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

Phase 3

Completed

• Conditions: MPN (Myeloproliferative Neoplasms)
• Interventions: Drug: Ruxolitinib; Drug: Placebo

• Registration Number: NCT00952289
• Lead Sponsor: Incyte Corporation

Brief Summary

This was a randomized, double-blind study comparing the efficacy and safety of ruxolitinib (INCB018424) tablets to matching placebo tablets in patients diagnosed with Myelofibrosis (either Primary Myelofibrosis (PMF) or Post-Polycythemia Vera Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET-MF).

Detailed Description

Patients with spleen growth of greater than 25% based on an increase in spleen volume from Baseline were eligible for early unblinding, and for patients on placebo, cross over to ruxolitinib prior to the primary study endpoint being reached. If this spleen growth occurred before Week 24, it must have been accompanied by specific worsening of symptoms, based on worsening early satiety accompanied by weight loss or worsening pain requiring daily narcotic use. After Week 24, asymptomatic spleen growth alone was sufficient for early unblinding and potential cross over. Patients found to have been randomized to ruxolitinib after early unblinding prior to Week 24 were discontinued.

When half of the patients remaining in the study completed the Week 36 visit and all patients enrolled completed Week 24 or discontinued, the database was frozen and the primary analysis was conducted. Once this was complete, all patients were unblinded and patients who had been randomized to placebo were given the opportunity to cross over to ruxolitinib treatment, provided hematology laboratory parameters were adequate; 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).

Study Timeline

• Study Start: 2009-08
• Study First Submitted: 2009-08-04
• Study First Submitted QC: 2009-08-05
• Study First Posted: 2009-08-06
• Disposition First Submitted: 2010-06-18
• Disposition First Submitted QC: 2010-06-18
• Disposition First Posted: 2010-06-22
• Primary Completion: 2010-11
• Results First Submitted: 2011-12-16
• Results First Submitted QC: 2011-12-16
• Results First Posted: 2012-01-24
• Study Completion: 2015-10
• Status Verified: 2018-02
• Last Update Submitted: 2018-02-12
• Last Update Posted: 2018-03-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 309

Inclusion Criteria

• Subjects must be diagnosed with primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PET-MF) according to the 2008 World Health Organization criteria
• Subjects with myelofibrosis requiring therapy must be classified as high risk OR intermediate risk level 2 according to the prognostic factors defined by the International Working Group
• Subjects with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2 or 3
• Subjects who have not previously received treatment with a Janus kinase (JAK) inhibitor

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Exclusion Criteria

• Subjects with a life expectancy of less than 6 months
• Subjects with inadequate bone marrow reserve as demonstrated by specific clinical laboratory counts
• Subjects with inadequate liver or renal function
• Subjects with clinically significant bacterial, fungal, parasitic or viral infection which require therapy
• Subjects with an active malignancy over the previous 5 years except specific skin cancers.
• Subjects with severe cardiac conditions
• Subjects who have had splenic irradiation within 12 months

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	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 certain protocol requirements detailed below were given the opportunity to cross over to ruxolitinib treatment.
Ruxolitinib	Ruxolitinib	Participants received ruxolitinib orally twice a day. The starting dose was determined 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	Ruxolitinib	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 certain protocol requirements detailed below were given the opportunity to cross over to ruxolitinib treatment.

Primary Outcome Measures

Name	Time	Method
Number of Participants Achieving ≥ 35% Reduction in Spleen Volume From Baseline to Week 24	Baseline and Week 24	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.

Secondary Outcome Measures

Name	Time	Method
Duration of Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib	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.
Number of Participants With a ≥ 50% Reduction in Total Symptom Score From Baseline to Week 24	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.	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.
Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib	Baseline Visit and every 12 weeks until the data cut-off date (up to 14 months).	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.
Overall Survival - Extended Data	From randomization to 4 months after the data cut-off date (up to 18 months).	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.
Overall Survival Time - Extended Data	From randomization to 4 months after the data cut-off date (up to 18 months).	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.
Change From Baseline to Week 24 in Total Symptom Score	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.	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 hence a negative change from baseline indicates improvement.
Overall Survival	From randomization to the data cut-off date (up to 14 months).	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.
Overall Survival Time	From randomization to the data cut-off date (up to 14 months).	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.
Overall Survival at Week 144	Week 144	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.
Overall Survival Time at Week 144	Week 144	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.