Clinical trial NCT02038036: Ruxolitinib Efficacy and Safety in Patients With HU Resistant or Intolerant Polycythemia Vera vs Best Available Therapy.
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Polycythemia Vera
Keywords: Polycythemia Vera
Hematologic Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Hydroxyurea
INC424
Ruxolitinib
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2014-01-16
Enrollment: 149
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study compared the efficacy and safety of ruxolitinib to Best Available Therapy (BAT) in patients with polycythemia vera (PV) who were hydroxyurea (HU) resistant or intolerant and did not have a palpable spleen.

Detailed description: This was a prospective, multi-center, open-label, randomized, Phase IIIb study evaluating efficacy and safety of ruxolitinib versus BAT as selected by the Investigator in patients with PV who are resistant to, or intolerant of HU.

The study comprised of the following periods:

Screening Period (up to 5 weeks: Day -35 to Day -1): Screening evaluations were performed at one or more clinic visits, and reviewed to determine eligibility before the patient was randomized in the study.

Core Treatment Period (Day 1 to Week 80):

Patients were randomized in 1:1 ratio to either treatment group (ruxolitinib or BAT) and were to be treated with their randomized treatment.

Crossover Treatment Period (Week 28 or after) for BAT patients only:

Patients randomized to BAT who did not respond by Week 28 were eligible to crossover and start treatment with ruxolitinib. Patients crossing over on or after Week 28 had to complete all assessments for the End of Treatment (EoT) visit of the Core Treatment Period followed by the assessments in Cross-over visit evaluation schedule.

Extended Treatment Period (Week 80 to Week 260):

Patients receiving ruxolitinib at Week 80 (including patients who have crossed over from BAT) were eligible to continue up to Week 260 in the Extended Treatment Period. Patients continued the ruxolitinib dose that they received at Week 80. Patients who received BAT at Week 80 were not eligible to enter the Extended Treatment Period and had to have the EoT visit at Week 80 and an End of study (EoS) visit 30 days after the EoT visit.

Follow-up Period:

Patients were followed for safety during 30 days after the last dose of study drug and EoS visit assessments were performed post 30 days after the last dose of study drug. Patients who completed EoT (Week 80 for patients who received BAT, Week 260 for patients who received ruxolitinib or from the time of premature discontinuation) were to be followed-up for every 3 months for survival till the end of the study.

Eligibility 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.

Primary outcomes:
measure: Number of Participants Achieving Hematocrit (Hct) Control at Week 28
timeFrame: Week 28
Secondary outcomes:
measure: Number of Participants Achieving a Complete Hematological Remission at Week 28
timeFrame: Week 28
measure: Number of Participants Achieving a Hematocrit (Hct) Control at Week 52 and Week 80
timeFrame: Week 52 and 80
measure: Number of Participants Achieving a Complete Hematological Remission at Week 52 and Week 80
timeFrame: Week 52 and 80
measure: Number of Participants With Phlebotomies Over Time
timeFrame: Baseline to Week 260
measure: Change From Baseline in Hematocrit (Hct) at Each Visit
timeFrame: Baseline, 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 260
measure: Change From Baseline in Hematocrit (Hct) at Each Scheduled Visit After Crossover in Participants Randomized to BAT Who Cross Over to Ruxolitinib
timeFrame: Baseline (last assessment before cross over), Week 4, 8, 12, 16, 20, 24, 28, 40, 52, 64, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206, 219 and 232 after cross-over
measure: Spleen Length by Visit
timeFrame: 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 260
measure: Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to Week 28
timeFrame: Baseline and Week 28
measure: Number of Participants 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
timeFrame: Week 28
measure: Number of Participants Who Achieved Partial Remission Based on the European Leukemia Net (ELN) and International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Criteria at Week 52 and Week 80
timeFrame: Week 52 and 80
measure: Number of Participants Achieving a Hematocrit (Hct) Control at Week 104, Week 156, Week 208 and Week 260.
timeFrame: From Week 8 to Week 104, 156, 208 and 260
measure: Number of Participants Achieving a Complete Hematological Remission at Week 104, Week 156, Week 208 and Week 260
timeFrame: From Week 8 to Week 104, 156, 208 and 260
measure: Number of Participants Who Achieved Partial Remission Based on the European Leukemia Net (ELN) and International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Criteria at Week 104, Week 156, Week 208 and Week 260.
timeFrame: From Week 8 to Week 104, 156, 208 and 260
measure: Number of Participants With Transformation Free Survival Events
timeFrame: Week 260 (ruxolitinib arm) and Week 80 (BAT arm)
measure: Number of Participants With Overall Survival (OS) Events
timeFrame: up to Week 260
measure: Change From Baseline in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)
timeFrame: Baseline, Week 4, 8, 16, 28, 40, 52, 80, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234 and 247
measure: Change From Baseline in Total Scores of MPN-SAF by Visit in Patients From BAT Group Who Cross Over to Ruxolitinib After Crossover
timeFrame: Baseline (last assessment before cross over), Week 4, 8, 16, 24, 28, 40, 52, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234 and 247 after cross-over
measure: Change From Baseline in Score as Per European Quality of Life 5-Dimension 5-level (EQ-5D-5L) Questionnaire
timeFrame: Baseline, Week 4, 8, 16, 28, 52, 80, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234 and 247
measure: Change From Baseline in EQ-5D-5L VAS, by Visit in Patients From BAT Group Who Cross Over to Ruxolitinib After Crossover
timeFrame: Baseline (last assessment before cross over), Week 4, 8, 16, 24, 28, 52, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234 and 247 after cross-over
measure: Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire
timeFrame: Baseline, Week 4, 8, 16, 28, 52 and 80
measure: Change From Baseline in Work Productivity and Activity Impairment Questionnaire (WPAI), by Visit in Patients From BAT Group Who Cross Over to Ruxolitinib After Crossover
timeFrame: Baseline (last assessment before cross over), Week 4, 8, 16, 24, 28 and 52 after cross-over
measure: Patient Global Impression of Change (PGIC)
timeFrame: Week 4, 8, 16, 28, 40, 52 and 80
measure: Summary of Patient Global Impression of Change (PGIC), by Visit in Patients From BAT Group Who Cross Over to Ruxolitinib After Crossover
timeFrame: Baseline (last assessment before cross over), Week 4, 8, 16, 24, 28, 40, and 52 after cross-over
measure: Number of Participants Developing Thrombosis
timeFrame: From randomization to Week 80 for BAT and Week 260 for Ruxolitinib
Other outcomes:
Locations:
city: Herston
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Antwerpen
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Bayonne
country: France
facility: Novartis Investigative Site
state: Bayonne Cedex
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Brest
country: France
facility: Novartis Investigative Site
city: Lille cedex
country: France
facility: Novartis Investigative Site
city: Nice Cedex
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Augsburg
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Magdeburg
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Minden
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Kaposvar
country: Hungary
facility: Novartis Investigative Site
city: Mumbai
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Vellore
country: India
facility: Novartis Investigative Site
state: Tamil Nadu
city: Nahariya
country: Israel
facility: Novartis Investigative Site
city: Netanya
country: Israel
facility: Novartis Investigative Site
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: Lazio
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Pavia
country: Italy
facility: Novartis Investigative Site
state: PV
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Varese
country: Italy
facility: Novartis Investigative Site
state: VA
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Salamanca
country: Spain
facility: Novartis Investigative Site
state: Castilla Y Leon
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Alicante
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: La Coruna
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Las Palmas de Gran Canaria
country: Spain
facility: Novartis Investigative Site
state: Las Palmas De G.C
city: Pamplona
country: Spain
facility: Novartis Investigative Site
state: Navarra
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Talas / Kayseri
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Passamonti F, Palandri F, Saydam G, Callum J, Devos T, Guglielmelli P, Vannucchi AM, Zor E, Zuurman M, Gilotti G, Zhang Y, Griesshammer M. Ruxolitinib versus best available therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study. Lancet Haematol. 2022 Jul;9(7):e480-e492. doi: 10.1016/S2352-3026(22)00102-8. Epub 2022 May 18.
citation: Kiladjian JJ, Guglielmelli P, Griesshammer M, Saydam G, Masszi T, Durrant S, Passamonti F, Jones M, Zhen H, Li J, Gadbaw B, Perez Ronco J, Khan M, Verstovsek S. Efficacy and safety of ruxolitinib after and versus interferon use in the RESPONSE studies. Ann Hematol. 2018 Apr;97(4):617-627. doi: 10.1007/s00277-017-3225-1. Epub 2018 Feb 2.
citation: Passamonti F, Griesshammer M, Palandri F, Egyed M, Benevolo G, Devos T, Callum J, Vannucchi AM, Sivgin S, Bensasson C, Khan M, Mounedji N, Saydam G. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol. 2017 Jan;18(1):88-99. doi: 10.1016/S1470-2045(16)30558-7. Epub 2016 Dec 2.