| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adults who require regular Red Blood Cell (RBC) transfusions due to Beta-Thalassemia. |
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| E.1.1.1 | Medical condition in easily understood language |
| Adults who require regular Red Blood Cell (RBC) transfusions due to a blood disorder that reduces the production of healthy Red Blood Cells. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054658 |
| E.1.2 | Term | Thalassemia |
| E.1.2 | System Organ Class | 100000011955 |
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| 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 objective of the study is:
- To determine the proportion of subjects treated with luspatercept plus BSC versus placebo plus BSC who achieved erythroid response, defined as ≥ 33% reduction from baseline in transfusion burden (units RBCs / time) with a reduction of at least 2 units, from Week 13 to Week 24.
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| E.2.2 | Secondary objectives of the trial |
The key secondary objectives are:
- To evaluate the proportion of subjects who achieve ≥ 33% reduction from baseline in transfusion burden from Week 37 to Week 48 versus placebo
- To evaluate the proportion of subjects who achieve ≥ 50% reduction from baseline in transfusion burden from Week 13 to Week 24 versus placebo
- To evaluate the proportion of subjects who achieve ≥ 50% reduction from baseline in transfusion burden from Week 37 and Week 48 versus placebo
- To evaluate the mean change from baseline in transfusion burden from Week 13 to Week 24
- To evaluate the mean change from baseline in liver iron concentration (LIC) versus placebo
- To evaluate the mean change from baseline in mean daily dose of iron chelation therapy (ICT) used versus placebo
- To evaluate the mean change from baseline in serum ferritin versus placebo
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, at least 18 years of age at the time of signing the informed consent document (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule (eg, not scheduled to receive HSCT) and other protocol requirements.
4. Documented diagnosis of β-thalassemia or Hemoglobin E/β-thalassemia.
5. Regularly transfused, defined as: 6-20 RBC units in the 24 weeks prior to randomization and no transfusion-free period for ≥ 35 days during that period.
6. Performance status: Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
7. A female of childbearing potential (FCBP) for this study is defined as a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). FCBP participating in the study must:
a. Have two negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
b. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks (approximately five times the mean terminal half-life of luspatercept based on multiple-dose PK data) after discontinuation of study therapy
8. Male subjects must:
a. Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks (approximately five times the mean terminal half-life of luspatercept based on multiple-dose PK data) following investigational product discontinuation, even if he has undergone a successful vasectomy.
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| E.4 | Principal exclusion criteria |
1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
3. Any condition that confounds the ability to interpret data from the study.
4. A diagnosis of Hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg, Hemoglobin H); β-thalassemia combined with α-thalassemia is allowed.
5. Evidence of active hepatitis C (HCV) infection, or active infectious hepatitis B, or known positive human immunodeficiency virus (HIV).
6. DVT or stroke requiring medical intervention ≤ 24 weeks prior to randomization.
7. Chronic anticoagulant therapy ≤ 28 days prior to randomization, LMW heparin for SVT and chronic aspirin are allowed.
8. Platelet count > 1000 x 109/L
9. Insulin-dependent diabetes, ie, chronic treatment with insulin.
10. Treatment with another investigational drug or device ≤ 28 days prior to randomization.
11. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).
12. Use of an erythropoiesis-stimulating agent (ESA) ≤ 24 weeks prior to randomization.
13. Iron chelation therapy, if initiated ≤ 24 weeks prior to randomization (allowed if initiated
> 24 weeks before or during treatment).
14. Hydroxyurea treatment ≤ 24 weeks prior to randomization.
15. Pregnant or lactating females.
16. Uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤ Grade 1 according to NCI CTCAE version 4.0 (current active minor version).
17. Major organ damage, including:
a. Liver disease with alanine aminotransferase (ALT) > 3 x the upper limit of normal (ULN) or histopathological evidence of liver cirrhosis/fibrosis on liver biopsy;
b. 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.
c. Lung disease, including pulmonary fibrosis or pulmonary hypertension which are clinically significant.
d. Creatinine clearance < 60 mL/min (per Cockroff-Gault method).
18. Proteinuria ≥ Grade 3 according to NCI CTCAE version 4.0 (current active minor version).
19. Adrenal insufficiency.
20. Major surgery ≤ 12 weeks prior to randomization (subjects must have completely recovered from any previous surgery prior to randomization).
21. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (see Investigator Brochure).
22. Cytotoxic agents, immunosuppressants ≤ 28 days prior to randomization. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints:
1. Proportion of subjects with hematological improvement, defined as ≥ 33% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units from Week 13 to Week 24 compared to the 12-week interval prior to randomization for luspatercept plus BSC versus placebo plus BSC.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Endpoints: Week 24
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| E.5.2 | Secondary end point(s) |
1. Proportion of subjects with hematological improvement, defined as ≥ 33% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units from Week 37 to Week 48 compared to the 12-week interval prior to randomization for luspatercept plus BSC versus placebo plus BSC.
2. Proportion of subjects with ≥ 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units from Week 13 to Week 24 compared to the 12-week interval prior to randomization for luspatercept plus BSC versus placebo plus BSC
3. Proportion of subjects ≥ 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units from Week 37 to Week 48 compared to the 12-week interval prior to randomization for luspatercept plus BSC versus placebo plus BSC
4. Mean change from baseline in transfusion burden (RBC units) from Week 13 to Week 24 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Week 48
2. Week 24
3. Week 48
4. Week 24 |
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| 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 |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| 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 |
| Algeria |
| Australia |
| Bulgaria |
| Canada |
| France |
| Germany |
| Greece |
| Israel |
| Italy |
| Lebanon |
| Malaysia |
| Morocco |
| Saudi Arabia |
| Taiwan |
| Thailand |
| Tunisia |
| Turkey |
| United Kingdom |
| United States |
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| 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
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| LVLS or the date of receipt of the last data point from the last subject that is required for primary, secondary, and/or exploratory analysis, as pre-specified in the protocol and/or Statistical Analysis Plan (SAP), whichever is the later date |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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