Phase II Study of Best Support Care (BSC) Plus ZD6474(Vandetanib) in Patients With Inoperable Hepatocellular Carcinoma (HCC)

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00508001
• Collaborator: (none)
• Enrollment: 67
• Locations: 3
• Arms: 3
• Duration (Months): 23
• Patients Per Site: 22.3
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

This is a multi-centre, phase II study to assess the efficacy and safety of ZD6474 in patients with Child-Pugh class A, inoperable HCC. This study comprises 2 phases, the primary treatment phase and the secondary treatment phase. The primary treatment phase is a randomised, double-blind, parallel-group phase II study to assess the efficacy and safety of ZD6474 300 mg plus best support care (BSC), ZD6474 100 mg plus BSC, and placebo plus BSC. The secondary treatment phase is an open-label expanded access program of ZD6474. In the primary treatment phase, patients will be randomised in a 1:1:1 ratio to receive ZD6474 300 mg plus BSC, ZD6474 100 mg plus BSC, or placebo plus BSC, respectively. Randomisation will be stratified on the basis of Cancer of the Liver Italian Programme (CLIP) tumour staging (CLIP score 0-2 versus 3-4). The primary treatment will continue until objective disease progression, according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria, or until patients meet any other withdrawal or discontinuation criteria.The primary endpoint is tumour stabilisation rate, and the secondary endpoints are objective response rate, progression-free survival, and overall survival. The purpose of the secondary treatment phase is to expand the access of ZD6474 so that every patient who is enrolled into this study can have the chance to receive the active medicine.Once an individual patient has progressive disease in the primary treatment phase, the blind will be broken for this patient. If this patient is in the ZD6474 100 mg arm or placebo arm, the patient will be offered the secondary treatment with ZD6474 300 mg per day. If this patient is randomised to the ZD6474 300 mg arm, the study medication will be discontinued unless the patient wishes to remain the treatment, and the patient is to be followed up for survival.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Hepatocellular	Drug: Vandetanib; Drug: Vandetanib; Drug: Best Supportive Care	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 67 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomised, Double-blind, Parallel Group, Multi-centre, Phase II Study to Assess the Efficacy and Safety of Best Support Care (BSC) Plus ZD6474(Vandetanib) 300 mg, BSC Plus ZD6474(Vandetanib) 100 mg, and BSC Plus Placebo in Patients With Inoperable Hepatocellular Carcinoma (HCC)
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Jun 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 1 Best Supportive Care + Placebo	Drug: Best Supportive Care; Placebo + Best Supportive Care
Experimental: 2 Best Supportive Care + ZD6474 100 mg	Drug: Vandetanib; ZD6474 100 mg; Other Names: Zactima ZD6474
Experimental: 3 Best Supportive Care + ZD6474 300 mg	Drug: Vandetanib; ZD6474 300mg; Other Names: Zactima ZD6474

Outcome Measures

Primary Outcome Measures

1. Tumour Stabilisation Rate [After 16 weeks of treatment.]

   Tumour stabilisation rate calculated as percentage of patients with best objective tumour response (Complete Response, Partial Response or Stable Disease) for >=16 weeks based on Response Evaluation Criteria in Solid Tumours (RECIST). Complete Response - Disappearance of all target lesions; Partial Response - >=30% decrease in the sum of longest diameter of target lesions; Progressive Disease - >=20% increase in the sum of longest diameter of target lesions; Stable Disease - neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Secondary Outcome Measures

1. Objective Response Rate [After 16 weeks of treatment.]

   Objective Response rate defined as percentage of patients with Complete Response [CR] or Partial Response [PR] based on Response Evaluation Criteria in Solid Tumours (RECIST). Partial response (PR) must have ≥ 30% decrease in the sum of longest diameter of all target lesions as assessed by Magnetic Resonance Imaging (MRI). Complete response (CR) must have disappearance of all target and non-target lesions as assessed by MRI.

2. Progression-free Survival [from the date of randomisation to the date of documented disease progression or death for any cause]

   Progression-free survival defined as the period from date of randomization(start of treatment) to date of disease progression or death.

3. Overall Survival [assessed up to 360 days]

   Overall survival defined as the time from randomization (start of treatment) until death from any cause.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Able to understand and provide informed consent

• Histologically diagnosed HCC, OR clinically diagnosed HCC for patients with difficulty in obtaining histological diagnosis. A clinically diagnosed HCC should fulfil ALL the criteria below.

• Chronic hepatitis B or C and/or evidence of liver cirrhosis

• Presence of hepatic tumour(s) with image findings (sonography, CT scan, or MRI scan) compatible with HCC, and no evidence of other gastrointestinal tumours

• A persistent elevation of serum a-fetoprotein level >= 400 ng/ml without any evidence of an existing a-fetoprotein-secreting germ cell tumour

• Locally advanced (for example, portal vein invasion, multiple nodules, or nodules in both lobes) or metastatic HCC with at least one measurable lesion by RECIST criteria that meets ANY the criteria below:

• HCC not suitable to receive local therapy, including surgical resection, percutaneous ethanol injection (PEI), or transarterial chemo-embolization (TACE)

• Disease recurred or was refractory to previous local therapy

• Patients refused local therapy

• At least one measurable lesion by RECIST criteria. Tumour lesions treated previously with local radiotherapy, percutaneous ethanol injection, radiofrequency ablation, or transarterial embolization are NOT considered measurable.

• If they completed percutaneous ethanol injection, radiofrequency ablation, transarterial embolization, or cryotherapy at least 4 weeks prior to enrollment, patients must have subsequent progression or recurrence with at least one new measurable lesion that has not been treated with any local procedure.

• Karnofsky performance status >= 70

• Life expectancy >= 2 months

• Child-Pugh class A liver function

• Adequate bone marrow reserve, defined as white blood cell count >= 3,000/ml, and platelet count >= 75,000/ml

• Liver transaminases (AST and ALT) <= 5 times upper normal limits (UNLs); serum bilirubin <= 1.5 times UNL <= 2 mg/dL

• Serum creatinine <= 1.5 times UNL

• Negative pregnancy test for women of childbearing potential. Patients of childbearing age as well as his/her partner must use effective contraception during the study period unless they are surgically sterile or one year post-menopausal

Exclusion Criteria:

• Receiving concurrent anti-cancer therapy for HCC, which includes local therapy, chemotherapy, or other experimental therapy

• Prior systemic cytotoxic chemotherapy

• Prior transarterial chemo-embolization (TACE) or hepatic arterial infusion (HAI), with any of the following conditions for those patients who have any target lesions in the liver:

• More than 5 TACE or HAI sessions undergone prior to enrollment

• The cumulative doses of doxorubicin > 120 mg/m2, mitomycin-C > 24 mg/m2, cisplatin > 120 mg/m2, or 5-fluorouracil > 2400 mg/m2

• Details of the TACE or HAI regimens are not available in the chart

• (Note: The number of sessions of prior TACE or HAI will not be limited for patients who have no target lesion in the liver).

• Local treatment including radiotherapy (except palliative radiotherapy), percutaneous ethanol injection, radiofrequency ablation, transarterial embolization, or cryotherapy completed within 4 weeks prior to enrollment

• Prior therapy targeting VEGF or EGF signalling pathways, including but not limited to bevacizumab, cetuximab, gefitinib, erlotinib, or sorafenib.

• Prior thalidomide therapy is not allowed but for patients who stop thalidomide due to intolerability and meet either one of following condition can be included:

• Patients who took thalidomide for no more than <= 3 days before enrolment

• Patients who took thalidomide for > 3 days but <= 14 days and are confirmed clinically not responding to thalidomide. 14 days washout period is needed before enrolment.

• Laboratory results:

• Serum potassium less than 4.0 mmol/L despite supplementation

• Serum calcium (ionized or adjusted for albumin) or magnesium out of their normal ranges despite supplementation

• Esophagogastroduodenoscopy reveals lesions that are considered high risk of gastrointestinal bleeding

• Brain or leptomeningeal metastases

• History of HCC tumour rupture

• History of upper gastrointestinal bleeding within 1 year

• Current or recent (within 10 days prior to enrollment) users of full-dose oral or parenteral anti-coagulants

• Surgical procedures, open biopsy, or significant traumatic injury within 28 days prior to enrollment. Fine-needle aspiration, core biopsy, and central venous line placement must be done at least 7 days prior to enrollment. Incompletely healed surgical incision prior to enrollment.

• Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardize compliance with the protocol.

• Clinically significant cardiac event such as myocardial infarction; New York Heart Association classification of heart disease > 2 within 3 months before entry; or other cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia.

• History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation), which is symptomatic, requires treatment (CTCAE grade 3), or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, if controlled on medication, will not be excluded.

• Previous history of QTc prolongation as a result of therapy with other medication that required discontinuation of that medication.

• Congenital long QT syndrome, or first-degree relative with unexplained sudden death under 40 years of age

• Presence of left bundle branch block

• QTc with Bazett's correction that is unmeasurable, or >= 480 msec on screening ECG

• Use of any concomitant medication that are generally accepted by authorities to have a risk of causing Torsades de Pointes within 2 weeks before enrollment (use of the concomitant medication that may be associated with Torsades de Pointes but lack substantial evidence of causing Torsades de Pointes is allowed, but the screening QTc must be less then 460 msec, and an additional ECG is required within the first 24 hours after the first dose of study medication is required).

• Use of any concomitant medication that induce CYP3A4 activity within 2 weeks before enrollment

• Use of interferon within 3 months before enrollment

• Hypertension not well controlled by medical therapy (systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg)

• Currently active diarrhea that may affect the ability of the patient to absorb the ZD6474 or diarrhea due to intolerability

• Current pregnancy or breast-feeding

• Other previous or current malignancies within the last 5 years, with the exception of adequately treated cervical carcinoma in situ and basal cell or squamous cell carcinoma of the skin

• Receipt of any investigational agents within 30 days prior to commencing protocol treatment

• Any unresolved toxicity greater than CTC grade 2 from previous anti-cancer therapy

• Known hypersensitivity to ZD6474 or any of its excipients

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Tainan		Taiwan
2	Research Site	Taipei		Taiwan
3	Research Site	Taoyuan		Taiwan

Sponsors and Collaborators

• Genzyme, a Sanofi Company

Investigators

• Study Director: Study Director Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT00508001
• Other Study ID Numbers: D4200C00072
• First Posted: Jul 27, 2007
• Last Update Posted: Oct 10, 2016
• Last Verified: Aug 1, 2016

• Keywords provided by Genzyme, a Sanofi Company: Hepatocellular carcinoma; Advanced solid, malignant tumour
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular

Study Results

Participant Flow

Recruitment Details	78 patients were recruited at medical clinic
Pre-assignment Detail	11 patients were screening failure due to inclusion criteria or exclusion criteria is not fulfilled

Arm/Group Title	ZD6474 300	ZD6474 100	Placebo
Arm/Group Description	ZD6474 (Vandetanib) 300 mg ( one tablet per day, orally). plus Best Support Care	ZD6474 (Vandetanib) 100 mg (one tablet per day, orally). plus Best Support Care	Placebo plus Best Support Care
Period Title: Overall Study
STARTED	19	25	23
Secondary Treatment Phase	0	13	16
COMPLETED	0	13	16
NOT COMPLETED	19	12	7

Baseline Characteristics

Arm/Group Title	ZD6474 300	ZD6474 100	Placebo	Total
Arm/Group Description	ZD6474 (Vandetanib) 300 mg ( one tablet per day, orally). plus Best Support Care	ZD6474 (Vandetanib) 100 mg (one tablet per day, orally). plus Best Support Care	Placebo plus Best Support Care	Total of all reporting groups
Overall Participants	19	25	23	67
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.6 (13.48)	61.2 (13.36)	57.3 (12.62)	58.37 (13.27)
Sex: Female, Male (Count of Participants)
Female	18 94.7%	17 68%	20 87%	55 82.1%
Male	1 5.3%	8 32%	3 13%	12 17.9%
Child-Pugh Score (Number) [Number]
Child-Pugh of 5	13 68.4%	19 76%	17 73.9%	49 73.1%
Child-Pugh of 6	6 31.6%	6 24%	6 26.1%	18 26.9%
CLIP Score (Number) [Number]
CLIP 0	2 10.5%	1 4%	0 0%	3 4.5%
CLIP 1	5 26.3%	5 20%	3 13%	13 19.4%
CLIP 2	2 10.5%	5 20%	8 34.8%	15 22.4%
CLIP 3	4 21.1%	8 32%	6 26.1%	18 26.9%
CLIP 4	6 31.6%	6 24%	6 26.1%	18 26.9%

Outcome Measures

1. Primary Outcome

Title	Tumour Stabilisation Rate
Description	Tumour stabilisation rate calculated as percentage of patients with best objective tumour response (Complete Response, Partial Response or Stable Disease) for >=16 weeks based on Response Evaluation Criteria in Solid Tumours (RECIST). Complete Response - Disappearance of all target lesions; Partial Response - >=30% decrease in the sum of longest diameter of target lesions; Progressive Disease - >=20% increase in the sum of longest diameter of target lesions; Stable Disease - neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time Frame	After 16 weeks of treatment.

Outcome Measure Data

Analysis Population Description

The analysis has been performed in the Intent-To-Treat (ITT) population.

Arm/Group Title	ZD6474 300	ZD6474 100	Placebo
Arm/Group Description	ZD6474 (Vandetanib) 300 mg ( one tablet per day, orally). plus Best Support Care	ZD6474 (Vandetanib) 100 mg (one tablet per day, orally). plus Best Support Care	Placebo plus Best Support Care
Measure Participants	19	25	23
Number [percentage of patients]	5.3	16.0	8.7

2. Secondary Outcome

Title	Objective Response Rate
Description	Objective Response rate defined as percentage of patients with Complete Response [CR] or Partial Response [PR] based on Response Evaluation Criteria in Solid Tumours (RECIST). Partial response (PR) must have ≥ 30% decrease in the sum of longest diameter of all target lesions as assessed by Magnetic Resonance Imaging (MRI). Complete response (CR) must have disappearance of all target and non-target lesions as assessed by MRI.
Time Frame	After 16 weeks of treatment.

Outcome Measure Data

Analysis Population Description

The analysis has been performed in the Intent-To-Treat (ITT) population.

Arm/Group Title	ZD6474 300	ZD6474 100	Placebo
Arm/Group Description	ZD6474 (Vandetanib) 300 mg ( one tablet per day, orally). plus Best Support Care	ZD6474 (Vandetanib) 100 mg (one tablet per day, orally). plus Best Support Care	Placebo plus Best Support Care
Measure Participants	19	25	23
Number [percentage of patients]	0	0	0

3. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival defined as the period from date of randomization(start of treatment) to date of disease progression or death.
Time Frame	from the date of randomisation to the date of documented disease progression or death for any cause

Outcome Measure Data

Analysis Population Description

The analysis has been performed in the Intent-To-Treat (ITT) population.

Arm/Group Title	ZD6474 300	ZD6474 100	Placebo
Arm/Group Description	ZD6474 (Vandetanib) 300 mg ( one tablet per day, orally). plus Best Support Care	ZD6474 (Vandetanib) 100 mg (one tablet per day, orally). plus Best Support Care	Placebo plus Best Support Care
Measure Participants	19	25	23
Mean (95% Confidence Interval) [Days]	32 (29)	53 (29)	29 (28)

4. Secondary Outcome

Title	Overall Survival
Description	Overall survival defined as the time from randomization (start of treatment) until death from any cause.
Time Frame	assessed up to 360 days

Outcome Measure Data

Analysis Population Description

The analysis performed in the intent-To-Treat population.

