| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| treatment naive severe aplastic anemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| treatment naive severe aplastic anemia |
|
| 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 | 10002969 |
| E.1.2 | Term | Aplastic anemia |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 efficacy of eltrombopag in combination with r-ATG and CsA in terms of
complete response (CR) rate at week 26 in East-Asian patients with treatment naive
severe aplastic anemia (SAA) |
|
| E.2.2 | Secondary objectives of the trial |
Objective 1: To evaluate complete response rate at 3, 12 months and yearly after
Objective 2: To evaluate overall response rate at 3, 6, 12 months and yearly after
Objective 3: To evaluate duration of response
Objective 4: To evaluate overall survival
Objective 5: To evaluate the need for transfusion (packed red blood cell (RBC) units and platelet units)
Objective 6: To evaluate safety and tolerability of eltrombopag in combination with r-ATG and CsA
Objective 7: To evaluate clonal evolution
Objective 8: To determine the pharmacokinetics (PK) of eltrombopag in East-Asian treatment naive SAA patients |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written study informed consent and (where applicable) assent from the participant, parent, or guardian must be obtained prior to participation in the study.
2. Participants of East Asian ancestry aged ≥ 6 years old at the time of written informed consent and assent form (if applicable).
3. SAA characterized by:
Bone marrow cellularity < 25%, or 25-50% with < 30% residual hematopoietic cells and pancytopenia, with at least two of the following parameters in peripheral blood:
Absolute neutrophil count < 0.5×109/L
Platelet count < 20×109/L
Absolute reticulocyte count < 20×109/L
4. HSCT is not suitable or available as a treatment option (determined as per local practices or national guidelines), or has been refused by participant. |
|
| E.4 | Principal exclusion criteria |
1. Prior IST with any ATG/ALG, alemtuzumab, high dose cyclophosphamide (≥ 45 mg/kg/day), CsA within 6 months, or prior thrombopoietin receptor agonists.
2. Eastern Cooperative Oncology Group (ECOG) performance status (age ≥ 16 years) >2, or Lansky performance status (age < 16 years) <50.
3. Prior and/or active medical history of:
Known underlying congenital/inherited bone marrow failure or aplastic anemia (e.g.,such as but not limited to Fanconi anemia, congenital dyskeratosis, congenital amegakaryocytic thrombocytopenia, or Shwachman-Diamond Syndrome)
Symptomatic paroxysmal nocturnal hemoglobinuria (PNH) and/or PNH clones >50% of polymorphonuclear neutrophil (PMN) or RCB at time of enrollment
Myelodysplastic syndrome (MDS)
Any cytogenetic abnormalities on karyotyping or FISH within 30 days of study enrollment (an evaluable karyotyping with at least 10 metaphases is mandatory for eligibility)
Other known or suspected underlying primary immunodeficiency
Any concomitant malignancies that have not fully recovered from treatment or have not been disease-free for 5 years
4. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN).
5. Creatinine ≥ 2.5×local ULN
6. Past medical history of thromboembolism within 6 months, and/or prior or current antiphospholipid antibody syndrome (APS).
7. Presence of clinically active uncontrolled significant (of such severity that it would preclude the participant's ability to consent, be compliant with study procedures, tolerate protocol therapy) infection, including bacterial, fungal, mycobacterial, parasitic or viral infection, or any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the participant or compliance with the protocol
8. Any severe and/or uncontrolled medical conditions which could cause unacceptable safety risks or compromise compliance with the protocol, such as:
Known hepatocellular disease (e.g. active hepatitis or cirrhosis)
Impairment of gastrointestinal (GI) function or gastrointestinal disease that may significantly alter the absorption of study treatment (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
Active skin, mucosa, ocular or GI disorders of Grade > 1
9. Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening. A positive serology for Hepatitis B (HB) is considered as a positive test for HBsAg. In addition, if serology is negative for HBsAg but hepatitis B core antibody (HBcAb) is positive (regardless of hepatitis B surface antibody (HBsAb) status), a hepatitis B virus (HBV) DNA test will be performed and if positive the patient will be excluded.
10. Cardiac disorder (participants with congestive heart disease of New York Heart Association (NYHA) functional classification Grade II/III/IV (for pediatric participants, refer to the Grade II/III/IV of Modified ross heart failure classification for Children) should not be enrolled; participants with NYHA Grade II due to cardiac disorder should not be enrolled but those with NYHA Grade II due to aplastic anemia (AA) may be enrolled.), arrhythmia with a risk of thrombosis (e.g. atrial fibrillation), pulmonary hypertension, or uncontrolled hypertension (>180/100 mmHg). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Complete Response rate at Week 26 (6 months) after starting the study treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Complete Response rate at Week 13 (3 months), Week 52 (12 months) and yearly after
- Overall response (Complete Response + Partial Response) rate at Week 13 (3 months), Week 26 (6 months), Week 52 (12 months) and yearly after
- Time from the date of the start of response to the date of relapse or death, whichever occurs first at any time during the study
- Time from the date of first dose of study treatment to the date of death
- Overall survival rate at Week 26, Week 52 and yearly after
- Time from the most recent transfusion to Week 13 and Week 26
- Proportion of participants who becomes (platelet/RBC) transfusion independent
- Frequency and severity of AEs, severe adverse events (SAEs), vital signs, electrocardiogram and laboratory abnormalities
- Time from the date of first dose of study treatment to the date of first occurrence of any of the clonal evolution events
- Plasma PK parameters and trough concentration of eltrombopag at steady state |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 13 (3 months), Week 26 (6 months), Week 52 (12 months) and yearly after |
|
| 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?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| 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 |
| Taiwan |
| China |
| Japan |
| Korea, Republic of |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| 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 | 1 |
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