E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe aplastic anemia (SAA) |
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E.1.1.1 | Medical condition in easily understood language |
Severe aplastic anemia (SAA) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
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 evaluate the safety and activity profile of eltrombopag in combination with horse anti-thymocyte globulin (h-ATG) and cyclosporine A (CsA) in treatment naïve SAA. |
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E.2.2 | Secondary objectives of the trial |
To evaluate hematological response at 3, 6 and 12 months and yearly thereafter; to evaluate relapse; to evaluate clonal evolution to PNH, clonal chromosomal population in bone marrow, myelodysplasia by morphology, or acute leukemia; to evaluate overall survival; to evaluate health-related quality of life (HRQL); to evaluate the effect of a 2 mg/kg/day CsA dose starting at month 6 for 18 months until month 24 on the rate of relapse of subjects deemed responders at month 6. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Severe aplastic anemia characterized by:
- Bone marrow cellularity <30% (excluding lymphocytes) and
At least two of the following:
• Absolute neutrophil count < 500/ μL
• Platelet count< 20,000/ μL
• Absolute reticulocyte count <60,000/ μL
Age > 2 years old
Weight > 12 kg |
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E.4 | Principal exclusion criteria |
- Known diagnosis of Fanconi anemia
- Evidence of a clonal disorder on cytogenetics performed within 12 weeks of study entry. Patients with super severe neutropenia (ANC less than 200 /microL) will not be excluded initially if cytogenetics are not available or pending. If evidence of a clonal disorder consistent with myelodysplasia is later identified, the patient will go off study.
- Prior immunosuppressive therapy with any ATG, alemtuzumab, or high dose cyclophosphamide
- SGOT or SGPT >5 times the upper limit of normal
- Subjects with known liver cirrhosis in severity that would preclude tolerability of cyclosporine and eltrombopag as evidenced by albumin < 35g/L
- Hypersensitivity to eltrombopag or its components
- Infection not adequately responding to appropriate therapy
- Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient s ability to tolerate protocol therapy, or that death within 7-10 days is likely
- Potential subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible
- Current pregnancy, or unwillingness to take oral contraceptives or use a barrier method of birth control or practice abstinence to refrain from pregnancy if of childbearing potential during the course of this study
- Inability to understand the investigational nature of the study or to give informed consent or does not have a legally authorized representative or surrogate that can provide informed consent. |
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E.5 End points |
E.5.1 | Primary end point(s) |
To evaluate the safety and activity profile of h-ATG/CsA/eltrombopag in treatment naïve SAA. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Toxicity profile in the 6 months following h-ATG/CsA/eltrombopag
- Complete response rate at 6 months following h ATG/CsA/eltrombopag |
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E.5.2 | Secondary end point(s) |
a)Complete response rates at 3 and 12 months and yearly thereafter
b)Overall response rates at 3, 6 12 months and yearly thereafter
c)Duration of complete responsea
d)Duration of overall responsea
e)Time to first occurrence of clonal evolution to PNH, clonal chromosomal population in bone marrow, myelodysplasia by morphology, or acute leukemia
f)Overall survival
g)Change from Baseline to post-Baseline assessments in PROMIS Global Health, Sleep Disturbance, Applied Cognition-Abilities, Anxiety and Depression scores
h)Change from Baseline to post-Baseline assessments in FACT- Anemia, Thrombocytopenia and Neutropenia scores
i)Rates of secondary complete response and overall response in re-treated subjects
j)Duration of response in subjects responding at month 6 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
a) Month 3, Month 6, Month 12, yearly thereafter
b) Anytime between Month 3 and year 5
c) Anytime within the 5 years following start of treatment
d) Anytime within the 5 years following start of treatment
e) Day 14 (Cohort 1 and 2), Month 3, Month 6, Month 12, yearly thereafter
f) Evaluated continuously
g) Anytime between Month 6 and Year 5
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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 | 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 | 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 | No |
E.8.1.1 | Randomised | No |
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 | 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 | No |
E.8.2.3 | Other | No |
E.8.3 |
Will this trial be conducted at a single site globally?
| Yes |
E.8.4 | Will this trial be conducted at multiple sites globally? | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA 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.8.9.2 | In all countries concerned by the trial years | 5 |