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Ruxolitinib Efficacy and Safety in Patients With HU Resistant or Intolerant Polycythemia Vera vs Best Available Therapy. (RESPONSE-2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02038036
Recruitment Status : Completed
First Posted : January 16, 2014
Last Update Posted : October 12, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This trial will compare the efficacy and safety of ruxolitinib to Best Available Therapy (BAT) in patients with polycythemia vera (PV) who are hyroxyurea (HU) resistant or intolerant and do not have a palpable spleen.

Condition or disease Intervention/treatment Phase
Polycythemia Vera Drug: Best Available Therapy Drug: Ruxolitinib Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 149 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized, Open Label, Multicenter Phase IIIb Study Evaluating the Efficacy and Safety of Ruxolitinib Versus Best Available Therapy in Patients With Polycythemia Vera Who Are Hydroxyurea Resistant or Intolerant (Response 2)
Actual Study Start Date : March 25, 2014
Actual Primary Completion Date : September 29, 2015
Actual Study Completion Date : April 7, 2020


Arm Intervention/treatment
Experimental: Ruxolitinib
Ruxolitinib at a starting dose of 10 mg twice a day (bid). Dose may be adjusted based on efficacy and safety parameters up to a maximum dose of 25 mg bid.
Drug: Ruxolitinib
Supplied as tablets. Starting dose of 10 mg bid. Based on efficacy and safety parameters, dose may be increased or decreased. Maximum dose allowed is 25mg bid.
Other Name: INC424

Active Comparator: Best Available Therapy (BAT)
Best Available Therapy as selected by the investigator from: Hydroxyurea, IFN/PEG-IFN, popobroman, anagrelide, IMIDs, or observation
Drug: Best Available Therapy
Best Available Therapy as selected by the investigator from the below: 1. Hydroxyurea 2. IFN/PEG-IFN 3. Pipobroman 4. Anagrelide 5. IMIDs 6. Observation only
Other Name: BAT




Primary Outcome Measures :
  1. Proportion of patients achieving hematocrit (Hct) control at Week 28 [ Time Frame: Week 28 ]

    Proportion of patients achieving Hct control at Week 28 as defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 28, with no more than one phlebotomy eligibility occurring post randomization and prior to Week 8.

    Phlebotomy eligibility will be defined by:

    • Confirmed Hct > 45% that is at least 3 percentage points higher than the Hct obtained at Baseline Or
    • Confirmed Hct > 48%, and
    • The confirmation will occur 2 to 14 days subsequent to the initial observation


Secondary Outcome Measures :
  1. Proportion of patients achieving a complete hematological remission at Week 28 [ Time Frame: Week 28 ]

    Proportion of patients achieving a complete hematological remission at Week 28 as defined by:

    • Hct control at Week 28 defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 28, with no more than one phlebotomy eligibility occurring post randomization and prior to Week 8, and
    • WBC < 10 x109/L at Week 28, and
    • Platelets ≤ 400 x 109/L at Week 28

  2. Proportion of patients achieving a Hct control at Week 52 and Week 80 [ Time Frame: Week 52 and Week 80 ]

    Proportion of patients achieving a Hct control at Week 52 as defined by:

    • The absence of phlebotomy eligibility starting at Week 8 and continuing through Week 52 and
    • No more than one phlebotomy eligibility occurring post randomization and prior to Week 8, and In the BAT arm, no change in the treatment regimen or crossover to the ruxolitinib arm.

    Endpoint for Week 80 is defined, similarly.


  3. Proportion of patients achieving a complete hematological remission at Week 52 and Week 80 [ Time Frame: Week 52 and Week 80 ]

    Proportion of patients achieving a complete hematological remission at

    Week 52, as defined by:

    • Hct control at Week 52, as defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 52 with no more than one phlebotomy eligibility occurring post randomization and prior to Week 8, and
    • White Blood Count (WBC) < 10 x10^9/L at Week 52, and
    • Platelets ≤ 400 x 10^9/L at Week 52, and In the BAT arm, no change in the treatment regimen or crossover to the ruxolitinib arm. Endpoint for Week 80 is defined, similarly.

  4. Number of phlebotomies from Baseline up to Week 28. [ Time Frame: From baseline up to Week 28 ]
    Number of phlebotomies from Baseline up to Week 28.

  5. Change from Baseline in Hct [ Time Frame: Baseline, and Week 4, 8, 12, 16, 20, 24, 28, 40, 52, 66, 80, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234, 247 and End of treatment (up to Week 260) ]
    Change from Baseline in Hct at each visit

  6. Spleen length by visit [ Time Frame: Week 4, 8, 12, 16, 20, 24, 28, 40, 52, 66, 80, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234, 247 and End of treatment (up to Week 260) ]
    Summary of spleen length by visit

  7. Change from baseline in Eastern Cooperative Oncology Group (ECOG) performance status [ Time Frame: From baseline up to Week 28 ]
    The ECOG scale of performance status describes the level of functioning of participants in terms of their ability to care for themselves, daily activity, and physical ability. The ECOG performance was recorded as per ECOG performance status grades ranging from 0 (fully active, able to carry on all pre-disease performance without restriction) to 5 (dead).

  8. Proportion of patients achieving a partial remission based on the European Leukemia Net (ELN) and International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria at Week 28 [ Time Frame: Week 28 ]

    Proportion of patients achieving a partial remission at Week 28, based on the ELN and IWG-MRT criteria, as defined by:

    • Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) score reduction of greater than or equal to 10 points from baseline to Week 28, and
    • Hct control defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 28, with no more than one phlebotomy eligibility occurring post randomization and prior to Week 8, and
    • WBC < 10 x10^9/L at Week 28, and
    • Platelets ≤ 400 x 10^9/L at Week 28, and
    • No palpable spleen at Week 28, and
    • No hemorrhagic or thrombotic events, and
    • No transformation into post-PV myelofibrosis, myelodysplastic syndrome (IWG-MRT criteria) or acute leukemia (WHO criteria).

  9. Proportion of patients who achieved partial remission based on the ELN and IWG-MRT criteria at Week 52 and Week 80 [ Time Frame: Week 52 and Week 80 ]

    Proportion of patients who achieved partial remission at Week 52 based on the ELN and IWG-MRT criteria, as defined by:

    • MPN-SAF TSS score reduction of greater than or equal to 10 points from baseline to Week 52 and
    • Hct control defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 52 with no more than one phlebotomy eligibility occurring post randomization and prior to Week 8, and
    • WBC < 10 x109/L at Week 52 and
    • Platelets ≤ 400 x 109/L at Week 52 and
    • No palpable spleen at Week 52 and
    • No hemorrhagic or thrombotic events, and
    • No transformation into post-PV myelofibrosis, myelodysplastic syndrome (IWG-MRT criteria) or acute leukemia (WHO criteria).

    In the BAT arm, no change in the treatment regimen or crossover to the ruxolitinib arm.

    Endpoint for Week 80 is defined, similarly.


  10. Change from Baseline (last assessment before cross over) in Hct at each scheduled visit after crossover in patients randomized to BAT who cross over to ruxolitinib [ Time Frame: Baseline (last assessment before cross over) and Week 4, 8, 12, 16, 20, 24, 28, 40, 52, 92, 104, 117, 130, 143, 156, 169,182,195,208,221,234, 247 and End of treatment (up to Week 260) after cross-over ]
    Change from Baseline (last assessment before cross over) in Hct at each scheduled visit after crossover in patients randomized to BAT who cross-over to ruxolitinib

  11. Proportion of patients achieving a Hct control at Week 104, Week 156, Week 208 and Week 260. [ Time Frame: Week 104, 156, 208 and 260 ]

    Proportion of patients achieving a Hct control at Week 104 as defined by:

    • The absence of phlebotomy eligibility starting at Week 8 and continuing through Week 104 and
    • With no more than one phlebotomy eligibility occurring post randomization and prior to Week 8 Endpoint for Week 156, Week 208 and Week 260 are defined, similarly.

  12. Proportion of patients achieving a complete hematological remission at Week 104, Week 156, Week 208 and Week 260 [ Time Frame: Week 104, 156, 208 and 260 ]

    Proportion of patients achieving a complete hematological remission at Week 104 as defined by:

    • Hct control defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 104, with no more than one phlebotomy eligibility occurring post randomization and prior to Week 8, and
    • WBC < 10 x10^9/L at Week 104, and
    • Platelets ≤ 400 x 10^9/L at Week 104 Endpoint for Week 156, Week 208 and Week 260 are defined, similarly.

  13. Proportion of patients who achieved partial remission based on the ELN and IWG-MRT criteria at Week 104, Week 156, Week 208 and Week 260. [ Time Frame: Week 104, 156, 208 and 260 ]

    Proportion of patients who achieved partial remission at Week 104, based on the ELN and IWG-MRT criteria, as defined by:

    • MPN-SAF TSS score reduction of greater than or equal to 10 points from baseline to Week 104, and
    • Hct control defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 104, with no more than one phlebotomy eligibility occurring post-randomization and prior to Week 8, and
    • WBC < 10 x10^9/L at Week 104, and
    • Platelets ≤ 400 x 10^9/L at Week 104, and
    • No palpable spleen at Week 104, and
    • No hemorrhagic or thrombotic events, and
    • No transformation into post-PV myelofibrosis, myelodysplastic syndrome (IWG-MRT criteria) or acute leukemia (WHO criteria) Endpoint for Week 156, Week 208 and Week 260 are defined, similarly.

  14. Transformation free survival [ Time Frame: During the course of the study, up to Week 260 ]

    Transformation-free survival is defined as the time from the date of randomization to the date of earliest development of one of the following:

    1. Myelofibrosis (MF) as evidenced by bone marrow biopsy, or
    2. Acute leukemia as evidenced by bone marrow blast counts of at least 20%, or peripheral blast counts of at least 20% lasting at least 2 weeks.
    3. Death due to any cause during treatment period

  15. Overall survival (OS) [ Time Frame: During the course of the study, up to Week 260 ]
    OS is defined as the time from the date of randomization to the date of death due to any cause.

  16. Change from baseline in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) [ Time Frame: Baseline, and Week 4, 8, 16, 28, 40, 52, 80, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234, 247 and End of treatment (up to Week 260) ]
    The MPN-SAF TSS is a disease specific questionnaire comprised of 10 items that measures fatigue related to MPN disease and the severity of nine of the most prevalent associated symptoms. Each item is scored on a scale ranging from 0 (no fatigue/absent) to 10 (As bad as you can imagine/worst imaginable).The MPN-SAF TSS is computed as the average of the observed items multiplied by 10 to achieve a 0-to-100 scale. The MPN-SAF TSS thus has a possible score range of 0 to 100

  17. Change from baseline in pruritus symtpom impact scale (PSIS) [ Time Frame: Baseline, and Week 4, 8, 16, 28, 40, 52, 80 and End of treatment (up to Week 260) ]
    The PSIS is a six-item instrument measures the severity and how bothersome the symptom of itching/pruritus has been for the patient different periods of time.

  18. Change from baseline in score as per European Quality of Life 5-Dimension 5-level (EQ-5D-5L) questionnaire [ Time Frame: Baseline, and Week 4, 8, 16, 28, 52, 80, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234, 247 and End of treatment (up to Week 260) ]
    Change from baseline in lung cancer related symptoms, functioning and other domains of HRQoL in both cohorts with the EQ-5D-5L (a standardized questionnaire developed to assess the quality of life of cancer patients

  19. Change from baseline in work productivity and activity impairment (WPAI) questionnaire from baseline [ Time Frame: Baseline, and Week 4, 8, 16, 28, 52, 80 and at the End of treatment (up to Week 260) ]
    The Work Productivity and Activity Impairment Questionnaire:SHP (WPAI:SHP) is a six item questionnaire which is intended to measure work and activity impairment associated with polycythemia vera.

  20. Patient global impression of change (PGIC) [ Time Frame: Week 4, 8, 16, 28, 40, 52, 80 and at the End of treatment (up to Week 260) ]
    The Patient Global Impression of Change (PGIC) is comprised of a single question intended to measure a patient's perspective of improvement or deterioration over time relative to treatment. The PGIC uses a seven-point scale where one (1) equals very much improved and seven (7) equals very much worse.

  21. Frequency, duration and severity of Adverse Events (AEs) of ruxolitinib and BAT patients [ Time Frame: From randomization up to Week 260 ]
    Safety will be assessed by monitoring the frequency, duration and severity of Adverse Events, and evaluating changes in vital signs, electrocardiograms (ECGs), serum chemistry, hematology and urinalysis results.

  22. Proportion of patients developing thrombosis [ Time Frame: From randomization to Week 260 ]
    Proportion of patients developing any arterial or venous thromboembolic event

  23. Frequency, duration and severity of Adverse Events (AEs) of BAT patients after they cross-over [ Time Frame: From cross-over to week 260 ]
    Safety will be assessed by monitoring the frequency, duration and severity of Adverse Events, and evaluating changes in vital signs, electrocardiograms (ECGs), serum chemistry, hematology and urinalysis results.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Confirmed diagnosis of PV according to the 2008 World Health Organization criteria, Non-palpable spleen, Phlebotomy dependent, Resistant to or intolerant of hydroxyurea, ECOG performance status of 0, 1 or 2.

