A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Trial of Lenvatinib (E7080) in 131I-Refractory Differentiated Thyroid Cancer (DTC) (SELECT)

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ClinicalTrials.gov Identifier: NCT01321554

Recruitment Status : Completed

First Posted : March 23, 2011

Results First Posted : December 12, 2016

Last Update Posted : June 22, 2023

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Sponsor:

Information provided by (Responsible Party):

Eisai Inc.

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition	Thyroid Cancer
Interventions	Drug: Lenvatinib Drug: Placebo
Enrollment	392

Participant Flow

Recruitment Details	Participants took part in the study at 117 investigative sites in Europe, North America, Asia Pacific, Japan, and Latin America from 17 March 2011 to 19 March 2019.
Pre-assignment Details	A total of 612 participants were screened for entry into the study. Of these 612 participants, 220 participants were screening failures and 392 participants were randomly assigned to receive either lenvatinib or placebo in a 2:1 ratio.


Arm/Group Title	Randomization Phase: Lenvatinib 24 mg	Randomization Phase: Placebo	OOL, Treatment Period: Lenvatinib 24 mg	OOL, Treatment Period: Lenvatinib 20 mg
Arm/Group Description	Participants received lenvatinib 24...	Participants received matching-plac...	Participants received lenvatinib 24...	Participants received lenvatinib 20...
Arm/Group Description	Participants received lenvatinib 24 milligram (mg), hard capsule, orally, once daily, until documentation of disease progression (confirmed by Investigator-Initiated Research [IIR]), development of unacceptable toxicity, or withdrawal of consent.	Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Participants received lenvatinib 24 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib. OOL refers to Optional Open-Label.	Participants received lenvatinib 20 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.
Period Title: Randomization Phase
Started	261	131	0	0
Completed	261	131	0	0
Not Completed	0	0	0	0
Period Title: OOL Lenvatinib Treatment Period
Started	0	0	85 ^[1]	30 ^[1]
Completed	0	0	85	30
Not Completed	0	0	0	0
[1] Participants from randomization phase were re-randomized to OOL, treatment period.

Baseline Characteristics

Arm/Group Title		Randomization Phase: Lenvatinib 24 mg	Randomization Phase: Placebo	Total
Arm/Group Description		Participants received lenvatinib 24...	Participants received matching-plac...	Total of all reporting groups
Arm/Group Description		Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Total of all reporting groups
Overall Number of Baseline Participants		261	131	392
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Geometric Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	261 participants	131 participants	392 participants
		62.1 (10.57)	61.5 (10.09)	61.9 (10.40)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	261 participants	131 participants	392 participants
	Female	136 52.1%	56 42.7%	192 49.0%
	Male	125 47.9%	75 57.3%	200 51.0%

Outcome Measures

1.Primary Outcome


Title	Progression Free Survival (PFS)
Description	PFS was defined as the time from the date of randomization to the date...
Description	PFS was defined as the time from the date of randomization to the date of first documentation of disease progression or death (whichever occurred first), as determined by blinded IIR using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for the double-blind treatment period (Randomization Phase). Disease progression per RECIST v1.1 was defined as at least a 20 percent (%) relative increase and 5 millimeter (mm) absolute 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.
Time Frame	Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

The full analysis set (Intent-to-Treat Analysis Set) included all randomized participants.


Arm/Group Title	Randomization Phase: Lenvatinib 24 mg	Randomization Phase: Placebo
Arm/Group Description:	Participants received lenvatinib 24...	Participants received matching-plac...
Arm/Group Description:	Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	261	131
Median (95% Confidence Interval) Unit of Measure: months
	18.3 ^[1] (15.1 to NA)	3.6 (2.2 to 3.7)

[1]

The upper limit of the 95% confidence interval was not estimable because an insufficient number of participants reached the event at the final assessment time point.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomization Phase: Lenvatinib 24 mg, Randomization Phase: Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 99% 0.14 to 0.31
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Overall Response Rate (ORR)
Description	ORR, defined as the percentage of participants who had best overall re...
Description	ORR, defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by blinded IIR using RECIST 1.1 for target lesions and assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans (for double blind treatment period i.e. Randomization Phase). CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR = CR + PR.
Time Frame	Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

The full analysis set (Intent-to-Treat Analysis Set) included all randomized participants.


Arm/Group Title	Randomization Phase: Lenvatinib 24 mg	Randomization Phase: Placebo
Arm/Group Description:	Participants received lenvatinib 24...	Participants received matching-plac...
Arm/Group Description:	Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	261	131
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	64.8 (59.0 to 70.5)	1.5 (0.0 to 3.6)

3.Secondary Outcome


Title	Overall Survival (OS)
Description	Overall survival measured from the date of randomization until date of...
Description	Overall survival measured from the date of randomization until date of death from any cause. Overall survival is adjusted with rank preserving structural failure time.
Time Frame	Date of randomization until date of death from any cause, assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

The full analysis set (Intent-to-Treat Analysis Set) included all randomized participants.


Arm/Group Title	Randomization Phase: Lenvatinib 24 mg	Randomization Phase: Placebo
Arm/Group Description:	Participants received lenvatinib 24...	Participants received matching-plac...
Arm/Group Description:	Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	261	131
Median (95% Confidence Interval) Unit of Measure: months
	NA ^[1] (22.0 to NA)	NA ^[1] (14.3 to NA)

[1]

The median OS was not yet reached for either the lenvatinib or the placebo arm (including crossover participants) at data cutoff date.

4.Secondary Outcome


Title	Pharmacokinetic (PK) Profile of Lenvatinib: Area Under the Plasma Concentration Curve
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Cycle 1 Days 1 and 15: 0-10 hours postdose; Cycle 2 Day 1: 0-12 hour postdose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all the participants who received at least one dose of study drug and had evaluable PK data.


Arm/Group Title	Randomization Phase: Lenvatinib 24 mg
Arm/Group Description:	Participants received lenvatinib 24...
Arm/Group Description:	Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	260
Median (Full Range) Unit of Measure: nanogramhour per milliliter (ngh/mL)
	3490 (1410 to 10700)

Adverse Events

Time Frame	For each participant, from the first dose till 30 days after the last dose up to approximately 8 years
Adverse Event Reporting Description	Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.

Arm/Group Title	Randomization Phase: Lenvatinib 24 mg		Randomization Phase: Placebo		OOL, Treatment Period: Lenvatinib 24 mg		OOL, Treatment Period: Lenvatinib 20 mg
Arm/Group Description	Participants received lenvatinib 24...		Participants received matching-plac...		Participants received lenvatinib 24...		Participants received lenvatinib 20...
Arm/Group Description	Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.		Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.		Participants received lenvatinib 24 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.		Participants received lenvatinib 20 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.
All-Cause Mortality
	Randomization Phase: Lenvatinib 24 mg		Randomization Phase: Placebo		OOL, Treatment Period: Lenvatinib 24 mg		OOL, Treatment Period: Lenvatinib 20 mg
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	161/261 (61.69%)		13/16 (81.25%)		62/85 (72.94%)		15/30 (50.00%)
Serious Adverse Events Serious Adverse Events
	Randomization Phase: Lenvatinib 24 mg		Randomization Phase: Placebo		OOL, Treatment Period: Lenvatinib 24 mg		OOL, Treatment Period: Lenvatinib 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	171/261 (65.52%)		31/131 (23.66%)		62/85 (72.94%)		16/30 (53.33%)
Blood and lymphatic system disorders
Anaemia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	1	1/30 (3.33%)	1
Neutropenia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Thrombocytopenia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Febrile neutropenia ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Splenic haemorrhage ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Cardiac disorders
Acute myocardial infarction ^† 1	5/261 (1.92%)	7	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Angina pectoris ^† 1	1/261 (0.38%)	1	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Bundle branch block right ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Cardio-respiratory arrest ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Coronary artery stenosis ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Myocardial infarction ^† 1	1/261 (0.38%)	1	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Pericardial effusion ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Right ventricular hypertrophy ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Sinus tachycardia ^† 1	0/261 (0.00%)	0	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Atrial fibrillation ^† 1	4/261 (1.53%)	6	0/131 (0.00%)	0	3/85 (3.53%)	4	0/30 (0.00%)	0
Atrial flutter ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Cardiac arrest ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Cardiac failure ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	2	0/30 (0.00%)	0
Acute coronary syndrome ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Angina unstable ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Atrioventricular block complete ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Cardiac failure congestive ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Coronary artery insufficiency ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Coronary artery occlusion ^† 1	1/261 (0.38%)	1	1/131 (0.76%)	1	0/85 (0.00%)	0	1/30 (3.33%)	1
Tachycardia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Ventricular hypokinesia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Ventricular tachycardia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Palpitations ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Acute left ventricular failure ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Eye disorders
Retinal vein thrombosis ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Retinal detachment ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Diplopia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Gastrointestinal disorders
Abdominal pain ^† 1	3/261 (1.15%)	3	0/131 (0.00%)	0	4/85 (4.71%)	5	0/30 (0.00%)	0
Anal fistula ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Abdominal pain upper ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Colitis ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Colitis ischaemic ^† 1	0/261 (0.00%)	0	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Constipation ^† 1	1/261 (0.38%)	1	1/131 (0.76%)	1	0/85 (0.00%)	0	2/30 (6.67%)	2
Diarrhoea ^† 1	2/261 (0.77%)	4	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Functional gastrointestinal disorder ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Gastrooesophageal reflux disease ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Intestinal obstruction ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Nausea ^† 1	0/261 (0.00%)	0	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Oesophageal stenosis ^† 1	0/261 (0.00%)	0	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Pneumatosis intestinalis ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Stomatitis ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Vomiting ^† 1	5/261 (1.92%)	5	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Diverticular perforation ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	2/85 (2.35%)	2	0/30 (0.00%)	0
