search
Back to results

Efficacy and Safety of Ruxolitinib in the Treatment of Anemic Myelofibrosis Patients. (REALISE)

Primary Purpose

Primary Myelofibrosis, Post-Polycythemia Vera-Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ruxolitinib
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Myelofibrosis focused on measuring Ruxolitinib, anemia, Primary Myelofibrosis, PMF, Post-Polycythemia Vera-Myelofibrosis, PPV-MF, Post-Essential Thrombocythemia Myelofibrosis, PET-MF, adult, INC424

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Written informed consent must be obtained prior to any screening procedures.

  1. Male or female patients aged ≥ 18 years of age.
  2. Patients must have been diagnosed with PMF, according to the 2016 revised International Standard Criteria, PPV MF or PET-MF, irrespective of JAK2 mutation status.
  3. Patients must have had palpable splenomegaly that is equal to or greater than 5 cm below the left costal margin.
  4. Patients must have had hemoglobin less than 10 g/dL
  5. Patients must have had a history of transfusions must have a documented transfusion record in the previous 12 weeks to baseline.
  6. Patients must have had ECOG performance status of 0, 1, or 2.
  7. Patients must have had a peripheral blood blast percentage count of < 10%.
  8. Patients must have recovered or stabilized sufficiently from any adverse drug reactions associated with prior treatments before beginning treatment with ruxolitinib.

Exclusion Criteria:

  1. Patients who had prior treatment with any JAK1 or JAK2 inhibitor.
  2. Patients who had known hypersensitivity to ruxolitinib or other JAK1/JAK2 inhibitors, or to their excipients.
  3. Patients who had been eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available).
  4. Patients who had inadequate bone marrow reserve at baseline as demonstrated by at least one of the following:

    1. ANC that is ≤ 1,000/µL.
    2. Platelet count that is <50,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions.
    3. Hemoglobin count that is ≤ 6.5 g/dL despite transfusions.
  5. Patients who had severely impaired renal function defined by: Creatinine clearance less than 30 mL/min.
  6. Patients who had inadequate liver function defined by any of these:

    1. Total bilirubin ≥ 2.5 x ULN and subsequent determination of direct bilirubin ≥ 2.5 x ULN;
    2. Alanine aminotransferase (ALT) > 2.5 x ULN;
    3. Aspartate aminotransferase (AST) > 2.5 x ULN.
  7. Patients who were being treated concurrently with a strong (potent) systemic inhibitor or inducer of CYP3A4 at the time of Screening.
  8. Presence of active bacterial, fungal, parasitic, or viral infection which requires therapy.
  9. Known history of human immunodeficiency virus (HIV) infection or other immunodeficiency syndromes such as X-linked agammaglobulinemia and common variable immune deficiency.
  10. Acute viral hepatitis or active chronic hepatitis B or C infection. Patients with inactive chronic infection (without viral replication) can be enrolled
  11. History of progressive multifocal leuko-encephalopathy.
  12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ruxolitinib .
  13. History or current diagnosis of uncontrolled or significant cardiac disease, including any of the following:

    1. Myocardial infarction within last 6 months
    2. Uncontrolled congestive heart failure
    3. Unstable angina within last 6 months
    4. Clinically significant (symptomatic) cardiac arrhythmias (e.g. bradyarrhythmias, sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker)
  14. Significant concurrent, uncontrolled medical condition which, in the investigator's opinion, would have jeopardized the safety of the patient or compliance with the protocol.
  15. Patients who were undergoing treatment with another investigational medication or had been treated with an investigational medication within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study drug.
  16. Patients who had a history of malignancy in the past 3 years, except for treated early stage squamous or basal cell carcinoma.
  17. Patients who were unable to comprehend or are unwilling to sign an ICF.
  18. Pregnant or nursing (lactating) women
  19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they were using highly effective methods of contraception throughout the study duration inclusive of 30 day safety follow up.

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

All Subjects

Arm Description

10 mg BID (2 tablets of 5mg) was self-administered as starting dose for all patients. This dose was maintained for the first 12 weeks and titrated up thereafter unless they had met criteria for dose hold or dose reduction. Dose was to have been increased or decreased per standardized dosing paradigm and not to have exceeded 25 mg bid.

Outcomes

Primary Outcome Measures

Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 24
Percentage of participants achieving a 50% reduction in spleen length at week 24. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen are imputed as 0. Subjects who had palpable, but missing spleen length at baseline is excluded from the analysis. Subjects with missing spleen length at Week 24 or who withdraw earlier from the study are considered as a non-responder. The 95% CI is computed using exact Clopper-Pearson method.

