| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10050245 |
| E.1.2 | Term | Autoimmune thrombocytopenia |
| E.1.2 | System Organ Class | 100000004851 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036735 |
| E.1.2 | Term | Primary thrombocytopenia |
| 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 compare the ability of eltrombopag in combination with a short course of dexamethasone to induce a sustained response off treatment at 52 weeks versus a defined course of dexamethasone |
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| E.2.2 | Secondary objectives of the trial |
1. To compare ability of eltrombopag in combination with short course of dexamethasone to induce overall response after treatment discontinuation at Week 52 versus defined course of dexamethasone
2. To assess duration of sustained response off treatment
3. To assess ability of eltrombopag to induce overall response by Week 4
4. To assess ability of eltrombopag to induce complete Response by Week 4
5. To quantify increase in platelet count from screening to baseline and to 1, 2, 4, 12, 26 and 52 weeks
6. To assess time to overall and complete response
7. To assess duration of overall and complete response
8. To evaluate patient-oriented outcomes for health-related quality of life
9. To evaluate safety and tolerability of eltrombopag + dexamethasone
10. To evaluate incidence and severity of bleeding events
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent must be obtained prior to participation in the study.
2. Men and women ≥ 18 years of age
3. Newly diagnosed with primary ITP (time from diagnosis within 3 months). Platelet count < 30 × 10^9/L at screening and a need for treatment (per physician’s discretion).
Note: If pre-treatment is necessary, platelet count data performed directly before pre-treatment (prior to signing the study specific informed consent form and start of screening for the study as per local practice or under a local protocol) will be used for study inclusion (screening value to be used for inclusion/exclusion check and for analysis as a covariate). Treatment-naïve patients will be included based on their platelet counts performed at screening.
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| E.4 | Principal exclusion criteria |
1. Previous history of treatment for ITP.
Note: Patients in need of immediate treatment for thrombocytopenia while diagnosis or eligibility are being determined may receive treatment with any ITP-directed therapy for a maximum of 3 days within 7 days before randomization. These therapies must be discontinued before the patient receives the first dose of study treatment
2. Patients with diagnosis of secondary thrombocytopenia
3. Patients who have life threatening bleeding complications per physician´s discretion
4. Patients with a history of thromboembolic events in the 6 months preceding enrollment or known risk factors for thromboembolism (e.g. Factor V Leiden, ATIII deficiency, antiphospholipid syndrome) are excluded. Patients with other risk factors which may pose an increased thromboembolic event (TEE) risk (prolonged periods of immobilization, malignancies, contraceptives and hormone replacement therapy, surgery/trauma, obesity and smoking) would be excluded according to the discretion of the investigator.
5. Presence of moderate to severe impaired renal function as indicated by any or all of the following criteria:
• Creatinine clearance < 45 mL/min as calculated using Cockcroft-Gault formula
• Serum creatinine > 1.5 mg/dL
6. Total bilirubin (TBIL) > 1.5 × upper limit of normal (ULN)
7. Aspartate transaminase (AST) > 3.0 × ULN
8. Alanine transaminase (ALT) > 3.0 × ULN
9. Patients who are human immunodeficiency virus (HIV), HCV or hepatitis B surface antigen (HBsAg) positive
10. Patients with hepatic impairment (Child-Pugh score > 5)
11. Patients with known active or uncontrolled infections not responding to appropriate therapy
12. History of current diagnosis of cardiac disease or impaired cardiac function denoted by any of the following:
• Corrected QTc >450 msec using Fridericia correction (QTcF) on the screening electrocardiogram (ECG)
• History of myocardial infarction and unstable angina within 6 months prior to starting study treatment
• Clinically significant cardiac arrhythmias or other clinically significant cardiovascular disease (e.g., congestive heart failure, uncontrolled hypertension) within the six months prior to starting study treatment
13. Patients who have active malignancy
14. Patients with evidence of current alcohol/drug abuse
15. Any serious and/or unstable pre-existing medical (including any advanced malignancy other than the disease under study), psychiatric disorder, or other conditions that could interfere with subject’s safety, obtaining informed consent or compliance with the study procedures.