Arm/Group Title	ZD6474 300	ZD6474 100	Placebo
Arm/Group Description	ZD6474 (Vandetanib) 300 mg ( one tablet per day, orally). plus Best Support Care	ZD6474 (Vandetanib) 100 mg (one tablet per day, orally). plus Best Support Care	Placebo plus Best Support Care
Measure Participants	19	25	23
Median (95% Confidence Interval) [Days]	181	175	130

Adverse Events

Arm/Group Title	ZD6474 300		ZD6474 100		Placebo
Arm/Group Description	ZD6474 (Vandetanib) 300 mg ( one tablet per day, orally). plus Best Support Care		ZD6474 (Vandetanib) 100 mg (one tablet per day, orally). plus Best Support Care		Placebo plus Best Support Care
All Cause Mortality
	ZD6474 300		ZD6474 100		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	ZD6474 300		ZD6474 100		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/19 (31.6%)		4/25 (16%)		4/23 (17.4%)
Cardiac disorders
Myocardial Ischaemia	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Gastrointestinal disorders
Gastrointestinal Haemorrhage	2/19 (10.5%)		0/25 (0%)		0/23 (0%)
Abdominal Pain	0/19 (0%)		1/25 (4%)		0/23 (0%)
Oesophageal Varices Haemorrhage	0/19 (0%)		0/25 (0%)		1/23 (4.3%)
Upper Gastrointestinal Haemorrhage	1/19 (5.3%)		0/25 (0%)		1/23 (4.3%)
Vomiting	0/19 (0%)		1/25 (4%)		0/23 (0%)
General disorders
Mucosal Inflammation	0/19 (0%)		1/25 (4%)		0/23 (0%)
Pyrexia	0/19 (0%)		1/25 (4%)		0/23 (0%)
Hepatobiliary disorders
Hepatic Failure	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Infections and infestations
Cellulitis	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Pneumonia	0/19 (0%)		1/25 (4%)		0/23 (0%)
Injury, poisoning and procedural complications
Fracture	0/19 (0%)		0/25 (0%)		1/23 (4.3%)
Weight Decreased	0/19 (0%)		0/25 (0%)		1/23 (4.3%)
Psychiatric disorders
Agitation	0/19 (0%)		1/25 (4%)		0/23 (0%)
Renal and urinary disorders
Renal Failure Acute	0/19 (0%)		0/25 (0%)		1/23 (4.3%)
Skin and subcutaneous tissue disorders
Stevens-Johnson Syndrome	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Vascular disorders
Hypertension	0/19 (0%)		1/25 (4%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	ZD6474 300		ZD6474 100		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/19 (94.7%)		24/25 (96%)		21/23 (91.3%)
Blood and lymphatic system disorders
Anaemia	0/19 (0%)		0/25 (0%)		2/23 (8.7%)
Deficiency Anaemia	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Leukocytosis	1/19 (5.3%)		1/25 (4%)		1/23 (4.3%)
Cardiac disorders
Tachycardia	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Ear and labyrinth disorders
Tinnitus	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Eye disorders
Vision Blurred	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Gastrointestinal disorders
Diarrhoea	8/19 (42.1%)		9/25 (36%)		7/23 (30.4%)
Constipation	2/19 (10.5%)		3/25 (12%)		5/23 (21.7%)
Vomiting	2/19 (10.5%)		3/25 (12%)		5/23 (21.7%)
Nausea	0/19 (0%)		3/25 (12%)		3/23 (13%)
Abdominal Distension	2/19 (10.5%)		0/25 (0%)		0/23 (0%)
Abdominal Pain Upper	1/19 (5.3%)		2/25 (8%)		2/23 (8.7%)
Dyspepsia	0/19 (0%)		2/25 (8%)		2/23 (8.7%)
Gastric Ulcer	2/19 (10.5%)		0/25 (0%)		0/23 (0%)
Mouth Ulceration	2/19 (10.5%)		0/25 (0%)		0/23 (0%)
Periodontitis	0/19 (0%)		2/25 (8%)		0/23 (0%)
Anal Fissure	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Dry Mouth	1/19 (5.3%)		1/25 (4%)		0/23 (0%)
Duodenitis	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Frequent Bowel Movements	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Gastrointestinal Disorder	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Haemorrhoidal Haemorrhage	2/19 (10.5%)		0/25 (0%)		0/23 (0%)
Haemorrhoids	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Irritable Bowel Syndrome	1/19 (5.3%)		0/25 (0%)		1/23 (4.3%)
Lip Ulceration	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Oral Pain	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Peptic Ulcer	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Rectal Tenesmus	1/19 (5.3%)		0/25 (0%)		1/23 (4.3%)
Stomatitis	1/19 (5.3%)		1/25 (4%)		0/23 (0%)
General disorders
Fatigue	1/19 (5.3%)		3/25 (12%)		1/23 (4.3%)
Oedema Peripheral	1/19 (5.3%)		1/25 (4%)		3/23 (13%)
Pyrexia	2/19 (10.5%)		4/25 (16%)		3/23 (13%)
Mucosal Inflammation	1/19 (5.3%)		3/25 (12%)		0/23 (0%)
Malaise	1/19 (5.3%)		1/25 (4%)		1/23 (4.3%)
Infections and infestations
Upper Respiratory Tract Infection	1/19 (5.3%)		4/25 (16%)		2/23 (8.7%)
Bronchitis	1/19 (5.3%)		2/25 (8%)		0/23 (0%)
Folliculitis	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Injury, poisoning and procedural complications
Post Procedural Complication	0/19 (0%)		0/25 (0%)		2/23 (8.7%)
Limb Injury	1/19 (5.3%)		1/25 (4%)		0/23 (0%)
Wound	1/19 (5.3%)		0/25 (0%)		1/23 (4.3%)
Electrocardiogram Qt Prolonged	2/19 (10.5%)		2/25 (8%)		1/23 (4.3%)
Weight Decreased	1/19 (5.3%)		1/25 (4%)		3/23 (13%)
Aspartate Aminotransferase Increased	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Metabolism and nutrition disorders
Decreased Appetite	4/19 (21.1%)		3/25 (12%)		6/23 (26.1%)
Hyperkalaemia	2/19 (10.5%)		0/25 (0%)		1/23 (4.3%)
Hypoglycaemia	0/19 (0%)		2/25 (8%)		0/23 (0%)
Hypomagnesaemia	0/19 (0%)		2/25 (8%)		0/23 (0%)
Hyperglycaemia	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Hyponatraemia	1/19 (5.3%)		0/25 (0%)		1/23 (4.3%)
Musculoskeletal and connective tissue disorders
Back Pain	0/19 (0%)		1/25 (4%)		2/23 (8.7%)
Musculoskeletal Pain	1/19 (5.3%)		2/25 (8%)		0/23 (0%)
Neck Pain	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Osteoarthritis	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Nervous system disorders
Dizziness	2/19 (10.5%)		1/25 (4%)		5/23 (21.7%)
Headache	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Poor Quality Sleep	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Psychiatric disorders
Insomnia	3/19 (15.8%)		4/25 (16%)		5/23 (21.7%)
Anxiety	1/19 (5.3%)		0/25 (0%)		2/23 (8.7%)
Renal and urinary disorders
Nocturia	0/19 (0%)		0/25 (0%)		3/23 (13%)
Dysuria	1/19 (5.3%)		1/25 (4%)		1/23 (4.3%)
Proteinuria	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Reproductive system and breast disorders
Scrotal Ulcer	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/19 (5.3%)		4/25 (16%)		3/23 (13%)
Nasal Congestion	0/19 (0%)		0/25 (0%)		2/23 (8.7%)
Rhinorrhoea	1/19 (5.3%)		0/25 (0%)		2/23 (8.7%)
Dyspnoea	1/19 (5.3%)		1/25 (4%)		0/23 (0%)
Hiccups	1/19 (5.3%)		0/25 (0%)		1/23 (4.3%)
Skin and subcutaneous tissue disorders
Rash	9/19 (47.4%)		6/25 (24%)		6/23 (26.1%)
Pruritus	3/19 (15.8%)		5/25 (20%)		2/23 (8.7%)
Acne	4/19 (21.1%)		4/25 (16%)		4/23 (17.4%)
Photosensitivity Reaction	1/19 (5.3%)		3/25 (12%)		0/23 (0%)
Rash Pruritic	0/19 (0%)		2/25 (8%)		0/23 (0%)
Dermatitis Contact	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Dry Skin	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Erythema	1/19 (5.3%)		1/25 (4%)		0/23 (0%)
Rash Erythematous	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Rash Macular	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Skin Plaque	1/19 (5.3%)		0/25 (0%)		0/23 (0%)
Vascular disorders
Hypertension	2/19 (10.5%)		5/25 (20%)		1/23 (4.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.