| 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 | 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 | 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 | 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.1.2 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.1.3 | 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 demonstrate that the efficacy of E5501 (in addition to standard of care) is superior to placebo (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 Phase
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 placebo (in addition to standard of care) as measured by platelet response rate at Day 8
• To demonstrate that the efficacy of E5501 (in addition to standard of care) is superior to the efficacy of placebo (in addition to standard of care) as measured by an alternate durable response
• To demonstrate that the efficacy of E5501 (in addition to standard of care) is superior to the efficacy of placebo (in addition to standard of care) as measured by the proportion of subjects with reduction in concomitant ITP medication use
• To evaluate the safety of E5501 compared with placebo
Extension Phase
• 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
ASH/BCSH guidelines, with 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 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 and activated
partial thromboplastin time must have been within 80% to 120% of the
normal range with no history of hypercoagulable state.
6. A complete blood count (excluding platelet count), within the
reference range (with white blood count [WBC] differential not
indicative of any significant hematological disorder), 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 is clearly attributable to ITP (excessive blood loss).
• Absolute neutrophil count (ANC) ≥ 1500/μL (1.5 x 109/L)was required
for inclusion (elevated WBC/ANC due to corticosteroid treatment is
acceptable).
• Elevated WBC or ANC (e.g., due to corticosteroid treatment) provided
this is discussed with the medical monitor (revised per Amendment 01)
Extension Phase
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., with
known Helicobacter pylori-induced ITP, subjects infected with known
human immunodeficiency virus [HIV] or hepatitis C virus [HCV] or
subjects with known systemic lupus erythematosus) (Revised per
Amendment 01)
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 gastric atrophy (added per Amendment 01)
6. History of pernicious anemia or subjects with vitamin B12 deficiency
(defined as <LLN) who have not had pernicious anemia excluded as a
cause (added per Amendment 01)
7. 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
8. 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 QTc > 450 msec, angina, coronary
artery stent placement, angioplasty, coronary artery bypass grafting)
9. Subjects with a history of cirrhosis, portal hypertension, and chronic
active hepatitis
10. Subjects with concurrent malignant disease
11. Use of immunoglobulins (IVIg and anti-D) within 1 week of
randomization
12. Splenectomy or use of rituximab within 12 weeks of randomization
13. Use of romiplostim or eltrombopag within 4 weeks of randomization
14. 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
15. 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
16. Use of cyclophosphamide or vinca alkaloid regimens within 4 weeks
of randomization.
17. Subjects who are currently treated with proton pump inhibitors
(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
18. Fasting gastrin-17 blood levels exceeding the upper limit of normal
(ULN) at Screening for subjects not on PPIs or H2 antagonists (revised
per Amendment 01)
19. Fasting gastrin-17 blood levels exceeding 1.5 times the ULN at
Screening for subjects on PPIs or H2 antagonists (added per Amendment
01)
20. Blood creatinine exceeding ULN by more than 20% OR total albumin
below the lower
limit (LLN) of normal by 10% (revised per Amendment 01)
21. Alanine aminotransferase (ALT) OR aspartate aminotransferase
(AST) levels exceeding 3 times the ULN OR total bilirubin exceeding 2
times the ULN (revised per Amendment 01)
22. 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.
23. Females who are pregnant (positive beta-human chorionic
gonadotropin positive [β-hCG] test) or breastfeeding
24. Subjects with a known allergy to E5501 or its excipients
25. Evidence of clinically significant disease (e.g., cardiac, respiratory,
gastrointestinal, renal disease) that in the opinion of the investigator(s)
could affect the subject's safety or study
conduct
26. Any history of or concomitant medical condition thatwould
compromise the subject's ability to safely complete the study
27. Subjects who have participated in another investigational trial within
30 days prior to Day 1 Baseline/Randomization
Extension Phase
1. Subjects for whom participation in the Extension Phase is considered
unsafe, based on the investigator’s judgment.
2. Subjects considered unable, or unwilling to comply with the study protocol requirements or give informed consent, as determined by the investigator.
3. Subjects requiring the following drugs or treatments at the time of
enrollment in the Extension Phase:
a) Rituximab
b) Splenectomy
c) Other TPO agonists |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Core Study
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., Visits 15 to 22, inclusive) over the 6-month treatment period in the 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 be defined as a platelet count < 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. |
|
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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
| 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 | 30 |
| 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 |
| Belgium |
| Bulgaria |
| China |
| Croatia |
| Czech Republic |
| Greece |
| Hong Kong |
| Hungary |
| Netherlands |
| New Zealand |
| Poland |
| Portugal |
| Romania |
| Singapore |
| Slovakia |
| South Africa |
| Ukraine |
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 24 |
| 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 | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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