| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Subjects with ring sideroblasts who require regular Red Blood Cell (RBC) Transfusions due to anemia due to Myelodysplastic Syndromes (MDS)
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects who require regular Red Blood Cell (RBC) Transfusions due to red blood cell count being lower than normal lead by a blood disorder due to damage in the blood-forming cells in the bone marrow |
|
| 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 | 10002272 |
| E.1.2 | Term | Anemia |
| E.1.2 | System Organ Class | 100000004851 |
|
| 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 RBC transfusion independence (RBC-TI) of luspatercept compared with placebo for the treatment of anemia due to IPSS-R very low, low, or intermediate risk MDS in subjects with ring sideroblasts who require RBC transfusions |
|
| E.2.2 | Secondary objectives of the trial |
1. To assess the safety and tolerability of luspatercept compared with placebo
2. To evaluate the effect of luspatercept on reduction in RBC transfusions, increase in hemoglobin, duration of RBC-TI, improvement in health-related quality of life (HRQoL) (ie, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]), increase in neutrophils, increase in platelets, decrease in serum ferritin, decrease in iron chelation therapy use, and time to RBC-TI compared with placebo
3. To evaluate population pharmacokinetics and exposure-response relationships 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. Documented diagnosis of MDS according to WHO/FAB classification that meets IPSS-R classification (Greenberg, 2012; Appendix D) of very low, low, or intermediate risk disease, and:
- Ring sideroblast ≥ 15% of erythroid precursors in bone marrow or ≥ 5% (but < 15%) if SF3B1 mutation is present,
- < 5% blasts in bone marrow
- Peripheral blood WBC count < 13,000/microL
4. Refractory or intolerant to, or ineligible for, prior ESA treatment, as defined by any one of the following:
- Refractory to prior ESA treatment - documentation of non-response or response that is no longer maintained to prior ESA-containing regimen, either as single agent or combination (eg, with G-CSF); ESA regimen must have been either:
a) recombinant human erythropoietin (rHu EPO) ≥ 40,000 IU/wk for at least 8 doses or equivalent;
OR
b) darbepoetin alpha ≥ 500 μg Q3W for at least 4 doses or equivalent;
- Intolerant to prior ESA treatment - documentation of discontinuation of prior ESAcontaining regimen, either as single agent or combination (eg, with G-CSF), at any time after introduction due to intolerance or an adverse event
- ESA ineligible - Low chance of response to ESA based on endogenous serum erythropoietin level > 200 U/L for subjects not previously treated with ESAs
5. If previously treated with ESAs or granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), both agents must have been discontinued ≥ 4 weeks prior to date of randomization.
6. Requires RBC transfusions, as documented by the following criteria:
- average transfusion requirement of ≥ 2 units/8 weeks of pRBCs confirmed for a minimum of 16 weeks immediately preceding randomization.
- Hemoglobin levels at the time of or within 7 days prior to administration of a RBC transfusion must have been ≤ 10.0 g/dL in order for the transfusion to be counted towards meeting eligibility criteria. Red blood cell transfusions administered when Hgb levels were > 10.0 g/dL and/or RBC transfusions administered for elective surgery will not qualify as a required transfusion for the purpose of meeting eligibility criteria.
- no consecutive 56-day period that was RBC transfusion-free during the 16 weeks immediately preceding randomization
7. 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 not undergone a hysterectomy or bilateral oophorectomy or 2) 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), must:
a) 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 C1D1). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment.
b) If sexually active, 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 agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (for example, polyurethane), 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.
10. Subject is willing and able to adhere to the study visit schedule and other protocol requirements. |
|
| E.4 | Principal exclusion criteria |
1. Prior therapy with disease modifying agents for underlying MDS disease.
a) subjects who previously received hypomethylating agents (HMA) or lenalidomide may be enrolled at the investigator’s discretion contingent that the subject received no more than 2 doses of HMA or no more than 1 calendar week of treatment with lenalidomide. The last dose must be ≥ 5 weeks from the date of randomization.
2. Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011)
3. MDS associated with del 5q cytogenetic abnormality
4. 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. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding
6. Prior allogeneic or autologous stem cell transplant
7. Known history of diagnosis of AML
8. Use of any of the following within 5 weeks prior to randomization:
- Anticancer cytotoxic chemotherapeutic agent or treatment
- 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)
- investigational drug or device, or approved therapy for investigational use. If the half-life of the previous investigational product is known, use within 5 times the halflife prior to randomization or within 5 weeks, whichever is longer is excluded
9. Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment
10. Absolute neutrophil count (ANC) < 500/μL (0.5 x 10^9/L)
11. Platelet count < 50,000/μL (50 x 10^9/L)
12. Estimated glomerular filtration rate (eGFR) or creatinine clearance < 40 mL/min
13. 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)
14. 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
- Subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either a positive Coombs’ test or over 50% indirect bilirubin
15. Prior history of malignancies, other than MDS, 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)
16. Major surgery within 8 weeks prior to randomization. Subjects must have completely recovered from any previous surgery prior to randomization
17. History of stroke, deep venous thrombosis (DVT), pulmonary or arterial embolism within 6 months prior to randomization
18. Pregnant or breastfeeding females
19. Myocardial infarction, uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator within 6 months prior to randomization. Subjects with a known ejection fraction < 35%, confirmed by a local ECHO or MUGA performed within 6 months prior to randomization are excluded
20. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment), known Human Immunodeficiency Virus (HIV), known evidence of active infectious Hepatitis B, and/or known evidence of active Hepatitis C. Local testing confirming HIV, Hepatitis B, and Hepatitis C status should not have been performed earlier than 4 weeks from the date of ICF signature
21. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product.
22. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness, or is considered vulnerable by local regulations (eg, imprisioned or institutionalized) that would prevent the subject from participating in the study.
23. 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.
24. Subject has any condition or concomitant medication that confounds the ability to interpret data from the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 weeks - Proportion of subjects who are RBC transfusion free over any consecutive 56-day period |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoint
1. RBC-TI ≥ 12 weeks - Proportion of subjects who are RBC transfusion free over any consecutive 84-day period
2. RBC-TI ≥ 8 weeks - Proportion of subjects who are RBC transfusion free over any consecutive 56-day period
3. Reduction in RBC units transfused over 16 weeks - Mean change in total RBC units transfused over a fixed 16-week period
4. Modified hematologic improvement - erythroid (mHI-E) per IWG - Proportion of subjects achieving modified HI-E over any consecutive 56-day period
5. Mean hemoglobin increase ≥ 1.0 g/dL - Proportion of subjects achieving hemoglobin (Hgb) increase from baseline ≥ 1.0 g/dL over any consecutive 56-day period in absence of RBC transfusions
6. Duration of RBC-TI - Maximum duration of RBC transfusion independence for
subjects who achieve RBC TI ≥ 8 weeks
7. Health-related quality of life (HRQoL) - Change in EORTC QLQC30 score
8. Hematologic improvement-platelets (HI-P) per IWG; hematologic improvement-neutrophils (HI-N) per IWG-Proportion of subjects achieving HI-N/HI-P over any consecutive 56-day period
9. Mean decrease in serum ferritin - Change in serum ferritin
10. Mean decrease in iron chelation therapy (ICT) use - Change in mean daily dose of ICT
11. Time to RBC-TI - Time from first dose to first onset of transfusion independence ≥ 8 weeks
12. Progression to AML - Number and percentage of subjects progressing to AML; time to AML progression
13. Overall survival - Time from date of randomization to death due to any cause
14. Safety - Type, frequency, severity of AEs and relationship of AEs to luspatercept/placebo
15. A population PK model - A Population PK model that describes the PK exposure data of luspatercept and associated variability.
16. Exposure-response relationship for the primary efficacy endpoint, AEs of interest, and selected secondary endpoints.
17. Anti-drug antibodies (ADA) - Frequency of anti-drug antibodies and effects on efficacy, or safety, or PK |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Week 1 to Week 24; Week 1 to Week 48
2. Week 1 to Week 48
3. Week 9 to 24; Week 33 to 48
4 + 5. Week 1 to Week 24; Week 1 to Week 48
6. Week 1 to Week 24; Week 1 to end of treatment
7. Week 1 to Week 24; Baseline to end of treatment
8. Week 1 to Week 24; Week 1 to Week 48
9 + 10. Week 9 to 24; Week 33 to 48
11. Week 1 to Week 24; Week 1 to Week 48
12 + 13. Randomization to at least 3 years post last dose; Week 1 to Week 48
14. Screening to 42 days post last dose; Week 1 to Week 48
15 + 16. Randomization through 1- year post first dose
17. Randomization through 1- year post first dose |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | No |
| 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 | 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 | No |
| 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
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 58 |
| 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 |
| Canada |
| Russian Federation |
| Turkey |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| United Kingdom |
|
| 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-treatment 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 and/or SAP, 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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