A Study on the Effect of E5501 (study drug) in Adults with Chronic Immune Thrombocytopenia

• Register: EUCTR
• Last refreshed on: 29 January 2018
• Main ID: EUCTR2011-000830-12-NL
• Date of registration: 23/08/2011
• Prospective Registration: Yes
• Primary sponsor: Eisai Limited
• Public title: A Study on the Effect of E5501 (study drug) in Adults with Chronic Immune Thrombocytopenia
• Scientific title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial with an Open-label Extension Phase to Evaluate the Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults with Chronic Immune Thrombocytopenia (Idiopathic Thrombocytopenic Purpura) - Not applicable
• Date of first enrolment: 28/08/2012
• Target sample size: 49
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-000830-12
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: yes; Other specify the comparator: Open-label extension; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Bulgaria, Czech Republic, Greece, Netherlands, New Zealand, Poland, Singapore, Slovakia, South Africa, Ukraine

Contacts

• Name: Medical Information
• Affiliation: Eisai Limited

• Name: Medical Information
• Affiliation: Eisai Limited

Key inclusion & exclusion criteria

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 Dsicontinuation)
3. No significant safety or tolerability concerns with the subject’s
participation of Randomization Phase as determined by the investigator.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 43
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 6

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 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 aminotrans

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Chronic Immune Thrombocytopenia (Idiopathic Thrombocytopenic Purpura)
MedDRA version: 16.1 Level: HLGT Classification code 10035534 Term: Platelet disorders System Organ Class: 10005329 - Blood and lymphatic system disorders
MedDRA version: 16.1 Level: PT Classification code 10043554 Term: Thrombocytopenia System Organ Class: 10005329 - Blood and lymphatic system disorders
MedDRA version: 16.1 Level: LLT Classification code 10036735 Term: Primary thrombocytopenia System Organ Class: 10005329 - Blood and lymphatic system disorders
MedDRA version: 16.1 Level: SOC Classification code 10005329 Term: Blood and lymphatic system disorders System Organ Class: 10005329 - Blood and lymphatic system disorders

Intervention(s)

Product Name: E5501
Product Code: E5501
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Avatrombopag (proposed)
CAS Number: 1254322-84-3
Current Sponsor code: E5501
Other descriptive name: AKR-501, YM-477
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: E5501
Product Code: E5501
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Avatrombopag (proposed)
CAS Number: 1254322-84-3
Current Sponsor code: E5501
Other descriptive name: AKR-501, YM-477
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: E5501
Product Code: E5501
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Avatrombopag (proposed)
CAS Number: 1254322-84-3
Current Sponsor code: E5501
Other descriptive name: AKR-501, YM-477
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: During 6 months of treatment (i.e., at Visit 3 to 22 inclusive).

Secondary Objective: 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 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 receving E5501

Main Objective: 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)

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 (ie, at Visit 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 not to 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.

Secondary Outcome(s)

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).

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.
• Proportion of subjects with a reduction in use of concomitant ITP medications from baseline

Secondary ID(s)

E5501-G000-302

Source(s) of Monetary Support

Eisai Incorporation