A Study to Evaluate the Effect of HER2 Activation on rhuMAb 2C4 (Pertuzumab) in Subjects With Advanced Ovarian Cancer

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00058552
• Collaborator: (none)
• Enrollment: 129
• Actual Duration (Months): 14

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if the study drug pertuzumab is effective in treating patients with advanced ovarian cancer that is refractory to, or has recurred following, prior chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer	Drug: Pertuzumab (rhuMAb 2C4)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 129 participants
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Open-label, Multicenter Study to Evaluate the Effect of Tumor-based HER2 Activation on the Efficacy of rhuMAb 2C4 (Pertuzumab) in Subjects With Advanced, Refractory or Recurrent Ovarian Cancer
• Actual Study Start Date: May 1, 2003
• Actual Primary Completion Date: Jul 1, 2004
• Actual Study Completion Date: Jul 1, 2004

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Best Overall Response of Complete Response (CR) or Partial Response (PR) Determined by Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 or Cancer Antigen 125 (CA-125) Changes [Screening and prior to infusion at Cycles 3, 5, 7, 9, 13, and 17 and at follow-up (30 days after the last dose of pertuzumab)]

   Response by tumor measurement occurred if there was documented and confirmed CR or PR determined by 2 consecutive investigator assessments that were at least 28 days apart. Response was assessed by either the RECIST v 1.1 or by CA-125 changes, based on measurable or non-measurable disease at baseline. Per RECIST v 1.1 (for measurable disease), CR: disappearance of all target and non-target lesions and normalization of tumor marker level; PR: at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Per CA-125 changes (for non-measurable disease), CR: decrease in the CA-125 to within the normal limits and less than (<) 40 international units per milliliter (IU/mL) and no clinical or radiological evidence of disease, PR: a greater than (>) 50 percent (%) decrease in CA-125 values from baseline, and no clinical or radiological evidence of new lesions.

Secondary Outcome Measures

1. Percentage of Participants With Disease Progression or Death (Progression Free Survival [PFS]) [Screening and prior to infusion at Cycles 3, 5, 7, 9, 13, and 17 and at follow-up (30 days after the last dose of pertuzumab)]

   PFS was defined as the time from the first day of study drug treatment to the time of documented disease progression or death, whichever came first. Participants who were lost to follow-up or who had not progressed at the time of study completion or early termination were censored at the date of last tumor assessment. The percentage of participants experiencing disease progression or death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100.

2. Median Time of PFS [Screening and prior to infusion at Cycles 3, 5, 7, 9, 13, and 17 and at follow-up (30 days after the last dose of pertuzumab)]

   PFS was defined as the time from the first day of study drug treatment to the time of documented disease progression or death, whichever came first. Participants who were lost to follow-up or who had not progressed at the time of study completion or early termination were censored at the date of last tumor assessment.

3. Duration of Response [Screening and prior to infusion at Cycles 3, 5, 7, 9, 13, and 17 and at follow-up (30 days after the last dose of pertuzumab)]

   Duration of response was defined as the time from the initial CR or PR to the time of disease progression.

4. Percentage of Participants Who Died [Days 1, 8, and 15 of Cycles 1 and 2, Day 1 of Cycles 3-17, follow-up (30 days after the last dose of pertuzumab) and then every 3 months until death or loss to follow-up (up to 5 years)]

   The percentage of participants experiencing death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100.

5. Overall Survival [Days 1, 8, and 15 of Cycles 1 and 2, Day 1 of Cycles 3-17, follow-up (30 days after the last dose of pertuzumab) and then every 3 months until death or loss to follow-up (up to 5 years)]

   Survival was the interval of time from date of first dose of study medication to date of death at any time. Participants who had not died were censored at the date of last contact when they were known to be alive.

6. Kaplan Meier Estimate of Percentage of Participants Who Were Free of Disease Progression at 3, 6, and 12 Months [3, 6, and 12 months]

   Per RECIST v 1.1, disease progression was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed informed consent

• Willingness to undergo tumor biopsy and disease that is amenable to biopsy (Cohort 1 only)

• Age >=18 years old

• Advanced, histologically documented carcinoma of the ovary

• Measurable disease with at least one lesion that can be accurately measured per RECIST in at least one dimension (longest dimension recorded). Each lesion must be >=20 mm when measured by conventional techniques, including palpation, plain X-ray, CT, and MRI, or >=10 mm when measured by spiral CT.

