A Phase 3, Multicenter, Randomized, Double-blind,Active-controlled, Parallel-group Trial With an Open-labelExtension Phase to Evaluate the Efficacy and Safety of OralE5501 Versus Eltrombopag, in Adults With Chronic ImmuneThrombocytopenia (Idiopathic Thrombocytopenic Purpura)

NCT ID: NCT01433978

Last Updated: 2018-02-06

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-03-26
• Study Completion Date: 2013-09-30

Brief Summary

Core study:

To compare the efficacy of avatrombopag (in addition to standard) of care to eltrombopag (in addition to standard of care) for the treatment of adult participants with chronic immune thrombocytopenia (idiopathic thrombocytopenic purpura [ITP]) as measured by durable platelet response.

Open-label Extension Phase:

To evaluate the safety and tolerability of long-term therapy with avatrombopag in participants with chronic ITP (cITP).

Detailed Description

The study consists of three phases: Prerandomization, Randomization (Core Study) and Extension Phase. Participants 18 years of age and over, who meet all the eligibility requirements will be randomized into the study. It will require that splenectomized participants make up at least 35% of the study population and no single platelet count is greater than 35x10^9/L. Participants will be centrally stratified at randomization by splenectomy status, baseline platelet count, and use of concomitant ITP medication at baseline and randomized to receive either double-blind avatrombopag or eltrombopag in a 1:1 ratio. Participants will receive blinded therapy at a starting dose of 20 mg avatrombopag once daily or 50 mg eltrombopag once daily. Participants will be allowed to have their dose titrated up (maximum dose 40 mg avatrombopag and 75 mg for eltrombopag) or down (minimum dose 5 mg for avatrombopag and 25 mg for eltrombopag) depending on their response to study drug. The goal of dose modification is to maintain the platelet count at levels greater than or equal to 50x10^9/L and less than or equal to 150x10^9/L, and to decrease the need for ITP-directed concomitant medications. The duration of treatment in the Core study and the Extension Phase is approximately 26 and 104 weeks, respectively.

Conditions

Idiopathic Thrombocytopenic Purpura

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Avatrombopag (Core Study)

Avatrombopag will be administered orally as 5 mg, 10 mg, 20 mg, 30 mg or 40 mg in a flexible dose design for 26 weeks. Participants will receive blinded therapy at a starting dose of 20 mg avatrombopag, once daily and allow to have their dose titrated up (maximum dose of 40 mg avatrombopag) or down (minimum dose of 5 mg avatrombopag) depending on their response to study drug.

Group Type: ACTIVE_COMPARATOR

Avatrombopag

Intervention Type: DRUG

Standard of care

Intervention Type: DRUG

Permitted ITP concomitant background therapies are as follows:

• Corticosteroids and/or azathioprine taken at a stable dose for 4 weeks before randomization;
• Mycophenolate mofetil (MMF) or danazol taken at a stable dose for at least 12 weeks before randomization;
• Cyclosporine A (CsA) (due to the fact that it is a P-glycoprotein-mediated transport [P-gp] inhibitor) is to be avoided unless deemed medically necessary; CsA taken at a stable dose for at least 12 weeks before randomization.

At the discretion of the investigator, participants will be allowed to use aspirin, other salicylates, or approved adenosine diphosphate (ADP) receptor antagonists, (eg, clopidogrel, prasugrel) during the study once their platelet count had risen.

Participants treated with proton pump inhibitors (PPIs) and H2 antagonist therapy will receive a stable dose for at least 6 weeks prior to randomization. Treatment with these therapies must have been completed at least 2 weeks prior to randomization.

Eltrombopag (Core Study)

Eltrombopag will be administered orally as 25 mg, 50 mg, or 75 mg in a flexible dose design for 26 weeks. Participants will receive blinded therapy at a starting dose of 50 mg eltrombopag once daily and allow to have their dose titrated up (maximum dose of 75 mg eltrombopag) or down (minimum dose of 25 mg eltrombopag) depending on their response to study drug.

Group Type: ACTIVE_COMPARATOR

Eltrombopag

Intervention Type: DRUG

Standard of care

Intervention Type: DRUG

Permitted ITP concomitant background therapies are as follows:

• Corticosteroids and/or azathioprine taken at a stable dose for 4 weeks before randomization;
• Mycophenolate mofetil (MMF) or danazol taken at a stable dose for at least 12 weeks before randomization;
• Cyclosporine A (CsA) (due to the fact that it is a P-glycoprotein-mediated transport [P-gp] inhibitor) is to be avoided unless deemed medically necessary; CsA taken at a stable dose for at least 12 weeks before randomization.

At the discretion of the investigator, participants will be allowed to use aspirin, other salicylates, or approved adenosine diphosphate (ADP) receptor antagonists, (eg, clopidogrel, prasugrel) during the study once their platelet count had risen.

Participants treated with proton pump inhibitors (PPIs) and H2 antagonist therapy will receive a stable dose for at least 6 weeks prior to randomization. Treatment with these therapies must have been completed at least 2 weeks prior to randomization.

Avatrombopag (Open-label Extension)

Participants who meet the eligibility requirements for the Open-label Extension (OLE) Phase or who discontinue the Core Study early because of lack of treatment effect will be eligible to continue into the OLE Phase for up to 104 weeks of open-label avatrombopag therapy. Participants who enter the OLE from the Core Study will receive a starting dose of open-label avatrombopag which will be determined by the last dose of study drug at the End of Treatment (EOT) Visit (Visit 22) of the Core Study. Participants who discontinue the Core Study early because of lack of treatment effect and enter the OLE will receive open-label avatrombopag at a starting dose of 20 mg once daily of open-label avatrombopag.

Group Type: EXPERIMENTAL

Avatrombopag

Intervention Type: DRUG

Standard of care

Intervention Type: DRUG

Permitted ITP concomitant background therapies are as follows:

• Corticosteroids and/or azathioprine taken at a stable dose for 4 weeks before randomization;
• Mycophenolate mofetil (MMF) or danazol taken at a stable dose for at least 12 weeks before randomization;
• Cyclosporine A (CsA) (due to the fact that it is a P-glycoprotein-mediated transport [P-gp] inhibitor) is to be avoided unless deemed medically necessary; CsA taken at a stable dose for at least 12 weeks before randomization.

At the discretion of the investigator, participants will be allowed to use aspirin, other salicylates, or approved adenosine diphosphate (ADP) receptor antagonists, (eg, clopidogrel, prasugrel) during the study once their platelet count had risen.

Participants treated with proton pump inhibitors (PPIs) and H2 antagonist therapy will receive a stable dose for at least 6 weeks prior to randomization. Treatment with these therapies must have been completed at least 2 weeks prior to randomization.

Interventions

Eltrombopag

Intervention Type: DRUG

Avatrombopag

Intervention Type: DRUG

Standard of care

Permitted ITP concomitant background therapies are as follows:

• Corticosteroids and/or azathioprine taken at a stable dose for 4 weeks before randomization;
• Mycophenolate mofetil (MMF) or danazol taken at a stable dose for at least 12 weeks before randomization;
• Cyclosporine A (CsA) (due to the fact that it is a P-glycoprotein-mediated transport [P-gp] inhibitor) is to be avoided unless deemed medically necessary; CsA taken at a stable dose for at least 12 weeks before randomization.

At the discretion of the investigator, participants will be allowed to use aspirin, other salicylates, or approved adenosine diphosphate (ADP) receptor antagonists, (eg, clopidogrel, prasugrel) during the study once their platelet count had risen.

Participants treated with proton pump inhibitors (PPIs) and H2 antagonist therapy will receive a stable dose for at least 6 weeks prior to randomization. Treatment with these therapies must have been completed at least 2 weeks prior to randomization.

Intervention Type: DRUG

Other Intervention Names

Promacta; Revolade; E5501; Avatrombopag maleate

Eligibility Criteria

Inclusion Criteria

1. Men and women greater than or equal to 18 years of age.

2. Participants diagnosed with cITP (greater than or equal to 12 months duration) according to the American Society for Hematology/British Committee for Standards in Hematology (ASH/BCSH) guidelines, and an average of 2 platelet counts less than 30x10^9/L). The physical exam should not suggest any disease which may cause thrombocytopenia other than ITP.

3. Participants who previously received one or more ITP therapies (including, but not limited to corticosteroids, immunoglobulins, azathioprine, danazol, cyclophosphamide and/or rituximab).

4. Participants must have had either initially responded (platelet count greater than 50x10^9/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 white blood count [WBC] differential not indicative of a disorder other than ITP), with the following exceptions: a) Hemoglobin: participants 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); b) Absolute neutrophil count (ANC) greater than or equal to 1500/uL (1.5x10^9/L) (elevated WBC/ANC due to corticosteroid treatment is acceptable).

Exclusion Criteria

Core Study

1. Participants with known secondary immune thrombocytopenia (e.g., participants 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. Participants considered unable, or unwilling to comply with the study protocol requirements or give informed consent, as determined by the investigator.

3. Participants with significant medical conditions that may impact the safety of the participant 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 participants 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. Participants 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], participants 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. Participants with a history of cirrhosis, portal hypertension, and chronic active hepatitis.

9. Participants 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. Participants 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. Participants 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. Participants 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% (revised per Amendment 01).

19. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels exceeding 2 times the ULN; total bilirubin exceeding 1.5 times the ULN.

20. Participants with a history of cancer treatment with cytotoxic chemotherapy and/or radiotherapy.

21. Participants with a history of ITP treatment with cytotoxic chemotherapy are still eligible for enrollment.

22. Females who are pregnant (positive beta-human chorionic gonadotropin [B-hCG] test) or breastfeeding.

23. Participants with a known allergy to E5501 or eltrombopag and any of their excipients.

24. Participants with a history of significant aminotransferase elevations while receiving eltrombopag (defined as ALT and/or AST elevation >3 x ULN).

25. Participants who are known nonresponders (defined as platelet counts that never exceed 50 x 10^9/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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eisai Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Joe McIntosh

Role: STUDY_DIRECTOR

Eisai Inc.

Locations

Prairie Lakes Health Care System

Watertown, South Dakota, United States

Countries

United States

Other Identifiers

E5501-G000-305

Identifier Type: -

Identifier Source: org_study_id