CTRI/2023/03/050272 [Registered on: 02/03/2023] Trial Registered Prospectively
Last Modified On:
02/08/2024
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Single Arm Study
Public Title of Study
luspatercept (drug to treat anemia) in patients to treat anemia associated with myelodysplastic syndromes (MDS-RS) and beta-thalassemia (Beta-Thal) in India
Scientific Title of Study
A Phase IV study of luspatercept for the treatment of transfusion-dependent anemia associated with myelodysplastic syndromes (MDS) & beta-thalassemia (Beta-Thal) in India
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
CA056023 ,Amendment no 01 dated 02 Sep 2022
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Designation
Affiliation
Address
Phone
Fax
Email
Details of Contact Person Scientific Query
Name
Dr Kartik Doshi
Designation
Study director
Affiliation
Bristol Myers Squibb India Pvt. Ltd.
Address
One International Centre, 6th Floor, Tower 1, Senapati Bapat Marg, Elphinstone (W), Mumbai - India
Mumbai (Suburban)
MAHARASHTRA
Mumbai MAHARASHTRA 400013 India
Phone
91-2266288600
Fax
Email
Kartik.Doshi@bms.com
Details of Contact Person Public Query
Name
Shilpi Sinha
Designation
RCO Lead India
Affiliation
Bristol Myers Squibb India Pvt. Ltd.
Address
One International Centre, 6th Floor, Tower 1, Senapati Bapat Marg, Elphinstone (W), Mumbai - India
Mumbai (Suburban)
MAHARASHTRA
Mumbai MAHARASHTRA 400013 India
Phone
91-2266288600
Fax
Email
Shilpi.Sinha@bms.com
Source of Monetary or Material Support
Bristol Myers Squibb Research and Development
Primary Sponsor
Name
BRISTOL MYERS SQUIBB INDIA PRIVATE LIMITED
Address
One International Centre, 6th Floor, Tower 1, Senapati Bapat Marg, Elphinstone (W), Mumbai - 400013
Department of Hematology, room no-5017, 5th floor, Teaching block floor, Dr. B.R.A. Institute Rotary Cancer Hospital, All India Institutes of Medical Sciences, Ansari Nagar, Department of Medical Oncology, New Delhi - 110029 New Delhi DELHI
011-26593363
drtulikaseth@gmail.com
Dr Jina Bhattacharyya
Gauhati Medical college & Hospital
Department of Clinical Haematology, 3rd floor, Bhangagarh, Guwahati - 781032, Assam Kamrup ASSAM
0361-2452244
drjinabhattacharyya@yahoo.in
Dr Nataraj KS
HCG - Bangalore institute of Oncology
Department Haematology, 4th floor, tower - 1, room no 512, P. kalingarao Road, Sampangiram nagar, Bangalore – 560027 Bangalore KARNATAKA
9482141773
drnatarajks@gmail.com
Dr S Chandrakala
KEM Hospital and Seth G S Medical College
Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Acharya Donde Marg, Parel - 400012, Mumbai, India Mumbai MAHARASHTRA
022-24107000
drchandra_s@rediffmail.com
Dr Tuphan Kanti Dolai
Nilratan Sircar Medical College and Hospital
138, Acharya Jagdish chandra bose Road, Nilratan Sircar Medical College and Hospital, Kolkatta 700014, West Bangal Kolkata WEST BENGAL
033-22443213
tkdolai75@gmail.com
Dr Pankaj Malhotra
Post Graduate Institute of Medical Education and Research
Department of clinical Haematology and Medical Oncology, Sector - 12, Uttaranchal, Chandigarh - 160012 Chandigarh CHANDIGARH
172-2756680
malhotrapankaj@hotmail.com
Dr Dinesh Bhurani
Rajiv Gandhi Cancer Institute and Research CentreÂ
3265, 2nd floor, D-Block, Heamato-oncology & Bone marrow transplantation, Sir Chotu Ram Marg, Rohini Institutional Area, Sector 5, Rohini, New Delhi - 110085 New Delhi DELHI
011-49575757
bhurani@gmail.com
Dr Sandip Shah
Vedanta Institute of Medical Science
Ground floor & first floor, Stadium Commerce road,
Near Samved hospital, Hemato Oncology Clinic Ahmedabad Pvt Ltd, “Vedanta†Institute of Medical Science Navarangpura,
Ahmedabad- 380009 Ahmadabad GUJARAT
Ethics Committee, N.R.S. Medical College & Hospital
Approved
HCG Central Ethics Committee
Approved
IEC - Basavatarakam Indo American Hospital
Approved
Institute Ethics Committee, All India Institute of Medical Sciences
Approved
Institutional Ethics Committee Post Graduate Institute of Medical Education and Research
Approved
Institutional Ethics Committee, Gauhati Medical college & Hospital
Approved
Institutional Ethics Committee- I Seth GS Medical College and KEM Hospital
Approved
Institutional Review Board - Rajiv Gandhi Cancer Institute and Research CentreÂ
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: D758||Other specified diseases of bloodand blood-forming organs,
Intervention / Comparator Agent
Type
Name
Details
Intervention
luspatercept
luspatercept is 1.0 mg/kg Sub Cuteneous rout, quater to 3 week for 48 week
Comparator Agent
Not Applicable
Not Applicable
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
Beta-Thalassemia
More than 18 years of age at the time of signing the informed consent form
Documented diagnosis of β-thalassemia or Hemoglobin E/β-thalassemia
Regularly transfused, defined as 6-20 Red Blood Cell (RBC) units in the 24 weeks prior to randomization and no transfusion-free period for more than 35 days during that period.
Sites who prescribe transfusions and have the transfusion records only in volumes should use for conversion of volume to units the below criteria, in order to obtain number of units within the last 24 weeks to assess the eligibility: 1 unit in this protocol refers to a quantity of packed RBCs approximately 200-350 mL. 1. sites who use transfusion bags within this range, or more than equal to 350 mL, the conversion in units should be done by dividing the volume transfused to the patient by 350 mL, 2. sites who use transfusion bags less than 200 mL, the conversion in units should be done by dividing the volume transfused to the patient by 200 mL.
Performance status: Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
MDS
More than 18 years of age at the time of signing the informed consent form
Subject had documented diagnosis of MDS according to WHO/FAB (2016) classification that met IPSS-R classification of very low-, low-, or intermediate-risk disease, and the following:
Ring sideroblasts (RS) more than equal to 15% of erythroid precursors in bone marrow. If the SF3B1 mutation is present, RS more than equal to 5% will be included.
Less than 5% blasts in bone marrow and less than 1% peripheral blood blasts
Peripheral blood white blood cell (WBC) count less than 13,000/μL
Subject was refractory or intolerant to, or ineligible for, prior ESA treatment, as defined by any one of the following:
Refractory to prior ESA treatment: Documentation of nonresponse or response that was no longer maintained to prior ESA-containing regimen, either as a single agent or in combination (e.g., with G-CSF). The ESA regimen must have been either:
Recombinant human erythropoietin more than equal to 40,000 IU/week for at least 8 doses or equivalent; or 1050 mg/kg/week for at least 8 doses or equivalent
Darbepoetin- darbepoetin alpha more than equal to 240 µg every week for at least 12 weeks or equivalentÂ
Intolerant to prior ESA treatment: Documentation of discontinuation of prior ESA-containing regimen, either as a single agent or in combination (e.g., with G-CSF), at any time after introduction due to intolerance or an AE
ESA ineligible: Low chance of response to ESA based on endogenous serum EPO level more than 200 U/L for subjects not previously treated with ESAs
If the patient was previously treated with ESAs or G-CSF/granulocyte-macrophage colony-stimulating factor (GM-CSF), both agents must have been discontinued more than equal to 4 weeks prior to the date of randomization
Required RBC transfusions, as documented by the following criteria:
Average transfusion requirement of more than equal to 2 units/8 weeks of packed RBCs (pRBCs) confirmed for a minimum of 16 weeks immediately preceding Luspatercept treatment
Hemoglobin levels at the time of or within 7 days prior to administration of a RBC transfusion must have been less than equal to 9.0 g/dL with symptoms of anemia or (less than equal to 7 g/dl in absence of symptoms) in order for the transfusion to be counted towards meeting eligibility criteria. Red blood cell transfusions administered when Hgb levels were more than 9 g/dL and/or RBC transfusions administered for elective surgery ,infections or bleeding events will qualify as a required transfusion for the purpose of meeting eligibility criteria
No consecutive 56-day period that was RBC transfusion free during the 16 weeks immediately preceding randomization
Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2
ExclusionCriteria
Details
Beta-Thalassemia
A diagnosis of Haemoglobin S/β-thalassemia or alpha (α)-thalassemia (e.g., Haemoglobin H).
