INV342: Combined Antiinflammatory and Angiostatic Therapy in Patients With Hormone-refractory Prostate Cancer

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00427999
• Collaborator: (none)
• Enrollment: 67
• Locations: 10
• Arm: 1
• Duration (Months): 101.9
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy, tolerability and safety of a multi-targeted therapy in patients with hormone-refractory prostate cancer.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: imatinib mesylate; Drug: Treosulfane; Drug: etoricoxib; Drug: pioglitazone; Drug: dexamethasone	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 67 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Stage Phase II, Multi-centre, Open Label Study of Imatinib in Combination With Pioglitazone, Etoricoxib, Dexamethasone and Low-dose Treosulfane for Anti-inflammatory and Angiostatic Treatment in Patients With Hormone-refractory Prostate Cancer
• Study Start Date: Feb 1, 2007
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: STI571+ pioglitazone+ etoricoxib + dexamethasone + treosulfane STI571 (imatinib) 400mg po daily + pioglitazone 60mg po daily + etoricoxib 60mg po daily + dexamethasone 1mg po daily + treosulfane 500mg po daily for 24 weeks	Drug: imatinib mesylate; Other Names: Gleevec Glivec ; Drug: Treosulfane; Other Names: Ovastat ; Drug: etoricoxib; Other Names: Arcoxia ; Drug: pioglitazone; Other Names: Actos ; Drug: dexamethasone; Other Names: Fortecortin

Outcome Measures

Primary Outcome Measures

1. PSA Response Rate [up to 24 weeks]

   To investigate the effect of a treatment with Imatinib mesylate, Pioglitazone , Etoricoxib, and Dexamethasone in combination with metronomic chemotherapy (Treosulfane) on the PSA response rate in patients with hormone refractory prostate cancer. A patient will be defined as a responder if a PSA decline of at least 50%, which must be confirmed by a second PSA value 4 weeks later, is observed. A patient will be defined as a non-responder if PSA has not decreased during treatment. Non-response is defined as a 25% increase over the baseline on-study which is confirmed (equal or more) by a second value 4 weeks apart. The absolute increase must account for > 5 ng/ml.

Secondary Outcome Measures

1. Time to PSA Response [every 4 weeks up to 24 weeks]

   Time to PSA response, defined as the time from first administration of study drugs to the first PSA value of a confirmed PSA response. Non-responders will be censored with date of final visit/premature discontinuation for the analysis. Median time to PSA response was not achieved

2. Time to Progression-free Survival [every 4 weeks up to 24 weeks]

   Progression-free survival, defined as the time from first administration of study drugs to the first PSA value of a PSA non-responder. Responders will be censored with date of PSA response for the analysis. The median time to PSA progression free survival was not achieved

3. Overall Survival Rate [every 4 weeks up to 24 weeks]

   Overall survival (OS) is defined as time from randomization to death from any cause or last date known alive. The median time to overall survival rate was not achieved

4. Quality of Life Assessed With EORTC-30 [baseline and Final Visit (week 24)]

   Health-related quality of life was assessed with the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-30) questionnaire and was presented descriptively. The EORTC QLQ-C30 is a questionnaire including following sub-scales: global health status, functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social activity), symptom scales (fatigue, nausea and vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea and financial difficulties). Scores are averaged for each scale and transformed to 0-100 scale; higher score indicates better quality of life on global health status and functional scales and worse quality of life on symptom scales and financial difficulty scale.

Eligibility Criteria

Criteria

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

Inclusion criteria:

• Histologically confirmed prostate carcinoma, which has proven progression after primary hormone therapy (surgical or medicinal castration).

• Patients must have increasing PSA levels (within 3 months prior to enrollment) with at least two consecutively increasing PSA levels.

• PSA value before inclusion must be at least 5 ng/ml

• At least 18 years of age.

• At least capable of self care and up of at least 50% of waking hours (ECOG performance status 0 - 2), adequate bone marrow function and lab results.

Exclusion criteria:

• Change of hormone therapy within 6 weeks prior inclusion

• Prior chemotherapy

• Therapy with Imatinib, or therapy with other inhibitors of tyrosinkinase.

• Second neoplasm diagnosed within 5 years before study start.

• Patients who require therapy with warfarin

• Known diagnosis of HIV, hepatitis B, or hepatitis C infection.

• Severe, unstable, or uncontrolled medical disease which would confound diagnoses or evaluations required by the protocol, including severe cardiac insufficiency

• Surgical therapy within 4 weeks before inclusion.

• Prior therapy with isotopes strontium or rhenium.

• Radiation therapy to > 25% of bone marrow within 4 weeks before inclusion.

• Treatment with other experimental substances within 30 days before study start.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Bad Reichenhall		Germany	83435
2	Novartis Investigative Site	Bonn		Germany	53105
3	Novartis Investigative Site	Hamburg		Germany	20246
4	Novartis Investigative Site	Hamburg		Germany	22607
5	Novartis Investigative Site	Kassel		Germany	34131
6	Novartis Investigative Site	Markkleeberg		Germany	04416
7	Novartis Investigative Site	Passau		Germany	94032
8	Novartis Investigative Site	Planegg		Germany	82152
9	Novartis Investigative Site	Regensburg		Germany	93053
10	Novartis Investigative Site	Tübingen		Germany	72076

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
• Study Director: Novartis Pharmaceuticals, Novartis Pharmeceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00427999
• Other Study ID Numbers: CSTI571BDE59; 2006-000218-19
• First Posted: Jan 29, 2007
• Last Update Posted: Nov 21, 2016
• Last Verified: Oct 1, 2016

• Keywords provided by Novartis Pharmaceuticals: Hormone-refractory; prostate cancer; multitargeted; tyrosinkinase
• Additional relevant MeSH terms: Prostatic Neoplasms; Pioglitazone; Dexamethasone; Dexamethasone acetate; Etoricoxib; Imatinib Mesylate

Study Results

Participant Flow

Recruitment Details	In 15 centers 72 patients were screened, 67 enrolled, of which 65 were treated and 33 completed the treatment phase. Intent to Treat (ITT) population included 61 patients. For the extension follow-up phase 19 patients were included in the safety analysis.

Arm/Group Title	STI571+ Pioglitazone+ Etoricoxib + Dexamethasone + Treosulfane
Arm/Group Description	STI571 (imatinib) 400mg po daily + pioglitazone 60mg po daily + etoricoxib 60mg po daily + dexamethasone 1mg po daily + treosulfane 500mg po daily for 24 weeks
Period Title: Overall Study
STARTED	65
Intent to Treat (ITT)	61
Extension Follow-up	19
COMPLETED	33
NOT COMPLETED	32

Baseline Characteristics

Arm/Group Title	STI571+ Pioglitazone+ Etoricoxib + Dexamethasone + Treosulfane
Arm/Group Description	STI571 (imatinib) 400mg po daily + pioglitazone 60mg po daily + etoricoxib 60mg po daily + dexamethasone 1mg po daily + treosulfane 500mg po daily for 24 weeks
Overall Participants	65
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67 (7.0)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	65 100%

Outcome Measures

1. Primary Outcome

Title	PSA Response Rate
Description	To investigate the effect of a treatment with Imatinib mesylate, Pioglitazone , Etoricoxib, and Dexamethasone in combination with metronomic chemotherapy (Treosulfane) on the PSA response rate in patients with hormone refractory prostate cancer. A patient will be defined as a responder if a PSA decline of at least 50%, which must be confirmed by a second PSA value 4 weeks later, is observed. A patient will be defined as a non-responder if PSA has not decreased during treatment. Non-response is defined as a 25% increase over the baseline on-study which is confirmed (equal or more) by a second value 4 weeks apart. The absolute increase must account for > 5 ng/ml.
Time Frame	up to 24 weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) includes the 61 patients treated.

Arm/Group Title	STI571+ Pioglitazone+ Etoricoxib + Dexamethasone + Treosulfane
Arm/Group Description	STI571 (imatinib) 400mg po daily + pioglitazone 60mg po daily + etoricoxib 60mg po daily + dexamethasone 1mg po daily + treosulfane 500mg po daily for 24 weeks
Measure Participants	61
PSA responder - No	38 58.5%
PSA responder - Yes	23 35.4%

2. Secondary Outcome

Title	Time to PSA Response
Description	Time to PSA response, defined as the time from first administration of study drugs to the first PSA value of a confirmed PSA response. Non-responders will be censored with date of final visit/premature discontinuation for the analysis. Median time to PSA response was not achieved
Time Frame	every 4 weeks up to 24 weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) includes the 61 patients treated.

Arm/Group Title	STI571+ Pioglitazone+ Etoricoxib + Dexamethasone + Treosulfane
Arm/Group Description	STI571 (imatinib) 400mg po daily + pioglitazone 60mg po daily + etoricoxib 60mg po daily + dexamethasone 1mg po daily + treosulfane 500mg po daily for 24 weeks
Measure Participants	61
Median (95% Confidence Interval) [days]	NA

3. Secondary Outcome

Title	Time to Progression-free Survival
Description	Progression-free survival, defined as the time from first administration of study drugs to the first PSA value of a PSA non-responder. Responders will be censored with date of PSA response for the analysis. The median time to PSA progression free survival was not achieved
Time Frame	every 4 weeks up to 24 weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) includes the 61 patients treated.

Arm/Group Title	STI571+ Pioglitazone+ Etoricoxib + Dexamethasone + Treosulfane
Arm/Group Description	STI571 (imatinib) 400mg po daily + pioglitazone 60mg po daily + etoricoxib 60mg po daily + dexamethasone 1mg po daily + treosulfane 500mg po daily for 24 weeks
Measure Participants	61
Median (95% Confidence Interval) [days]	NA

4. Secondary Outcome

Title	Overall Survival Rate
Description	Overall survival (OS) is defined as time from randomization to death from any cause or last date known alive. The median time to overall survival rate was not achieved
Time Frame	every 4 weeks up to 24 weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) includes the 61 patients treated.

Arm/Group Title	STI571+ Pioglitazone+ Etoricoxib + Dexamethasone + Treosulfane
Arm/Group Description	STI571 (imatinib) 400mg po daily + pioglitazone 60mg po daily + etoricoxib 60mg po daily + dexamethasone 1mg po daily + treosulfane 500mg po daily for 24 weeks
Measure Participants	61
Median (95% Confidence Interval) [days]	NA

5. Secondary Outcome

Title	Quality of Life Assessed With EORTC-30
Description	Health-related quality of life was assessed with the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-30) questionnaire and was presented descriptively. The EORTC QLQ-C30 is a questionnaire including following sub-scales: global health status, functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social activity), symptom scales (fatigue, nausea and vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea and financial difficulties). Scores are averaged for each scale and transformed to 0-100 scale; higher score indicates better quality of life on global health status and functional scales and worse quality of life on symptom scales and financial difficulty scale.
Time Frame	baseline and Final Visit (week 24)

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) includes the 61 patients treated

Arm/Group Title	STI571+ Pioglitazone+ Etoricoxib + Dexamethasone + Treosulfane
Arm/Group Description	STI571 (imatinib) 400mg po daily + pioglitazone 60mg po daily + etoricoxib 60mg po daily + dexamethasone 1mg po daily + treosulfane 500mg po daily for 24 weeks
Measure Participants	61
Baseline: financial difficulties (n=49)	11.6 (16.03)
Baseline: appetite loss (n=50)	16.0 (29.54)
Baseline: dyspnea (n=49)	20.4 (27.06)
Baseline: constipation (n=50)	14.0 (28.64)
Baseline: role functioning (n=50)	74.0 (28.80)
Baseline: insomnia (n=49)	34.0 (34.35)
Baseline: cognitive functioning (n=49)	87.1 (16.41)
Baseline: diarrhea (n=50)	9.3 (21.34)
Baseline: physical functioning (n=50)	81.7 (17.19)
Baseline: pain (n=50)	32.3 (32.89)
Baseline: emotional functioning (n=49)	64.6 (21.89)
Baseline: social functioning (n=49)	72.4 (26.69)
Baseline: fatigue (n=50)	32.9 (26.08)
Baseline: global health status (n=49)	60.0 (18.24)
Baseline: nausea & vomiting (n=50)	26.0 (28.80)
Final Visit: financial difficulties (n=42)	19.0 (28.65)
Final Visit: appetite loss (n=43)	24.0 (33.59)
Final Visit: dyspnea (n=43)	38.8 (29.03)
Final Visit: constipation (n=43)	6.2 (15.01)
Final Visit: role functioning (n=43)	55.4 (31.01)
Final Visit: insomnia (n=42)	31.7 (32.05)
Final Visit: cognitive functioning (n=43)	81.8 (20.51)
Final Visit: diarrhea (n=43)	13.2 (23.16)
Final Visit: physical functioning (n=43)	66.7 (25.32)
Final Visit: pain (n=43)	26.0 (30.06)
Final Visit: emotional functioning (n=43)	61.8 (28.42)
Final Visit: social functioning (n=43)	64.0 (32.52)
Final Visit: fatigue (n=43)	46.0 (29.05)
Final Visit: global health status (n=43)	51.0 (21.76)
Final Visit: nausea & vomiting (n=43)	44.6 (31.01)

Adverse Events

Adverse Event Reporting Description	In 15 centers 72 patients were screened, 67 enrolled, of which 65 were treated and 33 completed the treatment phase. Intent to Treat (ITT) population included 61 patients. For the extension follow-up phase 19 patients were included in the safety analysis.
Arm/Group Title	STI571+Pioglitazone+Etoricoxib+Dexamethasone+Treosulfane(Core)		STI571+Pioglitazone+Etoricoxib+Dexamethasone+Treosulfane(Ext)
Arm/Group Description	STI571 (imatinib) 400mg po daily + pioglitazone 60mg po daily + etoricoxib 60mg po daily + dexamethasone 1mg po daily + treosulfane 500mg po daily for 24 weeks (Core)		Extension follow-up
All Cause Mortality
	STI571+Pioglitazone+Etoricoxib+Dexamethasone+Treosulfane(Core)		STI571+Pioglitazone+Etoricoxib+Dexamethasone+Treosulfane(Ext)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	STI571+Pioglitazone+Etoricoxib+Dexamethasone+Treosulfane(Core)		STI571+Pioglitazone+Etoricoxib+Dexamethasone+Treosulfane(Ext)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/65 (33.8%)		7/19 (36.8%)
Blood and lymphatic system disorders
Anaemia	3/65 (4.6%)		0/19 (0%)
Febrile neutropenia	1/65 (1.5%)		0/19 (0%)
Leukopenia	1/65 (1.5%)		0/19 (0%)
Thrombocytopenia	0/65 (0%)		1/19 (5.3%)
Cardiac disorders
Atrial fibrillation	1/65 (1.5%)		1/19 (5.3%)
Cardio-respiratory arrest	1/65 (1.5%)		0/19 (0%)
Cardiovascular disorder	2/65 (3.1%)		0/19 (0%)
Right ventricular failure	1/65 (1.5%)		0/19 (0%)
Tachyarrhythmia	0/65 (0%)		1/19 (5.3%)
Tachycardia	1/65 (1.5%)		0/19 (0%)
Eye disorders
Cataract	1/65 (1.5%)		0/19 (0%)
Eyelid oedema	1/65 (1.5%)		0/19 (0%)
Gastrointestinal disorders
Constipation	0/65 (0%)		1/19 (5.3%)
Diarrhoea	0/65 (0%)		1/19 (5.3%)
Gastric haemorrhage	1/65 (1.5%)		0/19 (0%)
Haematemesis	1/65 (1.5%)		0/19 (0%)
Ileus	1/65 (1.5%)		0/19 (0%)
Nausea	1/65 (1.5%)		1/19 (5.3%)
Vomiting	1/65 (1.5%)		1/19 (5.3%)
General disorders
Asthenia	2/65 (3.1%)		0/19 (0%)
Chest pain	1/65 (1.5%)		1/19 (5.3%)
Disease progression	1/65 (1.5%)		1/19 (5.3%)
Drug ineffective	0/65 (0%)		1/19 (5.3%)
Drug intolerance	1/65 (1.5%)		0/19 (0%)
General physical health deterioration	2/65 (3.1%)		2/19 (10.5%)
Oedema peripheral	1/65 (1.5%)		0/19 (0%)
Pyrexia	1/65 (1.5%)		0/19 (0%)
Hepatobiliary disorders
Hepatitis	1/65 (1.5%)		0/19 (0%)
Infections and infestations
Bronchitis	1/65 (1.5%)		0/19 (0%)
Gastroenteritis	0/65 (0%)		1/19 (5.3%)
Haematoma infection	1/65 (1.5%)		0/19 (0%)
Infection	2/65 (3.1%)		0/19 (0%)
Pneumonia	3/65 (4.6%)		0/19 (0%)
Sepsis	2/65 (3.1%)		0/19 (0%)
Skin infection	1/65 (1.5%)		0/19 (0%)
Urosepsis	1/65 (1.5%)		0/19 (0%)
Injury, poisoning and procedural complications
Thoracic vertebral fracture	0/65 (0%)		1/19 (5.3%)
Investigations
Blood creatinine increased	1/65 (1.5%)		0/19 (0%)
Blood lactate dehydrogenase increased	1/65 (1.5%)		0/19 (0%)
C-reactive protein increased	1/65 (1.5%)		0/19 (0%)
Haemoglobin decreased	1/65 (1.5%)		0/19 (0%)
Metabolism and nutrition disorders
Dehydration	2/65 (3.1%)		1/19 (5.3%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/65 (0%)		1/19 (5.3%)
Osteonecrosis	0/65 (0%)		1/19 (5.3%)
Spinal column stenosis	1/65 (1.5%)		0/19 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	0/65 (0%)		1/19 (5.3%)
Bladder neoplasm	1/65 (1.5%)		0/19 (0%)
Malignant neoplasm progression	2/65 (3.1%)		0/19 (0%)
Metastases to bone	1/65 (1.5%)		0/19 (0%)
Neoplasm progression	1/65 (1.5%)		0/19 (0%)
Prostate cancer	2/65 (3.1%)		0/19 (0%)
Nervous system disorders
Burning sensation	1/65 (1.5%)		0/19 (0%)
Dizziness	1/65 (1.5%)		1/19 (5.3%)
Paraesthesia	1/65 (1.5%)		0/19 (0%)
Paraplegia	0/65 (0%)		1/19 (5.3%)
Paresis	1/65 (1.5%)		0/19 (0%)
Syncope	1/65 (1.5%)		0/19 (0%)
Psychiatric disorders
Alcohol withdrawal syndrome	1/65 (1.5%)		0/19 (0%)
Anxiety disorder	0/65 (0%)		1/19 (5.3%)
Renal and urinary disorders
Bladder obstruction	1/65 (1.5%)		0/19 (0%)
Bladder tamponade	1/65 (1.5%)		0/19 (0%)
Haematuria	1/65 (1.5%)		0/19 (0%)
Haemorrhage urinary tract	1/65 (1.5%)		0/19 (0%)
Hydronephrosis	1/65 (1.5%)		0/19 (0%)
Postrenal failure	2/65 (3.1%)		0/19 (0%)
Ureteric obstruction	1/65 (1.5%)		1/19 (5.3%)
Urinary retention	1/65 (1.5%)		0/19 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/65 (1.5%)		0/19 (0%)
Bronchospasm	1/65 (1.5%)		0/19 (0%)
Chronic obstructive pulmonary disease	1/65 (1.5%)		0/19 (0%)
Dyspnoea	2/65 (3.1%)		0/19 (0%)
Productive cough	1/65 (1.5%)		0/19 (0%)
Pulmonary oedema	1/65 (1.5%)		0/19 (0%)
Respiratory failure	1/65 (1.5%)		0/19 (0%)
Skin and subcutaneous tissue disorders
Diabetic foot	0/65 (0%)		1/19 (5.3%)
Vascular disorders
Diabetic vascular disorder	0/65 (0%)		1/19 (5.3%)
Hypertension	1/65 (1.5%)		1/19 (5.3%)
Hypotension	0/65 (0%)		1/19 (5.3%)
Peripheral artery stenosis	0/65 (0%)		1/19 (5.3%)
Venous thrombosis	1/65 (1.5%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	STI571+Pioglitazone+Etoricoxib+Dexamethasone+Treosulfane(Core)		STI571+Pioglitazone+Etoricoxib+Dexamethasone+Treosulfane(Ext)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	65/65 (100%)		19/19 (100%)
Blood and lymphatic system disorders
Anaemia	21/65 (32.3%)		7/19 (36.8%)
Anaemia macrocytic	0/65 (0%)		1/19 (5.3%)
Leukopenia	19/65 (29.2%)		7/19 (36.8%)
Thrombocytopenia	2/65 (3.1%)		1/19 (5.3%)
Cardiac disorders
Atrial fibrillation	1/65 (1.5%)		1/19 (5.3%)
Tachyarrhythmia	0/65 (0%)		1/19 (5.3%)
Ear and labyrinth disorders
Tinnitus	4/65 (6.2%)		0/19 (0%)
Vertigo	7/65 (10.8%)		3/19 (15.8%)
Vertigo positional	1/65 (1.5%)		1/19 (5.3%)
Endocrine disorders
Cushing's syndrome	11/65 (16.9%)		1/19 (5.3%)
Cushingoid	4/65 (6.2%)		3/19 (15.8%)
Hypogonadism male	0/65 (0%)		1/19 (5.3%)
Eye disorders
Eyelid oedema	5/65 (7.7%)		2/19 (10.5%)
Lacrimation increased	8/65 (12.3%)		0/19 (0%)
Visual acuity reduced	3/65 (4.6%)		1/19 (5.3%)
Gastrointestinal disorders
Abdominal pain upper	5/65 (7.7%)		2/19 (10.5%)
Abdominal wall haematoma	0/65 (0%)		1/19 (5.3%)
Constipation	4/65 (6.2%)		2/19 (10.5%)
Diarrhoea	27/65 (41.5%)		6/19 (31.6%)
Gastric polyps	0/65 (0%)		1/19 (5.3%)
Gastric ulcer	0/65 (0%)		1/19 (5.3%)
Gastrooesophageal reflux disease	0/65 (0%)		2/19 (10.5%)
Haemorrhoids	1/65 (1.5%)		1/19 (5.3%)
Hiatus hernia	1/65 (1.5%)		1/19 (5.3%)
Nausea	28/65 (43.1%)		5/19 (26.3%)
Toothache	3/65 (4.6%)		1/19 (5.3%)
Vomiting	16/65 (24.6%)		3/19 (15.8%)
General disorders
Asthenia	7/65 (10.8%)		1/19 (5.3%)
Face oedema	15/65 (23.1%)		4/19 (21.1%)
Fatigue	21/65 (32.3%)		9/19 (47.4%)
General physical health deterioration	1/65 (1.5%)		3/19 (15.8%)
Generalised oedema	1/65 (1.5%)		2/19 (10.5%)
Inflammation	1/65 (1.5%)		1/19 (5.3%)
Influenza like illness	1/65 (1.5%)		1/19 (5.3%)
Malaise	1/65 (1.5%)		1/19 (5.3%)
Mucosal inflammation	1/65 (1.5%)		1/19 (5.3%)
Necrosis	0/65 (0%)		1/19 (5.3%)
Oedema	24/65 (36.9%)		6/19 (31.6%)
Oedema peripheral	35/65 (53.8%)		12/19 (63.2%)
Pain	5/65 (7.7%)		0/19 (0%)
Pyrexia	2/65 (3.1%)		2/19 (10.5%)
Hepatobiliary disorders
Hepatitis	0/65 (0%)		1/19 (5.3%)
Infections and infestations
Bronchitis	0/65 (0%)		2/19 (10.5%)
Gingivitis	0/65 (0%)		1/19 (5.3%)
Infection	2/65 (3.1%)		2/19 (10.5%)
Influenza	2/65 (3.1%)		1/19 (5.3%)
Nasopharyngitis	7/65 (10.8%)		3/19 (15.8%)
Otitis media	0/65 (0%)		1/19 (5.3%)
Sinusitis	1/65 (1.5%)		1/19 (5.3%)
Urinary tract infection	5/65 (7.7%)		0/19 (0%)
Injury, poisoning and procedural complications
Contusion	0/65 (0%)		1/19 (5.3%)
Fall	0/65 (0%)		2/19 (10.5%)
Head injury	0/65 (0%)		1/19 (5.3%)
Muscle rupture	1/65 (1.5%)		1/19 (5.3%)
Investigations
Activated partial thromboplastin time prolonged	0/65 (0%)		1/19 (5.3%)
Alanine aminotransferase increased	4/65 (6.2%)		0/19 (0%)
Aspartate aminotransferase increased	5/65 (7.7%)		0/19 (0%)
Blood albumin decreased	3/65 (4.6%)		2/19 (10.5%)
Blood alkaline phosphatase increased	7/65 (10.8%)		1/19 (5.3%)
Blood creatinine increased	9/65 (13.8%)		5/19 (26.3%)
Blood fibrinogen increased	1/65 (1.5%)		1/19 (5.3%)
Blood lactate dehydrogenase increased	10/65 (15.4%)		4/19 (21.1%)
Blood potassium decreased	2/65 (3.1%)		1/19 (5.3%)
C-reactive protein increased	4/65 (6.2%)		3/19 (15.8%)
Haematocrit decreased	2/65 (3.1%)		2/19 (10.5%)
Lymphocyte count decreased	0/65 (0%)		1/19 (5.3%)
Monocyte count decreased	0/65 (0%)		1/19 (5.3%)
Monocyte count increased	0/65 (0%)		1/19 (5.3%)
Occult blood	0/65 (0%)		1/19 (5.3%)
Platelet count decreased	1/65 (1.5%)		1/19 (5.3%)
Prostatic specific antigen increased	2/65 (3.1%)		2/19 (10.5%)
Protein total decreased	0/65 (0%)		1/19 (5.3%)
Red blood cell count decreased	1/65 (1.5%)		2/19 (10.5%)
Reticulocyte count increased	0/65 (0%)		1/19 (5.3%)
Weight increased	13/65 (20%)		3/19 (15.8%)
Metabolism and nutrition disorders
Decreased appetite	0/65 (0%)		2/19 (10.5%)
Hypokalaemia	8/65 (12.3%)		5/19 (26.3%)
Hypomagnesaemia	0/65 (0%)		1/19 (5.3%)
Increased appetite	1/65 (1.5%)		1/19 (5.3%)
Obesity	1/65 (1.5%)		1/19 (5.3%)
Zinc deficiency	0/65 (0%)		1/19 (5.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/65 (7.7%)		1/19 (5.3%)
Back pain	7/65 (10.8%)		4/19 (21.1%)
Bone pain	4/65 (6.2%)		2/19 (10.5%)
Intervertebral disc protrusion	0/65 (0%)		1/19 (5.3%)
Joint swelling	1/65 (1.5%)		1/19 (5.3%)
Muscle spasms	16/65 (24.6%)		5/19 (26.3%)
Muscular weakness	2/65 (3.1%)		1/19 (5.3%)
Musculoskeletal chest pain	1/65 (1.5%)		2/19 (10.5%)
Musculoskeletal pain	4/65 (6.2%)		0/19 (0%)
Myalgia	2/65 (3.1%)		1/19 (5.3%)
Myopathy	0/65 (0%)		1/19 (5.3%)
Osteonecrosis	0/65 (0%)		1/19 (5.3%)
Pain in extremity	3/65 (4.6%)		5/19 (26.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/65 (0%)		1/19 (5.3%)
Metastases to bone	3/65 (4.6%)		1/19 (5.3%)
Metastases to central nervous system	0/65 (0%)		1/19 (5.3%)
Myelodysplastic syndrome	0/65 (0%)		1/19 (5.3%)
Nervous system disorders
Ageusia	3/65 (4.6%)		1/19 (5.3%)
Dizziness	6/65 (9.2%)		0/19 (0%)
Dysgeusia	7/65 (10.8%)		1/19 (5.3%)
Headache	11/65 (16.9%)		1/19 (5.3%)
Memory impairment	1/65 (1.5%)		1/19 (5.3%)
Paraesthesia	2/65 (3.1%)		2/19 (10.5%)
Polyneuropathy	7/65 (10.8%)		6/19 (31.6%)
Psychiatric disorders
Depression	4/65 (6.2%)		0/19 (0%)
Insomnia	6/65 (9.2%)		0/19 (0%)
Sleep disorder	6/65 (9.2%)		3/19 (15.8%)
Renal and urinary disorders
Kidney fibrosis	1/65 (1.5%)		1/19 (5.3%)
Pollakiuria	1/65 (1.5%)		1/19 (5.3%)
Renal pain	1/65 (1.5%)		1/19 (5.3%)
Reproductive system and breast disorders
Pelvic pain	1/65 (1.5%)		1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	4/65 (6.2%)		1/19 (5.3%)
Dyspnoea	23/65 (35.4%)		8/19 (42.1%)
Oropharyngeal pain	1/65 (1.5%)		1/19 (5.3%)
Skin and subcutaneous tissue disorders
Alopecia	1/65 (1.5%)		1/19 (5.3%)
Dry skin	0/65 (0%)		1/19 (5.3%)
Ecchymosis	0/65 (0%)		2/19 (10.5%)
Hyperhidrosis	5/65 (7.7%)		0/19 (0%)
Night sweats	8/65 (12.3%)		2/19 (10.5%)
Petechiae	0/65 (0%)		1/19 (5.3%)
Rash	7/65 (10.8%)		0/19 (0%)
Skin atrophy	0/65 (0%)		1/19 (5.3%)
Skin dystrophy	1/65 (1.5%)		1/19 (5.3%)
Skin ulcer	0/65 (0%)		1/19 (5.3%)
Vascular disorders
Extravasation blood	0/65 (0%)		1/19 (5.3%)
Haemorrhage	0/65 (0%)		1/19 (5.3%)
Hypertension	3/65 (4.6%)		2/19 (10.5%)
Hypotension	5/65 (7.7%)		0/19 (0%)
Lymphoedema	2/65 (3.1%)		1/19 (5.3%)
Peripheral arterial occlusive disease	0/65 (0%)		1/19 (5.3%)
Peripheral venous disease	0/65 (0%)		1/19 (5.3%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.