| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Beta thalassemia is a blood disorder that reduces the production of hemoglobin (iron-containing protein in red blood cells that carries oxygen to cells throughout the body). |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054660 |
| E.1.2 | Term | Thalassemia beta |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objectives of the study are:
- To determine the recommended dose (RD) of luspatercept that is safe and tolerable in pediatric participants with transfusion-dependent (TD) β-thalassemia
- To evaluate the pharmacokinetic (PK) profile of luspatercept in pediatric participants with TD β-thalassemia |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate:
• The safety of luspatercept in pediatric participants
• The immunogenicity of luspatercept
• The mean change in RBC transfusion burden
• The mean change in hemoglobin levels
• The mean change in mean daily dose of iron chelation therapy (ICT)
• The mean change in serum ferritin |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participants must be 6 years to < 18 years of age at the time of signing the informed consent form (ICF)/informed assent form (IAF).
2. Participants (and when applicable, parent/legal representative) must understand and voluntarily sign an ICF/IAF prior to conducting any study-related assessments/procedures.
3. Participants (and when applicable, parent/legal representative) is willing and able to adhere to the study visit schedule and other protocol requirements.
4. Participants must have documented diagnosis of β-thalassemia or HbE/β-thalassemia.
5. Participants 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. Participants must have a history of regular transfusions for at least 2 years.
6. Participants has Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status score ≥ 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 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. |
|
| E.4 | Principal exclusion criteria |
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/β-thalassemia or alpha (α)-thalassemia (eg, Hemoglobin H); β-thalassemia combined with α-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)
6. participant has severe infection ≤ 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 ≤ 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 ≤ 24 weeks prior to enrollment.
9. participant has chronic anticoagulant therapy ≤ 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 [SVT] and chronic aspirin are allowed).
10. participant has platelet count > 1000 x 109/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 ≤ 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) ≤ 24 weeks prior to enrollment.
16. participant use of iron chelation therapy (ICT), if initiated ≤ 8 weeks prior to enrollment (allowed if initiated > 8 weeks before or during treatment).
17. participant use of hydroxyurea treatment ≤ 24 weeks prior to enrollment.
18. participant is pregnant or breastfeeding female.
19. participant has uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤ 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) > 3X 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 ( for more details please refer to the full protocol)
21. Participant has proteinuria ≥ Grade 3 according to NCI CTCAE version 5.0 (which is equivalent to a urine protein/creatinine ratio > 215
mg/mmol of creatinine), or a urine albumin/creatinine ratio > 129 mg/mmol of creatinine.
22. Participant use of chronic systemic glucocorticoids ≤ 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 ≤ 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 ≤ 28 days prior to enrollment (ie, antithymocite globulin (ATG) or cyclosporine).
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Determination of the Recommended Dose
- PK parameters |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Cycle 1 Day 1 through Cycle 1 Day 22
- Cycle 1 Day 1 up to maximum 1 year post Cycle 1 Day 1 of Treatment Period |
|
| E.5.2 | Secondary end point(s) |
• Safety, including: Type, frequency, seriousness, and severity of AEs and relationship to luspatercept (per NCI CTCAE version 5.0)
• Immunogenicity
• Mean change in RBC transfusion burden
• Mean change in hemoglobin levels
• Mean change from baseline in mean daily dose of iron chelation therapy (ICT)
• Mean change from baseline in serum ferritin |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Cycle 1 Day 1 through 9 weeks post last dose. Only related SAEs and malignancies/ premalignancies from 9 weeks post last dose until End of Study
- Cycle 1 Day 1 up to maximum 1 year post Cycle 1 Day 1 of Treatment Period
- 12 weeks prior to enrollment; Treatment Period and Long-term Treatment Period through EOT
- 12 weeks prior to enrollment; Treatment Period and Long-term Treatment Period through EOT
- 12 weeks prior to enrollment; Treatment Period and Long-term Treatment Period through EOT
- 12 weeks prior to enrollment; Treatment Period and Long-term Treatment Period through EOT |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Dose-ascending Design
The study will be conducted in staggered manner, in descending order of age, with 2 parts:
• Part A: adolescent subjects from 12 to < 18 years of age
• Part B: younger children from 6 to < 12 years of age
Part A will include a Dose Escalation Phase, testing 2 ascending doses of 0.75 mg/kg and 1.0 mg/kg (Cohorts 1 and 2, respectively).
Part B will include a Dose Escalation Phase, testing 2 ascending doses of 1.0 mg/kg and 1.25 mg/kg (Cohorts 4 and 5, respectively). |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Thailand |
| United States |
| Germany |
| Greece |
| Italy |
| Turkey |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The Sponsor may end the study when key endpoints and objectives of the study have been analyzed (ie, after the primary analysis) and if a
separate Long-term Follow-up (LTFU) protocol exists into which any participants remaining on study may be consented and continue to
receive luspatercept treatment and be monitored for safety and/or complete the Post-treatment Follow-up Period.
EOT evaluation will be performed for participants who receive treatment for the full 5 years from Cycle 1 Day 1. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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