Secondary Outcome Measures

Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 48
Percentage of participants achieving a 50% reduction in spleen length at week 48. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen is imputed as 0. Subjects who had palpable, but missing spleen length at baseline is excluded from the analysis. Subjects with missing spleen length at Week 48 or who withdraw earlier from the study are considered as a non-responder. The 95% CI is computed using exact Clopper-Pearson method.
Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48
Participants who achieved a ≤ 50% reduction in spleen length at week 24 and 48 (reduction) and participants who had no increase greater than or equal to 50% (increase). The edge of the spleen shall be determined by palpation, measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen is imputed as 0.
Percentage of Participants With at Least a 50% Reduction in Myelofibrosis 7 Item Symptom Scale (MF-7) and Myelofibrosis Symptom Assessment Form (MFSAF) at Week 24
The MF-7 is a disease specific questionnaire comprised of 7 items that measures the severity of seven of the most prevalent associated symptoms including: tiredness, early satiety, abdominal discomfort, night sweats, itching (pruritus), bone pain (diffuse not joint or arthritis) and pain under ribs on left side. Each item was scored on a scale ranging from 0 (absent) to 10 (worst imaginable). The MF-7 score is computed as the sum of the observed scores in the individual items to achieve a 0 to 70 score. There would be one recall period of 24 hours used in this questionnaire. A separate question on Inactivity was to be measured for severity of this symptom on a scale from 0 (absent) to 10 (worst imaginable). This would allow the computation of the MFSAF v2.0 questionnaire results, as 6 out of 7 items in the latter PRO are in overlap with MF7 (they also share same 0-10 range Likert scale and ascending order, absent to worst imaginable).
Patient Global Impression of Change (PGIC) at Week 24 and Week 48
The PGIC is comprised of a single question intended to measure a subject's perspective of improvement or deterioration over time relative to treatment. The PGIC uses a seven-point scale where '1' equals very much improved and '7' equals very much worse.
Percentage of Participants Transfusion Independency From Baseline up to Week 96
Percentage is based on number of subjects who are transfusion dependent at baseline. Transfusion dependence (TD) is defined as subjects receiving 6 or more units of transfusions 12 weeks prior to baseline. Transfusion independence (TI) rate is defined as subjects who are transfusion dependent at baseline and require no unit of transfusion for ≥ 12 weeks at any time during the study. Transfusion response rate is defined as subjects who are TD at baseline and have 5 or less units of transfusion for ≥ 12 weeks at any time during the study.

Full Information

First Posted
October 18, 2016
Last Updated
April 28, 2020
Sponsor
Novartis Pharmaceuticals
search

1. Study Identification

Unique Protocol Identification Number
NCT02966353
Brief Title
Efficacy and Safety of Ruxolitinib in the Treatment of Anemic Myelofibrosis Patients.
Acronym
REALISE
Official Title
A Multicenter Phase II, Open Label, Single Arm Study to Evaluate the Efficacy and Safety of Ruxolitinib in the Treatment of Anemic Myelofibrosis Patients.
Study Type
Interventional

2. Study Status

Record Verification Date
April 2020
Overall Recruitment Status
Completed
Study Start Date
March 31, 2017 (Actual)
Primary Completion Date
July 24, 2018 (Actual)
Study Completion Date
February 15, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This was a study of treatment with ruxolitinib in patients who presented with transfusion dependent or independent anemia. Starting dose was 10 mg BID. This dose was maintained for the first 12 weeks of the study and up-titrated thereafter unless the subject met criteria for dose hold or dose reduction
Detailed Description
This was a study of treatment with ruxolitinib in patients who present with transfusion dependent or independent anemia at screening defined as an hemoglobin <10 g/dL with 10 mg BID starting dose with subsequent up titrations (maximum dose 25 mg BID) depending on safety and efficacy. This dosing approach for anemic MF patients will be systematically studied in this prospective multicenter phase II open label single arm trial to determine if the levels of spleen length reduction and symptom improvement are consistent with those reported in previous clinical trials with ruxolitinib in patients with anemia and doses according to platelet counts at the moment of treatment initiation, and whether this lower starting dose and up titration approach may minimize the initial hemoglobin and platelet declines and transfusion requirements.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Myelofibrosis, Post-Polycythemia Vera-Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis
Keywords
Ruxolitinib, anemia, Primary Myelofibrosis, PMF, Post-Polycythemia Vera-Myelofibrosis, PPV-MF, Post-Essential Thrombocythemia Myelofibrosis, PET-MF, adult, INC424

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
51 (Actual)

8. Arms, Groups, and Interventions

Arm Title
All Subjects
Arm Type
Experimental
Arm Description
10 mg BID (2 tablets of 5mg) was self-administered as starting dose for all patients. This dose was maintained for the first 12 weeks and titrated up thereafter unless they had met criteria for dose hold or dose reduction. Dose was to have been increased or decreased per standardized dosing paradigm and not to have exceeded 25 mg bid.
Intervention Type
Drug
Intervention Name(s)
ruxolitinib
Intervention Description
Ruxolitinib was supplied in 5 mg tablets to be taken orally approximately 12 hours apart (morning and night)
Primary Outcome Measure Information:
Title
Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 24
Description
Percentage of participants achieving a 50% reduction in spleen length at week 24. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen are imputed as 0. Subjects who had palpable, but missing spleen length at baseline is excluded from the analysis. Subjects with missing spleen length at Week 24 or who withdraw earlier from the study are considered as a non-responder. The 95% CI is computed using exact Clopper-Pearson method.
Time Frame
Baseline up to week 24
Secondary Outcome Measure Information:
Title
Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 48
Description
Percentage of participants achieving a 50% reduction in spleen length at week 48. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen is imputed as 0. Subjects who had palpable, but missing spleen length at baseline is excluded from the analysis. Subjects with missing spleen length at Week 48 or who withdraw earlier from the study are considered as a non-responder. The 95% CI is computed using exact Clopper-Pearson method.
Time Frame
Baseline up to week 48
Title
Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48
Description
Participants who achieved a ≤ 50% reduction in spleen length at week 24 and 48 (reduction) and participants who had no increase greater than or equal to 50% (increase). The edge of the spleen shall be determined by palpation, measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen is imputed as 0.
Time Frame
baseline, weeks 24 and 48
Title
Percentage of Participants With at Least a 50% Reduction in Myelofibrosis 7 Item Symptom Scale (MF-7) and Myelofibrosis Symptom Assessment Form (MFSAF) at Week 24
Description
The MF-7 is a disease specific questionnaire comprised of 7 items that measures the severity of seven of the most prevalent associated symptoms including: tiredness, early satiety, abdominal discomfort, night sweats, itching (pruritus), bone pain (diffuse not joint or arthritis) and pain under ribs on left side. Each item was scored on a scale ranging from 0 (absent) to 10 (worst imaginable). The MF-7 score is computed as the sum of the observed scores in the individual items to achieve a 0 to 70 score. There would be one recall period of 24 hours used in this questionnaire. A separate question on Inactivity was to be measured for severity of this symptom on a scale from 0 (absent) to 10 (worst imaginable). This would allow the computation of the MFSAF v2.0 questionnaire results, as 6 out of 7 items in the latter PRO are in overlap with MF7 (they also share same 0-10 range Likert scale and ascending order, absent to worst imaginable).
Time Frame
Baseline and week 24
Title
Patient Global Impression of Change (PGIC) at Week 24 and Week 48
Description
The PGIC is comprised of a single question intended to measure a subject's perspective of improvement or deterioration over time relative to treatment. The PGIC uses a seven-point scale where '1' equals very much improved and '7' equals very much worse.
Time Frame
Baseline up to week 48
Title
Percentage of Participants Transfusion Independency From Baseline up to Week 96
Description
Percentage is based on number of subjects who are transfusion dependent at baseline. Transfusion dependence (TD) is defined as subjects receiving 6 or more units of transfusions 12 weeks prior to baseline. Transfusion independence (TI) rate is defined as subjects who are transfusion dependent at baseline and require no unit of transfusion for ≥ 12 weeks at any time during the study. Transfusion response rate is defined as subjects who are TD at baseline and have 5 or less units of transfusion for ≥ 12 weeks at any time during the study.
Time Frame
Baseline up to week 96

