E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Beta-thalassemia intermedia 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 | 16.0 |
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 | 16.0 |
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 proportion of β-thalassemia intermedia patients who have an erythroid response, defined as: 1) a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days (in the absence of red blood cell [RBC]transfusions) in non-transfusion-dependent patients, or 2) ≥ 20% reduction in RBC transfusion burden compared to pretreatment in transfusion-dependent patients |
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E.2.2 | Secondary objectives of the trial |
Secondary:
-To evaluate safety and tolerability of ACE-536
-To evaluate the proportion of transfusion dependent patients who have ≥ 50% reduction of RBC transfusion burden compared to pretreatment
-To evaluate the time to erythroid response and duration of erythroid response
-To evaluate the change in hemoglobin level in non-transfusion dependent patients
-To evaluate the change in pre-transfusion hemoglobin levels in transfusion-dependent patients
-To evaluate changes in biomarkers of erythropoiesis, hemolysis, iron metabolism and bone metabolism
-To examine the pharmacokinetic (PK) profile of ACE-536 in patients with β-thalassemia intermedia
Exploratory:
-To evaluate biomarkers related to the TGFb superfamily |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men or women ≥ 18 years of age.
2. Documented diagnosis of β-thalassemia intermedia (transfusion dependent patients must not have begun regular transfusions at age < 4.0 years).
3. Prior splenectomy or spleen size < 18 cm in the longest diameter by abdominal ultrasound.
4. Anemia, defined as:
a. Mean hemoglobin concentration < 10.0 g/dL of 2 measurements (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 non-transfusion-dependent patients, defined as having received < 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1, OR
b. Transfusion-dependent, defined as requiring ≥ 4 units of RBCs every 8 weeks (confirmed over 6 months prior to Cycle 1 Day 1).
5. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN).
6. Serum creatinine ≤ 1.5 x ULN.
7. 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. 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.
8. Patients are able to adhere to the study visit schedule, understand and comply with all protocol requirements.
9. Understand and able to provide written informed consent. |
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E.4 | Principal exclusion criteria |
1. 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.
2. Folate deficiency.
3. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B (HBV) or active infectious hepatitis C (HCV).
4. 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).
5. Ejection fraction < 50% by echocardiogram, MUGA or cardiac MRI.
6. Uncontrolled hypertension defined as systolic blood pressure (BP) ≥ 150 mm Hg or diastolic BP ≥ 95 mm Hg.
7. Heart failure class 3 or higher (New York Heart Association, NYHA, Appendix 1).
8. QTc > 450 msec on screening ECG.
9. Platelet count < 100 x109/L or > 1,000 x109/L.
10. Proteinuria ≥ Grade 2.
11. Any active infection requiring parenteral antibiotic therapy within 28 days prior to Cycle 1 Day 1 or oral antibiotics within 14 days of Cycle 1 Day 1.
12. Treatment with another investigational drug 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.
13. Transfusion event within 7 days prior to Cycle 1 Day 1.
14. Patients receiving or planning to receive hydroxyurea treatment. Patients must not have had hydroxyurea within 56 days of Cycle 1 Day 1.
15. Splenectomy within 56 days prior to Cycle 1 Day 1.
16. 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.
17. Iron chelation therapy if initiated within 56 days prior to Cycle 1 Day 1
18. 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).
19. Pregnant or lactating females.
20. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant
proteins or excipients in the investigational drug.
21. Prior treatment with sotatercept (ACE-011) or ACE-536. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is erythroid response, defined as 1) a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days (in the absence of RBC transfusions) in non-transfusion-dependent patients or 2) ≥ 20% reduction in RBC transfusion burden compared to pretreatment in transfusion-dependent patients.
The erythroid response will be summarized using both a point estimate and its exact 95% confidence interval based on binomial distribution. The primary efficacy analysis will be performed using the EE population. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of Treatment (day 113) |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints will be assessed by examining other hematology, erythropoiesis, iron metabolism, and bone metabolism parameters, as well as MRI scan for liver iron content (LIC).
- Erythropoiesis parameters include serum erythropoietin levels, hemoglobin analysis (electrophoresis, globin chain RNA), reticulocytes, nucleated RBCs and RBC morphology
- Hemolysis parameters include haptoglobin, indirect bilirubin, and lactate dehydrogenase (LDH)
- Iron metabolism parameters include serum iron, total iron binding capacity (TIBC), transferrin, soluble transferrin receptor, ferritin, non-transferrin bound iron (NTBI), hepcidin, and liver iron content (LIC) by MRI
- Bone metabolism parameters include bone specific alkaline phosphatase (BSAP) and C-telopeptide of type I collagen (CTX)
Exploratory endpoints will include evaluation of biomarkers related to the TGF Beta superfamily.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of Treatment (day 113) |
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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
| 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 | 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 | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |