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

• Sponsor: Incyte Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00952289
• Collaborator: (none)
• Enrollment: 309
• Locations: 112
• Arms: 2
• Duration (Months): 74
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
MPN (Myeloproliferative Neoplasms)	Drug: Ruxolitinib; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 309 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Study of the JAK Inhibitor INCB018424 Tablets Administered Orally to Subjects With Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis or Post-Essential Thrombocythemia Myelofibrosis
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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).	Drug: Ruxolitinib; Ruxolitinib phosphate tablets 5 mg administered as oral doses.; Other Names: INCB018424
Placebo Comparator: 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.	Drug: Ruxolitinib; Ruxolitinib phosphate tablets 5 mg administered as oral doses.; Other Names: INCB018424 ; Drug: Placebo; Matching placebo tablets were administered as oral doses in the same manner as active drug.

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

Eligibility Criteria

Criteria

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

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Scottsdale	Arizona	United States
3		Baldwin Park	California	United States
4		Bellflower	California	United States
5		Beverly Hills	California	United States
6		Corona	California	United States
7		Fullerton	California	United States
8		Highland	California	United States
9		La Jolla	California	United States
10		Los Angeles	California	United States
11		Orange	California	United States
12		Palo Alto	California	United States
13		Panorama City	California	United States
14		Rancho Cucamonga	California	United States
15		Riverside	California	United States
16		Sacramento	California	United States
17		San Diego	California	United States
18		West Covina	California	United States
19		Aurora	Colorado	United States
20		Denver	Colorado	United States
21		Fort Collins	Colorado	United States
22		Norwalk	Connecticut	United States
23		Washington	District of Columbia	United States
24		Boynton Beach	Florida	United States
25		Gainesville	Florida	United States
26		Jacksonville	Florida	United States
27		West Palm Beach	Florida	United States
28		Winter Park	Florida	United States
29		Atlanta	Georgia	United States
30		Augusta	Georgia	United States
31		Honolulu	Hawaii	United States
32		Boise	Idaho	United States
33		Meridian	Idaho	United States
34		Twin Falls	Idaho	United States
35		Chicago	Illinois	United States
36		Beech Grove	Indiana	United States
37		Indianapolis	Indiana	United States
38		Ames	Iowa	United States
39		Iowa City	Iowa	United States
40		Sioux City	Iowa	United States
41		Waterloo	Iowa	United States
42		Louisville	Kentucky	United States
43		Alexandria	Louisiana	United States
44		New Orleans	Louisiana	United States
45		Baltimore	Maryland	United States
46		Ann Arbor	Michigan	United States
47		Detroit	Michigan	United States
48		Novi	Michigan	United States
49		Southfield	Michigan	United States
50		Minneapolis	Minnesota	United States
51		Rochester	Minnesota	United States
52		Saint Louis Park	Minnesota	United States
53		New Albany	Mississippi	United States
54		Saint Louis	Missouri	United States
55		Billings	Montana	United States
56		Denville	New Jersey	United States
57		Hackensack	New Jersey	United States
58		Morristown	New Jersey	United States
59		Somerville	New Jersey	United States
60		Albuquerque	New Mexico	United States
61		East Setauket	New York	United States
62		New York	New York	United States
63		Valhalla	New York	United States
64		Durham	North Carolina	United States
65		Hickory	North Carolina	United States
66		Winston-Salem	North Carolina	United States
67		Bismarck	North Dakota	United States
68		Akron	Ohio	United States
69		Canton	Ohio	United States
70		Cleveland	Ohio	United States
71		Dayton	Ohio	United States
72		Dover	Ohio	United States
73		Portland	Oregon	United States
74		Philadelphia	Pennsylvania	United States
75		Pittsburgh	Pennsylvania	United States
76		Charleston	South Carolina	United States
77		Germantown	Tennessee	United States
78		Memphis	Tennessee	United States
79		Nashville	Tennessee	United States
80		Dallas	Texas	United States
81		Houston	Texas	United States
82		New Braunfels	Texas	United States
83		San Antonio	Texas	United States
84		Salt Lake City	Utah	United States
85		Burlington	Vermont	United States
86		Everett	Washington	United States
87		Seattle	Washington	United States
88		Milwaukee	Wisconsin	United States
89		Darlinghurst	New South Wales	Australia
90		Kogarah	New South Wales	Australia
91		Randwick	New South Wales	Australia
92		St Leonards	New South Wales	Australia
93		Brisbane	Queensland	Australia
94		Douglas	Queensland	Australia
95		Herston	Queensland	Australia
96		Milton	Queensland	Australia
97		Woolloongabba	Queensland	Australia
98		Bedford Park	South Australia	Australia
99		Box Hill	Victoria	Australia
100		Clayton	Victoria	Australia
101		Frankston	Victoria	Australia
102		Ringwood East	Victoria	Australia
103		Fremantle	Western Australia	Australia
104		Perth	Western Australia	Australia
105		Vancouver	British Columbia	Canada
106		St. John's	Newfoundland and Labrador	Canada
107		Halifax	Nova Scotia	Canada
108		London	Ontario	Canada
109		Ottawa	Ontario	Canada
110		Toronto	Ontario	Canada
111		Levis	Quebec	Canada
112		Montreal	Quebec	Canada

Sponsors and Collaborators

• Incyte Corporation

Investigators

• Study Director: Srdan Verstovsek, MD, PhD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

• Verstovsek S, Mesa R, Gotlib J, et al. Results of COMFORT-I, a randomized double-blind phase III trial of JAK1/2 inhibitor INCB18424 (424) vs placebo (PB) for patients with myelofibrosis (MF). The 47th Annual ASCO meeting, Chicago, IL. J Clin Oncol 2011; 29 (suppl; abstract 6500). Verstovsek S, Mesa R, Gotlib J, et al. Results of COMFORT-I, a randomized, double-blind phase III trial of the JAK1 and JAK2 inhibitor ruxolitinib (INCB018424) versus placebo for patients with myelofibrosis. The 16th Annual EHA meeting, London, UK. Haematologica 2011; 96 (suppl 2; abstract 0505).

• Responsible Party: Incyte Corporation
• ClinicalTrials.gov Identifier: NCT00952289
• Other Study ID Numbers: INCB 18424-351
• First Posted: Aug 6, 2009
• Last Update Posted: Mar 12, 2018
• Last Verified: Feb 1, 2018

• Keywords provided by Incyte Corporation: Myelofibrosis; Post-Polycythemia Vera Myelofibrosis; Post-Essential Thrombocythemia Myelofibrosis
• Additional relevant MeSH terms: Polycythemia Vera; Primary Myelofibrosis; Myeloproliferative Disorders

Study Results

Participant Flow

Arm/Group Title	Ruxolitinib	Placebo
Arm/Group Description	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 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.
Period Title: All Participants
STARTED	155	154
Safety Population	155	151
COMPLETED	134	114
NOT COMPLETED	21	40
Period Title: All Participants
STARTED	0	111
COMPLETED	0	57
NOT COMPLETED	0	54

Baseline Characteristics

Arm/Group Title	Ruxolitinib	Placebo	Total
Arm/Group Description	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 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 of all reporting groups
Overall Participants	155	154	309
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.7 (8.82)	68.7 (8.66)	67.7 (8.78)
Sex/Gender, Customized (participants) [Number]
Female	76 49%	65 42.2%	141 45.6%
Male	79 51%	88 57.1%	167 54%
Race/Ethnicity, Customized (participants) [Number]
Black or African American	6 3.9%	7 4.5%	13 4.2%
White	138 89%	139 90.3%	277 89.6%
Asian	5 3.2%	4 2.6%	9 2.9%
Native Hawaiian or Other Pacific Islander	1 0.6%	0 0%	1 0.3%
Other	5 3.2%	3 1.9%	8 2.6%
Disease Subtype (participants) [Number]
Primary myelofibrosis	70 45.2%	84 54.5%	154 49.8%
Post-polycythemia vera-myelofibrosis	50 32.3%	47 30.5%	97 31.4%
Post-essential thrombocythemia-myelofibrosis	35 22.6%	22 14.3%	57 18.4%
Missing	0 0%	1 0.6%	1 0.3%
Spleen volume (cm˄3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm˄3]	2745.7 (1247.0)	2797.6 (1388.5)	2771.5 (1317.3)
JAK2 V617F Mutation Status (participants) [Number]
Positive	113 72.9%	123 79.9%	236 76.4%
Negative	40 25.8%	27 17.5%	67 21.7%
Unknown/Missing	2 1.3%	4 2.6%	6 1.9%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Achieving ≥ 35% Reduction in Spleen Volume From Baseline to Week 24
Description	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.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ruxolitinib	Placebo
Arm/Group Description	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 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.
Measure Participants	155	153
Number [participants]	65 41.9%	1 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ruxolitinib, Placebo
	Comments	The primary endpoint analyzed with a 2-sided alpha of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ruxolitinib
Arm/Group Description	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.
Measure Participants	91
Still Responder by 48 weeks	0.76 0.5%
Still Responder by 96 weeks	0.67 0.4%
Still Responder by 144 weeks	0.27 0.2%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ruxolitinib
Arm/Group Description	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.
Measure Participants	91
Median (95% Confidence Interval) [weeks]	135.0

4. Secondary Outcome

Title	Number of Participants With a ≥ 50% Reduction in Total Symptom Score From Baseline to Week 24
Description	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.
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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ruxolitinib	Placebo
Arm/Group Description	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 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.
Measure Participants	148	152
Number [participants]	68 43.9%	8 5.2%

5. Secondary Outcome

Title	Change From Baseline to Week 24 in Total Symptom Score
Description	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.
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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ruxolitinib	Placebo
Arm/Group Description	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 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.
Measure Participants	131	105
Baseline	18.0 (10.9)	16.5 (11.5)
Week 24	9.4 (9.7)	19.7 (13.7)
Change from Baseline	-8.6 (10.0)	3.2 (9.4)

6. Secondary Outcome

Title	Overall Survival
Description	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.
Time Frame	From randomization to the data cut-off date (up to 14 months).

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Ruxolitinib	Placebo
Arm/Group Description	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 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.
Measure Participants	155	154
Death events	10 6.5%	14 9.1%
Censored events	145 93.5%	140 90.9%

7. Secondary Outcome

Title	Overall Survival Time
Description	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.
Time Frame	From randomization to the data cut-off date (up to 14 months).

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Ruxolitinib	Placebo
Arm/Group Description	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 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.
Measure Participants	155	154
Median (95% Confidence Interval) [weeks]	NA	NA

8. Secondary Outcome

Title	Overall Survival - Extended Data
Description	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.
Time Frame	From randomization to 4 months after the data cut-off date (up to 18 months).

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Ruxolitinib	Placebo
Arm/Group Description	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 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.
Measure Participants	155	154
Death events	13 8.4%	24 15.6%
Censored events	142 91.6%	130 84.4%

9. Secondary Outcome

Title	Overall Survival Time - Extended Data
Description	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.
Time Frame	From randomization to 4 months after the data cut-off date (up to 18 months).

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Ruxolitinib	Placebo
Arm/Group Description	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 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.
Measure Participants	155	154
Median (95% Confidence Interval) [weeks]	NA	NA

10. Secondary Outcome

Title	Overall Survival at Week 144
Description	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.
Time Frame	Week 144

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Ruxolitinib	Placebo
Arm/Group Description	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 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.
Measure Participants	155	154
Death events	42 27.1%	54 35.1%
Censored events	113 72.9%	100 64.9%

11. Secondary Outcome

Title	Overall Survival Time at Week 144
Description	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.
Time Frame	Week 144

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Ruxolitinib	Placebo
Arm/Group Description	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 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.
Measure Participants	155	154
Number (95% Confidence Interval) [probability]	0.74	0.61