Dysphagia ^† 1	3/261 (1.15%)	3	3/131 (2.29%)	3	1/85 (1.18%)	1	0/30 (0.00%)	0
Inguinal hernia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Mesenteric artery thrombosis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Pancreatitis ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Abdominal mass ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Gastrointestinal inflammation ^† 1	1/261 (0.38%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Pneumoperitoneum ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Small intestinal obstruction ^† 1	2/261 (0.77%)	4	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Dental cyst ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Intestinal perforation ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Gastroenteritis viral ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	2	0/30 (0.00%)	0
General disorders
Asthenia ^† 1	3/261 (1.15%)	4	0/131 (0.00%)	0	2/85 (2.35%)	3	0/30 (0.00%)	0
Chest pain ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Device failure ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Impaired healing ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Multi-organ failure ^† 1	1/261 (0.38%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Non-cardiac chest pain ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	1/85 (1.18%)	3	0/30 (0.00%)	0
Pyrexia ^† 1	3/261 (1.15%)	3	1/131 (0.76%)	1	0/85 (0.00%)	0	1/30 (3.33%)	1
Sudden death ^† 1	1/261 (0.38%)	1	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Death ^† 1	2/261 (0.77%)	2	1/131 (0.76%)	1	3/85 (3.53%)	3	0/30 (0.00%)	0
Device breakage ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Fatigue ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
General physical health deterioration ^† 1	7/261 (2.68%)	9	0/131 (0.00%)	0	1/85 (1.18%)	2	0/30 (0.00%)	0
Pain ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Hepatobiliary disorders
Cholecystitis acute ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
Cholelithiasis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Cholecystitis ^† 1	4/261 (1.53%)	5	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Gallbladder mucocoele ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Gallbladder perforation ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Hepatic failure ^† 1	2/261 (0.77%)	4	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Hepatic function abnormal ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Liver injury ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Hepatocellular injury ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Hydrocholecystis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
Immune system disorders
Anaphylactic reaction ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Contrast media allergy ^† 1	0/261 (0.00%)	0	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Infections and infestations
Abscess intestinal ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Anal abscess ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Bronchitis ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Cellulitis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Colonic abscess ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Diverticulitis ^† 1	2/261 (0.77%)	3	0/131 (0.00%)	0	1/85 (1.18%)	2	0/30 (0.00%)	0
Empyema ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Abscess limb ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Abscess soft tissue ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Appendicitis ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Bacteraemia ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Chest wall abscess ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Chronic sinusitis ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Fungal skin infection ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Erysipelas ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Infection ^† 1	1/261 (0.38%)	1	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Gastroenteritis ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	1/85 (1.18%)	1	1/30 (3.33%)	1
Intervertebral discitis ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Lower respiratory tract infection ^† 1	4/261 (1.53%)	7	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Perineal abscess ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Pyelonephritis ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Sepsis ^† 1	6/261 (2.30%)	6	2/131 (1.53%)	3	1/85 (1.18%)	1	0/30 (0.00%)	0
Testicular abscess ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Urinary tract infection ^† 1	4/261 (1.53%)	4	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Urosepsis ^† 1	1/261 (0.38%)	1	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Wound infection ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Implant site infection ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Lobar pneumonia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Lung infection ^† 1	4/261 (1.53%)	6	0/131 (0.00%)	0	1/85 (1.18%)	3	2/30 (6.67%)	2
Lymph gland infection ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
Osteomyelitis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Pneumonia ^† 1	12/261 (4.60%)	14	3/131 (2.29%)	3	5/85 (5.88%)	5	2/30 (6.67%)	3
Pneumonia necrotising ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	2	0/30 (0.00%)	0
Pneumonia staphylococcal ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Bartholin's abscess ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Biliary tract infection ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Candida sepsis ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Cholecystitis infective ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Laryngitis ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Meningitis viral ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Subcutaneous abscess ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Tracheitis ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Appendicitis perforated ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Phlebitis infective ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
