Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
Condition: Chronic Thrombocytopenia; Immune Thrombocytopenia
MeSH terms: Thrombocytopenia; Purpura, Thrombocytopenic, Idiopathic
Intervention: Avatrombopag; Placebo; Standard of care
Intervention description: 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 MeSH terms: Maleic acid
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 49.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Chronic Immune Thrombocytopenia

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).
    

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 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