Adverse Events

Time Frame	From randomization through data cut-off of the primary analysis (02 November 2010).
Arm/Group Title	Ruxolitinib		Placebo
Arm/Group Description	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 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 Cause Mortality
	Ruxolitinib		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ruxolitinib		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/155 (27.7%)		53/151 (35.1%)
Blood and lymphatic system disorders
Anaemia	5/155 (3.2%)		3/151 (2%)
Disseminated intravascular coagulation	0/155 (0%)		1/151 (0.7%)
Febrile neutropenia	1/155 (0.6%)		0/151 (0%)
Leukocytosis	0/155 (0%)		1/151 (0.7%)
Splenic haemorrhage	1/155 (0.6%)		0/151 (0%)
Splenic infarction	1/155 (0.6%)		4/151 (2.6%)
Thrombocytopenia	3/155 (1.9%)		1/151 (0.7%)
Haemolytic anaemia	1/155 (0.6%)		0/151 (0%)
Cardiac disorders
Acute myocardial infarction	0/155 (0%)		1/151 (0.7%)
Atrial fibrillation	1/155 (0.6%)		1/151 (0.7%)
Cardiac failure	0/155 (0%)		1/151 (0.7%)
Cardiac failure congestive	1/155 (0.6%)		3/151 (2%)
Diastolic dysfunction	1/155 (0.6%)		0/151 (0%)
Right ventricular failure	0/155 (0%)		1/151 (0.7%)
Gastrointestinal disorders
Abdominal pain	0/155 (0%)		6/151 (4%)
Ascites	0/155 (0%)		2/151 (1.3%)
Diarrhoea	1/155 (0.6%)		0/151 (0%)
Gastrointestinal haemorrhage	2/155 (1.3%)		2/151 (1.3%)
Melaena	0/155 (0%)		1/151 (0.7%)
Nausea	1/155 (0.6%)		0/151 (0%)
Vomiting	1/155 (0.6%)		0/151 (0%)
Anal fistula	0/155 (0%)		1/151 (0.7%)
Colitis	1/155 (0.6%)		3/151 (2%)
Diverticulum	1/155 (0.6%)		0/151 (0%)
Faecaloma	0/155 (0%)		1/151 (0.7%)
Gastric ulcer	0/155 (0%)		1/151 (0.7%)
Gastric varices haemorrhage	0/155 (0%)		1/151 (0.7%)
Intestinal ischaemia	0/155 (0%)		1/151 (0.7%)
Intestinal perforation	0/155 (0%)		1/151 (0.7%)
Obturator hernia	1/155 (0.6%)		0/151 (0%)
Small intestinal obstruction	0/155 (0%)		1/151 (0.7%)
Varices oesophageal	0/155 (0%)		1/151 (0.7%)
General disorders
Asthenia	2/155 (1.3%)		1/151 (0.7%)
Chest pain	1/155 (0.6%)		1/151 (0.7%)
Disease progression	0/155 (0%)		3/151 (2%)
Fatigue	4/155 (2.6%)		0/151 (0%)
Oedema peripheral	1/155 (0.6%)		0/151 (0%)
Pyrexia	1/155 (0.6%)		1/151 (0.7%)
Chest discomfort	0/155 (0%)		1/151 (0.7%)
Multi-organ failure	0/155 (0%)		1/151 (0.7%)
Hepatobiliary disorders
Hepatosplenomegaly	0/155 (0%)		1/151 (0.7%)
Infections and infestations
Clostridial infection	1/155 (0.6%)		0/151 (0%)
Pneumonia	10/155 (6.5%)		5/151 (3.3%)
Sepsis	1/155 (0.6%)		2/151 (1.3%)
Staphylococcal infection	0/155 (0%)		1/151 (0.7%)
Upper respiratory tract infection	0/155 (0%)		1/151 (0.7%)
Appendicitis perforated	1/155 (0.6%)		0/151 (0%)
Bacteraemia	0/155 (0%)		1/151 (0.7%)
Bacterial infection	0/155 (0%)		1/151 (0.7%)
Gastroenteritis	1/155 (0.6%)		0/151 (0%)
Gastroenteritis viral	0/155 (0%)		1/151 (0.7%)
Lower respiratory tract infection	0/155 (0%)		1/151 (0.7%)
Necrotising fasciitis	1/155 (0.6%)		0/151 (0%)
Septic shock	1/155 (0.6%)		0/151 (0%)
Tooth abscess	1/155 (0.6%)		0/151 (0%)
Urinary tract infection	0/155 (0%)		2/151 (1.3%)
Urosepsis	1/155 (0.6%)		1/151 (0.7%)
Injury, poisoning and procedural complications
Fall	2/155 (1.3%)		2/151 (1.3%)
Subdural haematoma	1/155 (0.6%)		1/151 (0.7%)
Drug toxicity	1/155 (0.6%)		0/151 (0%)
Hip fracture	1/155 (0.6%)		0/151 (0%)
Post procedural haemorrhage	1/155 (0.6%)		1/151 (0.7%)
Splenic haematoma	0/155 (0%)		1/151 (0.7%)
Splenic injury	0/155 (0%)		1/151 (0.7%)
Transfusion reaction	0/155 (0%)		1/151 (0.7%)
Investigations
Haemoglobin decreased	3/155 (1.9%)		0/151 (0%)
Blast cells present	1/155 (0.6%)		0/151 (0%)
Blood alkaline phosphatase increased	1/155 (0.6%)		0/151 (0%)
Blood potassium increased	1/155 (0.6%)		0/151 (0%)
Blood urea increased	1/155 (0.6%)		0/151 (0%)
Metabolism and nutrition disorders
Dehydration	0/155 (0%)		1/151 (0.7%)
Fluid retention	1/155 (0.6%)		1/151 (0.7%)
Gout	0/155 (0%)		2/151 (1.3%)
Hyperkalaemia	1/155 (0.6%)		0/151 (0%)
Hyponatraemia	0/155 (0%)		1/151 (0.7%)
Hyperlipidaemia	1/155 (0.6%)		0/151 (0%)
Tumour lysis syndrome	0/155 (0%)		1/151 (0.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/155 (0.6%)		0/151 (0%)
Bone pain	0/155 (0%)		1/151 (0.7%)
Muscular weakness	1/155 (0.6%)		0/151 (0%)
Bursitis	1/155 (0.6%)		0/151 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelofibrosis	0/155 (0%)		1/151 (0.7%)
Neuroendocrine carcinoma of the skin	0/155 (0%)		1/151 (0.7%)
Acute myeloid leukaemia	2/155 (1.3%)		0/151 (0%)
Colon cancer	1/155 (0.6%)		0/151 (0%)
Non-small cell lung cancer metastatic	1/155 (0.6%)		0/151 (0%)
Nervous system disorders
Cerebral ischaemia	0/155 (0%)		1/151 (0.7%)
Hepatic encephalopathy	0/155 (0%)		1/151 (0.7%)
Trigeminal neuralgia	0/155 (0%)		1/151 (0.7%)
Renal and urinary disorders
Hydronephrosis	0/155 (0%)		1/151 (0.7%)
Nephrolithiasis	1/155 (0.6%)		1/151 (0.7%)
Renal colic	1/155 (0.6%)		1/151 (0.7%)
Renal failure	1/155 (0.6%)		2/151 (1.3%)
Renal failure acute	0/155 (0%)		2/151 (1.3%)
Urinary retention	0/155 (0%)		1/151 (0.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/155 (0.6%)		1/151 (0.7%)
Epistaxis	1/155 (0.6%)		1/151 (0.7%)
Pleural effusion	0/155 (0%)		1/151 (0.7%)
Pulmonary oedema	0/155 (0%)		3/151 (2%)
Respiratory distress	0/155 (0%)		1/151 (0.7%)
Respiratory failure	1/155 (0.6%)		0/151 (0%)
Pneumonitis	0/155 (0%)		1/151 (0.7%)
Pulmonary embolism	0/155 (0%)		1/151 (0.7%)
Pulmonary hypertension	0/155 (0%)		2/151 (1.3%)
Skin and subcutaneous tissue disorders
Skin ulcer	0/155 (0%)		1/151 (0.7%)
Vascular disorders
Hypotension	0/155 (0%)		2/151 (1.3%)
Other (Not Including Serious) Adverse Events
