COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment: The COMFORT-I Trial

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Incyte Corporation
ClinicalTrials.gov Identifier:
NCT00952289
First received: August 4, 2009
Last updated: May 13, 2013
Last verified: May 2013
Results First Received: December 16, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Myelofibrosis
Interventions: Drug: Ruxolitinib
Drug: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups
  Description
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 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 crossover to ruxolitinib treatment.

Participant Flow for 2 periods

Period 1:   All Participants
    Ruxolitinib     Placebo  
STARTED     155     154  
Safety Population     155     151 [1]
COMPLETED     134 [2]   114 [3]
NOT COMPLETED     21     40  
Death                 9                 9  
Adverse Event                 8                 8  
Disease progression                 3                 12  
Withdrawal by Subject                 1                 10  
Data lost during site relocation                 0                 1  
[1] Randomized patients who are documented to have received at least 1 dose of study medication.
[2] Represents the number of patients who were still in the study as of 02 November 2010
[3] Includes patients in the study as of 2 November 2010 (78) + those who crossed over to Ruxolitinib.

Period 2:   Patients Who Crossed Over to Ruxolitinib
    Ruxolitinib     Placebo  
STARTED     0     36  
COMPLETED     0     32 [1]
NOT COMPLETED     0     4  
Death                 0                 1  
Withdrawal by Subject                 0                 1  
Non-compliance to study medication                 0                 1  
Physician Decision                 0                 1  
[1] Number of crossover patients who were still in the study as of 02 November 2010



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups
  Description
Ruxolitinib 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 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 crossover to ruxolitinib treatment.
Total Total of all reporting groups

Baseline Measures
    Ruxolitinib     Placebo     Total  
Number of Participants  
[units: participants]
  155     154     309  
Age  
[units: years]
Mean ± Standard Deviation
  66.7  ± 8.82     68.7  ± 8.66     67.7  ± 8.78  
Gender [1]
[units: participants]
     
Female     76     65     141  
Male     79     88     167  
Race/Ethnicity, Customized [2]
[units: participants]
     
Black or African American     6     7     13  
White     138     139     277  
Asian     5     4     9  
Native Hawaiian or Other Pacific Islander     1     0     1  
Other     5     3     8  
Disease Subtype  
[units: participants]
     
Primary myelofibrosis     70     84     154  
Post-polycythemia vera-myelofibrosis     50     47     97  
Post-essential thrombocythemia-myelofibrosis     35     22     57  
Missing     0     1     1  
Spleen volume [3]
[units: cm˄3]
Mean ± Standard Deviation
  2745.7  ± 1247.0     2797.6  ± 1388.5     2771.5  ± 1317.3  
JAK2 V617F Mutation Status [4]
[units: participants]
     
Positive     113     123     236  
Negative     40     27     67  
Unknown/Missing     2     4     6  
[1] 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.
[2] Race 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.
[3] Spleen volume was measured by magnetic resonance imaging or computed tomography scans. Data for one patient in the placebo arm was not available because of loss of study data during a move by the clinical site.
[4] JAK2V617F is a mutation in the pseudokinase domain of Janus Kinase 2 (JAK2) (at amino acid 617, valine to phenylalanine) that results in constitutive activation of JAK2. Mutation status was determined using a validated assay on bone marrow as well as peripheral blood.



  Outcome Measures
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1.  Primary:   Number of Participants Achieving ≥ 35% Reduction in Spleen Volume From Baseline to Week 24   [ Time Frame: Baseline and Week 24 ]

2.  Secondary:   Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib   [ Time Frame: Baseline Visit and every 12 weeks until the data cut-off date (up to 14 months). ]

3.  Secondary:   Duration of Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib   [ Time Frame: Baseline Visit and every 12 weeks until the data cut-off date (up to 14 months). ]

4.  Secondary:   Number of Participants With a ≥ 50% Reduction in Total Symptom Score From Baseline to Week 24   [ Time Frame: 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. ]

5.  Secondary:   Change From Baseline to Week 24 in Total Symptom Score   [ Time Frame: 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. ]

6.  Secondary:   Overall Survival   [ Time Frame: From randomization to the data cut-off date (up to 14 months). ]

7.  Secondary:   Overall Survival Time   [ Time Frame: From randomization to the data cut-off date (up to 14 months). ]

8.  Secondary:   Overall Survival - Extended Data   [ Time Frame: From randomization to 4 months after the data cut-off date (up to 18 months). ]

9.  Secondary:   Overall Survival Time - Extended Data   [ Time Frame: From randomization to 4 months after the data cut-off date (up to 18 months). ]


  Serious Adverse Events


  Other Adverse Events
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Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Ruxolitinib 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 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 crossover to ruxolitinib treatment.

Other Adverse Events
    Ruxolitinib     Placebo  
Total, other (not including serious) adverse events      
# participants affected / at risk     150/155     147/151  
Blood and lymphatic system disorders      
Thrombocytopenia      
# participants affected / at risk     52/155 (33.55%)     14/151 (9.27%)  
Anaemia      
# participants affected / at risk     45/155 (29.03%)     20/151 (13.25%)  
Leukocytosis      
# participants affected / at risk     1/155 (0.65%)     8/151 (5.30%)  
Gastrointestinal disorders      
Abdominal pain      
# participants affected / at risk     16/155 (10.32%)     58/151 (38.41%)  
Diarrhoea      
# participants affected / at risk     36/155 (23.23%)     32/151 (21.19%)  
Nausea      
# participants affected / at risk     22/155 (14.19%)     29/151 (19.21%)  
Constipation      
# participants affected / at risk     20/155 (12.90%)     18/151 (11.92%)  
Vomiting      
# participants affected / at risk     18/155 (11.61%)     15/151 (9.93%)  
Abdominal distension      
# participants affected / at risk     13/155 (8.39%)     16/151 (10.60%)  
Abdominal pain upper      
# participants affected / at risk     9/155 (5.81%)     13/151 (8.61%)  
Dyspepsia      
# participants affected / at risk     9/155 (5.81%)     8/151 (5.30%)  
Flatulence      
# participants affected / at risk     8/155 (5.16%)     1/151 (0.66%)  
General disorders      
Fatigue      
# participants affected / at risk     38/155 (24.52%)     51/151 (33.77%)  
Oedema peripheral      
# participants affected / at risk     29/155 (18.71%)     34/151 (22.52%)  
Pyrexia      
# participants affected / at risk     16/155 (10.32%)     10/151 (6.62%)  
Asthenia      
# participants affected / at risk     6/155 (3.87%)     12/151 (7.95%)  
Early satiety      
# participants affected / at risk     1/155 (0.65%)     13/151 (8.61%)  
Pain      
# participants affected / at risk     4/155 (2.58%)     9/151 (5.96%)  
Chills      
# participants affected / at risk     8/155 (5.16%)     3/151 (1.99%)  
Performance status decreased      
# participants affected / at risk     2/155 (1.29%)     9/151 (5.96%)  
Hepatobiliary disorders      
Hepatomegaly      
# participants affected / at risk     5/155 (3.23%)     8/151 (5.30%)  
Infections and infestations      
Upper respiratory tract infection      
# participants affected / at risk     9/155 (5.81%)     13/151 (8.61%)  
Urinary tract infection      
# participants affected / at risk     11/155 (7.10%)     5/151 (3.31%)  
Nasopharyngitis      
# participants affected / at risk     2/155 (1.29%)     9/151 (5.96%)  
Investigations      
Haemoglobin decreased      
# participants affected / at risk     19/155 (12.26%)     6/151 (3.97%)  
Platelet count decreased      
# participants affected / at risk     15/155 (9.68%)     4/151 (2.65%)  
Cardiac murmur      
# participants affected / at risk     11/155 (7.10%)     5/151 (3.31%)  
Blast cell count increased      
# participants affected / at risk     4/155 (2.58%)     10/151 (6.62%)  
Weight increased      
# participants affected / at risk     10/155 (6.45%)     2/151 (1.32%)  
Weight decreased      
# participants affected / at risk     0/155 (0.00%)     9/151 (5.96%)  
Blood uric acid increased      
# participants affected / at risk     0/155 (0.00%)     8/151 (5.30%)  
Blood alkaline phosphatase increased      
# participants affected / at risk     5/155 (3.23%)     8/151 (5.30%)  
Metabolism and nutrition disorders      
Anorexia      
# participants affected / at risk     9/155 (5.81%)     10/151 (6.62%)  
Musculoskeletal and connective tissue disorders      
Pain in extremity      
# participants affected / at risk     19/155 (12.26%)     15/151 (9.93%)  
Arthralgia      
# participants affected / at risk     17/155 (10.97%)     13/151 (8.61%)  
Back pain      
# participants affected / at risk     11/155 (7.10%)     13/151 (8.61%)  
Muscle spasms      
# participants affected / at risk     10/155 (6.45%)     11/151 (7.28%)  
Bone pain      
# participants affected / at risk     5/155 (3.23%)     8/151 (5.30%)  
Musculoskeletal pain      
# participants affected / at risk     5/155 (3.23%)     8/151 (5.30%)  
Nervous system disorders      
Dizziness      
# participants affected / at risk     23/155 (14.84%)     10/151 (6.62%)  
Headache      
# participants affected / at risk     23/155 (14.84%)     8/151 (5.30%)  
Psychiatric disorders      
Insomnia      
# participants affected / at risk     18/155 (11.61%)     15/151 (9.93%)  
Anxiety      
# participants affected / at risk     3/155 (1.94%)     9/151 (5.96%)  
Respiratory, thoracic and mediastinal disorders      
Dyspnoea      
# participants affected / at risk     26/155 (16.77%)     25/151 (16.56%)  
Cough      
# participants affected / at risk     15/155 (9.68%)     13/151 (8.61%)  
Rales      
# participants affected / at risk     3/155 (1.94%)     8/151 (5.30%)  
Skin and subcutaneous tissue disorders      
Ecchymosis      
# participants affected / at risk     29/155 (18.71%)     14/151 (9.27%)  
Pruritus      
# participants affected / at risk     7/155 (4.52%)     23/151 (15.23%)  
Night sweats      
# participants affected / at risk     10/155 (6.45%)     18/151 (11.92%)  
Rash      
# participants affected / at risk     7/155 (4.52%)     8/151 (5.30%)  
Erythema      
# participants affected / at risk     1/155 (0.65%)     9/151 (5.96%)  
Vascular disorders      
Pallor      
# participants affected / at risk     8/155 (5.16%)     9/151 (5.96%)  
Hypotension      
# participants affected / at risk     5/155 (3.23%)     8/151 (5.30%)  



  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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