E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
β-Thalassemia Intermedia and β-Thalassemia major |
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E.1.1.1 | Medical condition in easily understood language |
Beta-thalassemia is a genetic (inherited) blood disorder that reduces the body’s ability to produce “normal” hemoglobin (red blood cells) and causes anemia. |
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10062923 |
E.1.2 | Term | Thalassemia intermedia |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054661 |
E.1.2 | Term | Thalassemia major |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054660 |
E.1.2 | Term | Thalassemia beta |
E.1.2 | System Organ Class | 100000004850 |
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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 |
To evaluate the long-term safety and tolerability of ACE-536 in patients with β-thalassemia who were previously enrolled in study A536-04. |
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E.2.2 | Secondary objectives of the trial |
To evaluate
- erythroid response
- the time to erythroid response and duration of erythroid response
- the mean change from baseline over an 8- or 12-week period in hemoglobin level in NTD patients not influenced by RBC transfusion
-mean % change from baseline in transfusion burden over an 8- or 12-week period in TD patients.
- mean change in pre-transfusion hemoglobin levels in TD patients
-changes in markers of erythropoiesis, hemolysis, iron overload, and iron metabolism
-To examine the pharmacokinetic (PK) profile of ACE-536 in patients with β-thalassemia
Exploratory:To evaluate
- biomarkers related to the (TGF-ß) superfamily
- patient self-reported quality of life using the FACT-An and SF-36 questionnaires
- change in extramedullary hematopoiesis (EMH) mass size
- change in spleen size
- change in leg ulcers |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All patients must meet the following criteria
1. Completion of the treatment period in the base study A536-04.
2. Females of child bearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal ≥ 24 consecutive months) must have negative urine or blood pregnancy test prior to enrollment and use adequate birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation and for 12 weeks following the last dose of ACE-536. Males must agree to use a latex condom during any sexual contact with females of child-bearing potential while participating in the study and for 12 weeks following the last dose of ACE-536, even if he has undergone a successful vasectomy. Patients must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of ACE-536.
3. Patient is able to adhere to the study visit schedule, understand and comply with all protocol requirements.
4. Patient understands and is able to provide written informed consent.
Patients with treatment interruption (defined as patients who complete the EOS visit for study A536-04 and are ≥ 28 days post EOS visit) must also meet the following criteria
5. Mean hemoglobin concentration < 10.0 g/dL of 2 measurements (not influenced by RBC transfusion) (one performed within one day prior to Cycle 1 Day 1 and the other performed during the screening period [Day -28 to Day -1]) in NTD patients.
6. Adequate folate levels or on folate therapy.
7. Platelet count ≥ 100 x 10^9/L and ≤ 1,000 x 10^9/L.
8. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN).
9. Serum creatinine ≤ 1.5 x ULN.
10. Ejection fraction ≥ 50% by Echocardiogram (ECHO) or Multi gated acquisition scan (MUGA). |
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E.4 | Principal exclusion criteria |
All patients must not meet any of the following criteria
1. Discontinuation/withdrawal from study A536-04 due to patient request, patient unwillingness or inability to comply with the protocol, pregnancy, use of prohibited medication (e.g., hydroxyurea), medical reason or AE, hypersensitivity reaction to the study drug, at the discretion of the sponsor, or loss to follow-up prior to completion of the treatment period.
2. Any clinically significant pulmonary (including pulmonary hypertension), cardiovascular, endocrine, neurologic, hepatic, gastrointestinal, infectious, immunological (including clinically significant allo- or auto-immunization) or genitourinary disease considered by the investigator as not adequately controlled prior to Cycle 1 Day 1.
3. Symptomatic splenomegaly.
4. Splenectomy within 56 days prior to Cycle 1 Day 1.
5. Major surgery (except splenectomy) within 28 days prior to Cycle 1 Day 1. Patients must have completely recovered from any previous surgery prior to Cycle 1 Day 1.
6. Patients receiving or planning to receive hydroxyurea treatment. Patients must not have had hydroxyurea within 90 days of Cycle 1 Day 1.
7. Iron chelation therapy if initiated within 56 days prior to Cycle 1 Day 1.
8. Cytotoxic agents, systemic corticosteroids, immunosuppressants, or anticoagulant therapy such as warfarin or heparin within 28 days prior to Cycle 1 Day 1 (prophylactic aspirin up to 100 mg/d is permitted).
9. Treatment with another investigational drug (including sotatercept [ACE-011]) or device, or approved therapy for investigational use ≤ 28 days prior to Cycle 1 Day 1, or if the half-life of the previous investigational product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer at any time between the end of treatment of the base study A536-04 and Cycle 1 Day 1.
10. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B (HBV) or active infectious hepatitis C (HCV).
11. Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 150 mm Hg or diastolic blood pressure (DBP) ≥ 100 mm Hg.
12. Known history of thromboembolic events ≥ grade 3 according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4.0 (current active minor version).
13. Pregnant or lactating females.
14. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug.
15. Any other condition not specifically noted above which, in the judgment of the investigator, would preclude the patient from participating in the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is to evaluate the long-term safety and tolerability of ACE-536 in patients with β-thalassemia who were previously enrolled in study A536-04. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
-To Evaluate erythroid response defined as the proportion of patients with:
o Mean hemoglobin increase ≥ 1.5 g/dL over a continuous 12-week interval compared to baseline in non-transfusion dependent (NTD)
patients, not influenced by RBC transfusion, OR
o Reduction in RBC transfusion burden by ≥ 50% over a continuous 12-week interval compared to the 12 weeks prior to the start of treatment in transfusion dependent (TD) patients.
-To evaluate erythroid response defined as proportion of patients with:
o Mean hemoglobin increase ≥ 1.5 g/dL over a continuous 8-week interval compared to baseline in NTD patients, not influenced by RBC transfusion, OR
o Reduction in RBC transfusion burden by ≥ 20% over a continuous 8-week interval compared to the 8 weeks prior to the start of treatment in TD patients.
To evaluate:
- Time to erythroid response and duration of erythroid response
- Mean change from baseline over an 8- or 12-week period in hemoglobin level in NTD patients not influenced by RBC transfusion
- Mean % change from baseline in transfusion burden over an 8- or 12-week period in TD patients
- Mean change in pre-transfusion hemoglobin levels in TD patients
- Changes in markers of erythropoiesis, hemolysis, iron overload, and
iron metabolism
- PK profile of ACE-536 in patients with β-thalassemia
Exploratory endpoints will include evaluation of biomarkers related to the TGF Beta superfamily and evaluation of self-reported quality of life using the FACT--An and SF-36 questionnaires and to evaluate change in;
extramedullary hematopoiesis (EMH) mass size, change in spleen size, change in leg ulcers. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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.8.3 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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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last visit of the last subject undergoing the trial |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |