A study to evaluate the benefit and safety of Luspatercept (ACE-536) in adults with Beta-Thalassemia who do not require regular red blood cell tranfusions

• Register: EUCTR
• Last refreshed on: 15 September 2020
• Main ID: EUCTR2015-003225-33-GR
• Date of registration: 27/10/2017
• Prospective Registration: Yes
• Primary sponsor: Celgene Corporation
• Public title: A study to evaluate the benefit and safety of Luspatercept (ACE-536) in adults with Beta-Thalassemia who do not require regular red blood cell tranfusions
• Scientific title: A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Determine the Efficacy and Safety of Luspatercept (ACE-536) versus Placebo in Adults with Non Transfusion Dependent Beta (ß)-Thalassemia - The BEYOND Study
• Date of first enrolment: 14/11/2017
• Target sample size: 150
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003225-33
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; Other trial design description: with Open Label Phase; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Greece, Italy, Lebanon, Thailand, United Kingdom, United States

Contacts

• Name: PPD Project Manager
• Affiliation: PPD

• Name: PPD Project Manager
• Affiliation: PPD

Key inclusion & exclusion criteria

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 ß-thalassemia or hemoglobin E/ ß-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

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 148
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 2

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/ß-thalassemia or alpha (a)-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 surge

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Non transfusion dependent ß-thalassemia
MedDRA version: 20.0 Level: LLT Classification code 10074356 Term: Non-transfusion dependent thalassemia System Organ Class: 100000004850

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Product Name: Luspatercept
Product Code: ACE-536
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: Luspatercept
CAS Number: 1373715-00-4
Current Sponsor code: ACE-536
Other descriptive name: ACE-536
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 37.5-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Product Name: Luspatercept
Product Code: ACE-536
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: Luspatercept
CAS Number: 1373715-00-4
Current Sponsor code: ACE-536
Other descriptive name: ACE-536
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 87.5-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Week 24

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

Main Objective: 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

Secondary Objective: Toevaluatetheeffectofluspaterceptversus placebo in anemia-related
symptoms in patients with ß-thalassemia, as measured by non transfusion dependent ß-thalassemia-patient reported outcome(NTDT-PRO) over a continuous 12-week interval To evaluate the effect of luspatercept versus placebo on functional and health-related quality of life (QoL) as measured by 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 To evaluate the effect of luspatercept versus placebo on iron overload, as measured by liver iron concentration (LIC) and iron chelation therapy (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 6-minute walk test (6MWT)

Secondary Outcome(s)

Secondary end point(s): 1. Mean change from baseline in non transfusion dependent ß-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) total score 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 Fatigue subscale 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)

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

Secondary ID(s)

2015-003225-33-GB

ACE-536-B-THAL-002

Source(s) of Monetary Support

Celgene Corporation

Ethics review

Status: Approved
Approval date: 27/10/2017
Contact: