| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Chronic Immune Thrombocytopenia (Idiopathic Thrombocytopenic Purpura)
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Low platelet count, which has lasted for more than a year, caused because platelets (and the cells that produce platelets in the bone marrow) are destroyed by antibodies in the blood. |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10043554 |
| E.1.2 | Term | 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 | 14.1 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10005329 |
| E.1.2 | Term | Blood and lymphatic system disorders |
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036735 |
| E.1.2 | Term | Primary thrombocytopenia |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 |
Core study
To compare the efficacy of E5501 (in addition to standard of care) to eltrombopag (in addition to standard of care) for the treatment of adult subjects with chronic immune thrombocytopenia (idiopathic thrombocytopenic purpura [ITP]) as measured by durable platelet response
Extension study
To evaluate the safety and tolerability of long-term therapy with
E5501 in subjects with chronic ITP (cITP) |
|
| E.2.2 | Secondary objectives of the trial |
Core study
• To demonstrate that the efficacy of E5501 (in addition to standard of care) is superior to the efficacy of eltrombopag (in addition to standard of care) as measured by platelet response rate at Day 8
• To evaluate the safety of E5501 compared with eltrombopag
Extension study
• To demonstrate the effectiveness of long-term therapy with E5501 as measured by platelet response, bleeding, and the use of rescue therapy
• To assess the reduction in use of steroids and concomitant ITP
medication in subjects receiving E5501 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Core study
1. Men and women ≥ 18 years of age
2. Subjects diagnosed with cITP (≥12 months duration) according to the American Society for Hematology/British Committee for Standards in Hematology (ASH/BCSH) guidelines, and an average of two platelet counts < 30 × 109/L (no single count may be >35 × 109/L). In addition, a peripheral blood smear should support the diagnosis of ITP with no evidence of other causes of thrombocytopenia (e.g., pseudothrombocytopenia, myelofibrosis). The physical examination should not suggest any disease which may cause thrombocytopenia other than ITP.
3. Subjects who previously received one or more ITP therapies (including, but not limited to, corticosteroids, immunoglobulins,
azathioprine, danazol, cyclophosphamide and/or rituximab)
4. Subjects must have had either initially responded (platelet count
>50 × 109/L) to a previous ITP therapy or have had a bone marrow examination consistent with ITP within 3 years to rule out
myelodysplastic syndrome (MDS) or other causes of thrombocytopenia.
5. Prothrombin time/International Normalized Ratio (PT/INR) and
activated partial thromboplastin time (aPTT) must have been within
80% to 120% of the normal range with no history of hypercoagulable state.
6. A complete blood count within the reference range (including WBC differential not indicative of a disorder other than ITP), with the following exceptions:
• Hemoglobin: Subjects with hemoglobin levels between 10 g/dL
(100 g/L) and the lower limit of normal (LLN) are eligible for inclusion, if anemia was clearly attributable to ITP (excessive blood loss).
• Absolute neutrophil count (ANC) ≥ 1500/μL (1.5 x 109/L)
(elevated WBC/ANC due to corticosteroid treatment is acceptable).
Extension study
1. Subjects who have completed 6 months of study treatment in the Randomization Phase or
2. Subjects who discontinue the Core Study early due to lack of treatment effects (see Study Drug Discontinuation)
3. No significant safety or tolerability concerns with the subject’s
participation of Randomization Phase as determined by the investigator |
|
| E.4 | Principal exclusion criteria |
Core study
1. Subjects with known secondary immune thrombocytopenia (e.g., subjects with known Helicobacter pylori-induced ITP, infected with known human immunodeficiency virus [HIV] or hepatitis C virus [HCV] or with known systemic lupus erythematosus [SLE])
2. Subjects considered unable, or unwilling to comply with the study protocol requirements or give informed consent, as determined by the investigator
3. Subjects with significant medical conditions that may impact the safety of the subject or interpretation of the study results (e.g., acute hepatitis, active chronic hepatitis; lymphoproliferative disease; myeloproliferative disorders, leukemia)
4. History of MDS
5. History of pernicious anemia or subjects with vitamin B12 deficiency who have not had pernicious anemia excluded as a cause
6. Any prior history of arterial or venous thrombosis (stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis, or pulmonary embolism), and more than two of the following risk factors:
estrogen-containing hormone replacement or contraceptive therapies, smoking, diabetes, hypercholesterolemia, medication for hypertension, cancer, hereditary thrombophilic disorders (e.g., Factor V Leiden, antithrombin III deficiency, etc.), or any other family history of arterial or venous thrombosis
7. Subjects with a history of significant cardiovascular disease (e.g., congestive heart failure [CHF] New York Heart Association Grade III/IV), arrhythmia known to increase the risk of thromboembolic events [e.g., atrial fibrillation], subjects with a QT interval corrected for heart rate of > 450 msec, angina, unstable angina, coronary artery stent placement, angioplasty, or coronary artery bypass grafting)
8. Subjects with a history of cirrhosis, portal hypertension, and chronic active hepatitis
9. Subjects with concurrent malignant disease
10. Use of immunoglobulins (IVIg and anti-D) within 1 week of randomization
11. Splenectomy or use of rituximab within 12 weeks of randomization
12. Use of romiplostim or eltrombopag within 4 weeks of randomization
13. Subjects who are currently treated with corticosteroids or azathioprine but have not been receiving a stable dose for at least 4 weeks prior to randomization or have not completed these therapies more than 4 weeks prior to randomization
14. Subjects who are currently treated with MMF, CsA, or danazol but have not been receiving a stable dose for at least 12 weeks prior to randomization or have not completed these therapies more than 4 weeks prior to randomization
15. Use of cyclophosphamide or vinca alkaloid regimens within 4 weeks of randomization.
16. Subjects who are currently treated with PPIs or H2 antagonist therapy but have not been receiving a stable dose for at least 6 weeks prior to randomization or have not completed these therapies more than 2 weeks prior to randomization
17. Fasting gastrin-17 blood levels exceeding ULN (including subjects on PPIs and H2 antagonists) at Screening
18. Blood creatinine exceeding ULN by more than 20% OR total albumin below the LLN by 10%
19. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels exceeding 2 times the ULN; total bilirubin exceeding 1.5 times the ULN
20. Subjects with a history of cancer treatment with cytotoxic chemotherapy and/or radiotherapy. Subjects with a history of ITP treatment with cytotoxic chemotherapy are still eligible for enrollment.
21. Females who are pregnant (positive beta-human chorionic gonadotropin [β-hCG] test) or breastfeeding
22. Subjects with a known allergy to E5501 or eltrombopag and any of their excipients
23. Subjects with a history of significant aminotransferase elevations while receiving eltrombopag (defined as ALT and/or AST elevation >3 x ULN)
24. Subjects who are known nonresponders (defined as platelet counts that never exceed 50 x 109/L) to all previous TPO agonist therapy (including previous E5501 therapy) who do not have a bone marrow examination consistent with ITP taken at any point after failure of TPO therapy to rule out MDS or other causes of thrombocytopenia
Extension Phase
1. Subjects for whom participation in the Extension Phase is considered unsafe, based on the investigator’s judgment
2. Subjects unwilling to undergo an endoscopy at the time of enrollment into the Extension Phase
3. Subjects considered unable or unwilling to comply with the study protocol requirements or give informed consent, as determined by the investigator
4. Subjects requiring the following drugs or treatments at the time of enrollment in the Extension Phase:
• Rituximab
• Splenectomy
• Other TPO agonists |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Core study
Durable platelet response rate as defined by:
• Proportion of subjects who have at least 6 of 8 (i.e., ≥75%) weekly platelet responses during the last 8 weeks of treatment (i.e., at Visits 15 through 22, inclusive) over the 6-month treatment period in absence of rescue therapy
• Subjects using rescue therapy at any time during the 6-month
treatment period will be considered to not have a durable platelet
response
• A platelet response will be defined as a platelet count of ≥ 50 x 109/L and nonresponse will also be defined as a platelet count of
< 50 x 109/L
• Missing platelet assessments at any given time point will be
considered to be a nonresponse at that time point. Subjects who
discontinue the study or who are lost to follow-up before 6 months will have all subsequent unobserved scheduled platelet assessments at the scheduled time points as having “missing” platelet values.
• All analyses of platelet counts will be based on local laboratory
results.
Extension study
Effectiveness will be assessed by measuring platelet counts, reduction of concomitant ITP medication, and bleeding events. Specifically:
• Time that subjects maintained a platelet count ≥ 50 x 109/L during the study
• Median platelet count of all subjects at selected time points (monthly)
• Maximum duration (in months) of continuous platelet response
(≥50 x 109/L)
• Proportion of subjects with a reduction in use of concomitant ITP
medications from baseline
• Proportion of subjects with a discontinuation in use of concomitant ITP medications from baseline
• Proportion of subjects needing rescue treatment
• Incidence and severity of bleeding (in accordance with the WHO
Bleeding Scale) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
During the last 8 weeks of treatment (i.e., at Visits 15 to 22, inclusive) over the 6-month treatment period in absence of rescue therapy.
|
|
| E.5.2 | Secondary end point(s) |
• Platelet response rate at Day 8 (as defined by the proportion of subjects with a platelet response ≥50 x 109/L at Day 8). Subjects with missing platelet counts at Day 8 or use of a rescue therapy before or on Day 8, will be considered platelet nonresponders.
• Alternative durable platelet response as defined by: proportion of subjects with at least 75% of platelet assessments between ≥ 50 x 109/L and ≤ 400 x 109/L from the time of first response over a 6-month treatment period in the absence of rescue therapy (durability by flexible period)
• Proportion of subjects with a reduction in use of concomitant ITP medications from baseline |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Day 8
• From the time of first response over a 6-month treatment period (in the absence of rescue therapy).
|
|
| 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 | Yes |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| France |
| Germany |
| Ireland |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| Russian Federation |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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