| CTRI Number |
CTRI/2024/10/075695 [Registered on: 23/10/2024] Trial Registered Prospectively |
| Last Modified On: |
15/10/2024 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug |
| Study Design |
Other |
|
Public Title of Study
|
Phase 2A Study of Luspatercept in Pediatric Participants With Beta (β)-Thalassemia |
|
Scientific Title of Study
|
A Phase 2A Study To Evaluate The Safety And Pharmacokinetics Of
Luspatercept (ACE-536) In Pediatric Participants With Beta (β)Thalassemia
|
| Trial Acronym |
NIL |
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| ACE-536-B-THAL-004_Protocol Amendment 3.1 dated 27Mar2024 |
Protocol Number |
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Details of Principal Investigator or overall Trial Coordinator (multi-center study)
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| Name |
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| Designation |
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| Affiliation |
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| Address |
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| Phone |
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| Fax |
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| Email |
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Details of Contact Person
Scientific Query
|
| Name |
Rashmi Chitgupi |
| Designation |
Country Head - Clinical Management |
| Affiliation |
PPD Pharmaceutical Development India Private Limited |
| Address |
PPD Pharmaceutical Development India Private Limited, 102, A Wing, Fulcrum, Hiranandani
Business Park, Sahar Road, Andheri East,
Mumbai
MAHARASHTRA
400099
India |
| Phone |
02266022900 |
| Fax |
912266022999 |
| Email |
rashmi.chitgupi@ppd.com |
|
Details of Contact Person
Public Query
|
| Name |
Rashmi Chitgupi |
| Designation |
Country Head - Clinical Management |
| Affiliation |
PPD Pharmaceutical Development India Private Limited |
| Address |
PPD Pharmaceutical Development India Private Limited, 102, A Wing, Fulcrum, Hiranandani
Business Park, Sahar Road, Andheri East,
MAHARASHTRA
400099
India |
| Phone |
02266022900 |
| Fax |
912266022999 |
| Email |
rashmi.chitgupi@ppd.com |
|
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Source of Monetary or Material Support
|
| Celgene Corporation
86 Morris Avenue
Summit, NJ 07901 |
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Primary Sponsor
|
| Name |
Celgene Corporation |
| Address |
86 Morris Avenue
Summit, NJ 07901 |
| Type of Sponsor |
Pharmaceutical industry-Global |
|
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Details of Secondary Sponsor
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Countries of Recruitment
|
China
Germany
Greece
India
Italy
Lebanon
Thailand
Turkey
United States of America |
|
Sites of Study
|
| No of Sites = 6 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Aby Abraham |
Christian Medical College Vellore |
Dept of Haematology,
A Block, 6th Floor,
CMC Vellore- Ranipet Campus,
Kilminnal Village, Ranipet District,
Tamilnadu- 632 517, India
Vellore
TAMIL NADU |
914172224553
aby@cmcvellore.ac.in |
| Dr Suman Jain |
Kamala Hospital and Research Centre for Thalassemia and Sickle Cell Patients |
A Unit of Thalassemia and Sickle Cell Society
Dr No. 8-13-95/1/C, Opp Lane to National Police Academy,
Raghavendra Colony, Shivarampally,Rajendranagar mandal 500052
Hyderabad
TELANGANA |
9989706399
sumanjaindr@gmail.com |
| Dr Riya Ballikar |
KIMS Kingsway Hospitals |
PANV Medisearch Lifesciences Private Limited
Parwana Bhawan, Near Kasturchand Park
Maharashtra - 440001, India
Nagpur
MAHARASHTRA |
7620963383
riabalikar86@gmail.com |
| Dr Mamta Manglani |
MCGM - Comprehensive Thalassemia Care, Pediatric Hematology-Oncology and BMT Centre |
CCI Compound, Opp. Kanakia Exotica, Borivali East, Mumbai
Suburban, Maharashtra -400066
Mumbai
MAHARASHTRA |
919821322071
mmanglani@hotmail.com |
| Dr Prosanto Chowdhury |
Peerless Hospitex Hospital and Research center limited |
Panchasayar, Kolkata- 700094
Kolkata
WEST BENGAL |
9830055287
drprosanto.chowdhury@gmail.com |
| Dr Nita Radhakrishnan |
Post Graduate Institute of Child Health |
Department of Pediatric Hematology and Oncology,
Sector 30, Noida, Gautam Buddha Nagar,
Uttar Pradesh-201303, India
Gautam Buddha Nagar
UTTAR PRADESH |
9999041524
nitark@gmail.com |
|
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Details of Ethics Committee
|
| No of Ethics Committees= 6 |
| Name of Committee |
Approval Status |
| Clinical Research Ethics Committee Peerless Hospitex Hospital & Research Center Ltd |
Approved |
| Institutional Ethics Committee of CTC, PHO and BMT Centre |
Submittted/Under Review |
| Institutional Ethics Committee Super Speciality Pediatric Hospital & PGTI |
Submittted/Under Review |
| Institutional Review Board, Christian Medical College |
Submittted/Under Review |
| Kingsway Hospitals Ethics Committee |
Submittted/Under Review |
| PH Health Ethics Committee, PI Health Cancer Hospital |
Submittted/Under Review |
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Regulatory Clearance Status from DCGI
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Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
(1) ICD-10 Condition: D561||Beta thalassemia, |
|
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Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Intervention |
Luspatercept (ACE-536) |
Luspatercept is a recombinant fusion protein consisting of a modified form of the extracellular
domain (ECD) of the human activin receptor IIB (ActRIIB) linked to the human immunoglobulin
G1 (IgG1) fragment crystallizable (Fc) domain. Luspatercept is a homodimeric protein comprised
of 2 disulfide-linked polypeptide chains, each with 335 amino acids. Each polypeptide chain
contains 3 sites for N-linked glycosylation (total of 6 N-linked glycosylation sites per molecule).
Peptide mapping and oligosaccharide analysis of luspatercept confirms the presence of highly
branched N-linked glycans, typical of a recombinant protein produced in Chinese hamster ovary
cells. |
| Comparator Agent |
NIL |
NIL |
|
|
Inclusion Criteria
|
| Age From |
6.00 Year(s) |
| Age To |
18.00 Year(s) |
| Gender |
Both |
| Details |
Participants must satisfy the following criteria to be enrolled into the study:
1) Participant must be 6 years to less than 18 years of age at the time of signing the informed consent
form ICF or informed assent form IAF.
2) Participant (and when applicable, parent/legal representative) must understand and voluntarily sign an ICF/IAF prior to conducting any study-related assessments/procedures.
3) Participant (and when applicable, parent/legal representative) is willing and able to adhere to the study visit schedule and other protocol requirements.
4) Participant must have documented diagnosis of β-thalassemia or HbE/β-thalassemia.
5) Transfusion dependence:
a) TD participant
i) Participant is regularly transfused, defined as: ≥ 4 RBC transfusion events in the
24 weeks prior to enrollment with no transfusion-free period ≥ 42 days during that
period.
Note For the purpose of the study, transfusions administered over 2 or 3 consecutive days are
considered as part of a single transfusion event. Participant must have a history of regular
transfusions for at least 2 years.
b) NTD participant ex-US sites only
i) Participant must have received less than 4 RBC transfusion events in the 24 weeks prior to
enrollment.
ii) Participant must not be on a regular transfusion program and must be RBC
transfusion-free for at least 8 weeks prior to enrollment.
iii) Participant must have mean baseline hemoglobin less than or equal to 10 g/dL, based on a minimum of 2 measurements greater than or equal to 1 week apart within 4 weeks prior to enrollment; hemoglobin values within 21 days post-transfusion will be excluded.
6) Participant has Karnofsky age greater than or equal to 16 years or Lansky age less than 16 years performance status score greater than or equal to 50 at screening.
7) Female children of childbearing potential (FCCBP), females of childbearing potential (FCBP), and male participants that have reached puberty (and when applicable, parent/legal representative) must agree to undergo physician-approved reproductive education and discuss the side effects of the study therapy on reproduction.
8) Female children of childbearing potential, defined as females who have achieved menarche and/or breast development in Tanner Stage 2 or greater and have not undergone a hysterectomy or bilateral oophorectomy and FCBP defined as a sexually mature woman who has achieved menarche at some point, has not undergone a hysterectomy or bilateral oophorectomy and has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) must meet the following conditions below (Note: Secondary amenorrhea from any cause does not rule out childbearing potential):
• Medically supervised serum pregnancy tests with a sensitivity of at least 25 mIU/mL must be conducted in FCCBP/FCBP, including those who commit to complete abstinence. Female children of childbearing potential/FCBP must have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy (one of these tests should be performed by central laboratory). Female children of childbearing potential/FCBP must agree to ongoing pregnancy testing during the course of the study at the EOT visit and at the 9 week Safety Follow-up visit.
• Female participants must, as appropriate to age and at the discretion of the site Investigator, either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting IP, during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal t1/2 of luspatercept based on multiple-dose PK data) after discontinuation of study therapy.
9) Male participants, as appropriate to age and the discretion of the study physician:
• Must practice true abstinence(which must be reviewed on a monthly basis) or agree to use a synthetic or latex condom during sexual contact with a pregnant female or a FCCBP/FCBP while participating in the study, during dose interruptions and for at least 12 weeks (approximately 5 times the mean terminal t1/2 of luspatercept based on multiple-dose PK data) following IP discontinuation, even if he has undergone a successful vasectomy. |
|
| ExclusionCriteria |
| Details |
1) Participant has any significant medical condition, laboratory abnormality, or psychiatric illness
that would prevent the participant from participating in the study.
2) Participant has any condition including the presence of laboratory abnormalities, which places
the participant at unacceptable risk if he/she were to participate in the study.
3) Participant has any condition that confounds the ability to interpret data from the study.
4) Participant has a diagnosis of Hemoglobin S/beta-thalassemia or alpha -thalassemia
(eg, Hemoglobin H); beta-thalassemia combined with alpha-thalassemia is allowed.
5) Participant has active hepatitis C (HCV) infection as demonstrated by a positive
HCV-ribonucleic acid (RNA) test of sufficient sensitivity, or active infectious hepatitis B as
demonstrated by the presence of hepatitis B surface antigen (HBsAG) and/or hepatitis B virus
(HBV)-deoxyribonucleic acid (DNA) positive, or known positive human immunodeficiency
virus (HIV).
Note: Participants receiving antiviral therapies should have 2 negative HCV-RNA tests 3 months apart before ICF/IAF signature, ie, one test at the end of the antiviral therapy and the second test 3 months following the first test.
6) Participant has severe infection less than equal to 28 days prior to enrollment. Additionally, in the case of prior SARS-CoV-2 infection, symptoms must have completely resolved, and based on Investigator
assessment in consultation with the Clinical Trial Physician, there are no sequelae that would
place the participant at a higher risk of receiving investigational treatment.
7) Participant has received a live COVID-19 vaccine less than equal to 28 days prior to screening.
8) Participant has deep vein thrombosis (DVT), stroke, or other thromboembolic event(s) (except
clogged indwelling catheter) requiring medical intervention less than equal to 24 weeks prior to enrollment.
9) Participant has chronic anticoagulant therapy less than equal to 28 days prior to enrollment (Anticoagulant
therapies used for prophylaxis for surgery or high risk procedures as well as low molecular
weight [LMW] heparin for superficial vein thrombosis and chronic aspirin are allowed)
10) Participant has platelet count greater than 1000 x 10 raise to 9/L.
11) Participant has poorly controlled diabetes mellitus within 24 weeks prior to enrollment as
defined by short term (eg, hyperosmolar or ketoacidotic crisis) and/or history of diabetic
cardiovascular complications (eg, stroke or myocardial infarction).
12) Participant has treatment with another investigational drug or device less than equal to 28 days prior to
enrollment.
13) Participant has prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).
14) Participant underwent or is scheduled for HSCT or gene therapy.
15) Participant has used an erythropoiesis-stimulating agent (ESA) less than equal to 24 weeks prior to enrollment.
16) Participant use of iron chelation therapy (ICT), if initiated less than equal to 8 weeks prior to enrollment
(allowed if initiated more than 8 weeks before or during treatment).
17) Participant use of hydroxyurea treatment less than equal to 24 weeks prior to enrollment.
18) Participant is pregnant or breastfeeding female.
19) Participant has uncontrolled hypertension. Controlled hypertension for this protocol is
considered less than equal to Grade 1 according to NCI CTCAE version 5.0.
20) Participant has major organ damage, including:
a) Symptomatic splenomegaly
b) Liver disease with alanine aminotransferase (ALT)/aspartate aminotransferase (AST) more than 3×
the upper limit of normal (ULN) for age
c) 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 enrollment
d) Lung disease, including pulmonary fibrosis or pulmonary hypertension which are clinically
significant.
e) Renal insufficiency defined as:
A serum creatinine based on age/gender as described below:
6 to less than 10 Years: Male and Female less than 1
10 to less than 13 Years: Male and Female less than 1.2
13 to lest 16 years: Male less than 1.5 and Female less than 1.4
more than or equal to 16 Years: Male less than 1.7 and Female less than 1.4
21) Participant has proteinuria less than equal to Grade 3 according to NCI CTCAE version 5.0. (which is
equivalent to a urine protein/creatinine ratio less than 215 mg/mmol of creatinine), or a urine
albumin/creatinine ratio less than 129 mg/mmol of creatinine.
22) Participant use of chronic systemic glucocorticoids less than equal to 12 weeks prior to enrollment
(physiologic replacement therapy for adrenal insufficiency is allowed). Single day
glucocorticoid treatment (eg, for prevention or treatment of transfusion reactions) is allowed.
23) Participant has major surgery less than equal to 12 weeks prior to enrollment (participants must have
completely recovered from any previous surgery prior to enrollment).
24) Participant has history of severe allergic or anaphylactic reactions or hypersensitivity to
recombinant proteins or excipients in the IP (refer to the IB).
25) Participant use of cytotoxic agents, immunosuppressants or immunomodulatory imide drugs
(IMiDs) less than equal to 28 days prior to enrollment (ie, antithymocite globulin [ATG] or cyclosporine or
thalidomide).
26) Participant has history of malignancy with the exception of:
a) Curatively resected nonmelanoma skin cancer.
b) Curatively treated cervical carcinoma in situ.
c) Other solid tumor with no known active disease in the opinion of the Investigator.
27) Participant who has EMH complications or requires treatment to control the growth of EMH
masse(s) during the screening period. |
|
|
Method of Generating Random Sequence
|
Not Applicable |
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Method of Concealment
|
Not Applicable |
|
Blinding/Masking
|
Open Label |
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Primary Outcome
|
| Outcome |
TimePoints |
• To determine the recommended dose (RD) of luspatercept that is safe and tolerable in pediatric participants with transfusion-dependent (TD) or non-transfusion-dependent (NTD) β-thalassemia
• To evaluate the pharmacokinetics (PK) of luspatercept in pediatric participants with TD or NTD β-thalassemia
|
• Cycle 1 Day 1 up to maximum 1 year post Cycle 1 Day 1
• Cycle 1 Day 1 up to maximum 1 year post Cycle 1 Day 1
|
|
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Secondary Outcome
|
| Outcome |
TimePoints |
For TD & NTD β-thalassemia Participants:
• The safety of luspatercept in pediatric participants
• The immunogenicity of luspatercept
• The mean change in mean daily dose of iron chelation therapy (ICT)
• The mean change in serum ferritin
For TD β-thalassemia Participants:
• The mean change in red blood cell (RBC) transfusion burden
For NTD β-thalassemia Participants:
• The mean change in hemoglobin levels. |
• 12 weeks prior to enrollment |
|
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Target Sample Size
|
Total Sample Size="99"
Sample Size from India="50"
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" |
|
Phase of Trial
|
Phase 2 |
|
Date of First Enrollment (India)
|
02/12/2024 |
| Date of Study Completion (India) |
Applicable only for Completed/Terminated trials |
| Date of First Enrollment (Global) |
04/08/2021 |
| Date of Study Completion (Global) |
Applicable only for Completed/Terminated trials |
|
Estimated Duration of Trial
|
Years="8"
Months="6"
Days="0" |
|
Recruitment Status of Trial (Global)
|
Open to Recruitment |
| Recruitment Status of Trial (India) |
Not Yet Recruiting |
|
Publication Details
|
N/A |
|
Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
|
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Brief Summary
|
This is a Phase 2a study to evaluate the safety and PK of luspatercept in pediatric participants with β-thalassemia and to determine the RD. The study will consist of the following periods: - Screening/Run-in Period
- Treatment Period
- Long-term Treatment Period
- Post-treatment Follow-up Period
Participant screening procedures will occur during the Screening/Run-in Period, within 12 weeks prior to the start of study treatment. Participants who meet the study eligibility criteria will be enrolled into the Treatment Period. The study will be conducted in a staggered manner, in descending order of age. |