Upper respiratory tract infection ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Injury, poisoning and procedural complications
Eschar ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Femur fracture ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Hip fracture ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Renal haematoma ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Vascular pseudoaneurysm ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Wound dehiscence ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Wound secretion ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Post procedural haemorrhage ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
Splenic rupture ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Incisional hernia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Lumbar vertebral fracture ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Subdural haematoma ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Traumatic fracture ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Thermal burn ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
Investigations
Blood uric acid increased ^† 1	2/261 (0.77%)	3	1/131 (0.76%)	2	1/85 (1.18%)	1	0/30 (0.00%)	0
Electrocardiogram T wave inversion ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
Alanine aminotransferase increased ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Aspartate aminotransferase increased ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Blood alkaline phosphatase increased ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Blood creatine phosphokinase increased ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Lipase increased ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Platelet count decreased ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Weight decreased ^† 1	2/261 (0.77%)	2	1/131 (0.76%)	2	0/85 (0.00%)	0	0/30 (0.00%)	0
Blood creatinine increased ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Blood calcium increased ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
Metabolism and nutrition disorders
Decreased appetite ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	2/85 (2.35%)	2	1/30 (3.33%)	1
Dehydration ^† 1	9/261 (3.45%)	9	0/131 (0.00%)	0	2/85 (2.35%)	3	1/30 (3.33%)	1
Hypercalcaemia ^† 1	2/261 (0.77%)	2	1/131 (0.76%)	1	1/85 (1.18%)	1	0/30 (0.00%)	0
Hypocalcaemia ^† 1	4/261 (1.53%)	8	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
Hyponatraemia ^† 1	2/261 (0.77%)	2	1/131 (0.76%)	1	1/85 (1.18%)	2	0/30 (0.00%)	0
Hypovolaemia ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Hypokalaemia ^† 1	3/261 (1.15%)	3	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Hypomagnesaemia ^† 1	1/261 (0.38%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	3/261 (1.15%)	3	1/131 (0.76%)	1	1/85 (1.18%)	1	1/30 (3.33%)	1
Back pain ^† 1	3/261 (1.15%)	3	0/131 (0.00%)	0	3/85 (3.53%)	3	0/30 (0.00%)	0
Flank pain ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Bone pain ^† 1	2/261 (0.77%)	3	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Musculoskeletal chest pain ^† 1	1/261 (0.38%)	1	1/131 (0.76%)	1	2/85 (2.35%)	3	0/30 (0.00%)	0
Muscular weakness ^† 1	1/261 (0.38%)	1	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Musculoskeletal pain ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Myalgia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Neck pain ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Osteoarthritis ^† 1	3/261 (1.15%)	3	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Pain in extremity ^† 1	1/261 (0.38%)	1	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Rhabdomyolysis ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Pathological fracture ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	2/85 (2.35%)	2	1/30 (3.33%)	1
Soft tissue necrosis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Foot deformity ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Osteonecrosis of jaw ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Mobility decreased ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intracranial tumour haemorrhage ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Malignant neoplasm progression ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	3/85 (3.53%)	4	0/30 (0.00%)	0
Malignant pleural effusion ^† 1	5/261 (1.92%)	5	1/131 (0.76%)	2	1/85 (1.18%)	2	0/30 (0.00%)	0
Metastases to bone ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Metastatic pain ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	3/85 (3.53%)	3	1/30 (3.33%)	1
Adenocarcinoma gastric ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Cancer pain ^† 1	3/261 (1.15%)	3	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Metastases to spine ^† 1	0/261 (0.00%)	0	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Plasmacytoma ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Tumour pain ^† 1	0/261 (0.00%)	0	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Lymphocytic leukaemia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Malignant melanoma ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Spindle cell sarcoma ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Squamous cell carcinoma of skin ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Metastatic pulmonary embolism ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Nervous system disorders
Cauda equina syndrome ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Cerebrovascular accident ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	3/85 (3.53%)	3	1/30 (3.33%)	1
Coma ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Diabetic encephalopathy ^† 1	0/261 (0.00%)	0	1/131 (0.76%)	1	1/85 (1.18%)	1	0/30 (0.00%)	0
Osmotic demyelination syndrome ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Cerebral ischaemia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Dizziness ^† 1	2/261 (0.77%)	4	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Epilepsy ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Haemorrhagic stroke ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Headache ^† 1	4/261 (1.53%)	4	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Ischaemic stroke ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Loss of consciousness ^† 1	1/261 (0.38%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Metabolic encephalopathy ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Monoparesis ^† 1	3/261 (1.15%)	6	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Parkinson's disease ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Posterior reversible encephalopathy syndrome ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Postictal paralysis ^† 1	1/261 (0.38%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Spinal cord compression ^† 1	4/261 (1.53%)	4	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Syncope ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	1/85 (1.18%)	1	1/30 (3.33%)	1
Transient ischaemic attack ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
Vocal cord paralysis ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Spinal cord ischaemia ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Subarachnoid haemorrhage ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
seizure ^† 1	4/261 (1.53%)	5	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Dementia ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
Facial paresis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Psychiatric disorders
Confusional state ^† 1	3/261 (1.15%)	4	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Anxiety ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Depression ^† 1	0/261 (0.00%)	0	1/131 (0.76%)	1	1/85 (1.18%)	3	0/30 (0.00%)	0
Suicidal ideation ^† 1	0/261 (0.00%)	0	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Delirium ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
Renal and urinary disorders
Acute prerenal failure ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Dysuria ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Nephrotic syndrome ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Renal failure ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Renal impairment ^† 1	1/261 (0.38%)	3	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Renal tubular necrosis ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Urinary retention ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Acute kidney injury ^† 1	6/261 (2.30%)	6	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Chronic kidney disease ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Haematuria ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Proteinuria ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Urinary incontinence ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Reproductive system and breast disorders
Postmenopausal haemorrhage ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Cystocele ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Rectocele ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Uterine prolapse ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Genital prolapse ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Chronic obstructive pulmonary disease ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	2	0/30 (0.00%)	0
Dyspnoea ^† 1	6/261 (2.30%)	12	5/131 (3.82%)	7	3/85 (3.53%)	5	1/30 (3.33%)	1
Dyspnoea exertional ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Haemoptysis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	2/85 (2.35%)	2	1/30 (3.33%)	1
Laryngeal necrosis ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Laryngeal obstruction ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Laryngeal oedema ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Lung disorder ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	2	0/30 (0.00%)	0
Pneumothorax ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Pulmonary haemorrhage ^† 1	1/261 (0.38%)	1	1/131 (0.76%)	1	1/85 (1.18%)	1	0/30 (0.00%)	0
Respiratory distress ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	2/85 (2.35%)	4	0/30 (0.00%)	0
Respiratory failure ^† 1	2/261 (0.77%)	2	2/131 (1.53%)	3	2/85 (2.35%)	3	0/30 (0.00%)	0
Acute respiratory failure ^† 1	2/261 (0.77%)	2	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Aspiration ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Bronchospasm ^† 1	1/261 (0.38%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Epistaxis ^† 1	2/261 (0.77%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Haemothorax ^† 1	1/261 (0.38%)	1	1/131 (0.76%)	2	0/85 (0.00%)	0	0/30 (0.00%)	0
Hypoxia ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Laryngeal haemorrhage ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Pleural effusion ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Pneumonia aspiration ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Pneumonitis ^† 1	1/261 (0.38%)	2	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Productive cough ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Pulmonary embolism ^† 1	6/261 (2.30%)	8	2/131 (1.53%)	2	0/85 (0.00%)	0	0/30 (0.00%)	0
Atelectasis ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Bronchial secretion retention ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Hydrothorax ^† 1	1/261 (0.38%)	5	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Oropharyngeal pain ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Pneumothorax spontaneous ^† 1	1/261 (0.38%)	5	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Pulmonary mass ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Pleuritic pain ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Respiratory depression ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Skin and subcutaneous tissue disorders
Angioedema ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Erythema ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Rash ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Skin ulcer ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Drug eruption ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Dermatitis contact ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Vascular disorders
Aneurysm ruptured ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
Hypertension ^† 1	10/261 (3.83%)	11	0/131 (0.00%)	0	1/85 (1.18%)	1	1/30 (3.33%)	2
Hypertensive crisis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	2/85 (2.35%)	2	0/30 (0.00%)	0
Hypotension ^† 1	5/261 (1.92%)	5	0/131 (0.00%)	0	2/85 (2.35%)	2	0/30 (0.00%)	0
Varicose vein ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	1
Deep vein thrombosis ^† 1	1/261 (0.38%)	1	0/131 (0.00%)	0	0/85 (0.00%)	0	0/30 (0.00%)	0
Vasculitis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	1/30 (3.33%)	3
Thrombophlebitis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	0/30 (0.00%)	0
1 Term from vocabulary, MedDRA 18.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Randomization Phase: Lenvatinib 24 mg		Randomization Phase: Placebo		OOL, Treatment Period: Lenvatinib 24 mg		OOL, Treatment Period: Lenvatinib 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	259/261 (99.23%)		118/131 (90.08%)		84/85 (98.82%)		29/30 (96.67%)
Blood and lymphatic system disorders
Lymphopenia ^† 1	20/261 (7.66%)	60	2/131 (1.53%)	2	0/85 (0.00%)	0	0/30 (0.00%)	0
Anaemia ^† 1	31/261 (11.88%)	60	6/131 (4.58%)	13	7/85 (8.24%)	11	3/30 (10.00%)	11
Thrombocytopenia ^† 1	25/261 (9.58%)	83	3/131 (2.29%)	4	7/85 (8.24%)	84	1/30 (3.33%)	1
Leukopenia ^† 1	15/261 (5.75%)	47	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Endocrine disorders
Hypothyroidism ^† 1	14/261 (5.36%)	26	0/131 (0.00%)	0	7/85 (8.24%)	7	2/30 (6.67%)	2
Gastrointestinal disorders
Oral pain ^† 1	26/261 (9.96%)	44	1/131 (0.76%)	3	5/85 (5.88%)	9	0/30 (0.00%)	0
Cheilitis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	5/85 (5.88%)	5	0/30 (0.00%)	0
Toothache ^† 1	18/261 (6.90%)	22	5/131 (3.82%)	5	7/85 (8.24%)	8	2/30 (6.67%)	3
Haemorrhoids ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	6/85 (7.06%)	6	1/30 (3.33%)	1
Glossodynia ^† 1	18/261 (6.90%)	32	0/131 (0.00%)	0	9/85 (10.59%)	12	0/30 (0.00%)	0
Abdominal pain upper ^† 1	46/261 (17.62%)	85	11/131 (8.40%)	11	11/85 (12.94%)	13	9/30 (30.00%)	11
Dry mouth ^† 1	46/261 (17.62%)	58	11/131 (8.40%)	13	11/85 (12.94%)	12	1/30 (3.33%)	1
Dyspepsia ^† 1	38/261 (14.56%)	66	6/131 (4.58%)	6	11/85 (12.94%)	14	3/30 (10.00%)	10
Dysphagia ^† 1	34/261 (13.03%)	47	9/131 (6.87%)	10	15/85 (17.65%)	15	3/30 (10.00%)	5
Abdominal pain ^† 1	50/261 (19.16%)	109	5/131 (3.82%)	10	20/85 (23.53%)	34	8/30 (26.67%)	15
Constipation ^† 1	83/261 (31.80%)	113	20/131 (15.27%)	26	25/85 (29.41%)	32	5/30 (16.67%)	8
Stomatitis ^† 1	100/261 (38.31%)	246	9/131 (6.87%)	10	28/85 (32.94%)	50	13/30 (43.33%)	22
Vomiting ^† 1	100/261 (38.31%)	217	19/131 (14.50%)	24	36/85 (42.35%)	67	9/30 (30.00%)	19
Nausea ^† 1	127/261 (48.66%)	295	34/131 (25.95%)	48	34/85 (40.00%)	67	12/30 (40.00%)	31
Diarrhoea ^† 1	182/261 (69.73%)	740	22/131 (16.79%)	27	55/85 (64.71%)	263	21/30 (70.00%)	66
Flatulence ^† 1	15/261 (5.75%)	18	1/131 (0.76%)	1	3/85 (3.53%)	4	2/30 (6.67%)	6
Abdominal distension ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	2/30 (6.67%)	2
Gastrooesophageal reflux disease ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	2/85 (2.35%)	2	2/30 (6.67%)	2
Gingival pain ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	2/85 (2.35%)	3	2/30 (6.67%)	2
General disorders
General physical health deterioration ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	6/85 (7.06%)	7	1/30 (3.33%)	1
Pyrexia ^† 1	41/261 (15.71%)	58	15/131 (11.45%)	17	10/85 (11.76%)	20	5/30 (16.67%)	8
Oedema peripheral ^† 1	65/261 (24.90%)	124	10/131 (7.63%)	12	18/85 (21.18%)	20	3/30 (10.00%)	8
Asthenia ^† 1	69/261 (26.44%)	209	18/131 (13.74%)	29	21/85 (24.71%)	43	10/30 (33.33%)	26
Fatigue ^† 1	116/261 (44.44%)	298	33/131 (25.19%)	45	35/85 (41.18%)	64	13/30 (43.33%)	28
Malaise ^† 1	17/261 (6.51%)	29	0/131 (0.00%)	0	5/85 (5.88%)	8	1/30 (3.33%)	1
Influenza like illness ^† 1	20/261 (7.66%)	25	4/131 (3.05%)	4	0/85 (0.00%)	0	0/30 (0.00%)	0
Non-cardiac chest pain ^† 1	14/261 (5.36%)	16	4/131 (3.05%)	5	3/85 (3.53%)	3	2/30 (6.67%)	2
Pain ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	2/30 (6.67%)	2
Infections and infestations
Urinary tract infection ^† 1	30/261 (11.49%)	54	7/131 (5.34%)	9	6/85 (7.06%)	8	3/30 (10.00%)	4
Pneumonia ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	6/85 (7.06%)	11	0/30 (0.00%)	0
Upper respiratory tract infection ^† 1	26/261 (9.96%)	40	7/131 (5.34%)	9	5/85 (5.88%)	10	3/30 (10.00%)	4
Nasopharyngitis ^† 1	28/261 (10.73%)	54	8/131 (6.11%)	8	6/85 (7.06%)	7	6/30 (20.00%)	6
Bronchitis ^† 1	17/261 (6.51%)	24	2/131 (1.53%)	2	5/85 (5.88%)	13	2/30 (6.67%)	3
Influenza ^† 1	16/261 (6.13%)	17	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Gastrointestinal infection ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	2/30 (6.67%)	2
Sinusitis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	6/85 (7.06%)	11	3/30 (10.00%)	5
Investigations
Platelet count decreased ^† 1	17/261 (6.51%)	108	0/131 (0.00%)	0	2/85 (2.35%)	2	5/30 (16.67%)	7
Aspartate aminotransferase increased ^† 1	17/261 (6.51%)	30	2/131 (1.53%)	2	6/85 (7.06%)	7	0/30 (0.00%)	0
Blood thyroid stimulating hormone increased ^† 1	18/261 (6.90%)	20	0/131 (0.00%)	0	5/85 (5.88%)	5	0/30 (0.00%)	0
Alanine aminotransferase increased ^† 1	21/261 (8.05%)	33	0/131 (0.00%)	0	8/85 (9.41%)	9	2/30 (6.67%)	2
Electrocardiogram QT prolonged ^† 1	27/261 (10.34%)	53	2/131 (1.53%)	3	9/85 (10.59%)	26	1/30 (3.33%)	5
Weight decreased ^† 1	142/261 (54.41%)	450	20/131 (15.27%)	22	44/85 (51.76%)	101	18/30 (60.00%)	49
Blood alkaline phosphatase increased ^† 1	18/261 (6.90%)	29	3/131 (2.29%)	3	5/85 (5.88%)	5	0/30 (0.00%)	0
Blood creatinine increased ^† 1	25/261 (9.58%)	54	2/131 (1.53%)	2	6/85 (7.06%)	8	1/30 (3.33%)	2
Ejection fraction decreased ^† 1	18/261 (6.90%)	31	1/131 (0.76%)	1	7/85 (8.24%)	9	2/30 (6.67%)	2
White blood cell count decreased ^† 1	14/261 (5.36%)	47	4/131 (3.05%)	4	0/85 (0.00%)	0	0/30 (0.00%)	0
Blood cholesterol increased ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	2/30 (6.67%)	2
Lipase increased ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	4/85 (4.71%)	7	2/30 (6.67%)	5
Metabolism and nutrition disorders
Hyperglycaemia ^† 1	15/261 (5.75%)	22	6/131 (4.58%)	7	5/85 (5.88%)	5	1/30 (3.33%)	3
Hypocalcaemia ^† 1	38/261 (14.56%)	74	0/131 (0.00%)	0	11/85 (12.94%)	23	3/30 (10.00%)	6
Hypoalbuminaemia ^† 1	27/261 (10.34%)	50	2/131 (1.53%)	2	12/85 (14.12%)	17	1/30 (3.33%)	3
Decreased appetite ^† 1	148/261 (56.70%)	352	24/131 (18.32%)	31	43/85 (50.59%)	86	11/30 (36.67%)	24
Dehydration ^† 1	24/261 (9.20%)	29	3/131 (2.29%)	3	0/85 (0.00%)	0	0/30 (0.00%)	0
Hypokalaemia ^† 1	41/261 (15.71%)	78	5/131 (3.82%)	5	0/85 (0.00%)	0	0/30 (0.00%)	0
Hypomagnesaemia ^† 1	20/261 (7.66%)	28	2/131 (1.53%)	2	6/85 (7.06%)	13	2/30 (6.67%)	2
Hyponatraemia ^† 1	17/261 (6.51%)	25	3/131 (2.29%)	6	5/85 (5.88%)	11	1/30 (3.33%)	1
Vitamin D deficiency ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	2/30 (6.67%)	2
Musculoskeletal and connective tissue disorders
Neck pain ^† 1	23/261 (8.81%)	33	15/131 (11.45%)	19	6/85 (7.06%)	8	1/30 (3.33%)	1
Muscle spasms ^† 1	22/261 (8.43%)	31	5/131 (3.82%)	5	11/85 (12.94%)	15	5/30 (16.67%)	13
Musculoskeletal chest pain ^† 1	32/261 (12.26%)	40	13/131 (9.92%)	14	11/85 (12.94%)	14	3/30 (10.00%)	5
Myalgia ^† 1	51/261 (19.54%)	95	6/131 (4.58%)	9	12/85 (14.12%)	16	9/30 (30.00%)	16
Pain in extremity ^† 1	48/261 (18.39%)	73	9/131 (6.87%)	13	12/85 (14.12%)	27	7/30 (23.33%)	9
Back pain ^† 1	52/261 (19.92%)	81	12/131 (9.16%)	14	18/85 (21.18%)	29	6/30 (20.00%)	7
Musculoskeletal pain ^† 1	46/261 (17.62%)	60	11/131 (8.40%)	13	14/85 (16.47%)	27	4/30 (13.33%)	6
Arthralgia ^† 1	85/261 (32.57%)	148	9/131 (6.87%)	15	19/85 (22.35%)	39	12/30 (40.00%)	25
Muscular weakness ^† 1	20/261 (7.66%)	23	3/131 (2.29%)	3	5/85 (5.88%)	8	0/30 (0.00%)	0
Flank pain ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	3/85 (3.53%)	3	3/30 (10.00%)	3
Joint swelling ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	2/85 (2.35%)	2	2/30 (6.67%)	2
Nervous system disorders
Dysgeusia ^† 1	48/261 (18.39%)	70	4/131 (3.05%)	4	10/85 (11.76%)	13	6/30 (20.00%)	9
Dizziness ^† 1	45/261 (17.24%)	77	13/131 (9.92%)	14	15/85 (17.65%)	19	8/30 (26.67%)	12
Headache ^† 1	105/261 (40.23%)	223	15/131 (11.45%)	21	19/85 (22.35%)	28	10/30 (33.33%)	35
Paraesthesia ^† 1	14/261 (5.36%)	18	4/131 (3.05%)	8	2/85 (2.35%)	2	3/30 (10.00%)	4
Hyperaesthesia ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	2/30 (6.67%)	2
Sciatica ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	2	2/30 (6.67%)	2
Psychiatric disorders
Anxiety ^† 1	15/261 (5.75%)	16	5/131 (3.82%)	6	5/85 (5.88%)	5	0/30 (0.00%)	0
Depression ^† 1	22/261 (8.43%)	31	3/131 (2.29%)	3	5/85 (5.88%)	7	3/30 (10.00%)	3
Insomnia ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	11/85 (12.94%)	13	3/30 (10.00%)	3
Renal and urinary disorders
Proteinuria ^† 1	99/261 (37.93%)	604	4/131 (3.05%)	5	26/85 (30.59%)	126	12/30 (40.00%)	24
Haematuria ^† 1	18/261 (6.90%)	22	3/131 (2.29%)	4	6/85 (7.06%)	9	0/30 (0.00%)	0
Dysuria ^† 1	15/261 (5.75%)	17	1/131 (0.76%)	1	0/85 (0.00%)	0	0/30 (0.00%)	0
Reproductive system and breast disorders
Pelvic pain ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	0/85 (0.00%)	0	3/30 (10.00%)	4
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain ^† 1	43/261 (16.48%)	86	2/131 (1.53%)	2	9/85 (10.59%)	13	4/30 (13.33%)	4
Dyspnoea ^† 1	47/261 (18.01%)	65	21/131 (16.03%)	29	16/85 (18.82%)	26	5/30 (16.67%)	5
Haemoptysis ^† 1	12/261 (4.60%)	17	12/131 (9.16%)	14	9/85 (10.59%)	10	3/30 (10.00%)	4
Epistaxis ^† 1	36/261 (13.79%)	58	1/131 (0.76%)	1	14/85 (16.47%)	20	5/30 (16.67%)	6
Cough ^† 1	77/261 (29.50%)	114	24/131 (18.32%)	36	23/85 (27.06%)	30	8/30 (26.67%)	13
Dysphonia ^† 1	87/261 (33.33%)	135	7/131 (5.34%)	8	33/85 (38.82%)	55	10/30 (33.33%)	13
Productive cough ^† 1	13/261 (4.98%)	23	8/131 (6.11%)	8	3/85 (3.53%)	3	2/30 (6.67%)	3
Dyspnoea exertional ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	2	2/30 (6.67%)	5
Skin and subcutaneous tissue disorders
Dermatitis acneiform ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	4/85 (4.71%)	5	2/30 (6.67%)	4
Alopecia ^† 1	34/261 (13.03%)	39	7/131 (5.34%)	7	9/85 (10.59%)	14	6/30 (20.00%)	8
Dry skin ^† 1	32/261 (12.26%)	35	8/131 (6.11%)	8	10/85 (11.76%)	11	2/30 (6.67%)	3
Rash ^† 1	55/261 (21.07%)	81	2/131 (1.53%)	4	14/85 (16.47%)	16	6/30 (20.00%)	8
Palmar-plantar erythrodysaesthesia syndrome ^† 1	86/261 (32.95%)	268	1/131 (0.76%)	1	24/85 (28.24%)	85	9/30 (30.00%)	44
Hyperkeratosis ^† 1	19/261 (7.28%)	36	2/131 (1.53%)	3	0/85 (0.00%)	0	0/30 (0.00%)	0
Pruritus ^† 1	19/261 (7.28%)	25	6/131 (4.58%)	6	0/85 (0.00%)	0	0/30 (0.00%)	0
Decubitus ulcer ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	5/85 (5.88%)	6	0/30 (0.00%)	0
Hyperhidrosis ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	2/85 (2.35%)	2	2/30 (6.67%)	2
Skin fissures ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	1/85 (1.18%)	1	2/30 (6.67%)	2
Vascular disorders
Hypotension ^† 1	0/261 (0.00%)	0	0/131 (0.00%)	0	8/85 (9.41%)	12	4/30 (13.33%)	5
Hypertension ^† 1	181/261 (69.35%)	720	19/131 (14.50%)	36	52/85 (61.18%)	84	21/30 (70.00%)	69
1 Term from vocabulary, MedDRA 18.0 † 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 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

