Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care: (The RESPONSE Trial)

• Sponsor: Incyte Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01243944
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 222
• Locations: 102
• Arms: 2
• Actual Duration (Months): 87.5
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This pivotal phase III trial (CINC424B2301) is designed to compare the efficacy and safety of ruxolitinib (INC424) to Best Available Therapy (BAT) in participants with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea (HU).

Condition or Disease	Intervention/Treatment	Phase
Polycythemia Vera	Drug: ruxolitinib tablets; Other: Best Available Therapy (BAT)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 222 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized, Open Label, Multicenter Phase III Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 Tablets Versus Best Available Care (The RESPONSE Trial)
• Actual Study Start Date: Oct 27, 2010
• Actual Primary Completion Date: Jan 15, 2014
• Actual Study Completion Date: Feb 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ruxolitinib tablets Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg once a day (QD) to 25 mg BID based on safety and efficacy	Drug: ruxolitinib tablets; Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy
Other: Best Available Therapy Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.	Other: Best Available Therapy (BAT); Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.; Other Names: BAT could include: Hydroxyurea IFN/PEG-IFN Pipobroman Anagrelide Lenalidomide Pomalidomide Observation only

Outcome Measures

Primary Outcome Measures

1. The Percentage of Participants Achieving a Primary Response at Week 32 [32 Weeks]

   Primary response was defined as having achieved hematocrit control (the absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32) and Spleen Volume Reduction (a greater than or equal to 35% reduction from baseline in spleen volume at Week 32).

Secondary Outcome Measures

1. The Percentage of Participants Achieving a Durable Primary Response at Week 48 [48 Weeks]

   Durable Primary Response was defined as any participant who achieved the primary outcome measure and who maintained their response up to 48 weeks after randomization.

2. The Percentage of Participants Achieving Complete Hematological Remission at Week 32 [32 Weeks]

   Complete Hematological Remission at Week 32 was defined as any participant who achieved hematocrit control with a platelet count less than or equal to 400 X 10^9/L and a white blood cell count less than or equal to 10 X 10^9/L.

3. The Percentage of Participants Who Achieved a Durable Complete Hematological Remission at Week 48 [48 Weeks]

   Durable Complete Hematological Remission was defined as any participant who achieved Complete Hematological Remission at Week 32 and maintained their response up to 48 weeks after randomization.

4. The Percentage of Participants Who Achieved a Durable Hematocrit Control at Week 48 [48 Weeks]

   Durable Hematocrit Control was defined as any participant who achieved phlebotomy eligibility independence from Week 8 to Week 32 and maintained hematocrit control up to 48 weeks after randomization.

5. The Percentage of Participants Who Achieved Durable Spleen Volume Reduction at Week 48 [48 Weeks]

   Durable Spleen Volume Reduction was defined as a participant who achieved at least 35% reduction from baseline in spleen volume at Week 32 and maintained that response 48 weeks after randomization.

6. Estimated Duration of the Primary Response [Through study completion, analysis was conducted when all participants had completed the Week 80 visit or discontinued the study]

   Duration of the primary response is defined as the time from the first occurrence when both components of the primary endpoint are met until the date of the first documented disease progression (end of response). Kaplan-Meier estimates are provided for duration of primary response.

7. The Percentage of Participants Who Achieved Overall Clinicohematologic Response at Week 32 [32 Weeks]

   Overall Clinicohematologic Response is defined as any participant who achieved a complete or partial clinicohematologic response per the European LeukemiaNet modified criteria for response in polycythemia vera (PV). A Complete Response (CR) is defined as: hematocrit control, spleen volume reduction at least 35% from baseline, platelet count less than or equal to 400 x 10(9)/L, and white blood cell count less than or equal to 10 x 10(9)/L. A Partial Response (PR) is defined as hematocrit control or response in all 3 of the other criteria.

8. The Percentage of Participants Achieving a Durable Complete or Partial Clinicohematologic Response at Week 48 [48 Weeks]

   Durable Complete or Partial Clinicohematologic Response was defined as any participant who achieved complete or partial clinicohematologic response per the European LeukemiaNet modified criteria for response in polycythemia vera at Week 32 and maintained that response 48 weeks after randomization.

