| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS) |
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| E.1.1.1 | Medical condition in easily understood language |
| Low or Medium Risk Myelodysplastic Syndrome (MDS) |
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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 | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028536 |
| E.1.2 | Term | Myelodysplastic syndromes |
| E.1.2 | System Organ Class | 100000004851 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess the superiority of darbepoetin alfa versus placebo on the incidence of RBC transfusions during the 24-week double-blind treatment period in anaemic subjects with low or intermediate-1 risk MDS.
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| E.2.2 | Secondary objectives of the trial |
• To assess the superiority of darbepoetin alfa treatment compared with placebo treatment on the proportion of subjects achieving International Working Group (IWG) erythroid response during the 24-week double-blind treatment period
• To assess safety of darbepoetin alfa compared with placebo
• To assess the health-related qualify of life (HRQOL) scores of darbepoetin alfa compared with placebo, and to assess the effect of haemoglobin change on HRQOL scores
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Low or intermediate-1 risk MDS patients per IPSS at the time of randomization, as determined by complete blood count (CBC) during screening and bone marrow examination and marrow cytogenetic analysis, performed within 16 weeks prior to randomisation. Subject cannot have been rendered low or intermediate-1 risk by prior disease modifying therapy
- World Health Organization (WHO) classification of refractory anaemia (RA), refractory anaemia with ring sideroblasts (RARS), refractory cytopenias with multilineage dysplasia (RCMD), MDS unclassified (MDS-U), MDS with isolated del(5q) (5q- syndrome) or refractory anaemia with excess blasts-1 (RAEB-1)
-Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 assessed during screening
-Haemoglobin level ≤10.0 g/dL as assessed by the local laboratory; sample obtained within 7 days prior to randomisation (retest during screening is acceptable).
-Adequate transferrin saturation (Tsat) (≥ 15%) and serum ferritin (≥ 10 ng/mL) as assessed by the central laboratory during screening (supplementation and retest during screening is acceptable)
-Adequate serum folate (≥ 4.5 nmol/L [ ≥2.0 ng/mL]) or RBC folate (≥317 nmol/L [ ≥140 ng/mL]) as assessed by the local laboratory during screening (supplementation and retest during screening is acceptable)
- Adequate vitamin B12 (≥148 pmol/L ≥200 pg/mL]) as assessed by the local laboratory during screening (supplementation and retest during screening is acceptable)
-18 years of age or older
- Subject or subject’s legally acceptable representative has provided informed consent
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| E.4 | Principal exclusion criteria |
- Previously diagnosed with intermediate-2 or high risk MDS per IPSS
- Therapy-related or secondary MDS
- History of acute leukemia
- Evidence of bone marrow collagen fibrosis
- Inherited anaemia, active hemorrhage, red cell aplasia, haemolytic anaemia
- History of malignancies other than curatively treated non-melanoma skin or in situ carcinoma
- History of thrombosis within 6 months prior to randomisation
- Previous bone marrow or stem cell transplantation
- Uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator at screening. Subjects with known myocardial infarction within 6 months prior to randomisation.
- Uncontrolled hypertension defined as systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg at screening
- Clinically significant systemic infection or uncontrolled chronic inflammatory disease
- History of seizure disorder
- Previous or ongoing use of ESA therapy, eg, rHuEpo, darbepoetin alfa
- High transfusion demand: receiving a total of ≥ 4 units of RBC transfusion during either of 2 consecutive 8-week periods
- Received any RBC transfusion within 14 days prior to randomisation
- Received cytotoxic chemotherapy for any oncologic indication or planning to receive cytotoxic chemotherapy during the double-blind treatment period of the study
- Received biologic response modifiers
- Received myeloablative or craniospinal radiation within 30 days prior to randomisation or planning to receive myeloablative or craniospinal radiation during the double-blind treatment period of the study
- Received G-CSF therapy within 30 days prior to randomisation or planning to receive G-CSF therapy during the double-blind treatment period of the study
- Abnormal renal function as assessed by the central laboratory
- Abnormal liver function as assessed by the central laboratory
- Serum endogenous EPO level > 500 mU/mL as assessed by the central laboratory at screening
- Known seropositivity for human immunodeficiency virus (HIV) or diagnosis of Acquired Immunodeficiency Syndrome (AIDS), positive for hepatitis B surface antigen, or seropositive for hepatitis C virus
- Subjects with active ethanol abuse
- Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s)
- Female subject is not willing to use highly effective contraception during treatment and for at least 1 month after the end of treatment
- Female subject is pregnant or planning to become pregnant within 1 month after the end of treatment
- Subject has known sensitivity to any of the products to be administered during dosing
- Subject has known sensitivity to any of the products to be administered during dosing
- Subject has previously been randomised into this study
- Subject will not be available for protocol required study visits, to the best of the subject and investigator’s knowledge
- Subject has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures
- Confirmed history of neutralising antibody activity to rHuEpo or darbepoetin alfa
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Incidence of at least 1 RBC transfusion from week 5 to the end of the double-blind treatment period (EOTP) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The analysis will be performed on subjects in the transfusions from Week 5 to end of double-blind treatment period. |
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| E.5.2 | Secondary end point(s) |
Achieving an IWG erythroid response during the double-blind treatment period. IWG erythroid response for non-transfusion dependent subjects is defined as achieving an initial ≥ 1.5 g/dL increase from baseline in haemoglobin level and sustaining an average rise of ≥ 1.5 g/dL in a rolling 56- consecutive day period in the absence RBC transfusion. IWG erythroid response will be determined based on central laboratory haemoglobin values. Secondary Safety Endpoints: Adverse events, including treatmentemergent adverse events of interest (eg, pure red cell aplasia [PRCA]; TVE [ATE and VTE]); Disease progression to AML through EOTP, EOATP, and LTFU; Malignancies other than AML, basal cell carcinoma, or squamous cell; carcinoma of the skin through EOTP; Mortality through EOTP, EOATP, and LTFU; Neutralising antibody formation to darbepoetin alfa
HRQOL Endpoints: Change in patient-reported fatigue and overall health status as measured by the FACIT-F; Attaining a clinically meaningful change from baseline to EOTP in FACIT-F |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of double-blind treatment period, end of treatment and end of long-term follow up to account for safety endpoints |
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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 | No |
| 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 | 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) | 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 | 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 66 |
| 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 | 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
|
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 7 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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