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
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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.

Serious Adverse Events
    Ruxolitinib     Placebo  
Total, serious adverse events      
# participants affected / at risk     43/155 (27.74%)     53/151 (35.10%)  
Blood and lymphatic system disorders      
Anaemia      
# participants affected / at risk     5/155 (3.23%)     3/151 (1.99%)  
Disseminated intravascular coagulation      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Febrile neutropenia      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Haemolytic anaemia      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Leukocytosis      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Splenic haemorrhage      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Splenic infarction      
# participants affected / at risk     1/155 (0.65%)     4/151 (2.65%)  
Thrombocytopenia      
# participants affected / at risk     3/155 (1.94%)     1/151 (0.66%)  
Cardiac disorders      
Acute myocardial infarction      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Atrial fibrillation      
# participants affected / at risk     1/155 (0.65%)     1/151 (0.66%)  
Cardiac failure      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Cardiac failure congestive      
# participants affected / at risk     1/155 (0.65%)     3/151 (1.99%)  
Diastolic dysfunction      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Right ventricular failure      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Gastrointestinal disorders      
Abdominal pain      
# participants affected / at risk     0/155 (0.00%)     6/151 (3.97%)  
Anal fistula      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Ascites      
# participants affected / at risk     0/155 (0.00%)     2/151 (1.32%)  
Colitis      
# participants affected / at risk     1/155 (0.65%)     3/151 (1.99%)  
Diarrhoea      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Diverticulum      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Faecaloma      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Gastric ulcer      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Gastric varices haemorrhage      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Gastrointestinal haemorrhage      
# participants affected / at risk     2/155 (1.29%)     2/151 (1.32%)  
Intestinal ischaemia      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Intestinal perforation      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Melaena      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Nausea      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Obturator hernia      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Small intestinal obstruction      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Varices oesophageal      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Vomiting      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
General disorders      
Asthenia      
# participants affected / at risk     2/155 (1.29%)     1/151 (0.66%)  
Chest discomfort      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Chest pain      
# participants affected / at risk     1/155 (0.65%)     1/151 (0.66%)  
Disease progression      
# participants affected / at risk     0/155 (0.00%)     3/151 (1.99%)  
Fatigue      
# participants affected / at risk     4/155 (2.58%)     0/151 (0.00%)  
Multi-organ failure      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Oedema peripheral      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Pyrexia      
# participants affected / at risk     1/155 (0.65%)     1/151 (0.66%)  
Hepatobiliary disorders      
Hepatosplenomegaly      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Infections and infestations      
Appendicitis perforated      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Bacteraemia      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Bacterial infection      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Clostridial infection      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Gastroenteritis      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Gastroenteritis viral      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Lower respiratory tract infection      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Necrotising fasciitis      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Pneumonia      
# participants affected / at risk     10/155 (6.45%)     5/151 (3.31%)  
Sepsis      
# participants affected / at risk     1/155 (0.65%)     2/151 (1.32%)  
Septic shock      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Staphylococcal infection      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Tooth abscess      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Upper respiratory tract infection      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Urinary tract infection      
# participants affected / at risk     0/155 (0.00%)     2/151 (1.32%)  
Urosepsis      
# participants affected / at risk     1/155 (0.65%)     1/151 (0.66%)  
Injury, poisoning and procedural complications      
Drug toxicity      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Fall      
# participants affected / at risk     2/155 (1.29%)     2/151 (1.32%)  
Hip fracture      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Post procedural haemorrhage      
# participants affected / at risk     1/155 (0.65%)     1/151 (0.66%)  
Splenic haematoma      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Splenic injury      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Subdural haematoma      
# participants affected / at risk     1/155 (0.65%)     1/151 (0.66%)  
Transfusion reaction      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Investigations      
Blast cells present      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Blood alkaline phosphatase increased      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Blood potassium increased      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Blood urea increased      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Haemoglobin decreased      
# participants affected / at risk     3/155 (1.94%)     0/151 (0.00%)  
Metabolism and nutrition disorders      
Dehydration      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Fluid retention      
# participants affected / at risk     1/155 (0.65%)     1/151 (0.66%)  
Gout      
# participants affected / at risk     0/155 (0.00%)     2/151 (1.32%)  
Hyperkalaemia      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Hyperlipidaemia      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Hyponatraemia      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Tumour lysis syndrome      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Musculoskeletal and connective tissue disorders      
Arthralgia      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Bone pain      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Bursitis      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Muscular weakness      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Acute myeloid leukaemia      
# participants affected / at risk     2/155 (1.29%)     0/151 (0.00%)  
Colon cancer      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Myelofibrosis      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Neuroendocrine carcinoma of the skin      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Non-small cell lung cancer metastatic      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Nervous system disorders      
Cerebral ischaemia      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Hepatic encephalopathy      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Trigeminal neuralgia      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Renal and urinary disorders      
Hydronephrosis      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Nephrolithiasis      
# participants affected / at risk     1/155 (0.65%)     1/151 (0.66%)  
Renal colic      
# participants affected / at risk     1/155 (0.65%)     1/151 (0.66%)  
Renal failure      
# participants affected / at risk     1/155 (0.65%)     2/151 (1.32%)  
Renal failure acute      
# participants affected / at risk     0/155 (0.00%)     2/151 (1.32%)  
Urinary retention      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Respiratory, thoracic and mediastinal disorders      
Dyspnoea      
# participants affected / at risk     1/155 (0.65%)     1/151 (0.66%)  
Epistaxis      
# participants affected / at risk     1/155 (0.65%)     1/151 (0.66%)  
Pleural effusion      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Pneumonitis      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Pulmonary embolism      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Pulmonary hypertension      
# participants affected / at risk     0/155 (0.00%)     2/151 (1.32%)  
Pulmonary oedema      
# participants affected / at risk     0/155 (0.00%)     3/151 (1.99%)  
Respiratory distress      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Respiratory failure      
# participants affected / at risk     1/155 (0.65%)     0/151 (0.00%)  
Skin and subcutaneous tissue disorders      
Skin ulcer      
# participants affected / at risk     0/155 (0.00%)     1/151 (0.66%)  
Vascular disorders      
Hypotension      
# participants affected / at risk     0/155 (0.00%)     2/151 (1.32%)  




  Other Adverse Events


  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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