• Or, clinically or radiologically detectable disease (e.g., ascites, peritoneal deposits, mesenteric thickening or lesions that do not fulfill RECIST for measurable disease). In addition, the subject must have two consecutive pre-treatment CA 125 levels that are both greater than 2× the institutional upper limit of normal (ULN) and

=40 IU/mL, taken at least 1 week and not more than 3 months apart. The second of the two measurements of CA 125 level should not be drawn within 28 days following the screening biopsy. The later value must be within 2 weeks of starting rhuMAb 2C4 treatment.

• One or more prior platinum-based chemotherapeutic regimens for the management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound

• Life expectancy >=12 weeks

• ECOG performance status 0 or 1

• Use of an effective means of contraception (for women of childbearing potential)

• Granulocyte count >=1500/uL, platelet count of >=75,000/uL, and hemoglobin >=9 g/dL (hemoglobin may be supported by transfusion or erythropoietin or other approved hematopoietic growth factors; darbopoeitin [Aranesp] is permitted)

• Serum bilirubin <=1.5× the ULN and alkaline phosphatase, AST, and ALT <=2.5× ULN (ALT, AST, and alkaline phosphatase <=5× ULN for subjects with liver metastases)

• Serum creatinine <=1.5× ULN

• International normalized ratio (INR) <1.5 and activated partial thromboplastin time (aPTT) <1.5 ULN (except for subjects receiving warfarin)

Exclusion Criteria:

• Prior treatment with experimental anti-cancer agents within 4 weeks prior to Day 1 (the day on which the first rhuMAb 2C4 infusion is administered)

• Prior treatment with HER pathway inhibitors (e.g., Herceptin [Trastuzumab], Iressa [gefitinib], Tarceva [erlotinib hydrochloride], C225, CI1033, and TAK165)

• History or clinical evidence of central nervous system or brain metastases

• Ejection fraction, determined by ECHO, <50%

• Uncontrolled hypercalcemia (>11.5 mg/dL)

• Prior exposure to doxorubicin or liposomal doxorubicin >360 mg/m2 , mitoxantrone >120 mg/m2 , or idarubicin >90 mg/m2

• History of other malignancies within 5 years of Day 1 except for adequately treated carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, or basal or squamous cell skin cancer

• History of serious systemic disease, including active infection, uncontrolled hypertension (diastolic blood pressure >100 mmHg on two consecutive occasions), unstable angina, congestive heart failure, or myocardial infarction within 6 months prior to Day 1, or unstable symptomatic arrhythmia requiring medication (subjects with chronic atrial arrhythmia, i.e., atrial fibrillation, paroxysmal supraventricular tachycardia, or controlled hypertension are eligible)

• Ongoing liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis

• Known human immunodeficiency virus infection

• Pregnancy or lactation

• Major surgery or significant traumatic injury within 3 weeks prior to Day 1 with the exception of tumor biopsy for the purposes of the study

• Inability to comply with study and follow-up procedures

• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the subject at high risk from treatment complications

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Genentech, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT00058552
• Other Study ID Numbers: TOC2689g; NCT00070408
• First Posted: Apr 9, 2003
• Last Update Posted: Mar 8, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by Genentech, Inc.: Advanced, refractory, or recurrent ovarian cancer
• Additional relevant MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Pertuzumab

Study Results

Participant Flow

Arm/Group Title	Pertuzumab 420 mg	Pertuzumab 1050 mg
Arm/Group Description	Participants in this group received pertuzumab intravenous (IV) infusion at a loading dose of 840 milligrams (mg) for Cycle 1 (1 Cycle equals to [=] 3 Weeks), followed by 420 mg for Cycles 2 and beyond, up to 1 year (17 cycles) or until disease progression.	Participants in this group received 1050 mg of pertuzumab IV infusion at each cycle (1 Cycle = 3 Weeks) up to 1 year (17 cycles) or until disease progression.
Period Title: Overall Study
STARTED	65	64
COMPLETED	0	2
NOT COMPLETED	65	62

Baseline Characteristics

Arm/Group Title	Pertuzumab 420 mg	Pertuzumab 1050 mg	Total
Arm/Group Description	Participants in this group received pertuzumab IV infusion at a loading dose of 840 mg for Cycle 1 (1 Cycle = 3 Weeks), followed by 420 mg for Cycles 2 and beyond, up to 1 year (17 cycles) or until disease progression.	Participants in this group received 1050 mg of pertuzumab IV infusion at each cycle (1 Cycle = 3 Weeks) up to 1 year (17 cycles) or until disease progression.	Total of all reporting groups
Overall Participants	61	62	123
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.1 (9.9)	56.5 (11.2)	57.3 (10.5)
Sex: Female, Male (Count of Participants)
Female	61 100%	62 100%	123 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Best Overall Response of Complete Response (CR) or Partial Response (PR) Determined by Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 or Cancer Antigen 125 (CA-125) Changes
Description	Response by tumor measurement occurred if there was documented and confirmed CR or PR determined by 2 consecutive investigator assessments that were at least 28 days apart. Response was assessed by either the RECIST v 1.1 or by CA-125 changes, based on measurable or non-measurable disease at baseline. Per RECIST v 1.1 (for measurable disease), CR: disappearance of all target and non-target lesions and normalization of tumor marker level; PR: at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Per CA-125 changes (for non-measurable disease), CR: decrease in the CA-125 to within the normal limits and less than (<) 40 international units per milliliter (IU/mL) and no clinical or radiological evidence of disease, PR: a greater than (>) 50 percent (%) decrease in CA-125 values from baseline, and no clinical or radiological evidence of new lesions.
Time Frame	Screening and prior to infusion at Cycles 3, 5, 7, 9, 13, and 17 and at follow-up (30 days after the last dose of pertuzumab)

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population: All participants who received at least 1 dose of study drug and either underwent at least one postbaseline assessment of response or died within 30 days after the last study treatment before any evaluation of response.

Arm/Group Title	Pertuzumab 420 mg	Pertuzumab 1050 mg
Arm/Group Description	Participants in this group received pertuzumab IV infusion at a loading dose of 840 mg for Cycle 1 (1 Cycle = 3 Weeks), followed by 420 mg for Cycles 2 and beyond, up to 1 year (17 cycles) or until disease progression.	Participants in this group received 1050 mg of pertuzumab IV infusion at each cycle (1 Cycle = 3 Weeks) up to 1 year (17 cycles) or until disease progression.
Measure Participants	55	62
Number (95% Confidence Interval) [percentage of participants]	3.6 5.9%	4.8 7.7%

2. Secondary Outcome

Title	Percentage of Participants With Disease Progression or Death (Progression Free Survival [PFS])
Description	PFS was defined as the time from the first day of study drug treatment to the time of documented disease progression or death, whichever came first. Participants who were lost to follow-up or who had not progressed at the time of study completion or early termination were censored at the date of last tumor assessment. The percentage of participants experiencing disease progression or death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100.
Time Frame	Screening and prior to infusion at Cycles 3, 5, 7, 9, 13, and 17 and at follow-up (30 days after the last dose of pertuzumab)

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population. Six participants in pertuzumab 420 mg treatment arm and 15 participants in pertuzumab 1050 mg treatment arm were censored for this analysis.

Arm/Group Title	Pertuzumab 420 mg	Pertuzumab 1050 mg
Arm/Group Description	Participants in this group received pertuzumab IV infusion at a loading dose of 840 mg for Cycle 1 (1 Cycle = 3 Weeks), followed by 420 mg for Cycles 2 and beyond, up to 1 year (17 cycles) or until disease progression.	Participants in this group received 1050 mg of pertuzumab IV infusion at each cycle (1 Cycle = 3 Weeks) up to 1 year (17 cycles) or until disease progression.
Measure Participants	55	62
Number [percentage of participants]	89.1 146.1%	75.8 122.3%

3. Secondary Outcome

Title	Median Time of PFS
Description	PFS was defined as the time from the first day of study drug treatment to the time of documented disease progression or death, whichever came first. Participants who were lost to follow-up or who had not progressed at the time of study completion or early termination were censored at the date of last tumor assessment.
Time Frame	Screening and prior to infusion at Cycles 3, 5, 7, 9, 13, and 17 and at follow-up (30 days after the last dose of pertuzumab)

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population. Six participants in pertuzumab 420 mg treatment arm and 15 participants in pertuzumab 1050 mg treatment arm were censored for this analysis.

Arm/Group Title	Pertuzumab 420 mg	Pertuzumab 1050 mg
Arm/Group Description	Participants in this group received pertuzumab IV infusion at a loading dose of 840 mg for Cycle 1 (1 Cycle = 3 Weeks), followed by 420 mg for Cycles 2 and beyond, up to 1 year (17 cycles) or until disease progression.	Participants in this group received 1050 mg of pertuzumab IV infusion at each cycle (1 Cycle = 3 Weeks) up to 1 year (17 cycles) or until disease progression.
Measure Participants	55	62
Median (95% Confidence Interval) [weeks]	7.6	6.1

4. Secondary Outcome

Title	Duration of Response
Description	Duration of response was defined as the time from the initial CR or PR to the time of disease progression.
Time Frame	Screening and prior to infusion at Cycles 3, 5, 7, 9, 13, and 17 and at follow-up (30 days after the last dose of pertuzumab)

Outcome Measure Data

Analysis Population Description

Only responders (CR or PR) were included in the analysis.

Arm/Group Title	Pertuzumab 420 mg	Pertuzumab 1050 mg
Arm/Group Description	Participants in this group received pertuzumab IV infusion at a loading dose of 840 mg for Cycle 1 (1 Cycle = 3 Weeks), followed by 420 mg for Cycles 2 and beyond, up to 1 year (17 cycles) or until disease progression.	Participants in this group received 1050 mg of pertuzumab IV infusion at each cycle (1 Cycle = 3 Weeks) up to 1 year (17 cycles) or until disease progression.
Measure Participants	2	3
Median (95% Confidence Interval) [weeks]	18.6	21.1

5. Secondary Outcome

Title	Percentage of Participants Who Died
Description	The percentage of participants experiencing death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100.
Time Frame	Days 1, 8, and 15 of Cycles 1 and 2, Day 1 of Cycles 3-17, follow-up (30 days after the last dose of pertuzumab) and then every 3 months until death or loss to follow-up (up to 5 years)

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population.

Arm/Group Title	Pertuzumab 420 mg	Pertuzumab 1050 mg
Arm/Group Description	Participants in this group received pertuzumab IV infusion at a loading dose of 840 mg for Cycle 1 (1 Cycle = 3 Weeks), followed by 420 mg for Cycles 2 and beyond, up to 1 year (17 cycles) or until disease progression.	Participants in this group received 1050 mg of pertuzumab IV infusion at each cycle (1 Cycle = 3 Weeks) up to 1 year (17 cycles) or until disease progression.
Measure Participants	55	62
Number [percentage of participants]	69.1 113.3%	46.8 75.5%

6. Secondary Outcome

Title	Overall Survival
Description	Survival was the interval of time from date of first dose of study medication to date of death at any time. Participants who had not died were censored at the date of last contact when they were known to be alive.
Time Frame	Days 1, 8, and 15 of Cycles 1 and 2, Day 1 of Cycles 3-17, follow-up (30 days after the last dose of pertuzumab) and then every 3 months until death or loss to follow-up (up to 5 years)

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population. Seventeen participants in pertuzumab 420 mg arm and 33 participants in pertuzumab 1050 mg were censored for this analysis.

Arm/Group Title	Pertuzumab 420 mg	Pertuzumab 1050 mg
Arm/Group Description	Participants in this group received pertuzumab IV infusion at a loading dose of 840 mg for Cycle 1 (1 Cycle = 3 Weeks), followed by 420 mg for Cycles 2 and beyond, up to 1 year (17 cycles) or until disease progression.	Participants in this group received 1050 mg of pertuzumab IV infusion at each cycle (1 Cycle = 3 Weeks) up to 1 year (17 cycles) or until disease progression.
Measure Participants	55	62
Median (95% Confidence Interval) [weeks]	46.7	NA

7. Secondary Outcome

Title	Kaplan Meier Estimate of Percentage of Participants Who Were Free of Disease Progression at 3, 6, and 12 Months
Description	Per RECIST v 1.1, disease progression was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions.
Time Frame	3, 6, and 12 months

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population.

Arm/Group Title	Pertuzumab 420 mg	Pertuzumab 1050 mg
Arm/Group Description	Participants in this group received pertuzumab at a loading dose of 840 mg for Cycle 1, followed by 420 mg for Cycles 2 and beyond, up to 1 year (17 cycles) or until disease progression (1 Cycle = 3 Weeks).	Participants in this group received 1050 mg of pertuzumab at each cycle (1 Cycle = 3 Weeks) up to 1 year (17 cycles) or until disease progression.
Measure Participants	55	62
% of participants free from PD at 3 months	25.5 41.8%	24.2 39%
% of participants free from PD at 6 months	7.3 12%	6.5 10.5%
% of participants free from PD at 12 months	0.0 0%	0.0 0%

Adverse Events

Arm/Group Title	Pertuzumab 420 mg		Pertuzumab 1050 mg
Arm/Group Description	Participants in this group received pertuzumab IV infusion at a loading dose of 840 mg for Cycle 1 (1 Cycle = 3 Weeks), followed by 420 mg for Cycles 2 and beyond, up to 1 year (17 cycles) or until disease progression.		Participants in this group received 1050 mg of pertuzumab IV infusion at each cycle (1 Cycle = 3 Weeks) up to 1 year (17 cycles) or until disease progression.
All Cause Mortality
	Pertuzumab 420 mg		Pertuzumab 1050 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pertuzumab 420 mg		Pertuzumab 1050 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/61 (42.6%)		18/62 (29%)
Cardiac disorders
Atrial fibrillation	1/61 (1.6%)		0/62 (0%)
Cardiac tamponade	0/61 (0%)		1/62 (1.6%)
Endocarditis noninfective	1/61 (1.6%)		0/62 (0%)
Pericardial effusion	0/61 (0%)		1/62 (1.6%)
Gastrointestinal disorders
Small intestinal obstruction	8/61 (13.1%)		6/62 (9.7%)
Intestinal obstruction	2/61 (3.3%)		2/62 (3.2%)
Abdomial pain	2/61 (3.3%)		1/62 (1.6%)
Ascites	2/61 (3.3%)		0/62 (0%)
Diarrhoea	2/61 (3.3%)		0/62 (0%)
Vomiting	2/61 (3.3%)		0/62 (0%)
Nausea	1/61 (1.6%)		0/62 (0%)
General disorders
Asthenia	1/61 (1.6%)		0/62 (0%)
Hepatobiliary disorders
Hepatic function abnormal	1/61 (1.6%)		0/62 (0%)
Infections and infestations
Abdominal abscess	1/61 (1.6%)		0/62 (0%)
Influenza	1/61 (1.6%)		0/62 (0%)
Pneumonia	1/61 (1.6%)		0/62 (0%)
Injury, poisoning and procedural complications
Intestinal stoma complication	1/61 (1.6%)		0/62 (0%)
Investigations
Ejection fraction decreased	0/61 (0%)		1/62 (1.6%)
Metabolism and nutrition disorders
Dehydration	1/61 (1.6%)		2/62 (3.2%)
Hypercalcaemia	0/61 (0%)		1/62 (1.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant ascites	1/61 (1.6%)		0/62 (0%)
Malignant pleural effusion	1/61 (1.6%)		0/62 (0%)
Ovarian cancer	0/61 (0%)		1/62 (1.6%)
Renal and urinary disorders
Bladder pain	0/61 (0%)		1/62 (1.6%)
Bladder spasm	0/61 (0%)		1/62 (1.6%)
Obstructive uropathy	1/61 (1.6%)		0/62 (0%)
Renal failure acute	0/61 (0%)		1/62 (1.6%)
Ureteric obstruction	0/61 (0%)		1/62 (1.6%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/61 (1.6%)		2/62 (3.2%)
Aspiration	2/61 (3.3%)		0/62 (0%)
Pulmonary embolism	0/61 (0%)		1/62 (1.6%)
Vascular disorders
Thrombosis	1/61 (1.6%)		0/62 (0%)
Other (Not Including Serious) Adverse Events
	Pertuzumab 420 mg		Pertuzumab 1050 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/61 (100%)		60/62 (96.8%)
Blood and lymphatic system disorders
Anaemia	9/61 (14.8%)		10/62 (16.1%)
Cardiac disorders
Tachycardia	5/61 (8.2%)		2/62 (3.2%)
Gastrointestinal disorders
Diarrhoea	40/61 (65.6%)		45/62 (72.6%)
Abdominal pain	25/61 (41%)		20/62 (32.3%)
Nausea	22/61 (36.1%)		22/62 (35.5%)
Vomiting	22/61 (36.1%)		17/62 (27.4%)
Constipation	17/61 (27.9%)		11/62 (17.7%)
Abdominal distention	13/61 (21.3%)		8/62 (12.9%)
Dyspepsia	6/61 (9.8%)		13/62 (21%)
Stomatitis	4/61 (6.6%)		8/62 (12.9%)
Abdominal pain upper	7/61 (11.5%)		4/62 (6.5%)
Ascites	5/61 (8.2%)		3/62 (4.8%)
Abdominal discomfort	2/61 (3.3%)		5/62 (8.1%)
Haematochezia	4/61 (6.6%)		2/62 (3.2%)
General disorders
Fatigue	21/61 (34.4%)		33/62 (53.2%)
Odema peripheral	13/61 (21.3%)		14/62 (22.6%)
Pyrexia	7/61 (11.5%)		4/62 (6.5%)
Asthenia	8/61 (13.1%)		2/62 (3.2%)
Pain	5/61 (8.2%)		3/62 (4.8%)
Chills	4/61 (6.6%)		3/62 (4.8%)
Early satiety	2/61 (3.3%)		4/62 (6.5%)
Oedema	4/61 (6.6%)		1/62 (1.6%)
Mucosal inflammation	4/61 (6.6%)		0/62 (0%)
Infections and infestations
Urinary tract infection	6/61 (9.8%)		8/62 (12.9%)
Sinusitis	4/61 (6.6%)		4/62 (6.5%)
Upper respiratory tract infection	4/61 (6.6%)		3/62 (4.8%)
Rhinitis	5/61 (8.2%)		1/62 (1.6%)
Investigations
Ejection fraction decreased	11/61 (18%)		13/62 (21%)
Weight decreased	10/61 (16.4%)		9/62 (14.5%)
Haemoglobin decreased	6/61 (9.8%)		4/62 (6.5%)
Metabolism and nutrition disorders
Anorexia	15/61 (24.6%)		12/62 (19.4%)
Dehydration	12/61 (19.7%)		7/62 (11.3%)
Hypokalaemia	6/61 (9.8%)		9/62 (14.5%)
Hypoalbuminaemia	5/61 (8.2%)		5/62 (8.1%)
Decreased appetite	5/61 (8.2%)		3/62 (4.8%)
Musculoskeletal and connective tissue disorders
Back pain	8/61 (13.1%)		4/62 (6.5%)
Arthralgia	3/61 (4.9%)		7/62 (11.3%)
Muscle spasms	0/61 (0%)		9/62 (14.5%)
Myalgia	4/61 (6.6%)		2/62 (3.2%)
Nervous system disorders
Headache	10/61 (16.4%)		6/62 (9.7%)
Dizziness	7/61 (11.5%)		6/62 (9.7%)
Dysgeusia	4/61 (6.6%)		2/62 (3.2%)
Paraesthesia	4/61 (6.6%)		2/62 (3.2%)
Hypoaesthesia	0/61 (0%)		4/62 (6.5%)
Psychiatric disorders
Insomnia	10/61 (16.4%)		5/62 (8.1%)
Anxiety	6/61 (9.8%)		5/62 (8.1%)
Depression	6/61 (9.8%)		2/62 (3.2%)
Renal and urinary disorders
Dysuria	7/61 (11.5%)		6/62 (9.7%)
Haematuria	5/61 (8.2%)		2/62 (3.2%)
Respiratory, thoracic and mediastinal disorders
Cough	9/61 (14.8%)		11/62 (17.7%)
Dyspnoea	10/61 (16.4%)		10/62 (16.1%)
Pharyngolaryngeal pain	3/61 (4.9%)		5/62 (8.1%)
Pleural effusion	6/61 (9.8%)		2/62 (3.2%)
Epistaxis	3/61 (4.9%)		4/62 (6.5%)
Nasal congestion	4/61 (6.6%)		1/62 (1.6%)
Skin and subcutaneous tissue disorders
Rash	14/61 (23%)		16/62 (25.8%)
Pruritis	8/61 (13.1%)		7/62 (11.3%)
Dry skin	5/61 (8.2%)		7/62 (11.3%)
Erythema	4/61 (6.6%)		6/62 (9.7%)
Rash erythematous	2/61 (3.3%)		4/62 (6.5%)
Nail disorder	4/61 (6.6%)		1/62 (1.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.