| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Thrombocytopenia in paediatric subjects with immune thrombocytopenia for ≥6 months duration who have had an insufficient response to a previous treatment |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 10043555 |
| E.1.2 | Term | Thrombocytopenias |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10083843 |
| E.1.2 | Term | Primary immune thrombocytopenia |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10083842 |
| E.1.2 | Term | Immune thrombocytopenia |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10035534 |
| E.1.2 | Term | Platelet disorders |
| 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 demonstrate that the efficacy of avatrombopag is superior to placebo for the treatment of pediatric subjects with ITP of ≥6 months duration who have had an insufficient response to a previous treatment |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of avatrombopag
• To evaluate the PK and PD of avatrombopag |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For the CORE phase:
1. Male or female subjects ≥1 and <18 years of age at Screening and Baseline.
2. Subject and/or subject’s legally authorized representative (LAR) must be able to provide informed consent and/or assent, as applicable.
3. Subject has a confirmed diagnosis of primary ITP according to the International Consensus Report on the Investigation and Management of Primary ITP (Provan, 2019) for ≥6 months duration and has had an insufficient response to a previous treatment, in the opinion of the Investigator.
4. Subject has an average of 2 platelet counts <30×109/L with no single count >35×109/L.
The platelet count obtained at the Screening Visit/Visit 1 and 1 other platelet count taken within 28 days on either side of the Screening Visit (may use a historical value collected per standard of care if within 28 days of Screening) will be averaged to obtain the study eligibility platelet count value, which must be <30×109/L. The 2 samples must be obtained ≥24 hours and ≤28 days apart and the results must be available prior to randomization.
5. Subjects being treated chronically with corticosteroids or azathioprine/6-mercaptopurine must be receiving a stable dose for at least 30 days prior to Day 1/Visit 2 or must have completed these therapies more than 30 days prior to Day 1/Visit 2.
6. Subjects being treated with mycophenolate mofetil (MMF), cyclosporine (CsA), sirolimus, or danazol must be receiving a stable dose for at least 90 days prior to Day 1/Visit 2 or must have completed these therapies more than 30 days prior to Day 1/Visit 2.
7. Previous therapy for ITP with immunoglobulins (IVIg and anti-D) or corticosteroid rescue therapy must have been completed at least 14 days prior to Day 1/Visit 2.
8. Cyclophosphamide and vinca alkaloid regimens must have been completed at least 30 days prior to Day 1/Visit 2.
9. Splenectomy and rituximab must have been completed at least 90 days prior to Day 1/
Visit 2.
10. Previous therapy with any other TPO-RAs (e.g., eltrombopag or romiplostim) or recombinant human TPO must have been completed 28 days prior to Day 1/Visit 2.
11. Previous therapy with vitamin K antagonists, antifibrinolytic agents, recombinant activated factor VII, heparin, factor Xa inhibitors, direct thrombin inhibitors, desmopressin, or chronic antiplatelet therapy must have been completed within 7 days of Day 1/Visit 2.
12. Previous therapy with moderate or strong dual inducers or moderate or strong dual inhibitors of cytochrome P450 (CYP)2C9 and CYP3A4 must have been completed within 7 days of Day1/Visit 2.
13. Platelet transfusion, or receipt of blood products containing platelets must have been completed within 7 days of Day 1/Visit 2. Packed red blood cells (RBCs) are permitted.
14. Females of childbearing potential must have a negative urine or serum pregnancy test at Screening and Day 1/Visit 2 and must not be breastfeeding.
15. Female subjects of childbearing potential and who are sexually active and male subjects who are sexually active must agree to use highly effective methods of contraception.
16. Subject and/or subject’s LAR is willing and able to comply with all aspects of the protocol.
For the EXTENSION phase:
1. Subject and/or the LAR must provide consent and/or assent, as applicable, to continue into the open-label Extension Phase. The consent for the Extension Phase will be part of the consent for the Core Phase.
2. Completed 12 weeks of treatment in the Core Phase or discontinued the Core Phase early due to lack of treatment effects.
3. Female subjects of childbearing potential and who are sexually active and male subjects who are sexually active must agree to use highly effective methods of contraception.
4. Subject and/or the subject’s LAR is willing and able to comply with all aspects of the protocol. |
|
| E.4 | Principal exclusion criteria |
For the CORE phase:
1. Known secondary ITP.
2. Body Mass Index (BMI) >30 kg/m2 or >95% for age.
3. Any history of arterial or venous thrombosis, including partial or complete thrombosis.
4. Subjects with known inherited thrombocytopenia (e.g., MYH-9 disorders).
5. History of myelodysplastic syndrome (MDS).
6. Known history of congenital heart abnormalities or arrhythmias.
7. History of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV).
8. Known history of disseminated intravascular coagulation (DIC), hemolytic uremic syndrome (HUS), or thrombotic thrombocytopenic purpura (TTP).
9. Subjects with Evans syndrome.
10. Concurrent malignant disease or previous history of myeloid hematologic malignancies.
11. Hemoglobin (Hgb) levels ≤9 g/dL in ages ≥1 year to <6 years and ≤8 g/dL in ages ≥6 to <18 years.
12. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2.
13. Serum total bilirubin >1.5× the upper limit of normal (ULN) for age, alanine transaminase (ALT) and aspartate aminotransferase (AST) >3× the ULN for age.
14. Known allergy to avatrombopag or any of its excipients.
15. Subject is unable to take oral medication or has a malabsorption syndrome, or has known hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption or any other uncontrolled gastrointestinal condition.
16. Enrollment in another clinical study with any investigational drug or device within 30 days of Day 1/Visit 2 (or 5 half-lives, whichever is longer); however, participation in observational studies within the previous 30 days is permitted.
17. Any clinically relevant abnormality which makes the subject unsuitable for participation in the study, in the opinion of the Investigator.
18. Considered unable or unwilling to comply with the study protocol requirements.
For the EXTENSION phase:
1. Significant safety or tolerability concerns with the subject’s participation, in the opinion of the Investigator.
2. Subjects requiring the following drugs or procedures at the time of enrollment into the Extension Phase:
• Rituximab
• Other TPO-RAs
• Splenectomy
• Moderate or strong dual inducers or moderate or strong dual inhibitors of CYP2C9 and CYP3A4.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
Durable platelet response as defined by the proportion of subjects achieving at least 6 out of 8 weekly platelet counts ≥50×109/L during the last 8 weeks of the 12 week Treatment Period in the Core Phase in the absence of rescue medication.
Alternative Primary Efficacy Endpoint:
Platelet response as defined by the proportion of subjects for whom at least 2 consecutive platelet assessments are ≥50×109/L over the 12 week Treatment Period in the Core Phase in the absence of rescue medication. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 12 week Treatment Period in the Core Phase |
|
| E.5.2 | Secondary end point(s) |
• The percentage of weeks subjects have a platelet count ≥50×109/L during 12 weeks of treatment in the Core Phase, in the absence of rescue therapy.
• Platelet response at Day 8 (defined by the proportion of subjects with a platelet count ≥50×109/L at Day 8, in the absence of rescue therapy).
• The percentage of weeks subjects have a platelet count between ≥50×109/L and ≤150×109/L, during 12 weeks of treatment in the Core Phase, in the absence of rescue therapy.
• The proportion of subjects who require rescue medications during 12 weeks of treatment in the Core Phase of the study.
• Incidence and severity of bleeding symptoms associated with ITP measured using the WHO Bleeding Scale. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After 12 week Treatment Period in the Core Phase |
|
| 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 | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| Ukraine |
| Russian Federation |
| United Kingdom |
| United States |
| France |
| Germany |
| Hungary |
| Poland |
| Türkiye |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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