Deep Vein Thrombosis (DVT) or stroke requiring medical intervention more than equal to 24 weeks prior to randomization.
Use of chronic anticoagulant therapy is excluded unless the treatment stopped at least 28 days prior to randomization. Anticoagulant therapies used for prophylaxis for surgery or high-risk procedures as well as low Molecular Weight (LMW) heparin for superficial venous thrombosis and chronic aspirin are allowed.
Platelet count more than 1000 x 109/L
Poorly controlled diabetes mellitus within 24 weeks prior to randomization as defined by short term (e.g., hyperosmolar or ketoacidotic crisis) and/or history of diabetic cardiovascular complications (e.g., stroke or myocardial infarction).
Pregnant or lactating females.
Uncontrolled hypertension. Controlled hypertension for this protocol is considered less than equal to Grade 1 according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (current active minor version).
Major organ damage, including:
Liver disease with alanine aminotransferase (ALT) more than 3 x the upper limit of normal (ULN) or history of evidence of cirrhosis.
Heart disease, heart failure as classified by the New York Heart Association (NYHA) classification 3 or higher, or significant arrhythmia requiring treatment, or recent myocardial infarction within 6 months of randomization.
Lung disease, including pulmonary fibrosis or pulmonary hypertension which are clinically significant i.e., more than equal to Grade 3 NCI CTCAE version 4.0 (current active minor version).
Creatinine clearance less than 60 mL/min (per Cockcroft-Gault formula).
MDS
MDS associated with del 5q cytogenetic abnormality
Secondary MDS, i.e., MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases.
Subject has known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding.
Iron deficiency to be determined by serum ferritin ≤ 15 μg/L and additional testing if clinically indicated (e.g., calculated transferrin saturation [iron/total iron binding capacity ≤ 20%] or bone marrow aspirate stain for iron)
Prior allogeneic or autologous stem cell transplant
Known history of diagnosis of AML
Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure
Subject has uncontrolled hypertension, defined as repeated elevations of systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment, or with a history of hypertensive crisis or hypertensive encephalopathy
Absolute neutrophil count (ANC) < 500/μL (0.5 x 109/L)
Platelet count < 50,000/μL (50 x 109/L)
Estimated glomerular filtration rate (eGRF) or creatinine clearance < 40 mL/min/1.73 m2 or creatinine clearance < 40 mL/min.
Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN)
Total bilirubin ≥ 2.0 x ULN.
higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (i.e., ineffective erythropoiesis).
subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either a positive Coombs’ test or over 50% indirect bilirubin
Method of Generating Random Sequence
Not Applicable
Method of Concealment
Not Applicable
Blinding/Masking
Not Applicable
Primary Outcome
Outcome
TimePoints
Beta-Thalassemia
Incidence of treatment related adverse events of grade 3 or higher adverse events: during the treatment period (up to 48 weeks) & during a 9-week follow-up period after the last cycle of study drug in B-Thalassemia.
MDS
Incidence of treatment related adverse events of grade 3 or higher adverse events: during the treatment period (up to 48 weeks) & during a 6-week follow-up period after the last cycle of study drug in MDS
screening visit,every 3 weeks (up to 48 weeks) & 9-week follow-up period after the last cycle of study drug in B-Thalassemia.
MDS
Screening visit, every 3 week (up to 48 weeks) & 6-week follow-up period after the last cycle of study drug in MDS
Secondary Outcome
Outcome
TimePoints
Beta-Thalassemia
% of Participants Who Achieved RBC Transfusion Burden Reduction (≥33% Reduction from Baseline) from Week 13 to Week 24 with a reduction of at least 2 red-cell units over this 12-week interval.
% of Participants Who Achieved RBC Transfusion Burden reduction of at least 33% from baseline during any 12-week interval with a reduction of at least 2 red-cell units over the interval
Incidence of all treatment related AEs in B-Thalassemia as defined as Type, frequency, severity, seriousness of AEs and relationship of AEs to Luspatercept. From Screening through 9 weeks post Luspatercept last cycle.
MDS
% Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) during any consecutive 56 day period from Week 1 Through Week 24.
Incidence of all treatment related AEs in MDS as defined as Type, frequency, severity, seriousness of AEs and relationship of AEs to Luspatercept. From Screening through 6 weeks post Luspatercept last cycle.
Beta-thalassemia
Week 13 to Week 24
MDS
56 day period from Week 1 Through Week 24
Beta-Thalassemia
% of Participants Who Achieved RBC Transfusion Burden Reduction (≥33% Reduction from Baseline) from Week 13 to Week 24 with a reduction of at least 2 red-cell units over this 12-week interval.
% of Participants Who Achieved RBC Transfusion Burden reduction of at least 33% from baseline during any 12-week interval with a reduction of at least 2 red-cell units over the interval
Incidence of all treatment related AEs in B-Thalassemia as defined as Type, frequency, severity, seriousness of AEs and relationship of AEs to Luspatercept. From Screening through 9 weeks post Luspatercept last cycle.
MDS
% Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) during any consecutive 56 day period from Week 1 Through Week 24.
Incidence of all treatment related AEs in MDS as defined as Type, frequency, severity, seriousness of AEs and relationship of AEs to Luspatercept. From Screening through 6 weeks post Luspatercept last cycle.
Beta-thalassemia
Week 13 to Week 24
MDS
56 day period from Week 1 Through Week 24
Beta-Thalassemia
% of Participants Who Achieved RBC Transfusion Burden Reduction (≥33% Reduction from Baseline) from Week 13 to Week 24 with a reduction of at least 2 red-cell units over this 12-week interval.
% of Participants Who Achieved RBC Transfusion Burden reduction of at least 33% from baseline during any 12-week interval with a reduction of at least 2 red-cell units over the interval
Incidence of all treatment related AEs in B-Thalassemia as defined as Type, frequency, severity, seriousness of AEs and relationship of AEs to Luspatercept. From Screening through 9 weeks post Luspatercept last cycle.
MDS
% Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) during any consecutive 56 day period from Week 1 Through Week 24.
Incidence of all treatment related AEs in MDS as defined as Type, frequency, severity, seriousness of AEs and relationship of AEs to Luspatercept. From Screening through 6 weeks post Luspatercept last cycle.
Beta-thalassemia
Week 13 to Week 24
MDS
56 day period from Week 1 Through Week 24
Target Sample Size
Total Sample Size="60" Sample Size from India="60" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
A PHASE 4 STUDY TO EVALUATE SAFETY AND EFFECTIVENESS OF LUSPATERCEPT (ACE-536) FOR THE TREATMENT OF ANEMIA DUE TO IPSS-R VERY LOW, LOW, OR INTERMEDIATE RISK MYELODYSPLASTIC SYNDROMES (MDS) WITH RING SIDEROBLASTS WHO REQUIRE RED BLOOD CELL TRANSFUSIONS IN SUBJECTS WHO HAVE HAD UNSATISFACTORY RESPONSE TO OR ARE INELIGIBLE TO ERYTHROPOIETIN BASED THERAPY AND IN SUBJECTS WITH TRANSFUSION DEPENDENT ANEMIA DUE TO BETA-THALASSEMIA