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Trial record 1 of 1 for:    CINC424A2353
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Phase III Study Investigating the Efficacy and Safety of Ruxolitinib in Early Myelofibrosis Patients With High Molecular Risk Mutations. (ReTHINK)

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: NCT02598297
Recruitment Status : Terminated (Unresolvable inability to recruit the patients.)
First Posted : November 5, 2015
Results First Posted : August 16, 2019
Last Update Posted : August 16, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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Brief Summary:
Myelofibrosis patients with high molecular risk mutations have an intrinsically aggressive disease with increased risk of leukemic transformation and reduced overall survival. As there are no therapies currently established in the subset of high molecular risk patients with early myelofibrosis, the study aimed to evaluate ruxolitinib in this patient population.

Condition or disease Intervention/treatment Phase
Myelofibrosis With High Molecular Risk Mutations Drug: Ruxolitinib Drug: Ruxolitinib Placebo Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 49 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double Blind, Placebo-controlled, Multicenter, Phase III Study Investigating the Efficacy and Safety of Ruxolitinib in Early Myelofibrosis Patients With High Molecular Risk Mutations
Actual Study Start Date : February 3, 2016
Actual Primary Completion Date : October 23, 2017
Actual Study Completion Date : October 23, 2017

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Ruxolitinib
Two tablets of ruxolitinib 5 mg were administered orally twice per day.
 Drug: Ruxolitinib
5 mg tablet for oral use
Other Name: INC424
Placebo Comparator: Ruxolitinib Placebo
Two tablets of 5mg placebo were administered orally twice per day.
 Drug: Ruxolitinib Placebo
5 mg placebo tablet for oral use


Outcome Measures
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Primary Outcome Measures :
  1. Progression Free Survival (PFS-1) [ Time Frame: From randomization till disease progression (estimated to be assessed up 48 months) ]

    Progression free survival (PFS-1) from date of randomization until the occurrence of any of the criteria for disease progression:

    • Progressive splenomegaly
    • Circulating peripheral blast counts > 10%
    • Leukemic transformation
    • Hb < 10g/dl with absolute decrease of at least 3 g/dl from baseline
    • White blood cell (WBC) counts > 25 x 103/ μL
    • MF-7 score ≥ 30
    • Death from any cause


Secondary Outcome Measures :
  1. Time to Primary Progression (TTP) [ Time Frame: From randomization till progression (estimated to be assessed up to 48 months) ]
    TTP is defined as time from randomization until disease progression as defined for PFS-1 excluding death as an event.

  2. Percentage Change in Spleen Volume From Baseline [ Time Frame: From baseline and assessed on 12 week intervals until end of treatment (EOT) ]
    Change in spleen volume (by MRI/CT) from baseline

  3. Percentage Change in Symptoms From Baseline Using MF-7 [ Time Frame: From Baseline and assessed every 4 weeks until end of treatment ]
    Percentage change from Baseline in MF-7 total symptom score and 7 individual symptoms at each visit was summarized with descriptive statistics. For this scale, symptoms range from 0 to 10 for the severity experienced within the past 24 hours, with 0 being for absence of symptoms and 10 for worst imaginable symptoms.

  4. Number of Participants With Specific Subscale Scores (From Baseline) Using EQ-5D [ Time Frame: From Baseline and assessed every 4 weeks until end of treatment ]

    EQ-ED5 profiles were summarized at baseline and at each scheduled assessment for each of the 5 dimensions separately (Mobility, self-care, usual activities, pain discomfort, anxiety/depression) Only participants with baseline score and at least one non-missing post-baseline score during the treatment period were included. Percentages were based on all these evaluable participants.

    The 5 scores for mobility, self-care, usual activities, pain/discomfort and anxiety/depression are all self-explanatory (eg "I have no problems walking" to "I am unable to walk"), except for the following overall health check, where 100 is the best of health, and 0 is the worst health.


  5. Overall Survival [ Time Frame: Time from randomization to date of death due to any cause (estimated to be assessed up to 48 months). ]
    To evaluate the effect of ruxolitinib on overall survival

  6. Plasma Ruxolitinib Concentrations [ Time Frame: Week 12, Wk 48 ]
    Characterize pharmacokinetics (PK)by utilizing a population PK approach.

  7. Progression Free Survival (PFS-2) [ Time Frame: From date of randomization until second disease progression or death, whichever comes first (estimated to be assessed up to 72 months) ]
    PFS-2 assessed by 25% increase over new baseline of PFS-1 in any of the following: ● Progressive splenomegaly ● 25 % increase in MF-7 score with absolute score ≥ 30

  8. Quality-adjusted Life Years From Baseline [ Time Frame: Change from Baseline compared with scheduled study visits at the following intervals every 4 weeks up to week 24, every 8 weeks up to Week 48, every 12 weeks past Wk 48 until End of treatment and 30 day follow up visit ]
    EQ-5D-5L (EuroQol-5D-5L, is a standardized instrument for measuring health outcomes, is consists of a descriptive system and a visual analogue scale - scores can be summarized into a single index score that provides a simple measure of health for clinical and economic appraisal ) The EQ-5D-5L health states will be converted into index values (utilities) from which the QALY (Quality - adjusted life years) will be calculated. QALY will be summarized descriptively by treatment arm.

  9. Time to First Progressive Splenomegaly (TTPS) [ Time Frame: From randomization until earliest time to progressive splenomegaly (estimated to be assessed up to 48 months) ]
    Time to first progressive splenomegaly as determined by spleen volume (by Magnetic Resonance Imaging (MRI)/Computed Tomography (CT).

  10. Time to First Symptomatic Progression (TTSP) [ Time Frame: From randomization until symptomatic progression (MF-7)(estimated to be assessed up to 48 months) ]
    Time to first symptomatic progression as determined by Myelofibrosis 7 Item Symptom Scale (MF-7)


Eligibility Criteria
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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 MF with bone marrow fibrosis of at least Grade 1; irrespective of JAK2 mutational status
  • Patients with at least one mutation in one of the five HMR genes (ASXL1, EZH2, SRSF2 and IDH1/2)
  • Patients with non-palpable spleen or spleen palpable ≤ 5 cm from the left costal margin to the point of greatest splenic protrusion
  • Patients with MF-7 score of ≤ 15, with each individual symptom score of ≤ 3

Exclusion Criteria:

  • Patients with prior treatment with ruxolitinib or other JAK inhibitors.
Contacts and Locations
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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): NCT02598297


Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] September 29, 2015
Statistical Analysis Plan  [PDF] July 25, 2017

More Information
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02598297    
Other Study ID Numbers: CINC424A2353
2014-004928-21 ( EudraCT Number )
First Posted: November 5, 2015    Key Record Dates
Results First Posted: August 16, 2019
Last Update Posted: August 16, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Early Myelofibrosis
high molecular risk mutations.
Ruxolitinib
 INC424
High molecular risk mutations
HMR
Additional relevant MeSH terms:
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Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases