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 |
Thrombocytopenia (low platelet counts) - in subjects with low or intermediate-1 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 | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028533 |
E.1.2 | Term | Myelodysplastic syndrome |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 romiplostim for the treatment of thrombocytopenia in subjects with international prognostic scoring system (IPSS) low or intermediate-1 risk MDS as measured by the number of clinically significant bleeding events. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the number of platelet transfusions
To evaluate the overall number of bleeding events
To evaluate the utilization of platelet transfusions
To evaluate platelet hematologic improvement (HI-P), per MDS IWG 2006 guidelines
To evaluate overall survival
To evaluate patient-reported bleeding events |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Disease related:
• Diagnosis of MDS using the WHO classification for myeloid neoplasms (Vardiman et al, 2002) as assessed during the screening period
• Per MDS IPSS, low or intermediate-1 risk MDS as assessed during the screening period
• The mean of the 2 platelet counts taken within 4 weeks prior to randomization must be:
≤ 20 x 109/L (with no individual count >30 x 109/L during the screening period), with or without a history of bleeding associated with the diagnosis of MDS, OR
≤ 50 x 109/L (with no individual count >60 x 109/L during the screening period), with a history of bleeding associated with the diagnosis of MDS
A standard of care platelet count taken prior to Informed Consent may be used as 1 of the 2 counts taken within 4 weeks prior to randomization.
Demographic:
• Subjects must be ≥18 and ≤ 90 years of age at the time of informed consent. Subjects between 85 and 90 years of age must have been diagnosed with MDS ≤ 5 years from study start.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
Laboratory:
• Adequate liver function, as evidenced by ALT ≤ 3 times the laboratory normal range, AST ≤ 3 times the laboratory normal range and total bilirubin ≤ 2.0 times the laboratory normal range.
(Adequate liver function for patients with a confirmed diagnosis of Gilbert’s Disease evidenced by ALT ≤ 3 times the laboratory normal range and AST ≤ 3 times the laboratory normal range).
• A serum creatinine concentration ≤ 2 mg/dl (≤176.8 µmol/L)
• Bone marrow biopsy and aspirate with cytogenetics within 3 months of the first dose of investigational product.
Ethical:
• Before any study-specific procedure, the appropriate written informed consent from the subject or his/her legally acceptable representative must be obtained. |
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E.4 | Principal exclusion criteria |
Disease Related:
• Have ever received any disease-modifying treatment for MDS (for a list of disease - modifying treatments please refer to section 6.5)
• Previously diagnosed with intermediate-2 or high risk MDS with IPSS
• Prior history of leukemia, aplastic anemia, or other non-MDS related bone marrow stem cell disorder
• Prior history of hematopoietic stem cell transplantation
• Persistent peripheral blood monocytosis (≥ 3 months with an absolute monocyte count > 1,000/μL) or known diagnosis of Chronic Myelomonocytic Leukemia per the FAB criteria (Bennett, et al, 1976)
• Prior malignancy (other than in situ cervical cancer, non-melanoma skin cancer, or in situ carcinoma) unless treated with curative intent and without evidence of disease for ≥3 years before randomization
• Active or uncontrolled infections
• Unstable angina, congestive heart failure (NYHA > class II), uncontrolled hypertension (diastolic > 100 mmHg), uncontrolled cardiac arrhythmia, or recent (within 1 year) myocardial infarction
• History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past year
• History of venous thrombosis that currently requires anti-coagulation therapy
Laboratory:
• Pregnant or breast feeding
Medications
• Received IL-11 within 4 weeks of the first dose of investigational product
• Have previously received any thrombopoietic growth factor
• Receipt of G-CSF, peg-G-CSF, or GM-CSF within 4 weeks of the first dose of investigational product.
• Planned receipt of peg-G-CSF or GM-CSF after the first dose of investigational product.
General:
• Subject of reproductive potential who is not using adequate contraceptive precautions, in the judgement of the investigator. Amgen recommends double barrier contraception is used for all applicable patients enrolled on this study. A double barrier method is defined as two methods of contraception, for example 2 actual barrier methods, or one actual barrier method and one hormonal method.
• Subject has known sensitivity to any E coli-derived product (eg, Infergen®, Neupogen®, Somatropin, and Actimmune®).
• Previously enrolled into the 20060198 study or another romiplostim study
• Inability to comply with study procedures.
• Subject currently is enrolled in or has not yet completed 30 days since ending other investigational device or drug study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the incidence of clinically significant bleeding events. A clinically significant bleeding event is defined as any bleeding event of grade ≥ 2 per the modified WHO bleeding scale. Any event occurring between study day 1 and the end of the 26-week test treatment period (up to week 27) will be included in the analysis. Subjects that discontinue the study early and are not observed to have a clinically significant bleeding event will be considered to not have had an event. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
To evaluate the efficacy of romiplostim for the treatment of thrombocytopenia in subjects with international prognostic scoring system (IPSS) low or intermediate-1 risk MDS as measured by the number of clinically significant bleeding events.
Time Frame: Test Treatment Period (W1-26). |
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E.5.2 | Secondary end point(s) |
1-The incidence of disease progression to acute myelogenous leukemia (AML).
2-The incidence of neutralizing romiplostim antibody formation and antibodies that crossreact react with eTPO.
3-To evaluate the number of platelet transfusions.
4-To evaluate the overall number of bleeding events.
5-To evaluate the utilization of platelet transfusions.
6-To evaluate platelet hematologic improvement (HI-P), per MDS IWG 2006 guidelines.
7-To evaluate overall survival.
8-To evaluate patient-reported bleeding events. Time Frame: Duration of the study.
9-The incidence and severity of all adverse events including clinically significant changes in laboratory values. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-Time Frame: Duration of the study .
2-Time Frame: Duration of the study .
3-Time Frame: Test Treatment Period (W1-26).
4-Time Frame: Test Treatment Period (W1-26).
5-Time Frame: Test Treatment Period (W1-26).
6-Time Frame: Test Treatment Period (W1-26).
7-Time Frame: Duration of the study.
8-Time Frame: Duration of the study.
9- Time Frame: Duration of the study.
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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 | No |
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) | 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 | 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 | 1 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 110 |
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 |
Australia |
Russian Federation |
Switzerland |
United States |
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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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End of Trial: the time when the last subject is assessed or receives an intervention for evaluation in the study, inclusive of the long-term follow-up beyond the EOS visit. |
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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 | 8 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |