| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non transfusion dependent β-thalassemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Blood disorder that reduces the production of healthy red blood cells |
|
| 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 | 10074356 |
| E.1.2 | Term | Non-transfusion dependent thalassemia |
| 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 |
| To evaluate the effect of luspatercept versus placebo on anemia, as measured by mean hemoglobin concentration in the absence of transfusions over a continuous 12-week interval, from Week 13 to Week 24, compared to baseline |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of luspatercept versus placebo in anemia-related
symptoms in patients with β-thalassemia, as measured by nontransfusion dependent β-thalassemia-patient reported outcome
(NTDTPRO) over continuous 12-week intervals
To evaluate the effect of luspatercept versus placebo on functional and health-related QoL as measured by the Medical Outcomes Study SF-36 and FACIT-F questionnaires
To evaluate the long-term effect of luspatercept versus placebo on anemia, as measured by mean hemoglobin concentration in the absence of transfusions over a continuous 12-week interval from Week 37 to Week 48, compared to baseline
To evaluate the effect of luspatercept versus placebo on iron overload, as measured by LIC and ICT daily dose
To evaluate the effect of luspatercept versus placebo on iron overload, as measured by serum ferritin
To evaluate the duration of erythroid response
To evaluate the effect of luspatercept versus placebo on physical activity measured by 6MWT |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects must be ≥ 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 hematopoietic stem cell transplantation) and other protocol requirements.
4. Subject must have documented diagnosis of β-thalassemia or hemoglobin E/ β-thalassemia. Concomitant alpha globin mutation and/or duplication are allowed.
5. Subject must be non-transfusion dependent, defined as 0 to 5 units of RBCs received during the 24-week period prior to randomization. Note: 1 unit defined for this entry criterion as approximately 200 to 350 mL of transfused packed RBCs.
6. Subject must not be on a regular transfusion program and must be RBC transfusion-free for at least ≥ 8 weeks prior to randomization
7. Subject must have mean baseline hemoglobin ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to randomization; hemoglobin values within 21 days post-transfusion will be excluded.
8. Subject must have performance status: Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1.
9. 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). A FCBP participating in the study must:
a. Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during 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). If a FCBP engages in sexual activity that may result in a pregnancy, she must 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 half-life of luspatercept based on multiple-dose pharmacokinetics [PK] data) after discontinuation of study therapy.
10. 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 5 times the mean terminal half-life 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. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Subject has 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. Subject has any condition that confounds the ability to interpret data from the study.
4. Subject has a diagnosis of hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg, Hemoglobin H).
5. Subject has active hepatitis C (HCV) infection as demonstrated by a positive HCV-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 DNA (HBV-DNA) positive, or known positive human immunodeficiency virus (HIV).
Note: Subjects receiving antiviral therapies should have 2 negative HCV-RNA test 3 months apart before ICF signature, ie, one test at the end of the anti-viral therapy and second test 3 months following the first test.
6. Subject had deep vein thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior to randomization.
7. Subjects on chronic anticoagulant therapy are excluded, unless they stopped the treatment at least 28 days prior to randomization. Anticoagulant therapies for prophylaxis and for surgery or high-risk procedures as well as low molecular weight (LMW) heparin for superficial vein thrombosis (SVT) and chronic aspirin are allowed before and during the study.
8. Subject has received treatment with another investigational drug or device ≤ 28 days prior to randomization.
9. Subject had prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).
10. Subject has platelet count > 1000 x 10^9/L.
11. Subjects on iron chelation therapy (ICT) at the time of ICF signature must have initiated the treatment with ICT at least 24 weeks before the predicted randomization date. ICT can be initiated at any time during treatment and should be used according to the label.
12. Subject had Hydroxyurea and ESA treatment ≤ 24 weeks prior to randomization, and no prior gene therapy.
13. Subject is pregnant or a lactating female.
14. Subject has uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤ Grade 1 according to National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) version 4.0 (current active minor version).
15. Subject has major organ damage, including:
a. Liver disease with alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN) or history/evidence of cirrhosis, as well as presence of masses/tumor detected by ultrasound at screening.
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 (MI) within 6 months of randomization.
c. Severe lung disease, including pulmonary fibrosis or pulmonary hypertension, ie, ≥G3 NCI CTCAE version 4.0 (current active minor version).
d. Estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 (per Modification of Diet in Renal Disease [MDRD] formula).
16. Subject has received chronic systemic glucocorticoids ≤ 12 weeks prior to randomization (physiologic replacement therapy for adrenal insufficiency is allowed).
17. Subject had major surgery ≤ 12 weeks prior to randomization (subjects must have completely recovered from any previous surgery prior to randomization).
18. Subject has history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (see Investigator Brochure).
19. Subject has received immunosuppressants ≤ 28 days prior to randomization.
20. Subject has history or current malignancies (solid tumors and hematological malignancies) unless the subject has been free of the disease (including completion of any active or adjuvant treatment for prior malignancy) for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed:
• Basal or squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix
• Carcinoma in situ of the breast
• Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects who have an increase from baseline ≥1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Mean change from baseline in non transfusion dependent β-thalassemia-patient reported outcome (NTDT-PRO) Tiredness and Weakness (T/W) domain score over a continuous 12-week interval from Week 13 to Week 24
2. Mean change from baseline in mean of hemoglobin values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions
3. Proportion of subjects who have an increase from baseline ≥1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Week 37 to Week 48 in the absence of transfusions
4. Mean change from baseline in mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue subscale score over a continuous 12-week interval from Week 13 to Week 24
5. Mean change from baseline in mean NTDT-PRO Shortness of Breath (SoB) domain over a continuous 12-week interval from Week 13 to Week 24
6. Mean change from baseline in mean hemoglobin values over a continuous 12-week interval from Week 37 to Week 48 in the absence of transfusions
7. Mean change from baseline in mean FACIT-F, mean NTDT-PRO TW domain and mean NTDT-PRO total score over a continuous 12-week interval from Week 37 to Week 48
8. Proportion of subjects with an increase from baseline ≥ 3 in mean FACIT-F score over a continuous 12-week interval from Week 13 to Week 24
9. Proportion of subjects with an increase from baseline ≥ 3 in mean FACIT-F score over a continuous 12-week interval from Week 37 to Week 48
10. Mean change from baseline in the physical component summary
(PCS) and mental component summary (MCS) scores of the Medical Outcomes Study 36-Item Short Form (SF-36) at Week 24 and Week 48
11. Proportion of subjects with improvement of iron overload at Week 24 and Week 48, as measured by:
o For subjects with baseline liver iron concentration (LIC) (by magnetic resonance imaging [MRI]) ≥3 mg/g dw: ≥20% reduction in LIC, OR ≥ 33% decrease in iron chelation therapy (ICT) daily dose
o For subjects with baseline LIC (by MRI) < 3 mg/g dw: no increase in LIC > 1 mg/g dw AND not starting treatment with ICT or no increase in ICT daily dose ≥ 33%, if on ICT at baseline
12. Mean change from baseline in serum ferritin at Week 24 and Week 48
13. Mean change from baseline in LIC at Week 24 and Week 48
14. Proportion of subjects who are transfusion-free over 24 weeks
15. Proportion of subjects who are transfusion-free over 48 weeks
16. Duration of the mean hemoglobin increase from baseline ≥1.0 g/dL
17. Mean change from baseline in the 6-minute walk test (6MWT) distance at Week 24 and Week 48
18. Proportion of subjects who have an increase from baseline ≥1.5 g/dL in mean of hemoglobin values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions
19. Safety and tolerability, including immunogenicity
20. Pharmacokinetics (PK) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Week 24
2. Week 24
3. Week 48
4. Week 24
5. Week 24
6. Week 48
7. Week 48
8. Week 24
9. Week 48
10. Week 24, Week 48
11. Week 24, Week 48
12. Week 24, Week 48
13. Week 24, Week 48
14. Week 24
15. Week 48
16. Week 24, Week 48
17. Week 24, Week 48
18. Week 24
19. Week 24, Week 48
20. Week 24, Week 48 |
|
| 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 | 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) | 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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
| 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 |
| Lebanon |
| Thailand |
| United States |
|
| 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 End of Trial is defined as the date all subjects complete the OLP (if
allowed to access the OLP or discontinue earlier, 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 prespecified in the protocol, whichever is the later date |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 13 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
