAS) included all randomized participants regardless of the treatment actually received.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	357 participants	355 participants	357 participants	1069 participants
		61.9 (10.86)	62.3 (10.23)	60.8 (9.96)	61.7 (10.36)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	357 participants	355 participants	357 participants	1069 participants
	Female	91 25.5%	100 28.2%	82 23.0%	273 25.5%
	Male	266 74.5%	255 71.8%	275 77.0%	796 74.5%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	357 participants	355 participants	357 participants	1069 participants
	Hispanic or Latino	23 6.4%	12 3.4%	20 5.6%	55 5.1%
	Not Hispanic or Latino	328 91.9%	339 95.5%	334 93.6%	1001 93.6%
	Unknown or Not Reported	6 1.7%	4 1.1%	3 0.8%	13 1.2%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	357 participants	355 participants	357 participants	1069 participants
	White	254 71.1%	263 74.1%	270 75.6%	787 73.6%
	Black or African American	1 0.3%	2 0.6%	3 0.8%	6 0.6%
	Asian	77 21.6%	81 22.8%	67 18.8%	225 21.0%
	American Indian or Alaskan Native	1 0.3%	0 0.0%	0 0.0%	1 0.1%
	Native Hawaiian or Other Pacific Islander	1 0.3%	0 0.0%	0 0.0%	1 0.1%
	Other	7 2.0%	4 1.1%	7 2.0%	18 1.7%
	Missing	16 4.5%	5 1.4%	10 2.8%	31 2.9%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) by Independent Imaging Review (IIR)
Description	PFS assessed by IIR was defined as the time from the date of randomization to the date of the first documentation of progressive disease (PD) or death (whichever occurred first) using Response Evaluation Criteria in Solid Tumors (RECIST 1.1). PD was defined as at least a 20 percent (%) increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier method.
Time Frame	From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first or up to data cutoff date 28 Aug 2020 (up to approximately 46 months)

Outcome Measure Data

Analysis Population Description

The FAS included all randomized participants regardless of the treatment actually received.

Arm/Group Title	Lenvatinib 18 mg Plus Everolimus 5 mg	Lenvatinib 20 mg Plus Pembrolizumab 200 mg	Sunitinib 50 mg
Arm/Group Description:	Participants received lenvatinib 18 milligrams (mg) administered orally, once daily in each 21-day cycle, plus everolimus 5 mg administered orally, once daily in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent.	Participants received lenvatinib 20 mg administered orally, once daily in each 21-day cycle, plus pembrolizumab 200 mg administered intravenously, every 3 weeks in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent, completion of 35 treatments (approximately 2 years) with pembrolizumab, or sponsor termination of the study.	Participants received sunitinib 50 mg administered orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off treatment until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent.
Overall Number of Participants Analyzed	357	355	357
Median (95% Confidence Interval); Unit of Measure: months
	14.7; (11.1 to 16.7)	23.9; (20.8 to 27.7)	9.2; (6.0 to 11.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenvatinib 18 mg Plus Everolimus 5 mg, Sunitinib 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Log-rank Test
	Comments	Hazard ratio is based on a Cox Proportional Hazards Model including treatment group as a factor.
Method of Estimation	Estimation Parameter	Stratified Hazard Ratio
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.80
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenvatinib 20 mg Plus Pembrolizumab 200 mg, Sunitinib 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Log-rank Test
	Comments	Hazard ratio is based on a Cox Proportional Hazards Model including treatment group as a factor.
Method of Estimation	Estimation Parameter	Stratified Hazard Ratio
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95%; 0.32 to 0.49
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	ORR is defined as the proportion of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by IIR using RECIST 1.1. CR is defined as disappearance of all (targeted and non-target [NT]) lesions. All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. To be considered a BOR, all responses had to be confirmed no less than 4 weeks after the initial assessment of response. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame	Up to approximately 69 months

Outcome Measure Data Not Reported

3. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time from the date of randomization to the date of death from any cause. Participants who were lost to follow-up and those who were alive at the data cutoff date were censored, either at the last date the participant was last known alive or at the data cutoff date, whichever occurred first. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame	Up to approximately 69 months

Outcome Measure Data Not Reported

4. Secondary Outcome

Title	Number of Participants With At Least One Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description	TEAEs were defined as those adverse events (AEs) that occurred (or worsened, if present at Baseline) after the first dose of study drug through 30 days after the last dose of study drug.An AE was defined as any untoward medical occurrence in a participants or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with medicinal product. A SAE was defined as any AE if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame	Up to approximately 69 months

Outcome Measure Data Not Reported

5. Secondary Outcome

Title	Number of Participants Who Discontinued Treatment Due to Toxicity
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame	Up to approximately 69 months

Outcome Measure Data Not Reported

6. Secondary Outcome

Title	Time to Treatment Failure Due to Toxicity
Description	Time to treatment failure due to toxicity is defined as time from the date of randomization to the date that a participant discontinued study treatment due to TEAEs. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame	Up to approximately 69 months

Outcome Measure Data Not Reported

7. Secondary Outcome

Title	Health-Related Quality of Life (HRQoL) Assessed by Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS) Scores
Description	The FKSI-DRS consisted of 9 items that experts and participants had indicated are important targets for the treatment of advanced kidney cancer, and that clinical experts had indicated are primarily disease-related, as opposed to treatment-related. Symptoms assessed on the FKSI-DRS included lack of energy, fatigue, weight loss, pain, bone pain, shortness of breath, cough, fever, or hematuria. Each item was scored on a 5-point Likert-type scale (0 = not at all; 4 = very much) where total score ranged from 0 (worst) to 36 (best), where higher scores correspond to better outcomes. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame	Up to approximately 69 months

Outcome Measure Data Not Reported

8. Secondary Outcome

Title	HRQoL Assessed by European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Score
Description	EORTC QLQ-C30 is a questionnaire including 30 questions that rate the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0 to 100 using a standard EORTC algorithm. For the overall HRQoL and functioning scales, a higher score is correlated with better HRQoL, whereas a higher score represents worse HRQoL for symptom scales. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame	Up to approximately 69 months

Outcome Measure Data Not Reported

9. Secondary Outcome

Title	HRQoL Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Score
Description	EQ-5D-3L is a health profile questionnaire consisting of the EQ-5D descriptive system and the EuroQol visual analog scale (EQ-VAS). For the EQ-5D, participants rate 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) at 1 of 3 levels (1=no problems; 2=some problems; 3=extreme problems). The EQ-5D Health Utilities Index (HUI) is derived from the five dimensions of the EQ-5D, using country-specific preference weights (tariffs) to summarize how good or bad each health state is on a scale from 1 (full health) to <0 (worse health/dead). The EQ-VAS measures self-rated global health status using a vertically oriented VAS, where 100 represents the "best imaginable health state" and 0 represents the "worst imaginable health state." Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame	Up to approximately 69 months

Outcome Measure Data Not Reported

10. Secondary Outcome

Title	PFS on Next-line of Therapy (PFS2)
Description	PFS2 is defined as the time from randomization to disease progression as assessed by investigator on next-line treatment or death from any cause (whichever occurred first). Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame	Up to approximately 69 months

Outcome Measure Data Not Reported

11. Secondary Outcome

Title	PFS by Investigator Assessment
Description	PFS by investigator assessment is defined as the time from the date of randomization to the date of first documentation of disease progression based on the investigator assessment per RECIST 1.1 or death (whichever occurred first). Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame	Up to approximately 69 months

Outcome Measure Data Not Reported

12. Secondary Outcome

Title	Model-predicted Clearance for Lenvatinib and Everolimus
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame	Cycles 1 and 2 Day 1; 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: predose and 2-12 hours postdose; Cycles 3, 4, 5 and 6 Day 1: predose (Cycle length=21 days)

Outcome Measure Data Not Reported

13. Secondary Outcome

Title	Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib and Everolimus
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame	Cycles 1 and 2 Day 1; 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: predose and 2-12 hours postdose; Cycles 3, 4, 5 and 6 Day 1: predose (Cycle length = 21 days

