Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)

Phase 3

Completed

• Conditions: Chronic Thrombocytopenia; Immune Thrombocytopenia
• Interventions: Drug: Placebo; Drug: Avatrombopag; Drug: Standard of care

• Registration Number: NCT01438840
• Lead Sponsor: Eisai Inc.

Brief Summary

Core Study:

To demonstrate that the efficacy of avatrombopag (in addition to standard of care) is superior to placebo (in addition to standard of care) for the treatment of adult participants with chronic immune thrombocytopenia (idiopathic thrombocytopenic purpura) (ITP) as measured by cumulative number of weeks of platelet response over 6 months of once daily treatment in adults participants who received at least 1 prior ITP therapy.

Extension Phase:

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

Detailed Description

This study consists three phases: Prerandomization, Randomization (Core Study) and Extension study. The overall duration of treatment (Core and Extension) is approximately 104 weeks with the Core study being 26 weeks and the Extension study being 76 weeks. Approximately 45 participants 18 years of age and over who meet all the eligibility requirements will be randomized. No single platelet count should be greater than 35x10\^9/L (liter). 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 placebo in a 2:1 ratio. Participants will receive blinded therapy at a starting dose of 20 mg avatrombopag or placebo once daily. Participants will be allowed to have their dose titrated up (maximum dose 40 mg avatrombopag or matching placebo) or down (minimum dose 5 mg for avatrombopag or matching placebo) 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.

Study Timeline

• Study First Submitted: 2011-09-19
• Study First Submitted QC: 2011-09-21
• Study First Posted: 2011-09-22
• Study Start: 2012-02-16
• Primary Completion: 2013-11
• Study Completion: 2014-03
• Disposition First Submitted: 2015-06-29
• Disposition First Submitted QC: 2015-06-29
• Disposition First Posted: 2015-07-22
• Results First Submitted: 2017-12-05
• Results First Submitted QC: 2017-12-05
• Status Verified: 2018-01
• Results First Posted: 2018-01-05
• Last Update Submitted: 2018-01-09
• Last Update Posted: 2018-02-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 49

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 greater 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: 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); 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

1. Participants with known secondary immune thrombocytopenia (e.g., with known Helicobacter pylori-induced ITP participants infected with known human immunodeficiency virus [HIV] or hepatitis C virus [HCV] or participants with known systemic lupus erythematosus). (Revised per Amendment 01)
2. Participants with significant medical conditions that may impact on the safety of the participant or interpretation of the study results (e.g., acute hepatitis, active chronic hepatitis; lymphoproliferative disease; myeloproliferative disorders, leukemia)
3. History of MDS
4. History of gastric atrophy (added per Amendment 01)
5. History of pernicious anemia or participants with vitamin B12 deficiency (defined as less than LLN) who have not had pernicious anemia excluded as a cause (added per Amendment 01)
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: hormone replacement therapy, 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, coronary artery stent placement, angioplasty, 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 the ULN at Screening for participants not on PPIs or H2 antagonists (Revised per Amendment 01)
18. Fasting gastrin-17 blood levels exceeding 1.5 times the upper limit of normal (ULN) at Screening for participants on PPIs or H2 antagonists (Added per Amendment 01)
19. Blood creatinine exceeding ULN by more than 20% OR total albumin below the lower limit of normal (LLN) by 10%
20. Alanine aminotransferase (ALT) OR aspartate aminotransferase (AST) levels exceeding 3 times the ULN or total bilirubin exceeding 2 times the ULN
21. Participants with a history of cancer treatment with cytotoxic chemotherapy and/or radiotherapy.
22. Participants 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 [B-hCG] test) or breastfeeding
24. Participants with a known allergy to avatrombopag (E5501) or its excipients

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Avatrombopag (Open-Label Extension)	Standard of care	Participants who meet all eligibility criteria requirements of extension phase and who discontinue the core study because of lack of treatment effect will continue into the extension phase. Avatrombopag will be administered to participants who enter extension phase, with a starting dose of 20 mg avatrombopag, once daily for 76 weeks and undergo dose titration.
Placebo (Core Study)	Placebo	Placebo will be administered as 5 mg, 10 mg, 20 mg, 30 mg or 40 mg in a flexible dose design for 26 weeks. Placebo will be administered orally at a starting dose of 20 mg, once daily. Afterwards the dose can be titrated up (maximum dose of 40 mg avatrombopag) or down (minimum dose of 5 mg avatrombopag) depending on the participant's response to the study drug; placebo titration will be used to maintain the blind.
Avatrombopag (Core Study)	Standard of care	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, one daily and allowed 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.
Placebo (Core Study)	Standard of care	Placebo will be administered as 5 mg, 10 mg, 20 mg, 30 mg or 40 mg in a flexible dose design for 26 weeks. Placebo will be administered orally at a starting dose of 20 mg, once daily. Afterwards the dose can be titrated up (maximum dose of 40 mg avatrombopag) or down (minimum dose of 5 mg avatrombopag) depending on the participant's response to the study drug; placebo titration will be used to maintain the blind.
Avatrombopag (Core Study)	Avatrombopag	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, one daily and allowed 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.
Avatrombopag (Open-Label Extension)	Avatrombopag	Participants who meet all eligibility criteria requirements of extension phase and who discontinue the core study because of lack of treatment effect will continue into the extension phase. Avatrombopag will be administered to participants who enter extension phase, with a starting dose of 20 mg avatrombopag, once daily for 76 weeks and undergo dose titration.

Primary Outcome Measures

Name	Time	Method
Number of Weeks With Platelet Count Greater Than or Equal to 50 x 10^9/L During 6-Month Treatment Period	Week 1 to Week 26	The cumulative number of weeks of platelet response is defined as the total numbers of weeks in which the platelet count is greater than or equal to 50 x 10\^ 9/L during 6 months of treatment of core study in the absence of rescue therapy.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With a Reduction in Use of Concomitant Immune/Idiopathic Thrombocytopenic Purpura (ITP) Medication	Week 1 through Week 26	Only participants on concomitant ITP medications at baseline were included.
Number of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Day 8	Week 1 (Day 8)	Participants with platelet response at Day 8 are defined as those who had a platelet count greater than or equal to 50 x 10\^9/L at day 8 in the absence of rescue therapy on or before Day 8.