| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Myelodysplastic syndrome (MDS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Umbrella term for disorders of the bone marrow, leading to a reduced number of 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 | 10068361 |
| E.1.2 | Term | MDS |
| E.1.2 | System Organ Class | 100000004864 |
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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 efficacy of luspatercept on red blood cell transfusion independence (RBC-TI; for 12 weeks [84 days] with an associated concurrent mean hemoglobin increase ≥ 1.5 g/dL) compared with epoetin alfa for the treatment of anemia due to very low, low, or intermediate risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System -Revised IPSS-R) in erythropoiesis stimulating agent (ESA) naïve subjects who require RBC transfusions. |
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| E.2.2 | Secondary objectives of the trial |
• To assess the safety and efficacy of luspatercept compared to epoetin alfa
• To assess health-related quality of life (HRQoL) and anemia outcome measures (ie, the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire [EORTC QLQ-C30] and the Functional Assessment of Cancer Therapy - Anemia (FACT-An) questionnaire for subjects treated with luspatercept compared to epoetin alfa
• To evaluate pharmacokinetics for luspatercept in MDS subjects |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is ≥ 18 years of age the time of signing the informed consent form (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 and other protocol requirements.
4. Subject has a documented diagnosis of MDS according to WHO 2016 classification that meets IPSS R classification of very low, low, or intermediate risk disease, and < 5% blasts in bone marrow.
5. Subject has an endogenous serum erythropoietin (sEPO) level of < 500 U/L.
6. Subject requires RBC transfusions, as documented by the following criteria:
• A transfusion requirement of 2 to 6 pRBCs units/8 weeks confirmed for a minimum of 8 weeks immediately preceding randomization.
Hemoglobin levels at the time of or within 7 days prior to administration of a RBC transfusion must have been ≤ 9.0 g/dL (5.6 mmol/L) with symptoms of anemia (or ≤ 7 g/dL [4.3 mmol/L] in the absence of symptoms) in order for the transfusion to be counted towards meeting eligibility criteria. Red blood cell transfusions administered when Hgb levels were > 9.0 g/dL (or > 7 g/dL in the absence of symptoms) and/or RBC transfusions administered for elective surgery, infections or bleeding events will not qualify as a required transfusion for the purpose of meeting eligibility criteria or stratification.
The hemoglobin level after the last RBC transfusion prior to randomization must be < 11.0 g/dL (6.8 mmol/L) (centrally or locally analyzed).
7. Subject has Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.
8. Females of childbearing potential (FCBP), defined as a sexually mature woman who:
1) has achieved menarche at some point, 2) not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy or amenorrhea due to other medical reasons 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), must:
•Have two negative pregnancy tests as verified by the investigator prior to starting study therapy (unless the screening pregnancy test was done within 72 hours of W1D1). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment.
•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, highly effective contraception without interruption, 5 weeks prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy.
9. Male subjects must:
•Practice true abstinence (which must be reviewed prior to each IP administration or on a monthly basis [eg, in the event of dose delays]) or agree to use a condom (latex or non-latex, but not made out of natural [animal] membrane) 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 following investigational product discontinuation, even if he has undergone a successful vasectomy.
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| E.4 | Principal exclusion criteria |
1. Subject with the any of the following prior treatments:
•Erythropoiesis-stimulating agents (ESAs)
Subjects may be randomized at the investigator’s discretion contingent on the fact that the subject received no more than 2 doses of epoetin alfa (prior treatment with darbepoetin not acceptable for entry into the study). The last dose of epoetin alfa must be ≥ 8 weeks from the date of randomization. A blood sample to determine the endogenous sEPO level (central laboratory) for stratification must be taken within 5 days of randomization unless a prior screening sample analyzed by the central laboratory demonstrated an endogenous sEPO level ≤ 500 U/L
•Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), within 8 weeks prior to randomization, unless given for treatment of febrile neutropenia
•Disease modifying agents (eg, immune-modulatory drug [IMiDs such as lenalidomide]
Except if the subject received ≤ 1 week of treatment with a disease modifying agent ≥ 8 weeks from randomization, at the investigator’s discretion.
•Hypomethylating agents
Subjects may be randomized at the investigator’s discretion contingent that the subject received no more than 2 doses of HMA. The last dose must be ≥ 8 weeks from the date of randomization.
•Luspatercept (ACE-536) or sotatercept (ACE-011)
•Immunosuppressive therapy for MDS
•Hematopoietic cell transplant
2. Subject with MDS associated with del(5q) cytogenetic abnormality or MDS unclassifiable (MDS-U) according to WHO 2016 classification.
3. Subject with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) according to WHO 2016 classification (ie, Chronic myelomonocytic leukemia (CMML), Atypical chronic myeloid leukemia (aCML), BCR-ABL12, Juvenile myelomonocytic leukemia (JMML), MDS/MPN unclassifiable.
4. Subject with secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases.
5. Subject with known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or hypothyroidism, or any type of known clinically significant bleeding or sequestration. Subject with drug induced anemia (eg, mycophenolate).
•Iron deficiency to be determined by serum ferritin < 100 µg/L and additional testing if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding capacity ≤ 20%] or bone marrow aspirate stain for iron).
6. Subject with known history of diagnosis of AML.
7. Subject receiving any of the following treatment within 8 weeks prior to randomization:
•Anticancer cytotoxic chemotherapeutic agent or treatment
•Systemic corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS
•Iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 weeks prior to randomization
•Other RBC hematopoietic growth factors (eg, Interleukin-3)
•Androgens, unless to treat hypogonadism
•Hydroxyurea
•Oral retinoids (except for topical retinoids)
•Arsenic trioxide
•Interferon and interleukins
•Investigational drug or device, or approved therapy for investigational use (if 5 times the half-life of the previous investigational drug exceeds 8 weeks, then the time of exclusion should be extended up to 5 times the half-life of the investigational drug)
8. Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment.
9. Subject with any of the following laboratory abnormalities:
•Absolute neutrophil count (ANC) < 500/μL (0.5 x 10^9/L)
•Platelet count < 50,000/μL (50 x 10^9/L)
•Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 (Appendix F)
•Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN)
•Total bilirubin ≥ 2.0 x ULN.
Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis) or in the presence of known history of Gilbert Syndrome.
10. Subject with prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 5 years (see details in the Protocol).
11. Subject has history of active SARS-CoV-2 infection within 4 weeks prior to screening, unless the subject has adequately recovered from COVID symptoms and related complications as per investigator’s discretion and following a discussion with the Medical Monitor. Use of a live COVID-19 vaccine is prohibited within 4 weeks prior to randomization.
Further exclusion criteria are noted in the Protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects who are RBC transfusion-free for any 12-week period associated with a concurrent mean hemoglobin increase ≥ 1.5 g/dL compared to baseline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Proportion of subjects who are RBC transfusion-free from Week 1 through Week 24
2. Mean hemoglobin change over the 24-week period of Week 1 through Week 24 compared to baseline
3. Proportion of subjects achieving HI-E over any consecutive 56-day period
4. Time from first dose to first onset of achieving HI-E
5. Proportion of subjects who are RBC transfusion-free over a consecutive 84-day period
6. Maximum duration of RBC transfusion independence for subjects who achieve RBC-TI ≥ 84 days
7. Time from first dose to first onset of transfusion independence ≥ 84 days
8. Time from first dose to first transfusion on treatment
9. Total number of RBC units transfused on treatment
10. Proportion of subjects who are RBC transfusion-free over a consecutive 56-day period
11. Proportion of subjects who are RBC transfusion-free for a consecutive 24-week period in the first 48 weeks from first dose
12. Evaluation of EORTC QLQ-C30 score and FACT-An
13. Type, frequency, severity of AEs and relationship of AEs to luspatercept/epoetin alfa
14. A Population PK model that describes the PK exposure data of luspatercept and associated variability.
Exposure-response relationship for selected endpoints of efficacy and safety
15. Frequency of antidrug antibodies and effects on efficacy, or safety, or PK
16. Number and percentage of subjects progressing to AML; time to AML progression
17. Time from date of randomization to death due to any cause
18. Evaluation of biomarkers that may potentially impact luspatercept efficacy, predict response or relapse, help to better understand MOA and/or provide further prognostic classification of MDS subtypes.
Molecular markers (eg, SF3B1) include evaluation of MDSassociated gene mutations and their impact on drug efficacy, clinical response or relapse, drug MOA and prognostication of MDS.
19. Evaluation of healthcare resource use (eg, hospitalization) associated with investigational product (IP) during study
20. Description of QUALMS-P and Treatment Satisfaction |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 2, 3, 4, 5, 7, 9, 10: Week 1 through Week 24
6, 8: Week 1 through End of Treatment
11, : Week 1 through Week 48
12, 19, 20: Screening through Week 24
13: Screening through 42 days post last dose; Randomization through Week 48
14, 15: Randomization through 1 year post first dose
16, 17: Randomization through 5 years from first dose or 3 years from last dose (whichever occurs later)
18: Baseline through End of Treatment
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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 | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 111 |
| 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 |
| Australia |
| Canada |
| Israel |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
| Austria |
| Belgium |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Lithuania |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| Czechia |
|
| 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
|
| Either the date of the last visit of the last subject to complete the post-treatement follow-up, 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. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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