Outcome Measure Data Not Reported

Adverse Events

Time Frame	From first dose of study drug (Baseline) up to 30 days after last dose of study drug or up to data cutoff date 28 Aug 2020 (up to approximately 46 months)
Adverse Event Reporting Description	Safety analysis set included all participants who received at least 1 dose of any study drug.
Arm/Group Title	Lenvatinib 18 mg Plus Everolimus 5 mg	Lenvatinib 20 mg Plus Pembrolizumab 200 mg	Sunitinib 50 mg
Arm/Group Description	Participants received lenvatinib 18 milligrams (mg) administered orally, once daily in each 21-day cycle, plus everolimus 5 mg administered orally, once daily in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent.	Participants received lenvatinib 20 mg administered orally, once daily in each 21-day cycle, plus pembrolizumab 200 mg administered intravenously, every 3 weeks in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent, completion of 35 treatments (approximately 2 years) with pembrolizumab, or sponsor termination of the study.	Participants received sunitinib 50 mg administered orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off treatment until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent.
All-Cause Mortality
	Lenvatinib 18 mg Plus Everolimus 5 mg	Lenvatinib 20 mg Plus Pembrolizumab 200 mg	Sunitinib 50 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	119/355 (33.52%)	78/352 (22.16%)	99/340 (29.12%)
Serious Adverse Events
	Lenvatinib 18 mg Plus Everolimus 5 mg	Lenvatinib 20 mg Plus Pembrolizumab 200 mg	Sunitinib 50 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	164/355 (46.20%)	178/352 (50.57%)	113/340 (33.24%)
Blood and lymphatic system disorders
Anaemia † 1	3/355 (0.85%)	0/352 (0.00%)	4/340 (1.18%)
Blood loss anaemia † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Eosinophilia myalgia syndrome † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Febrile neutropenia † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Leukopenia † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Neutropenia † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Thrombocytopenia † 1	2/355 (0.56%)	1/352 (0.28%)	5/340 (1.47%)
Thrombotic thrombocytopenic purpura † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Cardiac disorders
Acute coronary syndrome † 1	0/355 (0.00%)	2/352 (0.57%)	0/340 (0.00%)
Acute myocardial infarction † 1	0/355 (0.00%)	5/352 (1.42%)	0/340 (0.00%)
Angina unstable † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Arrhythmia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Atrial fibrillation † 1	0/355 (0.00%)	1/352 (0.28%)	1/340 (0.29%)
Atrial flutter † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Bradycardia † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Cardiac arrest † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Cardiac failure † 1	3/355 (0.85%)	0/352 (0.00%)	1/340 (0.29%)
Cardiac failure acute † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Cardiac failure congestive † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Cardio-respiratory arrest † 1	0/355 (0.00%)	2/352 (0.57%)	0/340 (0.00%)
Cardiogenic shock † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Cardiomyopathy † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Congestive cardiomyopathy † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Myocardial infarction † 1	3/355 (0.85%)	6/352 (1.70%)	1/340 (0.29%)
Myocarditis † 1	0/355 (0.00%)	2/352 (0.57%)	0/340 (0.00%)
Pericardial effusion † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Postinfarction angina † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Stress cardiomyopathy † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Tachycardia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Ventricular arrhythmia † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Endocrine disorders
Adrenal insufficiency † 1	0/355 (0.00%)	7/352 (1.99%)	0/340 (0.00%)
Hypophysitis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Hypopituitarism † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Hypothyroidism † 1	2/355 (0.56%)	3/352 (0.85%)	0/340 (0.00%)
Secondary hypothyroidism † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Steroid withdrawal syndrome † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Eye disorders
Cataract † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Eyelid ptosis † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Retinal vascular occlusion † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Retinal vein occlusion † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Vogt-Koyanagi-Harada disease † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Gastrointestinal disorders
Abdominal hernia † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Abdominal pain † 1	6/355 (1.69%)	5/352 (1.42%)	1/340 (0.29%)
Abdominal pain upper † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Anal fissure † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Anal fistula † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Ascites † 1	1/355 (0.28%)	0/352 (0.00%)	2/340 (0.59%)
Colitis † 1	1/355 (0.28%)	2/352 (0.57%)	0/340 (0.00%)
Colonic fistula † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Constipation † 1	0/355 (0.00%)	3/352 (0.85%)	0/340 (0.00%)
Diarrhoea † 1	14/355 (3.94%)	12/352 (3.41%)	4/340 (1.18%)
Diverticular perforation † 1	1/355 (0.28%)	0/352 (0.00%)	1/340 (0.29%)
Duodenal ulcer perforation † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Dyspepsia † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Dysphagia † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Enteritis † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Enterocolitis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Eosinophilic gastritis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Food poisoning † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Gastric haemorrhage † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Gastric ulcer † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Gastritis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Gastroduodenal haemorrhage † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Gastrointestinal haemorrhage † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Haematemesis † 1	0/355 (0.00%)	2/352 (0.57%)	1/340 (0.29%)
Ileus † 1	2/355 (0.56%)	0/352 (0.00%)	0/340 (0.00%)
Immune-mediated enterocolitis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Immune-mediated pancreatitis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Inguinal hernia † 1	2/355 (0.56%)	1/352 (0.28%)	0/340 (0.00%)
Intestinal obstruction † 1	2/355 (0.56%)	1/352 (0.28%)	0/340 (0.00%)
Intestinal perforation † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Intra-abdominal haemorrhage † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Large intestinal haemorrhage † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Large intestine perforation † 1	3/355 (0.85%)	0/352 (0.00%)	0/340 (0.00%)
Lower gastrointestinal haemorrhage † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Mallory-Weiss syndrome † 1	1/355 (0.28%)	0/352 (0.00%)	1/340 (0.29%)
Mechanical ileus † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Melaena † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Nausea † 1	5/355 (1.41%)	5/352 (1.42%)	1/340 (0.29%)
Obstructive pancreatitis † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Odynophagia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Pancreatitis † 1	1/355 (0.28%)	6/352 (1.70%)	0/340 (0.00%)
Pancreatitis acute † 1	2/355 (0.56%)	1/352 (0.28%)	1/340 (0.29%)
Proctitis † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Retroperitoneal haemorrhage † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Small intestinal haemorrhage † 1	0/355 (0.00%)	1/352 (0.28%)	1/340 (0.29%)
Subileus † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Upper gastrointestinal haemorrhage † 1	0/355 (0.00%)	1/352 (0.28%)	1/340 (0.29%)
Vomiting † 1	10/355 (2.82%)	10/352 (2.84%)	3/340 (0.88%)
General disorders
Asthenia † 1	4/355 (1.13%)	2/352 (0.57%)	4/340 (1.18%)
Death † 1	2/355 (0.56%)	1/352 (0.28%)	2/340 (0.59%)
Face oedema † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Fatigue † 1	2/355 (0.56%)	0/352 (0.00%)	2/340 (0.59%)
General physical health deterioration † 1	3/355 (0.85%)	1/352 (0.28%)	3/340 (0.88%)
Generalised oedema † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Inadequate analgesia † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Malaise † 1	2/355 (0.56%)	0/352 (0.00%)	1/340 (0.29%)
Multiple organ dysfunction syndrome † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Non-cardiac chest pain † 1	1/355 (0.28%)	2/352 (0.57%)	0/340 (0.00%)
Oedema † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Oedema peripheral † 1	2/355 (0.56%)	0/352 (0.00%)	1/340 (0.29%)
Pain † 1	2/355 (0.56%)	2/352 (0.57%)	1/340 (0.29%)
Pyrexia † 1	4/355 (1.13%)	6/352 (1.70%)	7/340 (2.06%)
Hepatobiliary disorders
Autoimmune hepatitis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Bile duct obstruction † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Bile duct stone † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Biliary colic † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Cholangitis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Cholecystitis † 1	5/355 (1.41%)	2/352 (0.57%)	1/340 (0.29%)
Cholecystitis acute † 1	8/355 (2.25%)	2/352 (0.57%)	1/340 (0.29%)
Cholecystitis chronic † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Cholelithiasis † 1	2/355 (0.56%)	1/352 (0.28%)	0/340 (0.00%)
Drug-induced liver injury † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Hepatic function abnormal † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Immune-mediated hepatitis † 1	0/355 (0.00%)	4/352 (1.14%)	0/340 (0.00%)
Portal vein thrombosis † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Cholestasis † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Infections and infestations
Abdominal infection † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Acute sinusitis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Anal abscess † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Appendicitis † 1	0/355 (0.00%)	2/352 (0.57%)	0/340 (0.00%)
Bacteraemia † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Bronchitis † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
COVID-19 pneumonia † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Cellulitis † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Cholecystitis infective † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Clostridium difficile infection † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Colonic abscess † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Diverticulitis † 1	2/355 (0.56%)	0/352 (0.00%)	0/340 (0.00%)
Ear infection † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Empyema † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Encephalitis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Encephalitis viral † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Enteritis infectious † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Enterocolitis infectious † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Gastroenteritis † 1	3/355 (0.85%)	2/352 (0.57%)	2/340 (0.59%)
Gastroenteritis viral † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Infection † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Infectious pleural effusion † 1	2/355 (0.56%)	0/352 (0.00%)	0/340 (0.00%)
Influenza † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Klebsiella sepsis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Localised infection † 1	0/355 (0.00%)	1/352 (0.28%)	1/340 (0.29%)
Necrotising fasciitis † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Oropharyngeal candidiasis † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Osteomyelitis † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Otitis externa † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Peritonitis † 1	0/355 (0.00%)	1/352 (0.28%)	1/340 (0.29%)
Peritonitis bacterial † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Peritonsillar abscess † 1	0/355 (0.00%)	2/352 (0.57%)	0/340 (0.00%)
Pharyngitis † 1	2/355 (0.56%)	0/352 (0.00%)	0/340 (0.00%)
Pneumocystis jirovecii pneumonia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Pneumonia † 1	15/355 (4.23%)	7/352 (1.99%)	6/340 (1.76%)
Pneumonia influenzal † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Pneumonia necrotising † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Postoperative wound infection † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Prostatic abscess † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Pyelonephritis † 1	0/355 (0.00%)	1/352 (0.28%)	1/340 (0.29%)
Respiratory tract infection † 1	0/355 (0.00%)	2/352 (0.57%)	1/340 (0.29%)
Retroperitoneal abscess † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Sepsis † 1	2/355 (0.56%)	3/352 (0.85%)	3/340 (0.88%)
Septic arthritis staphylococcal † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Sinusitis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Skin infection † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Staphylococcal bacteraemia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Subdiaphragmatic abscess † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Urinary tract infection † 1	3/355 (0.85%)	4/352 (1.14%)	4/340 (1.18%)
Urosepsis † 1	2/355 (0.56%)	2/352 (0.57%)	0/340 (0.00%)
Wound infection † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Injury, poisoning and procedural complications
Accidental overdose † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Arterial injury † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Fall † 1	3/355 (0.85%)	0/352 (0.00%)	0/340 (0.00%)
Femoral neck fracture † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Femur fracture † 1	2/355 (0.56%)	0/352 (0.00%)	0/340 (0.00%)
Head injury † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Incisional hernia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Infusion related reaction † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Lower limb fracture † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Radiation injury † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Radiation proctitis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Rib fracture † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Spinal cord injury cervical † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Spinal fracture † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Stress fracture † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Subdural haematoma † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Tibia fracture † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Toxicity to various agents † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Upper limb fracture † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Wound dehiscence † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Investigations
Alanine aminotransferase increased † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Amylase increased † 1	0/355 (0.00%)	2/352 (0.57%)	0/340 (0.00%)
Aspartate aminotransferase increased † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Blood bilirubin increased † 1	0/355 (0.00%)	1/352 (0.28%)	2/340 (0.59%)
Blood calcium increased † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Blood creatinine increased † 1	2/355 (0.56%)	1/352 (0.28%)	0/340 (0.00%)
Ejection fraction decreased † 1	0/355 (0.00%)	0/352 (0.00%)	2/340 (0.59%)
Electrocardiogram T wave inversion † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Electrocardiogram change † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Glomerular filtration rate decreased † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Haemoglobin increased † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Hepatic enzyme increased † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Lipase increased † 1	0/355 (0.00%)	4/352 (1.14%)	0/340 (0.00%)
Neutrophil count decreased † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Platelet count decreased † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Transaminases increased † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Troponin increased † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Weight decreased † 1	0/355 (0.00%)	2/352 (0.57%)	0/340 (0.00%)
White blood cell count decreased † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Metabolism and nutrition disorders
Cachexia † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Decreased appetite † 1	4/355 (1.13%)	3/352 (0.85%)	0/340 (0.00%)
Dehydration † 1	4/355 (1.13%)	1/352 (0.28%)	4/340 (1.18%)
Diabetes mellitus † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Diabetic ketoacidosis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Electrolyte imbalance † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Hypercalcaemia † 1	5/355 (1.41%)	0/352 (0.00%)	1/340 (0.29%)
Hypercholesterolaemia † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Hyperglycaemia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Hyperglycaemic hyperosmolar nonketotic syndrome † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Hyperkalaemia † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Hypocalcaemia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Hypoglycaemia † 1	1/355 (0.28%)	1/352 (0.28%)	2/340 (0.59%)
Hyponatraemia † 1	4/355 (1.13%)	2/352 (0.57%)	2/340 (0.59%)
Hypophosphataemia † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	3/355 (0.85%)	2/352 (0.57%)	1/340 (0.29%)
Back pain † 1	3/355 (0.85%)	2/352 (0.57%)	4/340 (1.18%)
Bone lesion † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Bone pain † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Flank pain † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Musculoskeletal chest pain † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Musculoskeletal pain † 1	2/355 (0.56%)	0/352 (0.00%)	0/340 (0.00%)
Myalgia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Myositis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Neck pain † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Osteoarthritis † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Osteonecrosis † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Osteoporotic fracture † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Pain in extremity † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Pathological fracture † 1	3/355 (0.85%)	6/352 (1.70%)	2/340 (0.59%)
Spinal stenosis † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Rhabdomyolysis † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain † 1	3/355 (0.85%)	2/352 (0.57%)	1/340 (0.29%)
Chronic myeloid leukaemia † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
External ear neoplasm malignant † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Malignant ascites † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Malignant neoplasm progression † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Malignant pleural effusion † 1	2/355 (0.56%)	0/352 (0.00%)	1/340 (0.29%)
Metastases to bone † 1	0/355 (0.00%)	0/352 (0.00%)	2/340 (0.59%)
Metastases to central nervous system † 1	0/355 (0.00%)	1/352 (0.28%)	2/340 (0.59%)
Metastases to chest wall † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Metastases to lung † 1	1/355 (0.28%)	1/352 (0.28%)	1/340 (0.29%)
Metastases to skin † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Metastases to spine † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Pericardial effusion malignant † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Prostate cancer † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Tumour associated fever † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Tumour haemorrhage † 1	0/355 (0.00%)	2/352 (0.57%)	0/340 (0.00%)
Tumour pain † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Nervous system disorders
Ataxia † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Carotid artery stenosis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Cerebral ischaemia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Cerebrovascular accident † 1	1/355 (0.28%)	2/352 (0.57%)	0/340 (0.00%)
Cytotoxic oedema † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Dementia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Depressed level of consciousness † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Dizziness † 1	0/355 (0.00%)	2/352 (0.57%)	0/340 (0.00%)
Dysgeusia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Encephalopathy † 1	0/355 (0.00%)	2/352 (0.57%)	0/340 (0.00%)
Generalised tonic-clonic seizure † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Haemorrhage intracranial † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Headache † 1	2/355 (0.56%)	2/352 (0.57%)	2/340 (0.59%)
Hypertensive encephalopathy † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Ischaemic stroke † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Loss of consciousness † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Myasthenic syndrome † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Noninfective encephalitis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Paralysis † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Paralysis recurrent laryngeal nerve † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Paraparesis † 1	1/355 (0.28%)	0/352 (0.00%)	1/340 (0.29%)
Peripheral sensory neuropathy † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Posterior reversible encephalopathy syndrome † 1	0/355 (0.00%)	2/352 (0.57%)	1/340 (0.29%)
Seizure † 1	0/355 (0.00%)	0/352 (0.00%)	2/340 (0.59%)
Somnolence † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Spinal cord compression † 1	2/355 (0.56%)	1/352 (0.28%)	2/340 (0.59%)
Subarachnoid haemorrhage † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Syncope † 1	1/355 (0.28%)	2/352 (0.57%)	1/340 (0.29%)
Transient ischaemic attack † 1	2/355 (0.56%)	2/352 (0.57%)	0/340 (0.00%)
Product Issues
Device deposit issue † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Psychiatric disorders
Confusional state † 1	2/355 (0.56%)	0/352 (0.00%)	0/340 (0.00%)
Delirium † 1	1/355 (0.28%)	2/352 (0.57%)	0/340 (0.00%)
Mania † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Mental status changes † 1	0/355 (0.00%)	5/352 (1.42%)	0/340 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	10/355 (2.82%)	8/352 (2.27%)	5/340 (1.47%)
Haematuria † 1	0/355 (0.00%)	0/352 (0.00%)	4/340 (1.18%)
Haemorrhage urinary tract † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Nephritis † 1	0/355 (0.00%)	3/352 (0.85%)	0/340 (0.00%)
Oliguria † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Proteinuria † 1	2/355 (0.56%)	1/352 (0.28%)	0/340 (0.00%)
Renal failure † 1	2/355 (0.56%)	4/352 (1.14%)	2/340 (0.59%)
Renal haemorrhage † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Ureterolithiasis † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Urinary retention † 1	1/355 (0.28%)	2/352 (0.57%)	1/340 (0.29%)
Urinary tract obstruction † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Reproductive system and breast disorders
Scrotal pain † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Bronchial obstruction † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Chronic obstructive pulmonary disease † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Cough † 1	3/355 (0.85%)	0/352 (0.00%)	0/340 (0.00%)
Dyspnoea † 1	6/355 (1.69%)	7/352 (1.99%)	2/340 (0.59%)
Epistaxis † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Haemoptysis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Haemothorax † 1	0/355 (0.00%)	1/352 (0.28%)	1/340 (0.29%)
Hypoxia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Interstitial lung disease † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Lung disorder † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Pleural effusion † 1	3/355 (0.85%)	4/352 (1.14%)	5/340 (1.47%)
Pneumonia aspiration † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Pneumonitis † 1	0/355 (0.00%)	9/352 (2.56%)	0/340 (0.00%)
Pneumothorax † 1	3/355 (0.85%)	1/352 (0.28%)	1/340 (0.29%)
Pneumothorax spontaneous † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Pulmonary embolism † 1	2/355 (0.56%)	5/352 (1.42%)	3/340 (0.88%)
Pulmonary haemorrhage † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Pulmonary mass † 1	1/355 (0.28%)	1/352 (0.28%)	0/340 (0.00%)
Respiratory failure † 1	2/355 (0.56%)	1/352 (0.28%)	2/340 (0.59%)
Skin and subcutaneous tissue disorders
Erythema multiforme † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Hyperhidrosis † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Pyoderma gangrenosum † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Rash † 1	1/355 (0.28%)	2/352 (0.57%)	0/340 (0.00%)
Rash maculo-papular † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Skin ulcer † 1	0/355 (0.00%)	1/352 (0.28%)	1/340 (0.29%)
Stevens-Johnson syndrome † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Toxic epidermal necrolysis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Urticaria † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Surgical and medical procedures
Spinal laminectomy † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Vascular disorders
Aneurysm ruptured † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Aortic dissection † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Aortic stenosis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Deep vein thrombosis † 1	0/355 (0.00%)	2/352 (0.57%)	1/340 (0.29%)
Embolism venous † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Haematoma † 1	1/355 (0.28%)	0/352 (0.00%)	0/340 (0.00%)
Hypertension † 1	2/355 (0.56%)	8/352 (2.27%)	2/340 (0.59%)
Hypertensive crisis † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Hypotension † 1	0/355 (0.00%)	0/352 (0.00%)	2/340 (0.59%)
Peripheral ischaemia † 1	0/355 (0.00%)	1/352 (0.28%)	0/340 (0.00%)
Phlebitis † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
Thrombophlebitis migrans † 1	0/355 (0.00%)	0/352 (0.00%)	1/340 (0.29%)
1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Lenvatinib 18 mg Plus Everolimus 5 mg	Lenvatinib 20 mg Plus Pembrolizumab 200 mg	Sunitinib 50 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	353/355 (99.44%)	351/352 (99.72%)	332/340 (97.65%)
Blood and lymphatic system disorders
Anaemia † 1	57/355 (16.06%)	43/352 (12.22%)	66/340 (19.41%)
Thrombocytopenia † 1	39/355 (10.99%)	14/352 (3.98%)	53/340 (15.59%)
Neutropenia † 1	11/355 (3.10%)	9/352 (2.56%)	46/340 (13.53%)
Leukopenia † 1	4/355 (1.13%)	5/352 (1.42%)	23/340 (6.76%)
Endocrine disorders
Hypothyroidism † 1	95/355 (26.76%)	164/352 (46.59%)	90/340 (26.47%)
Hyperthyroidism † 1	9/355 (2.54%)	28/352 (7.95%)	12/340 (3.53%)
Gastrointestinal disorders
Diarrhoea † 1	233/355 (65.63%)	214/352 (60.80%)	166/340 (48.82%)
Stomatitis † 1	169/355 (47.61%)	122/352 (34.66%)	131/340 (38.53%)
Nausea † 1	139/355 (39.15%)	125/352 (35.51%)	113/340 (33.24%)
Vomiting † 1	107/355 (30.14%)	91/352 (25.85%)	67/340 (19.71%)
Constipation † 1	73/355 (20.56%)	87/352 (24.72%)	64/340 (18.82%)
Abdominal pain † 1	72/355 (20.28%)	72/352 (20.45%)	28/340 (8.24%)
Dyspepsia † 1	34/355 (9.58%)	39/352 (11.08%)	55/340 (16.18%)
Abdominal pain upper † 1	45/355 (12.68%)	34/352 (9.66%)	26/340 (7.65%)
Dry mouth † 1	23/355 (6.48%)	36/352 (10.23%)	11/340 (3.24%)
Gastrooesophageal reflux disease † 1	16/355 (4.51%)	16/352 (4.55%)	30/340 (8.82%)
Toothache † 1	24/355 (6.76%)	19/352 (5.40%)	9/340 (2.65%)
Haemorrhoids † 1	19/355 (5.35%)	20/352 (5.68%)	11/340 (3.24%)
Abdominal discomfort † 1	19/355 (5.35%)	8/352 (2.27%)	8/340 (2.35%)
General disorders
Fatigue † 1	149/355 (41.97%)	141/352 (40.06%)	124/340 (36.47%)
Asthenia † 1	63/355 (17.75%)	77/352 (21.88%)	61/340 (17.94%)
Oedema peripheral † 1	72/355 (20.28%)	42/352 (11.93%)	35/340 (10.29%)
Pyrexia † 1	44/355 (12.39%)	48/352 (13.64%)	41/340 (12.06%)
Infections and infestations
Nasopharyngitis † 1	34/355 (9.58%)	40/352 (11.36%)	25/340 (7.35%)
Urinary tract infection † 1	32/355 (9.01%)	24/352 (6.82%)	23/340 (6.76%)
Sinusitis † 1	14/355 (3.94%)	19/352 (5.40%)	6/340 (1.76%)
Upper respiratory tract infection † 1	24/355 (6.76%)	31/352 (8.81%)	21/340 (6.18%)
Investigations
Weight decreased † 1	116/355 (32.68%)	105/352 (29.83%)	31/340 (9.12%)
Platelet count decreased † 1	59/355 (16.62%)	21/352 (5.97%)	61/340 (17.94%)
Lipase increased † 1	22/355 (6.20%)	64/352 (18.18%)	44/340 (12.94%)
Aspartate aminotransferase increased † 1	52/355 (14.65%)	39/352 (11.08%)	37/340 (10.88%)
Alanine aminotransferase increased † 1	49/355 (13.80%)	42/352 (11.93%)	35/340 (10.29%)
Blood creatinine increased † 1	36/355 (10.14%)	48/352 (13.64%)	34/340 (10.00%)
Amylase increased † 1	16/355 (4.51%)	62/352 (17.61%)	28/340 (8.24%)
Blood thyroid stimulating hormone increased † 1	22/355 (6.20%)	39/352 (11.08%)	21/340 (6.18%)
Blood cholesterol increased † 1	41/355 (11.55%)	24/352 (6.82%)	14/340 (4.12%)
Neutrophil count decreased † 1	14/355 (3.94%)	7/352 (1.99%)	40/340 (11.76%)
Blood triglycerides increased † 1	21/355 (5.92%)	22/352 (6.25%)	15/340 (4.41%)
White blood cell count decreased † 1	11/355 (3.10%)	9/352 (2.56%)	33/340 (9.71%)
Blood creatine phosphokinase increased † 1	19/355 (5.35%)	14/352 (3.98%)	17/340 (5.00%)
Electrocardiogram QT prolonged † 1	15/355 (4.23%)	22/352 (6.25%)	13/340 (3.82%)
Blood alkaline phosphatase increased † 1	20/355 (5.63%)	17/352 (4.83%)	9/340 (2.65%)
Metabolism and nutrition disorders
Decreased appetite † 1	143/355 (40.28%)	142/352 (40.34%)	105/340 (30.88%)
Hypertriglyceridaemia † 1	80/355 (22.54%)	42/352 (11.93%)	41/340 (12.06%)
Hypercholesterolaemia † 1	37/355 (10.42%)	31/352 (8.81%)	7/340 (2.06%)
Hyperglycaemia † 1	31/355 (8.73%)	24/352 (6.82%)	18/340 (5.29%)
Hypophosphataemia † 1	32/355 (9.01%)	22/352 (6.25%)	15/340 (4.41%)
Hyponatraemia † 1	17/355 (4.79%)	27/352 (7.67%)	20/340 (5.88%)
Hypokalaemia † 1	30/355 (8.45%)	22/352 (6.25%)	11/340 (3.24%)
Hyperkalaemia † 1	14/355 (3.94%)	27/352 (7.67%)	18/340 (5.29%)
Hypomagnesaemia † 1	17/355 (4.79%)	27/352 (7.67%)	13/340 (3.82%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	75/355 (21.13%)	99/352 (28.13%)	52/340 (15.29%)
Back pain † 1	60/355 (16.90%)	57/352 (16.19%)	52/340 (15.29%)
Musculoskeletal pain † 1	39/355 (10.99%)	48/352 (13.64%)	21/340 (6.18%)
Pain in extremity † 1	33/355 (9.30%)	41/352 (11.65%)	33/340 (9.71%)
Myalgia † 1	34/355 (9.58%)	56/352 (15.91%)	12/340 (3.53%)
Muscle spasms † 1	14/355 (3.94%)	24/352 (6.82%)	12/340 (3.53%)
Musculoskeletal chest pain † 1	20/355 (5.63%)	16/352 (4.55%)	11/340 (3.24%)
Nervous system disorders
Headache † 1	81/355 (22.82%)	80/352 (22.73%)	54/340 (15.88%)
Dysgeusia † 1	59/355 (16.62%)	42/352 (11.93%)	95/340 (27.94%)
Dizziness † 1	17/355 (4.79%)	34/352 (9.66%)	29/340 (8.53%)
Psychiatric disorders
Insomnia † 1	40/355 (11.27%)	38/352 (10.80%)	21/340 (6.18%)
Renal and urinary disorders
Haematuria † 1	15/355 (4.23%)	17/352 (4.83%)	19/340 (5.59%)
Proteinuria † 1	121/355 (34.08%)	104/352 (29.55%)	43/340 (12.65%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	84/355 (23.66%)	70/352 (19.89%)	53/340 (15.59%)
Dysphonia † 1	84/355 (23.66%)	105/352 (29.83%)	14/340 (4.12%)
Dyspnoea † 1	50/355 (14.08%)	51/352 (14.49%)	32/340 (9.41%)
Epistaxis † 1	70/355 (19.72%)	25/352 (7.10%)	37/340 (10.88%)
Oropharyngeal pain † 1	33/355 (9.30%)	23/352 (6.53%)	12/340 (3.53%)
Pneumonitis † 1	19/355 (5.35%)	12/352 (3.41%)	0/340 (0.00%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome † 1	81/355 (22.82%)	101/352 (28.69%)	127/340 (37.35%)
Rash † 1	87/355 (24.51%)	95/352 (26.99%)	47/340 (13.82%)
Pruritus † 1	47/355 (13.24%)	58/352 (16.48%)	26/340 (7.65%)
Dry skin † 1	31/355 (8.73%)	22/352 (6.25%)	27/340 (7.94%)
Rash maculo-papular † 1	23/355 (6.48%)	28/352 (7.95%)	7/340 (2.06%)
Yellow skin † 1	1/355 (0.28%)	0/352 (0.00%)	32/340 (9.41%)
Dermatitis acneiform † 1	23/355 (6.48%)	5/352 (1.42%)	3/340 (0.88%)
Vascular disorders
Hypertension † 1	162/355 (45.63%)	194/352 (55.11%)	141/340 (41.47%)
Hypotension † 1	17/355 (4.79%)	24/352 (6.82%)	6/340 (1.76%)
1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Eisai Medical Information
• Organization: Eisai, Inc.
• Phone: +1-888-274-2378
• EMail: esi_oncmedinfo@eisai.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Motzer R, Porta C, Alekseev B, Rha SY, Choueiri TK, Mendez-Vidal MJ, Hong SH, Kapoor A, Goh JC, Eto M, Bennett L, Wang J, Pan JJ, Saretsky TL, Perini RF, He CS, Mody K, Cella D. Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study. Lancet Oncol. 2022 Jun;23(6):768-780. doi: 10.1016/S1470-2045(22)00212-1. Epub 2022 Apr 27.

Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grunwald V, Hutson TE, Kopyltsov E, Mendez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. doi: 10.1056/NEJMoa2035716. Epub 2021 Feb 13.

Hofmann F, Hwang EC, Lam TB, Bex A, Yuan Y, Marconi LS, Ljungberg B. Targeted therapy for metastatic renal cell carcinoma. Cochrane Database Syst Rev. 2020 Oct 14;10(10):CD012796. doi: 10.1002/14651858.CD012796.pub2.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT02811861
• Other Study ID Numbers: E7080-G000-307; KEYNOTE-581 ( Other Identifier: Merck ); 2016-000916-14 ( EudraCT Number )
• First Submitted: June 21, 2016
• First Posted: June 23, 2016
• Results First Submitted: August 27, 2021
• Results First Posted: September 24, 2021
• Last Update Posted: July 10, 2023