Study of the Effect of Intravenous AVE0005 (VEGF Trap) in Advanced Ovarian Cancer Patients With Recurrent Symptomatic Malignant Ascites

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00327444
• Collaborator: Regeneron Pharmaceuticals (Industry)
• Enrollment: 58
• Locations: 9
• Arms: 2
• Duration (Months): 39
• Patients Per Site: 6.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study was designed to characterize the effect of aflibercept in participants with advanced chemoresistant ovarian cancer.

Primary objective: Compare the effect of aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®) to placebo treatment on repeat paracentesis in symptomatic malignant ascites in participants with advanced ovarian cancer

Secondary objectives: Safety, tolerability, paracentesis-related parameters, participant-reported outcome.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Neoplasms; Ascites	Drug: aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®); Drug: Placebo; Drug: aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)	Phase 2/Phase 3

Detailed Description

The study included:

• A Thirty (30)-day screening phase

• The double blind treatment period for a minimum of 60 days. Day 1 of the double-blind treatment period was defined as the date of the qualifying paracentesis (ie, withdrawal of >= 1 Liter of ascitic fluid). Participants were randomized after adequate recovery from the qualifying paracentesis (The first dose was administered on Day 1 or Day 2).

• The optional open-label extension (until treatment discontinuation criteria were met)

• A posttreatment follow-up phase lasting 60 days.

Criteria for discontinuation included:

1. Participant or his legally authorized representative request discontinuation

2. In the Investigator's opinion, continuation of treatment would be detrimental to the participant's well being, such as disease progression, unacceptable toxicity, noncompliance, or logistical considerations

3. Sponsor request

4. Intercurrent illness that prevented further administration of investigational product(IP)

5. More than 2 IP dose reductions

6. Unacceptable adverse events (AE) not manageable by symptomatic therapy, dose delay, or dose modification

7. Arterial thromboembolic events, including cerebrovascular accidents, myocardial infarctions, transient ischemic attacks, new onset or worsening of preexisting angina

8. Radiographic evidence of intestinal obstruction (for example, dilated loops of bowel accompanied by air-fluid levels) or gastrointestinal perforation (for example, presence of extraluminal gas) requiring surgical intervention

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-arm Study of the Effect of Intravenous Aflibercept Administered Every 2 Weeks in Advanced Ovarian Cancer Patients With Recurrent Symptomatic Malignant Ascites
• Study Start Date: Jul 1, 2006
• Actual Primary Completion Date: Oct 1, 2009
• Actual Study Completion Date: Oct 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants with advanced ovarian cancer administered placebo in the double-blind (DB) period. In the open-label (OL) period, participants had the option to receive aflibercept or be withdrawn from the study.	Drug: Placebo; Placebo was administered intravenously (IV) over 1 hour once every 2 weeks in the DB period.; Drug: aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®); 4.0 mg/kg aflibercept was administered intravenously (IV) over 1 hour once every 2 weeks in the OL period.
Experimental: Aflibercept Participants with advanced ovarian cancer administered aflibercept in the double-blind (DB) period. In the open-label (OL) period, participants had the option to continue to receive aflibercept or be withdrawn from the study.	Drug: aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®); 4.0 mg/kg aflibercept was administered intravenously (IV) over 1 hour once every 2 weeks in the DB period.; Drug: aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®); 4.0 mg/kg aflibercept was administered intravenously (IV) over 1 hour once every 2 weeks in the OL period.

Outcome Measures

Primary Outcome Measures

1. Time to Repeat Paracentesis (TRP) [From Day 1 up to 6 months from randomization]

   TRP was defined as the number of days between the date of randomization and the date of the first post-randomization paracentesis. For participants who did not undergo a postrandomization paracentesis on study, TRP was calculated from randomization to the end of the double-blind treatment period.

Secondary Outcome Measures

1. Area Under the Curve (AUC) for Participant Assessed Ascites Impact Measure (AIM) [From Day 1 up to 60 days from randomization to the first postrandomization paracentesis]

   AIM 4 symptoms (abdominal discomfort, abdominal bloating, abdominal pain, and ability to move normally) are scored from 0 to 5, where higher scores represent worst outcomes. An AIM total score ranges from 0-20. A plot for (The AIM questionnaire total score - Baseline score) versus time were generated. AIM AUC represents the overall improvement (scored positive) if the area is below the baseline value or worsening (scored negative) if the area is above the baseline. AIM AUC for a participant is the sum of individual areas representing improvement (+) or worsening (-).

2. 60-Day Frequency of Paracentesis (FOP) [From Day 1 up to 60 days from randomization]

   60-Day FOP was defined as the total number of paracenteses performed within the first 60 days after randomization during the double blind treatment period.

3. Plasma Levels of Free and VEGF-bound Aflibercept [Following every biweekly treatment administration up to 60 days after treatment discontinuation]

   Free aflibercept and VEGF-bound aflibercept plasma concentrations were measured by separate enzyme-linked immunosorbent assay (ELISA). The limit of quantitation of free aflibercept was 15.6 ng/mL, and of VEGF-bound aflibercept was 43.9 ng/mL. Peak free aflibercept was estimated at the end of Cycle 1 (C1) administration. The median free and VEGF-bound trough concentrations were determined for each participant beyond Cycle 3 (C3), then mean values were estimated from these median values.

Eligibility Criteria

Criteria

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

Participants who met the following criteria were eligible to participate in this study.

Inclusion Criteria:

• Advanced ovarian epithelial cancer, treated with paracentesis

• Platinum-resistant, and topotecan-resistant and/or liposomal doxorubicin-resistant disease;

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2.

Exclusion Criteria:

• Pseudomyxoma peritonei or peritoneal mesothelioma;

• Transudative ascites;

• Peritoneovenous or other shunt placed for malignant ascites management;

• Recent (<6 months) cardiovascular event (pulmonary embolus, myocardial infarction, stroke) or gastrointestinal disease (ulcer, hepatic cirrhosis);

• Known brain metastases;

• Uncontrolled hypertension;

• Recent treatment with chemotherapy, surgery or radiotherapy;

• Prior treatment with VEGF or VEGFR inhibitor.

The above information is not intended to contain all considerations relevant to participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sanofi-Aventis Administrative Office	Bridgewater	New Jersey	United States	08807
2	Sanofi-Aventis Administrative Office	Vienna		Austria
3	Sanofi-Aventis Administrative Office	Diegem		Belgium
4	Sanofi-Aventis Administrative Office	Laval		Canada
5	Sanofi-Aventis Administrative Office	Budapest		Hungary
6	Sanofi-Aventis Administrative Office	Mumbai		India
7	Sanofi-Aventis Administrative Office	Natanya		Israel
8	Sanofi-Aventis Administrative Office	Barcelona		Spain
9	Sanofi-Aventis Administrative Office	Guildford Surrey		United Kingdom

Sponsors and Collaborators

• Sanofi
• Regeneron Pharmaceuticals

Investigators

• Principal Investigator: Walter GOTLIEB, Director of Gynecologic Oncology and Colposcopy Associate Professor of Oncology, McGill University - Montreal - Quebec Canada

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT00327444
• Other Study ID Numbers: EFC6125; EudraCT : 2005-005026-31; AVE0005A /3001
• First Posted: May 18, 2006
• Last Update Posted: Jan 1, 2013
• Last Verified: Jul 1, 2011

• Keywords provided by Sanofi: Ovarian neoplasm; Ascites; Angiogenesis inhibitor; Vascular Endothelial Growth Factor A; Recombinant fusion protein
• Additional relevant MeSH terms: Ovarian Neoplasms; Ascites; Aflibercept

Study Results

Participant Flow

Recruitment Details	Fifty-eight (58) participants from a total of 23 sites in 7 countries were enrolled in the study.
Pre-assignment Detail	55 were randomized (started population). 3 participants were not randomized but they were treated, and permanently withdrawn from the study due to disease progression (1 participant), fatal disease progression (1 participant) and a treatment emergent adverse event (1 participant).

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description	Participants with advanced ovarian cancer administered placebo intravenously, once every two weeks in the DB period and 4.0 mg/kg aflibercept intravenously, once every two weeks in the OL period.	Participants with advanced ovarian cancer administered 4.0 mg/kg aflibercept intravenously, once every two weeks in the DB period and the OL period.
Period Title: Double Blind Treatment (DB) Period
STARTED	26	29
SAFETY	25	30
COMPLETED	0	0
NOT COMPLETED	26	29
Period Title: Double Blind Treatment (DB) Period
STARTED	11	10
ONGOING TREATMENT	1	0
COMPLETED	0	0
NOT COMPLETED	11	10

Baseline Characteristics

Arm/Group Title	Placebo	Aflibercept	Total
Arm/Group Description	Participants with advanced ovarian cancer administered placebo intravenously, once every two weeks in the DB period and 4.0 mg/kg aflibercept intravenously, once every two weeks in the OL period.	Participants with advanced ovarian cancer administered 4.0 mg/kg aflibercept intravenously, once every two weeks in the DB period and the OL period.	Total of all reporting groups
Overall Participants	26	29	55
Age, Customized (participants) [Number]
< 35 years	0 0%	1 3.4%	1 1.8%
>=35 to <45 years	5 19.2%	1 3.4%	6 10.9%
>=45 to <55 years	10 38.5%	7 24.1%	17 30.9%
>=55 to <65 years	4 15.4%	11 37.9%	15 27.3%
>=65 to <75 years	6 23.1%	7 24.1%	13 23.6%
>=75 years	1 3.8%	2 6.9%	3 5.5%
Sex: Female, Male (Count of Participants)
Female	26 100%	29 100%	55 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	19 73.1%	22 75.9%	41 74.5%
Black	1 3.8%	0 0%	1 1.8%
Asian, Oriental	6 23.1%	7 24.1%	13 23.6%

Outcome Measures

1. Primary Outcome

Title	Time to Repeat Paracentesis (TRP)
Description	TRP was defined as the number of days between the date of randomization and the date of the first post-randomization paracentesis. For participants who did not undergo a postrandomization paracentesis on study, TRP was calculated from randomization to the end of the double-blind treatment period.
Time Frame	From Day 1 up to 6 months from randomization

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population - all participants who were randomized in the study.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description	Participants with advanced ovarian cancer administered placebo intravenously, once every two weeks in the DB period and 4.0 mg/kg aflibercept intravenously, once every two weeks in the OL period.	Participants with advanced ovarian cancer administered 4.0 mg/kg aflibercept intravenously, once every two weeks in the DB period and the OL period.
Measure Participants	26	29
Least Squares Mean (Standard Error) [days]	23.3 (7.70)	55.1 (7.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aflibercept
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments	Estimated using Wilcoxon rank-sum test with stratification of baseline paracentesis (=<2 weeks versus >2 weeks) at randomization.
	Method	ANOVA
	Comments	Estimated from ANOVA model with stratification of baseline paracentesis (=<2 weeks versus >2 weeks).
Method of Estimation	Estimation Parameter	Least squares (LS) Mean difference
	Estimated Value	31.8
	Confidence Interval	(2-Sided) 95%; 10.56 to 53.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.59
	Estimation Comments	The LS mean difference is estimated for aflibercept versus placebo (aflibercept-placebo).

2. Secondary Outcome

Title	Area Under the Curve (AUC) for Participant Assessed Ascites Impact Measure (AIM)
Description	AIM 4 symptoms (abdominal discomfort, abdominal bloating, abdominal pain, and ability to move normally) are scored from 0 to 5, where higher scores represent worst outcomes. An AIM total score ranges from 0-20. A plot for (The AIM questionnaire total score - Baseline score) versus time were generated. AIM AUC represents the overall improvement (scored positive) if the area is below the baseline value or worsening (scored negative) if the area is above the baseline. AIM AUC for a participant is the sum of individual areas representing improvement (+) or worsening (-).
Time Frame	From Day 1 up to 60 days from randomization to the first postrandomization paracentesis

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population - all participants who were randomized in the study, and had evaluable AIM scores.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description	Participants with advanced ovarian cancer administered placebo intravenously, once every two weeks in the DB period and 4.0 mg/kg aflibercept intravenously, once every two weeks in the OL period.	Participants with advanced ovarian cancer administered 4.0 mg/kg aflibercept intravenously, once every two weeks in the DB period and the OL period.
Measure Participants	15	16
Least Squares Mean (Standard Error) [(units on a 4-symptom scale)*day]	29.8 (148.07)	405.3 (143.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aflibercept
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0160
	Comments	Estimated using Wilcoxon rank-sum test with stratification of baseline paracentesis (=<2 weeks versus >2 weeks) at randomization.
	Method	ANOVA
	Comments	Estimated from ANOVA model with stratification of baseline paracentesis (=<2 weeks versus >2 weeks).
Method of Estimation	Estimation Parameter	Least squares (LS) Mean difference
	Estimated Value	375.5
	Confidence Interval	(2-Sided) 95%; -46.48 to 797.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 205.99
	Estimation Comments	The LS mean difference was estimated for aflibercept versus placebo (aflibercept-placebo).

3. Secondary Outcome

Title	60-Day Frequency of Paracentesis (FOP)
Description	60-Day FOP was defined as the total number of paracenteses performed within the first 60 days after randomization during the double blind treatment period.
Time Frame	From Day 1 up to 60 days from randomization

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population - all participants who were randomized in the study.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description	Participants with advanced ovarian cancer administered placebo intravenously, once every two weeks in the DB period and 4.0 mg/kg aflibercept intravenously, once every two weeks in the OL period.	Participants with advanced ovarian cancer administered 4.0 mg/kg aflibercept intravenously, once every two weeks in the DB period and the OL period.
Measure Participants	26	29
Least Squares Mean (Standard Error) [paracentesis]	5.1 (0.69)	2.7 (0.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aflibercept
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0035
	Comments	Estimated using Wilcoxon rank-sum test with stratification of baseline paracentesis (=<2 weeks versus >2 weeks) at randomization.
	Method	ANOVA
	Comments	Estimated from ANOVA model with stratification of baseline paracentesis (=<2 weeks versus >2 weeks).
Method of Estimation	Estimation Parameter	Least squares (LS) Mean difference
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -4.33 to -0.54
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.94
	Estimation Comments	The LS mean difference is estimated for aflibercept versus placebo (aflibercept-placebo).

4. Secondary Outcome

Title	Plasma Levels of Free and VEGF-bound Aflibercept
Description	Free aflibercept and VEGF-bound aflibercept plasma concentrations were measured by separate enzyme-linked immunosorbent assay (ELISA). The limit of quantitation of free aflibercept was 15.6 ng/mL, and of VEGF-bound aflibercept was 43.9 ng/mL. Peak free aflibercept was estimated at the end of Cycle 1 (C1) administration. The median free and VEGF-bound trough concentrations were determined for each participant beyond Cycle 3 (C3), then mean values were estimated from these median values.
Time Frame	Following every biweekly treatment administration up to 60 days after treatment discontinuation

Outcome Measure Data

Analysis Population Description

The analysis was performed using the safety population with evaluable blood samples. 42 participants were evaluated.

Arm/Group Title	Double Blind (DB) Period	Open-Label (OL) Period
Arm/Group Description	Participants with advanced ovarian cancer administered placebo or 4.0 mg/kg aflibercept intravenously, once every two weeks in the DB period.	Participants with advanced ovarian cancer administered 4.0 mg/kg aflibercept intravenously, once every two weeks in the OL period.
Measure Participants	30	21
Peak Free Aflibercept (C1) (N=20, N=15)	69.8 (29.7)	62.1 (29.5)
Trough Free Aflibercept (Beyond C3) (N=15, N=19)	5.33 (3.67)	5.10 (5.29)
Trough Bound Aflibercept (Beyond C3) (N=16, N=17)	3.02 (1.29)	3.49 (1.48)

