Phase III Study Investigating the Efficacy and Safety of Ruxolitinib in Early Myelofibrosis Patients With High Molecular Risk Mutations.

Study Overview
=================
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.

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

Conditions
-----------------
Myelofibrosis With High Molecular Risk Mutations

Intervention / Treatment
-----------------
* Drug: Ruxolitinib
* Drug: Ruxolitinib Placebo


Participation Criteria
=================
Eligibility 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ruxolitinib<br>Two tablets of ruxolitinib 5 mg were administered orally twice per day. | Drug: Ruxolitinib<br>* 5 mg tablet for oral use<br>* Other names: INC424;|
| Placebo Comparator: Ruxolitinib Placebo<br>Two tablets of 5mg placebo were administered orally twice per day. | Drug: Ruxolitinib Placebo<br>* 5 mg placebo tablet for oral use<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS-1) | 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 | From randomization till disease progression (estimated to be assessed up 48 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Primary Progression (TTP) | TTP is defined as time from randomization until disease progression as defined for PFS-1 excluding death as an event. | From randomization till progression (estimated to be assessed up to 48 months) | 
| Percentage Change in Spleen Volume From Baseline | Change in spleen volume (by MRI/CT) from baseline | From baseline and assessed on 12 week intervals until end of treatment (EOT) | 
| Percentage Change in Symptoms From Baseline Using MF-7 | 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. | From Baseline and assessed every 4 weeks until end of treatment | 
| Number of Participants With Specific Subscale Scores (From Baseline) Using EQ-5D | 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. | From Baseline and assessed every 4 weeks until end of treatment | 
| Overall Survival | To evaluate the effect of ruxolitinib on overall survival | Time from randomization to date of death due to any cause (estimated to be assessed up to 48 months). | 
| Plasma Ruxolitinib Concentrations | Characterize pharmacokinetics (PK)by utilizing a population PK approach. | Week 12, Wk 48 | 
| Progression Free Survival (PFS-2) | 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 | From date of randomization until second disease progression or death, whichever comes first (estimated to be assessed up to 72 months) | 
| Quality-adjusted Life Years From Baseline | 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. | 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 | 
| Time to First Progressive Splenomegaly (TTPS) | Time to first progressive splenomegaly as determined by spleen volume (by Magnetic Resonance Imaging (MRI)/Computed Tomography (CT). | From randomization until earliest time to progressive splenomegaly (estimated to be assessed up to 48 months) | 
| Time to First Symptomatic Progression (TTSP) | Time to first symptomatic progression as determined by Myelofibrosis 7 Item Symptom Scale (MF-7) | From randomization until symptomatic progression (MF-7)(estimated to be assessed up to 48 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Early Myelofibrosis, high molecular risk mutations., Ruxolitinib, INC424, High molecular risk mutations, HMR