Trial Outcomes & Findings for COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment: The COMFORT-I Trial (NCT NCT00952289)

Last Updated: 2018-03-12

Results Overview

Spleen volume was assessed by magnetic resonance imaging (MRI) or by computed tomography (CT) scans if MRI was not suitable, and analyzed by a blinded central laboratory reader. Patients who withdrew, crossed over to ruxolitinib prior to the visit, or had a missing value at the visit were considered non-responders.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

309 participants

Primary outcome timeframe

Baseline and Week 24

Results posted on

2018-03-12

Participant Flow

Participant milestones

Participant milestones
Measure	Ruxolitinib Participants received ruxolitinib orally twice a day. The starting dose was based on Baseline platelet count. Patients with Baseline platelet count \> 200,000/μL began a dose regimen of 20 mg twice daily. Patients with Baseline platelet count of 100,000/μL to 200,000/μL (inclusive) began a dose regimen of 15 mg twice daily. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily. Patients receiving benefit could continue treatment until the later of marketing approval or when the last randomized patient remaining in the study had completed Week 144 (36 months).	Placebo Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
All Participants STARTED	155	154
All Participants Safety Population	155	151
All Participants COMPLETED	134	114
All Participants NOT COMPLETED	21	40
Patients Who Crossed Over to Ruxolitinib STARTED	0	111
Patients Who Crossed Over to Ruxolitinib COMPLETED	0	57
Patients Who Crossed Over to Ruxolitinib NOT COMPLETED	0	54

Reasons for withdrawal

Reasons for withdrawal
Measure	Ruxolitinib Participants received ruxolitinib orally twice a day. The starting dose was based on Baseline platelet count. Patients with Baseline platelet count \> 200,000/μL began a dose regimen of 20 mg twice daily. Patients with Baseline platelet count of 100,000/μL to 200,000/μL (inclusive) began a dose regimen of 15 mg twice daily. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily. Patients receiving benefit could continue treatment until the later of marketing approval or when the last randomized patient remaining in the study had completed Week 144 (36 months).	Placebo Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
All Participants Death	9	9
All Participants Adverse Event	8	8
All Participants Disease progression	3	12
All Participants Withdrawal by Subject	1	10
All Participants Data lost during site relocation	0	1
Patients Who Crossed Over to Ruxolitinib Adverse Event	0	19
Patients Who Crossed Over to Ruxolitinib Disease progression	0	15
Patients Who Crossed Over to Ruxolitinib Withdrawal by Subject	0	11
Patients Who Crossed Over to Ruxolitinib Non-compliance to study medication	0	2
Patients Who Crossed Over to Ruxolitinib Other Unspecified	0	7

Baseline Characteristics

Gender data for one patient in the placebo arm was not available because of loss of study data during a move to a new location by the clinical site.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ruxolitinib n=155 Participants Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily.	Placebo n=154 Participants Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.	Total n=309 Participants Total of all reporting groups
Age, Continuous	66.7 years STANDARD_DEVIATION 8.82 • n=155 Participants	68.7 years STANDARD_DEVIATION 8.66 • n=154 Participants	67.7 years STANDARD_DEVIATION 8.78 • n=309 Participants
Sex/Gender, Customized Female	76 participants n=155 Participants • Gender data for one patient in the placebo arm was not available because of loss of study data during a move to a new location by the clinical site.	65 participants n=153 Participants • Gender data for one patient in the placebo arm was not available because of loss of study data during a move to a new location by the clinical site.	141 participants n=308 Participants • Gender data for one patient in the placebo arm was not available because of loss of study data during a move to a new location by the clinical site.
Sex/Gender, Customized Male	79 participants n=155 Participants • Gender data for one patient in the placebo arm was not available because of loss of study data during a move to a new location by the clinical site.	88 participants n=153 Participants • Gender data for one patient in the placebo arm was not available because of loss of study data during a move to a new location by the clinical site.	167 participants n=308 Participants • Gender data for one patient in the placebo arm was not available because of loss of study data during a move to a new location by the clinical site.
Race/Ethnicity, Customized Black or African American	6 participants n=155 Participants	7 participants n=154 Participants	13 participants n=309 Participants
Race/Ethnicity, Customized White	138 participants n=155 Participants	139 participants n=154 Participants	277 participants n=309 Participants
Race/Ethnicity, Customized Asian	5 participants n=155 Participants	4 participants n=154 Participants	9 participants n=309 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 participants n=155 Participants	0 participants n=154 Participants	1 participants n=309 Participants
Race/Ethnicity, Customized Other	5 participants n=155 Participants	3 participants n=154 Participants	8 participants n=309 Participants
Disease Subtype Primary myelofibrosis	70 participants n=155 Participants	84 participants n=154 Participants	154 participants n=309 Participants
Disease Subtype Post-polycythemia vera-myelofibrosis	50 participants n=155 Participants	47 participants n=154 Participants	97 participants n=309 Participants
Disease Subtype Post-essential thrombocythemia-myelofibrosis	35 participants n=155 Participants	22 participants n=154 Participants	57 participants n=309 Participants
Disease Subtype Missing	0 participants n=155 Participants	1 participants n=154 Participants	1 participants n=309 Participants
Spleen volume	2745.7 cm˄3 STANDARD_DEVIATION 1247.0 • n=155 Participants	2797.6 cm˄3 STANDARD_DEVIATION 1388.5 • n=154 Participants	2771.5 cm˄3 STANDARD_DEVIATION 1317.3 • n=309 Participants
JAK2 V617F Mutation Status Positive	113 participants n=155 Participants	123 participants n=154 Participants	236 participants n=309 Participants
JAK2 V617F Mutation Status Negative	40 participants n=155 Participants	27 participants n=154 Participants	67 participants n=309 Participants
JAK2 V617F Mutation Status Unknown/Missing	2 participants n=155 Participants	4 participants n=154 Participants	6 participants n=309 Participants

PRIMARY outcome

Timeframe: Baseline and Week 24

Population: Intent-to-treat (ITT) population included all subjects randomized in the study. Treatment groups for this population were defined according to the treatment assignment at randomization. One patient was not included in the analysis due to a missing baseline spleen volume value.

Outcome measures

Outcome measures
Measure	Ruxolitinib n=155 Participants Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily.	Placebo n=153 Participants Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
Number of Participants Achieving ≥ 35% Reduction in Spleen Volume From Baseline to Week 24	65 participants	1 participants

SECONDARY outcome

Timeframe: Baseline Visit and every 12 weeks until the data cut-off date (up to 14 months).

Population: Patients who had at least 1 measurement of ≥ 35% reduction from Baseline in spleen volume at any time during the study and had at least 1 subsequent measurement or withdrew prior to another assessment.

The maintenance of ≥ 35% reduction from Baseline in spleen volume was assessed up until the data cutoff date using the Kaplan-Meier method for patients who had at least one measured ≥ 35% reduction, and who either had at least one subsequent measurement or who subsequently dropped out prior to another assessment.

Outcome measures

Outcome measures
Measure	Ruxolitinib n=91 Participants Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily.	Placebo Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib Still Responder by 48 weeks	0.76 proportion of participants Interval 0.66 to 0.84	—
Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib Still Responder by 96 weeks	0.67 proportion of participants Interval 0.55 to 0.76	—
Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib Still Responder by 144 weeks	0.27 proportion of participants Interval 0.02 to 0.63	—

SECONDARY outcome

Timeframe: Baseline Visit and every 12 weeks until the data cut-off date (up to 14 months).

The duration of ≥ 35% reduction from Baseline in spleen volume was defined as the longest duration of consecutive measurements of ≥ 35% reduction observed before the data cut-off date for patients who had at least one measured ≥ 35% reduction, and who either had at least one subsequent measurement or, who subsequently dropped out prior to another assessment. The duration of a ≥ 35% reduction from Baseline in spleen volume was analyzed using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Ruxolitinib n=91 Participants Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily.	Placebo Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
Duration of Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib	135.0 weeks Interval 107.6 to Data not evaluable due to a single loss of response with few subjects having spleen measurement follow-up data beyond 128 weeks from start of response.	—

SECONDARY outcome

Timeframe: Baseline and Week 24. Baseline total score was the average of the daily total scores for the last 7 days prior to randomization. The Week 24 total score was the average of daily total scores from the 28 days prior to the Week 24 visit.

Population: ITT evaluable population included patients with Baseline data and who did not have a 0 total score at both Baseline \& Week 24; data measured after the cross over date were excluded. Patients who withdrew, met cross over criteria prior to Week 24 or had a 0 Baseline score \& a nonzero/missing score at Week 24 were considered not meeting the endpoint.

Symptoms of myelofibrosis were assessed using a modified Myelofibrosis Symptom Assessment Form (MFSAF) Version 2.0 diary. Using the diary, patients rated the following symptoms on a scale from 0 (absent) to 10 (worst imaginable): night sweats, itching, abdominal discomfort, pain under ribs on left, feeling of fullness (early satiety), and muscle/bone pain. The total symptom score ranged from 0-60 and was calculated as the sum of the 6 symptom scores. A higher score indicates worse symptoms.

Outcome measures

Outcome measures
Measure	Ruxolitinib n=148 Participants Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily.	Placebo n=152 Participants Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
Number of Participants With a ≥ 50% Reduction in Total Symptom Score From Baseline to Week 24	68 participants	8 participants

SECONDARY outcome

Population: This analysis only includes patients who had a non-missing change from Baseline to Week 24. Data collected after the date of treatment cross over were not included in this analysis.

Outcome measures

Outcome measures
Measure	Ruxolitinib n=131 Participants Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily.	Placebo n=105 Participants Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
Change From Baseline to Week 24 in Total Symptom Score Baseline	18.0 scores on a scale Standard Deviation 10.9	16.5 scores on a scale Standard Deviation 11.5
Change From Baseline to Week 24 in Total Symptom Score Week 24	9.4 scores on a scale Standard Deviation 9.7	19.7 scores on a scale Standard Deviation 13.7
Change From Baseline to Week 24 in Total Symptom Score Change from Baseline	-8.6 scores on a scale Standard Deviation 10.0	3.2 scores on a scale Standard Deviation 9.4

SECONDARY outcome

Timeframe: From randomization to the data cut-off date (up to 14 months).

Population: ITT population

Overall survival is reported here by the number of deaths from randomization until the data cut-off. Patients were censored at the time of database cut-off or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of data cut. The survival time was analyzed using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Ruxolitinib n=155 Participants Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily.	Placebo n=154 Participants Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
Overall Survival Death events	10 participants	14 participants
Overall Survival Censored events	145 participants	140 participants

SECONDARY outcome

Timeframe: From randomization to the data cut-off date (up to 14 months).

Population: ITT population

Overall survival was assessed by the time to death or censoring. Patients were censored at the time of database cut-off or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of data cut. The survival time was analyzed using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Ruxolitinib n=155 Participants Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily.	Placebo n=154 Participants Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
Overall Survival Time	NA weeks The median overall survival was not reached as more than 50% of patients were still live at the time of the data cut-off using the Kaplan-Meier method.	NA weeks The median overall survival was not reached as more than 50% of patients were still live at the time of the data cut-off using the Kaplan-Meier method.

SECONDARY outcome

Timeframe: From randomization to 4 months after the data cut-off date (up to 18 months).