Adverse Events

Time Frame	From treatment initiation to October 30, 2009
Adverse Event Reporting Description	Adverse events were collected and reported per arm only as there was no washout period between the double-blind and open label treatment periods.
Arm/Group Title	Placebo		Aflibercept
Arm/Group Description	Participants with advanced ovarian cancer administered placebo intravenously, once every two weeks in the DB period and 4.0 mg/kg aflibercept intravenously, once every two weeks in the OL period.		Participants with advanced ovarian cancer administered 4.0 mg/kg aflibercept intravenously, once every two weeks in the DB period and the OL period.
All Cause Mortality
	Placebo		Aflibercept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Aflibercept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/25 (72%)		27/30 (90%)
Blood and lymphatic system disorders
Anaemia	1/25 (4%)		0/30 (0%)
Febrile neutropenia	1/25 (4%)		0/30 (0%)
Pancytopenia	1/25 (4%)		0/30 (0%)
Cardiac disorders
Cardiopulmonary failure	0/25 (0%)		1/30 (3.3%)
Pericardial effusion	1/25 (4%)		0/30 (0%)
Gastrointestinal disorders
Abdominal pain	0/25 (0%)		3/30 (10%)
Ascites	2/25 (8%)		1/30 (3.3%)
Colonic fistula	1/25 (4%)		0/30 (0%)
Diarrhoea	0/25 (0%)		2/30 (6.7%)
Gastric ulcer haemorrhage	1/25 (4%)		0/30 (0%)
Intestinal obstruction	2/25 (8%)		0/30 (0%)
Intestinal perforation	0/25 (0%)		1/30 (3.3%)
Large intestinal obstruction	0/25 (0%)		1/30 (3.3%)
Large intestine perforation	0/25 (0%)		1/30 (3.3%)
Nausea	0/25 (0%)		2/30 (6.7%)
Obstruction gastric	0/25 (0%)		1/30 (3.3%)
Small intestinal obstruction	1/25 (4%)		3/30 (10%)
Small intestinal perforation	0/25 (0%)		1/30 (3.3%)
Vomiting	3/25 (12%)		6/30 (20%)
General disorders
Asthenia	0/25 (0%)		1/30 (3.3%)
Death	0/25 (0%)		1/30 (3.3%)
Disease progression	8/25 (32%)		10/30 (33.3%)
Fatigue	2/25 (8%)		0/30 (0%)
Multi-organ failure	1/25 (4%)		0/30 (0%)
Oedema peripheral	1/25 (4%)		0/30 (0%)
Pain	0/25 (0%)		1/30 (3.3%)
Pyrexia	1/25 (4%)		0/30 (0%)
Hepatobiliary disorders
Bile duct obstruction	0/25 (0%)		1/30 (3.3%)
Infections and infestations
Abscess	1/25 (4%)		0/30 (0%)
Fungal skin infection	0/25 (0%)		1/30 (3.3%)
Pneumonia	0/25 (0%)		1/30 (3.3%)
Sepsis	1/25 (4%)		1/30 (3.3%)
Upper respiratory tract infection	0/25 (0%)		1/30 (3.3%)
Injury, poisoning and procedural complications
Hip fracture	1/25 (4%)		0/30 (0%)
Investigations
Blood electrolytes abnormal	0/25 (0%)		1/30 (3.3%)
Metabolism and nutrition disorders
Anorexia	1/25 (4%)		0/30 (0%)
Dehydration	4/25 (16%)		4/30 (13.3%)
Failure to thrive	0/25 (0%)		1/30 (3.3%)
Hypoglycaemia	1/25 (4%)		0/30 (0%)
Nervous system disorders
Headache	0/25 (0%)		1/30 (3.3%)
Psychiatric disorders
Confusional state	0/25 (0%)		1/30 (3.3%)
Renal and urinary disorders
Renal failure acute	1/25 (4%)		0/30 (0%)
Respiratory, thoracic and mediastinal disorders
Aspiration	1/25 (4%)		0/30 (0%)
Dyspnoea	1/25 (4%)		6/30 (20%)
Pleural effusion	0/25 (0%)		1/30 (3.3%)
Pleuritic pain	0/25 (0%)		1/30 (3.3%)
Pneumonia aspiration	0/25 (0%)		1/30 (3.3%)
Pulmonary embolism	0/25 (0%)		1/30 (3.3%)
Respiratory distress	2/25 (8%)		1/30 (3.3%)
Vascular disorders
Hypertension	0/25 (0%)		1/30 (3.3%)
Hypotension	0/25 (0%)		1/30 (3.3%)
Other (Not Including Serious) Adverse Events
	Placebo		Aflibercept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/25 (88%)		28/30 (93.3%)
Blood and lymphatic system disorders
Anaemia	4/25 (16%)		3/30 (10%)
Cardiac disorders
Tachycardia	1/25 (4%)		2/30 (6.7%)
Gastrointestinal disorders
Abdominal distension	2/25 (8%)		5/30 (16.7%)
Abdominal pain	5/25 (20%)		5/30 (16.7%)
Abdominal pain upper	1/25 (4%)		6/30 (20%)
Constipation	3/25 (12%)		5/30 (16.7%)
Diarrhoea	5/25 (20%)		12/30 (40%)
Dyspepsia	2/25 (8%)		5/30 (16.7%)
Nausea	9/25 (36%)		11/30 (36.7%)
Oral pain	0/25 (0%)		2/30 (6.7%)
Stomatitis	2/25 (8%)		1/30 (3.3%)
Vomiting	13/25 (52%)		19/30 (63.3%)
General disorders
Asthenia	3/25 (12%)		7/30 (23.3%)
Chest pain	0/25 (0%)		2/30 (6.7%)
Fatigue	14/25 (56%)		10/30 (33.3%)
Gait disturbance	1/25 (4%)		2/30 (6.7%)
Mucosal inflammation	0/25 (0%)		2/30 (6.7%)
Oedema peripheral	10/25 (40%)		11/30 (36.7%)
Pyrexia	2/25 (8%)		3/30 (10%)
Infections and infestations
Nasopharyngitis	0/25 (0%)		2/30 (6.7%)
Pneumonia	0/25 (0%)		3/30 (10%)
Upper respiratory tract infection	0/25 (0%)		2/30 (6.7%)
Urinary tract infection	4/25 (16%)		1/30 (3.3%)
Investigations
Weight decreased	0/25 (0%)		5/30 (16.7%)
Metabolism and nutrition disorders
Anorexia	9/25 (36%)		8/30 (26.7%)
Dehydration	2/25 (8%)		4/30 (13.3%)
Hypoalbuminaemia	1/25 (4%)		2/30 (6.7%)
Hypocalcaemia	0/25 (0%)		3/30 (10%)
Hypomagnesaemia	0/25 (0%)		2/30 (6.7%)
Hyponatraemia	2/25 (8%)		2/30 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/25 (12%)		0/30 (0%)
Back pain	4/25 (16%)		7/30 (23.3%)
Muscle spasms	2/25 (8%)		3/30 (10%)
Muscular weakness	2/25 (8%)		3/30 (10%)
Myalgia	3/25 (12%)		2/30 (6.7%)
Pain in extremity	2/25 (8%)		2/30 (6.7%)
Nervous system disorders
Dizziness	1/25 (4%)		2/30 (6.7%)
Dysgeusia	1/25 (4%)		2/30 (6.7%)
Headache	1/25 (4%)		7/30 (23.3%)
Psychiatric disorders
Confusional state	0/25 (0%)		2/30 (6.7%)
Insomnia	0/25 (0%)		2/30 (6.7%)
Renal and urinary disorders
Dysuria	2/25 (8%)		1/30 (3.3%)
Pollakiuria	0/25 (0%)		3/30 (10%)
Proteinuria	1/25 (4%)		4/30 (13.3%)
Respiratory, thoracic and mediastinal disorders
Cough	3/25 (12%)		8/30 (26.7%)
Dysphonia	1/25 (4%)		7/30 (23.3%)
Dyspnoea	9/25 (36%)		6/30 (20%)
Dyspnoea exertional	0/25 (0%)		3/30 (10%)
Epistaxis	0/25 (0%)		2/30 (6.7%)
Oropharyngeal pain	0/25 (0%)		3/30 (10%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome	0/25 (0%)		2/30 (6.7%)
Petechiae	0/25 (0%)		2/30 (6.7%)
Pruritus	0/25 (0%)		3/30 (10%)
Rash	2/25 (8%)		4/30 (13.3%)
Vascular disorders
Hypertension	3/25 (12%)		4/30 (13.3%)
Hypotension	2/25 (8%)		2/30 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The investigator shall have the right to independently publish study results from his site after a multicenter publication, or 12 months after the completion of the study by all sites. He must provide the sponsor a copy of any such publication derived from the study for review and comment at least 45 days (20 days) in advance of any submission, and delay publication till the approval of the publication is given in writing by the Sponsor (not to exceed ninety days).