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Written informed consent must be obtained prior to any screening procedures. Male or female patients aged ≥ 18 years of age. Patients must have been diagnosed with PMF, according to the 2016 revised International Standard Criteria, PPV MF or PET-MF, irrespective of JAK2 mutation status. Patients must have had palpable splenomegaly that is equal to or greater than 5 cm below the left costal margin. Patients must have had hemoglobin less than 10 g/dL Patients must have had a history of transfusions must have a documented transfusion record in the previous 12 weeks to baseline. Patients must have had ECOG performance status of 0, 1, or 2. Patients must have had a peripheral blood blast percentage count of < 10%. Patients must have recovered or stabilized sufficiently from any adverse drug reactions associated with prior treatments before beginning treatment with ruxolitinib. Exclusion Criteria: Patients who had prior treatment with any JAK1 or JAK2 inhibitor. Patients who had known hypersensitivity to ruxolitinib or other JAK1/JAK2 inhibitors, or to their excipients. Patients who had been eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available). Patients who had inadequate bone marrow reserve at baseline as demonstrated by at least one of the following: ANC that is ≤ 1,000/µL. Platelet count that is <50,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions. Hemoglobin count that is ≤ 6.5 g/dL despite transfusions. Patients who had severely impaired renal function defined by: Creatinine clearance less than 30 mL/min. Patients who had inadequate liver function defined by any of these: Total bilirubin ≥ 2.5 x ULN and subsequent determination of direct bilirubin ≥ 2.5 x ULN; Alanine aminotransferase (ALT) > 2.5 x ULN; Aspartate aminotransferase (AST) > 2.5 x ULN. Patients who were being treated concurrently with a strong (potent) systemic inhibitor or inducer of CYP3A4 at the time of Screening. Presence of active bacterial, fungal, parasitic, or viral infection which requires therapy. Known history of human immunodeficiency virus (HIV) infection or other immunodeficiency syndromes such as X-linked agammaglobulinemia and common variable immune deficiency. Acute viral hepatitis or active chronic hepatitis B or C infection. Patients with inactive chronic infection (without viral replication) can be enrolled History of progressive multifocal leuko-encephalopathy. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ruxolitinib . History or current diagnosis of uncontrolled or significant cardiac disease, including any of the following: Myocardial infarction within last 6 months Uncontrolled congestive heart failure Unstable angina within last 6 months Clinically significant (symptomatic) cardiac arrhythmias (e.g. bradyarrhythmias, sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker) Significant concurrent, uncontrolled medical condition which, in the investigator's opinion, would have jeopardized the safety of the patient or compliance with the protocol. Patients who were undergoing treatment with another investigational medication or had been treated with an investigational medication within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study drug. Patients who had a history of malignancy in the past 3 years, except for treated early stage squamous or basal cell carcinoma. Patients who were unable to comprehend or are unwilling to sign an ICF. Pregnant or nursing (lactating) women Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they were using highly effective methods of contraception throughout the study duration inclusive of 30 day safety follow up.
Facility Information:
Facility Name
Novartis Investigative Site
City
Vienna
ZIP/Postal Code
A-1090
Country
Austria
Facility Name
Novartis Investigative Site
City
Antwerpen
ZIP/Postal Code
2060
Country
Belgium
Facility Name
Novartis Investigative Site
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Novartis Investigative Site
City
Sofia
ZIP/Postal Code
1413
Country
Bulgaria
Facility Name
Novartis Investigative Site
City
Sofia
ZIP/Postal Code
1756
Country
Bulgaria
Facility Name
Novartis Investigative Site
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V5Z 1M9
Country
Canada
Facility Name
Novartis Investigative Site
City
Halle S
ZIP/Postal Code
06120
Country
Germany
Facility Name
Novartis Investigative Site
City
Athens
State/Province
GR
ZIP/Postal Code
115 27
Country
Greece
Facility Name
Novartis Investigative Site
City
Bologna
State/Province
BO
ZIP/Postal Code
40138
Country
Italy
Facility Name
Novartis Investigative Site
City
Firenze
State/Province
FI
ZIP/Postal Code
50134
Country
Italy
Facility Name
Novartis Investigative Site
City
Palermo
State/Province
PA
ZIP/Postal Code
90127
Country
Italy
Facility Name
Novartis Investigative Site
City
Bunkyo ku
State/Province
Tokyo
ZIP/Postal Code
113-8431
Country
Japan
Facility Name
Novartis Investigative Site
City
Moscow
ZIP/Postal Code
125167
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Moscow
ZIP/Postal Code
129110
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Petrozavodsk
ZIP/Postal Code
185019
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08036
Country
Spain
Facility Name
Novartis Investigative Site
City
Alicante
State/Province
Comunidad Valenciana
ZIP/Postal Code
03010
Country
Spain
Facility Name
Novartis Investigative Site
City
Santiago de Compostela
State/Province
Galicia
ZIP/Postal Code
15706
Country
Spain
Facility Name
Novartis Investigative Site
City
Istanbul
ZIP/Postal Code
34093
Country
Turkey
Facility Name
Novartis Investigative Site
City
Kocaeli
ZIP/Postal Code
41380
Country
Turkey

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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

Learn more about this trial

Efficacy and Safety of Ruxolitinib in the Treatment of Anemic Myelofibrosis Patients.

We'll reach out to this number within 24 hrs