Population: ITT population

Overall survival is reported here by the number of deaths from randomization until 01 March 2011. Patients were censored at this time or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of data cut. The survival time was analyzed using the Kaplan-Meier method. This outcome reports data from August 2009 through March 2011 to coincide with a pre-planned New Drug Application (NDA) 120-day safety update.

Outcome measures

Outcome measures
Measure	Ruxolitinib n=155 Participants Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily.	Placebo n=154 Participants Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
Overall Survival - Extended Data Death events	13 participants	24 participants
Overall Survival - Extended Data Censored events	142 participants	130 participants

SECONDARY outcome

Timeframe: From randomization to 4 months after the data cut-off date (up to 18 months).

Population: ITT population

Overall survival was assessed by the time to death or censoring up until 01 March 2011. Patients were censored at this time or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of data cut. The survival time was analyzed using the Kaplan-Meier method. This outcome reports data from August 2009 through March 2011 to coincide with a pre-planned New Drug Application (NDA) 120-day safety update.

Outcome measures

Outcome measures
Measure	Ruxolitinib n=155 Participants Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily.	Placebo n=154 Participants Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
Overall Survival Time - Extended Data	NA weeks The median overall survival was not reached as more than 50% of patients were still living at the time of the database cut-off using the Kaplan-Meier method.	NA weeks The median overall survival was not reached as more than 50% of patients were still living at the time of the database cut-off using the Kaplan-Meier method.

SECONDARY outcome

Timeframe: Week 144

Population: ITT population

Overall survival is reported here by the number of deaths from randomization until the data cut-off. Patients were censored at the time of database cut-off or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of database cut-off. The survival time was analyzed using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Ruxolitinib n=155 Participants Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily.	Placebo n=154 Participants Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
Overall Survival at Week 144 Death events	42 participants	54 participants
Overall Survival at Week 144 Censored events	113 participants	100 participants

SECONDARY outcome

Timeframe: Week 144

Population: ITT population

Overall survival was assessed by the time to death or censoring. Patients were censored at the time of database cut-off or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of database cut-off. The survival time was analyzed using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Ruxolitinib n=155 Participants Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily.	Placebo n=154 Participants Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
Overall Survival Time at Week 144	0.74 probability Interval 0.66 to 0.81	0.61 probability Interval 0.53 to 0.69

Adverse Events

Ruxolitinib

Serious events: 43 serious events

Other events: 150 other events

Deaths: 0 deaths

Placebo

Serious events: 53 serious events

Other events: 147 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Incyte Corporation

Phone: 855 463-3463

Results disclosure agreements

Principal investigator is a sponsor employee Following the first publication, the Institution and/or Principal Investigator may publish data or results from the Study, provided, however, that the Institution and/or Principal Investigator submits the proposed publication to the Sponsor for review at least sixty (60) days prior to the date of the proposed publication. Sponsor may remove from the proposed publication any information that is considered confidential and/or proprietary other than Study data and results.
Publication restrictions are in place

Restriction type: OTHER

Measure	Ruxolitinib n=155 participants at risk Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily.	Placebo n=151 participants at risk Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment.
Blood and lymphatic system disorders Thrombocytopenia	33.5% 52/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	9.3% 14/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Blood and lymphatic system disorders Anaemia	29.0% 45/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	13.2% 20/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Blood and lymphatic system disorders Leukocytosis	0.65% 1/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	5.3% 8/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Gastrointestinal disorders Abdominal pain	10.3% 16/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	38.4% 58/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Gastrointestinal disorders Diarrhoea	23.2% 36/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	21.2% 32/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Gastrointestinal disorders Nausea	14.2% 22/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	19.2% 29/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Gastrointestinal disorders Constipation	12.9% 20/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	11.9% 18/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Gastrointestinal disorders Vomiting	11.6% 18/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	9.9% 15/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Gastrointestinal disorders Abdominal distension	8.4% 13/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	10.6% 16/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Gastrointestinal disorders Abdominal pain upper	5.8% 9/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	8.6% 13/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Gastrointestinal disorders Dyspepsia	5.8% 9/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	5.3% 8/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Gastrointestinal disorders Flatulence	5.2% 8/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	0.66% 1/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
General disorders Fatigue	24.5% 38/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	33.8% 51/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
General disorders Oedema peripheral	18.7% 29/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	22.5% 34/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
General disorders Pyrexia	10.3% 16/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	6.6% 10/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
General disorders Asthenia	3.9% 6/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	7.9% 12/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
General disorders Early satiety	0.65% 1/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	8.6% 13/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
General disorders Pain	2.6% 4/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	6.0% 9/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
General disorders Chills	5.2% 8/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	2.0% 3/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
General disorders Performance status decreased	1.3% 2/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	6.0% 9/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Hepatobiliary disorders Hepatomegaly	3.2% 5/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	5.3% 8/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Infections and infestations Upper respiratory tract infection	5.8% 9/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	8.6% 13/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Infections and infestations Urinary tract infection	7.1% 11/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	3.3% 5/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Infections and infestations Nasopharyngitis	1.3% 2/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	6.0% 9/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Investigations Haemoglobin decreased	12.3% 19/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	4.0% 6/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Investigations Platelet count decreased	9.7% 15/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	2.6% 4/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Investigations Cardiac murmur	7.1% 11/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	3.3% 5/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Investigations Blast cell count increased	2.6% 4/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	6.6% 10/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Investigations Weight increased	6.5% 10/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	1.3% 2/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Investigations Weight decreased	0.00% 0/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	6.0% 9/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Investigations Blood uric acid increased	0.00% 0/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	5.3% 8/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Metabolism and nutrition disorders Anorexia	5.8% 9/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	6.6% 10/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Musculoskeletal and connective tissue disorders Pain in extremity	12.3% 19/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	9.9% 15/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Musculoskeletal and connective tissue disorders Arthralgia	11.0% 17/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	8.6% 13/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Musculoskeletal and connective tissue disorders Back pain	7.1% 11/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	8.6% 13/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Musculoskeletal and connective tissue disorders Muscle spasms	6.5% 10/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	7.3% 11/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Musculoskeletal and connective tissue disorders Bone pain	3.2% 5/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	5.3% 8/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Musculoskeletal and connective tissue disorders Musculoskeletal pain	3.2% 5/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	5.3% 8/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Nervous system disorders Dizziness	14.8% 23/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	6.6% 10/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Nervous system disorders Headache	14.8% 23/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	5.3% 8/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Psychiatric disorders Insomnia	11.6% 18/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	9.9% 15/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Psychiatric disorders Anxiety	1.9% 3/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	6.0% 9/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Respiratory, thoracic and mediastinal disorders Dyspnoea	16.8% 26/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	16.6% 25/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Respiratory, thoracic and mediastinal disorders Cough	9.7% 15/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	8.6% 13/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Respiratory, thoracic and mediastinal disorders Rales	1.9% 3/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	5.3% 8/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Skin and subcutaneous tissue disorders Ecchymosis	18.7% 29/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	9.3% 14/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Skin and subcutaneous tissue disorders Pruritus	4.5% 7/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	15.2% 23/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Skin and subcutaneous tissue disorders Night sweats	6.5% 10/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	11.9% 18/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Skin and subcutaneous tissue disorders Rash	4.5% 7/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	5.3% 8/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Skin and subcutaneous tissue disorders Erythema	0.65% 1/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	6.0% 9/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Vascular disorders Pallor	5.2% 8/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	6.0% 9/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Vascular disorders Hypotension	3.2% 5/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	5.3% 8/151 • From randomization through data cut-off of the primary analysis (02 November 2010).
Investigations Blood alkaline phosphatase increased	3.2% 5/155 • From randomization through data cut-off of the primary analysis (02 November 2010).	5.3% 8/151 • From randomization through data cut-off of the primary analysis (02 November 2010).