	Ruxolitinib		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	150/155 (96.8%)		147/151 (97.4%)
Blood and lymphatic system disorders
Thrombocytopenia	52/155 (33.5%)		14/151 (9.3%)
Anaemia	45/155 (29%)		20/151 (13.2%)
Leukocytosis	1/155 (0.6%)		8/151 (5.3%)
Gastrointestinal disorders
Abdominal pain	16/155 (10.3%)		58/151 (38.4%)
Diarrhoea	36/155 (23.2%)		32/151 (21.2%)
Nausea	22/155 (14.2%)		29/151 (19.2%)
Constipation	20/155 (12.9%)		18/151 (11.9%)
Vomiting	18/155 (11.6%)		15/151 (9.9%)
Abdominal distension	13/155 (8.4%)		16/151 (10.6%)
Abdominal pain upper	9/155 (5.8%)		13/151 (8.6%)
Dyspepsia	9/155 (5.8%)		8/151 (5.3%)
Flatulence	8/155 (5.2%)		1/151 (0.7%)
General disorders
Fatigue	38/155 (24.5%)		51/151 (33.8%)
Oedema peripheral	29/155 (18.7%)		34/151 (22.5%)
Pyrexia	16/155 (10.3%)		10/151 (6.6%)
Asthenia	6/155 (3.9%)		12/151 (7.9%)
Early satiety	1/155 (0.6%)		13/151 (8.6%)
Pain	4/155 (2.6%)		9/151 (6%)
Chills	8/155 (5.2%)		3/151 (2%)
Performance status decreased	2/155 (1.3%)		9/151 (6%)
Hepatobiliary disorders
Hepatomegaly	5/155 (3.2%)		8/151 (5.3%)
Infections and infestations
Upper respiratory tract infection	9/155 (5.8%)		13/151 (8.6%)
Urinary tract infection	11/155 (7.1%)		5/151 (3.3%)
Nasopharyngitis	2/155 (1.3%)		9/151 (6%)
Investigations
Haemoglobin decreased	19/155 (12.3%)		6/151 (4%)
Platelet count decreased	15/155 (9.7%)		4/151 (2.6%)
Cardiac murmur	11/155 (7.1%)		5/151 (3.3%)
Blast cell count increased	4/155 (2.6%)		10/151 (6.6%)
Weight increased	10/155 (6.5%)		2/151 (1.3%)
Weight decreased	0/155 (0%)		9/151 (6%)
Blood uric acid increased	0/155 (0%)		8/151 (5.3%)
Blood alkaline phosphatase increased	5/155 (3.2%)		8/151 (5.3%)
Metabolism and nutrition disorders
Anorexia	9/155 (5.8%)		10/151 (6.6%)
Musculoskeletal and connective tissue disorders
Pain in extremity	19/155 (12.3%)		15/151 (9.9%)
Arthralgia	17/155 (11%)		13/151 (8.6%)
Back pain	11/155 (7.1%)		13/151 (8.6%)
Muscle spasms	10/155 (6.5%)		11/151 (7.3%)
Bone pain	5/155 (3.2%)		8/151 (5.3%)
Musculoskeletal pain	5/155 (3.2%)		8/151 (5.3%)
Nervous system disorders
Dizziness	23/155 (14.8%)		10/151 (6.6%)
Headache	23/155 (14.8%)		8/151 (5.3%)
Psychiatric disorders
Insomnia	18/155 (11.6%)		15/151 (9.9%)
Anxiety	3/155 (1.9%)		9/151 (6%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	26/155 (16.8%)		25/151 (16.6%)
Cough	15/155 (9.7%)		13/151 (8.6%)
Rales	3/155 (1.9%)		8/151 (5.3%)
Skin and subcutaneous tissue disorders
Ecchymosis	29/155 (18.7%)		14/151 (9.3%)
Pruritus	7/155 (4.5%)		23/151 (15.2%)
Night sweats	10/155 (6.5%)		18/151 (11.9%)
Rash	7/155 (4.5%)		8/151 (5.3%)
Erythema	1/155 (0.6%)		9/151 (6%)
Vascular disorders
Pallor	8/155 (5.2%)		9/151 (6%)
Hypotension	5/155 (3.2%)		8/151 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.