Layout table for Results Point of Contact information

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):

Taylor MH, Takahashi S, Capdevila J, Tahara M, Leboulleux S, Kiyota N, Dutcus CE, Xie R, Robinson B, Sherman S, Habra MA, Elisei R, Wirth LJ. Correlation of Performance Status and Neutrophil-Lymphocyte Ratio with Efficacy in Radioiodine-Refractory Differentiated Thyroid Cancer Treated with Lenvatinib. Thyroid. 2021 Aug;31(8):1226-1234. doi: 10.1089/thy.2020.0779. Epub 2021 Apr 29.

Tahara M, Kiyota N, Hoff AO, Badiu C, Owonikoko TK, Dutcus CE, Suzuki T, Ren M, Wirth LJ. Impact of lung metastases on overall survival in the phase 3 SELECT study of lenvatinib in patients with radioiodine-refractory differentiated thyroid cancer. Eur J Cancer. 2021 Apr;147:51-57. doi: 10.1016/j.ejca.2020.12.032. Epub 2021 Feb 19.

Tahara M, Brose MS, Wirth LJ, Suzuki T, Miyagishi H, Fujino K, Dutcus CE, Gianoukakis A. Impact of dose interruption on the efficacy of lenvatinib in a phase 3 study in patients with radioiodine-refractory differentiated thyroid cancer. Eur J Cancer. 2019 Jan;106:61-68. doi: 10.1016/j.ejca.2018.10.002. Epub 2018 Nov 22.

Tahara M, Schlumberger M, Elisei R, Habra MA, Kiyota N, Paschke R, Dutcus CE, Hihara T, McGrath S, Matijevic M, Kadowaki T, Funahashi Y, Sherman SI. Exploratory analysis of biomarkers associated with clinical outcomes from the study of lenvatinib in differentiated cancer of the thyroid. Eur J Cancer. 2017 Apr;75:213-221. doi: 10.1016/j.ejca.2017.01.013. Epub 2017 Feb 24.

Robinson B, Schlumberger M, Wirth LJ, Dutcus CE, Song J, Taylor MH, Kim SB, Krzyzanowska MK, Capdevila J, Sherman SI, Tahara M. Characterization of Tumor Size Changes Over Time From the Phase 3 Study of Lenvatinib in Thyroid Cancer. J Clin Endocrinol Metab. 2016 Nov;101(11):4103-4109. doi: 10.1210/jc.2015-3989. Epub 2016 Aug 22.

Kiyota N, Schlumberger M, Muro K, Ando Y, Takahashi S, Kawai Y, Wirth L, Robinson B, Sherman S, Suzuki T, Fujino K, Gupta A, Hayato S, Tahara M. Subgroup analysis of Japanese patients in a phase 3 study of lenvatinib in radioiodine-refractory differentiated thyroid cancer. Cancer Sci. 2015 Dec;106(12):1714-21. doi: 10.1111/cas.12826. Epub 2015 Nov 2.

Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, Habra MA, Newbold K, Shah MH, Hoff AO, Gianoukakis AG, Kiyota N, Taylor MH, Kim SB, Krzyzanowska MK, Dutcus CE, de las Heras B, Zhu J, Sherman SI. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015 Feb 12;372(7):621-30. doi: 10.1056/NEJMoa1406470.

Layout table for additonal information

Responsible Party:	Eisai Inc.
ClinicalTrials.gov Identifier:	NCT01321554
Other Study ID Numbers:	E7080-G000-303 2010-023783-41 ( EudraCT Number )
First Submitted:	March 10, 2011
First Posted:	March 23, 2011
Results First Submitted:	March 13, 2015
Results First Posted:	December 12, 2016
Last Update Posted:	June 22, 2023

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