16. Patients with a known immediate or delayed hypersensitivity reaction or idiosyncrasy to eltrombopag or drugs chemically related to eltrombopag or excipients that contraindicate their participation
17. Patients with pre-existing medical conditions that are known precautions with corticosteroid use, in whom the potential risks of participating in the study outweigh the potential benefits as determined by the investigator
18. Female subjects who are nursing or pregnant (positive serum or urine B-human chorionic gonadotrophin (B-hCG) pregnancy test) at screening or pre-dose on Day 1
19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 7 days after stopping medication. Highly effective contraception methods include:
• combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of Ovulation [1]:
- oral
- intravaginal
- transdermal
• progestogen-only hormonal contraception associated with inhibition of Ovulation[1]:
- oral
- injectable
- implantable[2]
• intrauterine device (IUD)[2]
• intrauterine hormone-releasing system (IUS)[2]
• bilateral tubal occlusion[2]
• vasectomised Partner[2,3]
• sexual abstinence[4]
[1]Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the contraception method (see section 4.3).
[2] Contraception methods that in the context of this guidance are considered to have low user dependency.
[3] Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success.
[4] In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the proportion of patients with sustained response off treatment at 52 weeks.
Sustained response off treatment is defined as:
• reach platelet count ≥ 30×10^9/L and then maintain platelet counts ≥ 30 × 10^9/L after treatment discontinuation AND
• maintain platelet count ≥ 30 × 10^9/L in the absence of bleeding events ≥ Grade 2 and without the use of any rescue therapy at all visits until Week 52.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. To compare the ability of eltrombopag in combination with a short course of high dose dexamethasone to induce overall response (OR) after treatment discontinuation at week 52 versus a defined course of dexamethasone
Proportion (%) of patients with platelet count ≥ 30×10^9/L and a 2-fold increase of screening platelet count after treatment discontinuation in the absence of bleeding events ≥ Grade II and no rescue therapy at all visits until Week 52 will be provided, analysis will be equivalent to the primary endpoint analysis.
2. To assess the duration of sustained response off treatment, median duration of response off treatment (weeks) counted from last dose of study treatment (eltrombopag or dexamethasone) until loss of response will be calculated using a Kaplan-Meier analysis.
3. To assess the ability of eltrombopag to induce overall response (OR) by week 4
Number (%) of patients with platelet count ≥ 30×10^9/L and a 2-fold increase of screening platelet count at least once within the first 4 weeks without bleeding events ≥ Grade II and no rescue therapy will be provided, analysis will be equivalent to the primary endpoint analysis.
4. To assess the ability of eltrombopag to induce a complete response (CR) by week 4
Number (%) of patients with platelet count ≥ 100×10^9/L at least once within the first 4 weeks without bleeding events ≥ Grade II and no rescue therapy will be provided, analysis will be equivalent to the primary endpoint analysis.
5. To assess the platelet count from screening to baseline and to 1, 2, 4, 12, 26 and 52 weeks; absolute and relative change in platelet count from screening to baseline and to 1, 2, 4, 12, 26 and 52 weeks and EOS will be provided. Box plots for absolute and/or relative change in platelet counts from screening to baseline and to different time points will also be provided.
6. To assess the time to response for overall and complete response using a Kaplan Meier analysis.
7. To assess the duration of response for overall and complete response using a Kaplan Meier analysis.
8. To evaluate patient HRQoL outcome measures for Health-Related Quality of Life (fatigue level of the patient through FACIT), FACT-Th6 and SF-36v2 questionnaires.
Change in each domain score and total score of HRQoL parameters through FACIT and SF-36v2 questionnaires from baseline to 1, 2, 4, 12, 26, 52 weeks and EOS (for patients with premature study withdrawal before W53D1) will be provided.
9. To evaluate the safety and tolerability of eltrombopag see Section 12.5.2.
10. To evaluate the incidence and severity of bleeding events |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At week 52
2. From last dose of study treatment (eltrombopag or dexamethasone) until loss of response
3. By week 4
4. By week 4
5. From screening to baseline and to week 1, 2, 4, 12, 26, 52 and end of study
6. From screening to time reaching the overall response and complete response
7. From time reaching the overall and complete response to the time of loss of response
8. From baseline to week 1, 2, 4, 12, 26, 52 and end of study
9. From baseline to end of study
10. From baseline to end of 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.3.1 | Comparator description |
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| 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 | 25 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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| Study completion is defined as when the last subject finishes their Study Completion visit and any repeat assessments associated with this visit have been documented and followed up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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