Exclusion Criteria:

Inadequate liver or renal function, Significant bacterial, fungal, parasitic, or viral infection requiring treatment, Active malignancy within the past 5 years, excluding specific skin cancers, Previously received treatment with a JAK inhibitor, Being treated with any investigational agent, Women who are pregnant or nursing.

Other inclusion/exclusion criteria apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02038036


Locations
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Australia, Queensland
Novartis Investigative Site
Herston, Queensland, Australia, 4029
Belgium
Novartis Investigative Site
Antwerpen, Belgium, 2060
Novartis Investigative Site
Leuven, Belgium, 3000
Canada, Ontario
Novartis Investigative Site
Toronto, Ontario, Canada, M4N 3M5
France
Novartis Investigative Site
Bayonne, Bayonne Cedex, France, 64109
Novartis Investigative Site
Bordeaux, France, 33076
Novartis Investigative Site
Brest, France, 29200
Novartis Investigative Site
Lille cedex, France, 59020
Novartis Investigative Site
Nice Cedex, France, 06202
Novartis Investigative Site
Paris, France, 75010
Novartis Investigative Site
Toulouse, France, 31059
Germany
Novartis Investigative Site
Mannheim, Baden-Wuerttemberg, Germany, 68305
Novartis Investigative Site
Augsburg, Germany, 86150
Novartis Investigative Site
Dresden, Germany, 01307
Novartis Investigative Site
Jena, Germany, 07740
Novartis Investigative Site
Leipzig, Germany, 04103
Novartis Investigative Site
Magdeburg, Germany, 39120
Novartis Investigative Site
Mainz, Germany, 55131
Novartis Investigative Site
Minden, Germany, 32429
Novartis Investigative Site
Ulm, Germany, 89081
Hungary
Novartis Investigative Site
Budapest, Hungary, 1085
Novartis Investigative Site
Debrecen, Hungary, 4032
Novartis Investigative Site
Kaposvar, Hungary, 7400
India
Novartis Investigative Site
Mumbai, Maharashtra, India, 400012
Novartis Investigative Site
Vellore, Tamil Nadu, India, 632 004
Israel
Novartis Investigative Site
Nahariya, Israel, 22100
Novartis Investigative Site
Netanya, Israel, 42150
Novartis Investigative Site
Tel Aviv, Israel, 6423906
Italy
Novartis Investigative Site
Bologna, BO, Italy, 40138
Novartis Investigative Site
Firenze, FI, Italy, 50134
Novartis Investigative Site
Roma, Lazio, Italy, 00168
Novartis Investigative Site
Milano, MI, Italy, 20122
Novartis Investigative Site
Pavia, PV, Italy, 27100
Novartis Investigative Site
Torino, TO, Italy, 10126
Novartis Investigative Site
Varese, VA, Italy, 21100
Korea, Republic of
Novartis Investigative Site
Seoul, Korea, Republic of, 03080
Novartis Investigative Site
Seoul, Korea, Republic of, 03722
Spain
Novartis Investigative Site
Malaga, Andalucia, Spain, 29010
Novartis Investigative Site
Salamanca, Castilla Y Leon, Spain, 37007
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site
Alicante, Comunidad Valenciana, Spain, 03010
Novartis Investigative Site
La Coruna, Galicia, Spain, 15006
Novartis Investigative Site
Las Palmas de Gran Canaria, Las Palmas De G.C, Spain, 35010
Novartis Investigative Site
Pamplona, Navarra, Spain, 31008
Novartis Investigative Site
Madrid, Spain, 28034
Novartis Investigative Site
Madrid, Spain, 28046
Turkey
Novartis Investigative Site
Izmir, Turkey, 35040
Novartis Investigative Site
Talas / Kayseri, Turkey, 38039
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02038036    
Other Study ID Numbers: CINC424B2401
First Posted: January 16, 2014    Key Record Dates
Last Update Posted: October 12, 2020
Last Verified: September 2020
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Polycythemia Vera
Hematologic Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Hydroxyurea
INC424
Ruxolitinib
Additional relevant MeSH terms:
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Polycythemia Vera
Polycythemia
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Neoplasms
Bone Marrow Diseases
Myeloproliferative Disorders