9. Estimated Duration of the Complete Hematological Remission [Through study completion, analysis was conducted when all participants had completed the Week 80 visit or discontinued the study]

   Duration of the complete hematological remission is defined as the time from the first occurrence of complete hematological remission until the date of the first documented progression (end of response). Kaplan-Meier estimates are provided for duration of complete hematological remission.

10. Duration of the Absence of Phlebotomy Eligibility [256 Weeks]

    Duration of the absence of phlebotomy eligibility is defined as the time from the first occurrence of absence of phlebotomy eligibility until the date of the first documented progression.

11. Duration of Reduction in Spleen Volume [256 Weeks]

    Duration of spleen volume reduction is defined as the time from the first occurrence of a >=35% reduction from baseline in spleen volume until the date of the first documented progression.

12. Duration of The Overall Clinicohematologic Response [256 Weeks]

    Duration of the overall clinicohematologic response was defined as the time from the first occurrence of complete response (CR) or partial response (PR) until the date of the first documented disease progression.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Participants diagnosed with PV for at least 24 weeks prior to screening according to the 2008 World Health Organization criteria

• Participants resistant to or intolerant of hydroxyurea

• Participants with a phlebotomy requirement

• Participants with splenomegaly (palpable or non-palpable) and a spleen volume, as measured by MRI (or CT in applicable participants ), of greater than or equal to 450 cubic centimeters

• Participants with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

Exclusion Criteria:

• Women who are pregnant or nursing

• Participants with inadequate liver or renal function

• Participants with significant bacterial, fungal, parasitic, or viral infection requiring treatment

• Participants with an active malignancy within the past 5 years, excluding specific skin cancers

• Participants with known active hepatitis or HIV positivity

• Participants who have previously received treatment with a JAK inhibitor

• Participants being treated with any investigational agent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Scottsdale	Arizona	United States
3		Pomona	California	United States
4		Sacramento	California	United States
5		San Diego	California	United States
6		Bridgeport	Connecticut	United States
7		New Haven	Connecticut	United States
8		Boynton Beach	Florida	United States
9		Fort Myers	Florida	United States
10		Jacksonville	Florida	United States
11		Winter Park	Florida	United States
12		Boise	Idaho	United States
13		Chicago	Illinois	United States
14		Lafayette	Louisiana	United States
15		Scarborough	Maine	United States
16		Baltimore	Maryland	United States
17		Columbia	Maryland	United States
18		Southfield	Michigan	United States
19		Jefferson City	Missouri	United States
20		Saint Louis	Missouri	United States
21		Omaha	Nebraska	United States
22		Morristown	New Jersey	United States
23		Somerville	New Jersey	United States
24		Charleston	South Carolina	United States
25		Greenville	South Carolina	United States
26		Nashville	Tennessee	United States
27		Houston	Texas	United States
28		Seattle	Washington	United States
29		Buenos Aires		Argentina
30		Brisbane		Australia
31		Parkville		Australia
32		Tweed Heads		Australia
33		Antwerp		Belgium
34		Brugge		Belgium
35		Bruxelles		Belgium
36		Leuven		Belgium
37		Hamilton		Canada
38		Montreal		Canada
39		Toronto		Canada
40		Beijing		China
41		Hangzhou		China
42		Avignon		France
43		Bayonne		France
44		Brest		France
45		Lille		France
46		Nantes		France
47		Paris		France
48		Vandœuvre-lès-Nancy		France
49		Aachen		Germany
50		Berlin		Germany
51		Bonn		Germany
52		Freiburg		Germany
53		Hamburg		Germany
54		Jena		Germany
55		Magdeburg		Germany
56		Mannheim		Germany
57		Minden		Germany
58		Munchen		Germany
59		Ulm		Germany
60		Budapest		Hungary
61		Kecskemet		Hungary
62		Szeged		Hungary
63		Szombathely		Hungary
64		Bari		Italy
65		Bergamo		Italy
66		Bologna		Italy
67		Firenze		Italy
68		Milano		Italy
69		Napoli		Italy
70		Orbassano		Italy
71		Pavia		Italy
72		Reggio Calabria		Italy
73		Roma		Italy
74		Varese		Italy
75		Vicenza		Italy
76		Chiba		Japan
77		Chuo-city Yamanashi		Japan
78		Maebashi		Japan
79		Nagoya-city Aichi		Japan
80		Osaka		Japan
81		Tokyo		Japan
82		Seoul		Korea, Republic of
83		Enschede		Netherlands
84		Rotterdam		Netherlands
85		Moscow		Russian Federation
86		St. Petersburg		Russian Federation
87		Barcelona		Spain
88		Coruña		Spain
89		Las Palmas de Gran Canaria		Spain
90		Madrid		Spain
91		Majadahonda		Spain
92		Malaga		Spain
93		Pamplona		Spain
94		Salamanca		Spain
95		Valencia		Spain
96		Bangkok		Thailand
97		Ankara		Turkey
98		Istanbul		Turkey
99		Izmir		Turkey
100		Bournemouth		United Kingdom
101		Cardiff		United Kingdom
102		London		United Kingdom

Sponsors and Collaborators

• Incyte Corporation
• Novartis Pharmaceuticals

Investigators

• Study Director: Srdan Verstovsek, MD,PhD, M.D. Anderson Cancer Center
• Study Director: Mark Jones, MD, Incyte Corporation

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Incyte Corporation
• ClinicalTrials.gov Identifier: NCT01243944
• Other Study ID Numbers: CINC424B2301
• First Posted: Nov 19, 2010
• Last Update Posted: Mar 6, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Incyte Corporation: INCB018424
• Additional relevant MeSH terms: Polycythemia Vera; Polycythemia; Lenalidomide; Pomalidomide; Hydroxyurea; Pipobroman; Anagrelide

Study Results

Participant Flow

Recruitment Details	Participants may be treated beyond 256 weeks due to the 14 day visit window.

Arm/Group Title	Ruxolitinib	Best Available Therapy
Arm/Group Description	Starting dose of 10 mg twice a day (BID) with individualized dose titration ranging from 5 mg once a day (QD) to 25 mg BID based on safety and efficacy	Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.
Period Title: Overall Study
STARTED	110	112
Treated	110	111
Followed for Survival	22	21
COMPLETED	65	61
NOT COMPLETED	45	51

Baseline Characteristics

Arm/Group Title	Ruxolitinib	Best Available Therapy	Total
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy	Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.	Total of all reporting groups
Overall Participants	110	112	222
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.1 (10.48)	59.1 (10.25)	60.1 (10.39)
Age, Customized (participants) [Number]
< 60 years	49 44.5%	54 48.2%	103 46.4%
≥ 60 years	61 55.5%	58 51.8%	119 53.6%
Sex: Female, Male (Count of Participants)
Female	44 40%	32 28.6%	76 34.2%
Male	66 60%	80 71.4%	146 65.8%
Race/Ethnicity, Customized (participants) [Number]
White/Caucasian	98 89.1%	96 85.7%	194 87.4%
Black/African American	1 0.9%	0 0%	1 0.5%
Asian	11 10%	16 14.3%	27 12.2%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	76.6 (14.09)	79.0 (17.34)	77.8 (15.83)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	172.2 (8.44)	173.3 (9.79)	172.8 (9.14)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.8 (3.82)	26.1 (4.24)	25.9 (4.03)
ECOG performance status (participants) [Number]
0	76 69.1%	77 68.8%	153 68.9%
1	31 28.2%	34 30.4%	65 29.3%
2	3 2.7%	1 0.9%	4 1.8%

Outcome Measures

1. Primary Outcome

Title	The Percentage of Participants Achieving a Primary Response at Week 32
Description	Primary response was defined as having achieved hematocrit control (the absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32) and Spleen Volume Reduction (a greater than or equal to 35% reduction from baseline in spleen volume at Week 32).
Time Frame	32 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all participants to whom study treatment had been assigned by randomization.

Arm/Group Title	Ruxolitinib	Best Available Therapy
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy	Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.
Measure Participants	110	112
Number (95% Confidence Interval) [percentage of participants]	22.7 20.6%	0.9 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ruxolitinib, Best Available Therapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Exact Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio, log
	Estimated Value	32.67
	Confidence Interval	(2-Sided) 95%; 5.04 to 1337
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	The Percentage of Participants Achieving a Durable Primary Response at Week 48
Description	Durable Primary Response was defined as any participant who achieved the primary outcome measure and who maintained their response up to 48 weeks after randomization.
Time Frame	48 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all participants to whom study treatment had been assigned by randomization.

Arm/Group Title	Ruxolitinib	Best Available Therapy
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy	Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.
Measure Participants	110	112
Number (95% Confidence Interval) [percentage of participants]	20.0 18.2%	0.9 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ruxolitinib, Best Available Therapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Exact Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	28.01
	Confidence Interval	(2-Sided) 95%; 4.24 to 1144
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	The Percentage of Participants Achieving Complete Hematological Remission at Week 32
Description	Complete Hematological Remission at Week 32 was defined as any participant who achieved hematocrit control with a platelet count less than or equal to 400 X 10^9/L and a white blood cell count less than or equal to 10 X 10^9/L.
Time Frame	32 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all participants to whom study treatment had been assigned by randomization.

Arm/Group Title	Ruxolitinib	Best Available Therapy
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy	Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.
Measure Participants	110	112
Number (95% Confidence Interval) [percentage of participants]	23.6 21.5%	8.0 7.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ruxolitinib, Best Available Therapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0016
	Comments
	Method	Exact Cochran-Mantel-Haenszel
	Comments	P-value was calculated using stratified exact Cochran-Mantel-Haenszel test by adjusting for the WBC/platelet status (abnormal vs normal) at baseline.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.57
	Confidence Interval	(2-Sided) 95%; 1.50 to 9.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	The Percentage of Participants Who Achieved a Durable Complete Hematological Remission at Week 48
Description	Durable Complete Hematological Remission was defined as any participant who achieved Complete Hematological Remission at Week 32 and maintained their response up to 48 weeks after randomization.
Time Frame	48 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all participants to whom study treatment had been assigned by randomization.

Arm/Group Title	Ruxolitinib	Best Available Therapy
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy	Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.
Measure Participants	110	112
Number (95% Confidence Interval) [percentage of participants]	20.9 19%	0.9 0.8%

5. Secondary Outcome

Title	The Percentage of Participants Who Achieved a Durable Hematocrit Control at Week 48
Description	Durable Hematocrit Control was defined as any participant who achieved phlebotomy eligibility independence from Week 8 to Week 32 and maintained hematocrit control up to 48 weeks after randomization.
Time Frame	48 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all participants to whom study treatment had been assigned by randomization.

Arm/Group Title	Ruxolitinib	Best Available Therapy
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy	Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.
Measure Participants	110	112
Number (95% Confidence Interval) [percentage of participants]	54.5 49.5%	1.8 1.6%

6. Secondary Outcome

Title	The Percentage of Participants Who Achieved Durable Spleen Volume Reduction at Week 48
Description	Durable Spleen Volume Reduction was defined as a participant who achieved at least 35% reduction from baseline in spleen volume at Week 32 and maintained that response 48 weeks after randomization.
Time Frame	48 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all participants to whom study treatment had been assigned by randomization.

Arm/Group Title	Ruxolitinib	Best Available Therapy
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy	Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.
Measure Participants	110	112
Number (95% Confidence Interval) [percentage of participants]	37.3 33.9%	0.9 0.8%

7. Secondary Outcome

Title	Estimated Duration of the Primary Response
Description	Duration of the primary response is defined as the time from the first occurrence when both components of the primary endpoint are met until the date of the first documented disease progression (end of response). Kaplan-Meier estimates are provided for duration of primary response.
Time Frame	Through study completion, analysis was conducted when all participants had completed the Week 80 visit or discontinued the study

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all participants to whom study treatment had been assigned by randomization. Duration of response was pre-specified in the protocol to be analyzed for the ruxolitinib arm only considering the study design which allowed crossover for the BAT arm beginning at Week 32.

Arm/Group Title	Ruxolitinib
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy
Measure Participants	110
16 weeks	1.00
32 weeks	1.00
48 weeks	0.92
64 weeks	0.92
80 weeks	0.92
96 weeks	0.88
112 weeks	0.84
128 weeks	0.84
144 weeks	0.84
160 weeks	0.79
176 weeks	0.79
192 weeks	0.74
208 weeks	0.74
224 weeks	0.74
240 weeks	NA
256 weeks	NA

8. Secondary Outcome

Title	The Percentage of Participants Who Achieved Overall Clinicohematologic Response at Week 32
Description	Overall Clinicohematologic Response is defined as any participant who achieved a complete or partial clinicohematologic response per the European LeukemiaNet modified criteria for response in polycythemia vera (PV). A Complete Response (CR) is defined as: hematocrit control, spleen volume reduction at least 35% from baseline, platelet count less than or equal to 400 x 10(9)/L, and white blood cell count less than or equal to 10 x 10(9)/L. A Partial Response (PR) is defined as hematocrit control or response in all 3 of the other criteria.
Time Frame	32 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all participants to whom study treatment had been assigned by randomization.

Arm/Group Title	Ruxolitinib	Best Available Therapy
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy	Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.
Measure Participants	110	112
Complete response rate	8.2 7.5%	0.9 0.8%
Partial response rate	54.5 49.5%	18.8 16.8%

9. Secondary Outcome

Title	The Percentage of Participants Achieving a Durable Complete or Partial Clinicohematologic Response at Week 48
Description	Durable Complete or Partial Clinicohematologic Response was defined as any participant who achieved complete or partial clinicohematologic response per the European LeukemiaNet modified criteria for response in polycythemia vera at Week 32 and maintained that response 48 weeks after randomization.
Time Frame	48 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all participants to whom study treatment had been assigned by randomization.

Arm/Group Title	Ruxolitinib	Best Available Therapy
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy	Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.
Measure Participants	110	112
Complete response rate	7.3 6.6%	0.9 0.8%
Partial response rate	50.9 46.3%	0.9 0.8%

10. Secondary Outcome

Title	Estimated Duration of the Complete Hematological Remission
Description	Duration of the complete hematological remission is defined as the time from the first occurrence of complete hematological remission until the date of the first documented progression (end of response). Kaplan-Meier estimates are provided for duration of complete hematological remission.
Time Frame	Through study completion, analysis was conducted when all participants had completed the Week 80 visit or discontinued the study

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all participants to whom study treatment had been assigned by randomization. Duration of response was pre-specified in the protocol to be analyzed for the ruxolitinib arm only considering the study design which allowed crossover for the BAT arm beginning at Week 32.

Arm/Group Title	Ruxolitinib
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy
Measure Participants	110
16 weeks	1.00
32 weeks	1.00
48 weeks	0.88
64 weeks	0.83
80 weeks	0.74
96 weeks	0.74
112 weeks	0.69
128 weeks	0.69
144 weeks	0.65
160 weeks	0.65
176 weeks	0.55
192 weeks	0.55
208 weeks	0.55
224 weeks	0.55
240 weeks	NA
256 weeks	NA

11. Secondary Outcome

Title	Duration of the Absence of Phlebotomy Eligibility
Description	Duration of the absence of phlebotomy eligibility is defined as the time from the first occurrence of absence of phlebotomy eligibility until the date of the first documented progression.
Time Frame	256 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all participants to whom study treatment had been assigned by randomization. Duration of the absence of phlebotomy eligibility was pre-specified in the protocol to be analyzed for the ruxolitinib arm only considering the study design which allowed crossover for the BAT arm beginning at Week 32.

Arm/Group Title	Ruxolitinib
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy
Measure Participants	110
16 weeks	1.00
32 weeks	1.00
48 weeks	0.97
64 weeks	0.92
80 weeks	0.91
96 weeks	0.91
112 weeks	0.87
128 weeks	0.84
144 weeks	0.84
160 weeks	0.82
176 weeks	0.79
192 weeks	0.77
208 weeks	0.73
224 weeks	0.73
240 weeks	0.73
256 weeks	0.73

12. Secondary Outcome

Title	Duration of Reduction in Spleen Volume
Description	Duration of spleen volume reduction is defined as the time from the first occurrence of a >=35% reduction from baseline in spleen volume until the date of the first documented progression.
Time Frame	256 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all participants to whom study treatment had been assigned by randomization. Duration of the reduction in spleen volume was pre-specified in the protocol to be analyzed for the ruxolitinib arm only considering the study design which allowed crossover for the BAT arm beginning at Week 32.

Arm/Group Title	Ruxolitinib
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy
Measure Participants	110
16 weeks	1.00
32 weeks	1.00
48 weeks	1.00
64 weeks	1.00
80 weeks	1.00
96 weeks	0.98
112 weeks	0.95
128 weeks	0.95
144 weeks	0.95
160 weeks	0.93
176 weeks	0.93
192 weeks	0.93
208 weeks	0.87
224 weeks	0.72
240 weeks	NA
256 weeks	NA

13. Secondary Outcome

Title	Duration of The Overall Clinicohematologic Response
Description	Duration of the overall clinicohematologic response was defined as the time from the first occurrence of complete response (CR) or partial response (PR) until the date of the first documented disease progression.
Time Frame	256 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all participants to whom study treatment had been assigned by randomization. Duration of the overall clinicohematologic response was pre-specified in the protocol to be analyzed for the ruxolitinib arm only considering the study design which allowed crossover for the BAT arm beginning at Week 32.

Arm/Group Title	Ruxolitinib
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy
Measure Participants	110
16 weeks	1.00
32 weeks	0.99
48 weeks	0.96
64 weeks	0.91
80 weeks	0.88
96 weeks	0.88
112 weeks	0.85
128 weeks	0.82
144 weeks	0.82
160 weeks	0.80
176 weeks	0.75
192 weeks	0.70
208 weeks	0.67
224 weeks	0.67
240 weeks	0.67
256 weeks	0.67

Adverse Events

Time Frame	The initial data reported was for the study up to Week 32. This time frame defines the comparative phase of the study where the majority of participants remained on their original randomized assignment and exposure between ruxolitinib and best available therapy was similar. Data inclusive of end of study was reported up to week 256 for Ruxolitinib group. Long term Follow Up for BAT was not reported as all patients have completed the study or crossed over to Ruxolitinib group by week 80.
Adverse Event Reporting Description	Safety population: All participants who were enrolled and took at least 1 dose of study medication. The initial data reported at Week 32 was based on MedDRA 15.1; the remaining data reported for end of study was based on MedDRA 20.1.
Arm/Group Title	Ruxolitinib - Through Week 32		Best Available Therapy - Through Week 32		Ruxolitinib - Week 256 Close Out
Arm/Group Description	Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy		Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.		Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy
All Cause Mortality
	Ruxolitinib - Through Week 32		Best Available Therapy - Through Week 32		Ruxolitinib - Week 256 Close Out
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ruxolitinib - Through Week 32		Best Available Therapy - Through Week 32		Ruxolitinib - Week 256 Close Out
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/110 (13.6%)		10/111 (9%)		44/110 (40%)
Blood and lymphatic system disorders
Leukocytosis	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Neutropenia	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Thrombocytopenia	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Cardiac disorders
Atrial fibrillation	0/110 (0%)		1/111 (0.9%)		3/110 (2.7%)
Cardiac failure congestive	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Acute myocardial infarction	0/110 (0%)		1/111 (0.9%)		0/110 (0%)
Tachycardia	0/110 (0%)		1/111 (0.9%)		0/110 (0%)
Atrioventricular block complete	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Eye disorders
Cataract	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Glaucoma	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Retinal detachment	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Gastrointestinal disorders
Dental necrosis	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Rectal haemorrhage	0/110 (0%)		0/111 (0%)		2/110 (1.8%)
Anal fistula	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Gastric varices haemorrhage	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Haematochezia	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Ileus	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Incarcerated inguinal hernia	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Large intestinal stenosis	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Varices oesophageal	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Volvulus	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
General disorders
Chest pain	1/110 (0.9%)		0/111 (0%)		2/110 (1.8%)
Hepatobiliary disorders
Cholecystitis acute	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Cholelithiasis	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Infections and infestations
Bronchitis viral	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Diverticulitis	1/110 (0.9%)		1/111 (0.9%)		1/110 (0.9%)
Pneumonia	1/110 (0.9%)		1/111 (0.9%)		5/110 (4.5%)
Vulvovaginitis trichomonal	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Cellulitis	0/110 (0%)		1/111 (0.9%)		1/110 (0.9%)
Gastroenteritis	0/110 (0%)		1/111 (0.9%)		0/110 (0%)
Appendicitis	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Herpes zoster	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Lung infection	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Osteomyelitis	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Peritonitis	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Sepsis	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Staphylococcal infection	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Tooth abscess	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Urinary tract infection	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Injury, poisoning and procedural complications
Lumbar vertebral fracture	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Post procedural haemorrhage	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Splenic rupture	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Fall	0/110 (0%)		1/111 (0.9%)		1/110 (0.9%)
Subdural haematoma	0/110 (0%)		1/111 (0.9%)		0/110 (0%)
Post procedural haematoma	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Rib fracture	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Metabolism and nutrition disorders
Gout	0/110 (0%)		1/111 (0.9%)		0/110 (0%)
Dehydration	0/110 (0%)		0/111 (0%)		2/110 (1.8%)
Musculoskeletal and connective tissue disorders
Muscular weakness	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Intervertebral disc protrusion	0/110 (0%)		0/111 (0%)		3/110 (2.7%)
Lumbar spinal stenosis	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Musculoskeletal pain	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Spondylolisthesis	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/110 (0.9%)		0/111 (0%)		3/110 (2.7%)
Acute leukaemia	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Breast cancer	1/110 (0.9%)		0/111 (0%)		0/110 (0%)
Myelofibrosis	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Malignant melanoma	0/110 (0%)		1/111 (0.9%)		1/110 (0.9%)
Squamous cell carcinoma	0/110 (0%)		0/111 (0%)		4/110 (3.6%)
Metastatic squamous cell carcinoma	0/110 (0%)		0/111 (0%)		2/110 (1.8%)
Squamous cell carcinoma of skin	0/110 (0%)		0/111 (0%)		2/110 (1.8%)
Adenocarcinoma gastric	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Carcinoma in situ of skin	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Chronic myeloid leukaemia	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Hairy cell leukaemia	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Invasive ductal breast carcinoma	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Keratoacanthoma	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Mediastinum neoplasm	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Metastases to central nervous system	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Metastasis	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Neoplasm malignant	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Prostate cancer	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Rectosigmoid cancer	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Nervous system disorders
Neurological symptom	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Cerebral infarction	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Metabolic encephalopathy	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Psychiatric disorders
Attention deficit/hyperactivity disorder	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Renal and urinary disorders
Bladder disorder	0/110 (0%)		1/111 (0.9%)		0/110 (0%)
Acute kidney injury	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/110 (0.9%)		0/111 (0%)		1/110 (0.9%)
Pulmonary embolism	0/110 (0%)		1/111 (0.9%)		0/110 (0%)
Atelectasis	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Respiratory failure	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Vascular disorders
Deep vein thrombosis	0/110 (0%)		1/111 (0.9%)		0/110 (0%)
Hypotension	0/110 (0%)		0/111 (0%)		1/110 (0.9%)
Other (Not Including Serious) Adverse Events
	Ruxolitinib - Through Week 32		Best Available Therapy - Through Week 32		Ruxolitinib - Week 256 Close Out
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	105/110 (95.5%)		104/111 (93.7%)		107/110 (97.3%)
Blood and lymphatic system disorders
Anaemia	20/110 (18.2%)		3/111 (2.7%)		38/110 (34.5%)
Thrombocytopenia	9/110 (8.2%)		12/111 (10.8%)		19/110 (17.3%)
Ear and labyrinth disorders
Tinnitus	6/110 (5.5%)		3/111 (2.7%)		9/110 (8.2%)
Vertigo	0/110 (0%)		0/111 (0%)		7/110 (6.4%)
Gastrointestinal disorders
Diarrhoea	16/110 (14.5%)		8/111 (7.2%)		30/110 (27.3%)
Abdominal pain	10/110 (9.1%)		13/111 (11.7%)		16/110 (14.5%)
Constipation	9/110 (8.2%)		3/111 (2.7%)		14/110 (12.7%)
Nausea	7/110 (6.4%)		4/111 (3.6%)		15/110 (13.6%)
Abdominal pain upper	6/110 (5.5%)		5/111 (4.5%)		12/110 (10.9%)
Abdominal distension	0/110 (0%)		0/111 (0%)		6/110 (5.5%)
Dyspepsia	0/110 (0%)		0/111 (0%)		7/110 (6.4%)
Vomiting	0/110 (0%)		0/111 (0%)		6/110 (5.5%)
General disorders
Fatigue	16/110 (14.5%)		17/111 (15.3%)		22/110 (20%)
Asthenia	8/110 (7.3%)		12/111 (10.8%)		16/110 (14.5%)
Oedema peripheral	7/110 (6.4%)		7/111 (6.3%)		9/110 (8.2%)
Oedema	0/110 (0%)		0/111 (0%)		7/110 (6.4%)
Pyrexia	0/110 (0%)		0/111 (0%)		17/110 (15.5%)
Infections and infestations
Nasopharyngitis	10/110 (9.1%)		9/111 (8.1%)		19/110 (17.3%)
Herpes zoster	7/110 (6.4%)		0/111 (0%)		19/110 (17.3%)
Bronchitis	0/110 (0%)		0/111 (0%)		14/110 (12.7%)
Influenza	0/110 (0%)		0/111 (0%)		13/110 (11.8%)
Pharyngitis	0/110 (0%)		0/111 (0%)		6/110 (5.5%)
Upper respiratory tract infection	0/110 (0%)		0/111 (0%)		10/110 (9.1%)
Urinary tract infection	0/110 (0%)		0/111 (0%)		10/110 (9.1%)
Injury, poisoning and procedural complications
Contusion	0/110 (0%)		0/111 (0%)		6/110 (5.5%)
Investigations
Weight increased	6/110 (5.5%)		1/111 (0.9%)		26/110 (23.6%)
Gamma-glutamyltransferase increased	6/110 (5.5%)		3/111 (2.7%)		9/110 (8.2%)
Alanine aminotransferase increased	0/110 (0%)		0/111 (0%)		7/110 (6.4%)
Aspartate aminotransferase increased	0/110 (0%)		0/111 (0%)		7/110 (6.4%)
Blood cholesterol increased	0/110 (0%)		0/111 (0%)		6/110 (5.5%)
Metabolism and nutrition disorders
Decreased appetite	3/110 (2.7%)		6/111 (5.4%)		9/110 (8.2%)
Musculoskeletal and connective tissue disorders
Muscle spasms	13/110 (11.8%)		5/111 (4.5%)		22/110 (20%)
Arthralgia	8/110 (7.3%)		7/111 (6.3%)		24/110 (21.8%)
Back pain	6/110 (5.5%)		4/111 (3.6%)		17/110 (15.5%)
Myalgia	5/110 (4.5%)		8/111 (7.2%)		7/110 (6.4%)
Bone pain	3/110 (2.7%)		6/111 (5.4%)		4/110 (3.6%)
Musculoskeletal pain	0/110 (0%)		0/111 (0%)		7/110 (6.4%)
Osteoarthritis	0/110 (0%)		0/111 (0%)		6/110 (5.5%)
Pain in extremity	0/110 (0%)		0/111 (0%)		10/110 (9.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/110 (0%)		0/111 (0%)		16/110 (14.5%)
Myelofibrosis	0/110 (0%)		0/111 (0%)		8/110 (7.3%)
Squamous cell carcinoma of skin	0/110 (0%)		0/111 (0%)		7/110 (6.4%)
Nervous system disorders
Headache	18/110 (16.4%)		21/111 (18.9%)		25/110 (22.7%)
Dizziness	13/110 (11.8%)		11/111 (9.9%)		17/110 (15.5%)
Paraesthesia	5/110 (4.5%)		7/111 (6.3%)		7/110 (6.4%)
Hypoaesthesia	0/110 (0%)		0/111 (0%)		6/110 (5.5%)
Neuralgia	0/110 (0%)		0/111 (0%)		6/110 (5.5%)
Neuropathy peripheral	0/110 (0%)		0/111 (0%)		6/110 (5.5%)
Psychiatric disorders
Insomnia	5/110 (4.5%)		6/111 (5.4%)		11/110 (10%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	11/110 (10%)		2/111 (1.8%)		19/110 (17.3%)
Cough	9/110 (8.2%)		6/111 (5.4%)		20/110 (18.2%)
Epistaxis	7/110 (6.4%)		3/111 (2.7%)		9/110 (8.2%)
Skin and subcutaneous tissue disorders
Pruritus	15/110 (13.6%)		25/111 (22.5%)		30/110 (27.3%)
Night sweats	6/110 (5.5%)		9/111 (8.1%)		13/110 (11.8%)
Vascular disorders
Haematoma	6/110 (5.5%)		3/111 (2.7%)		11/110 (10%)
Hypertension	0/110 (0%)		0/111 (0%)		17/110 (15.5%)

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.