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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.
ClinicalTrials.gov Identifier:
NCT01438840
First received: September 19, 2011
Last updated: March 10, 2016
Last verified: February 2016
  Purpose

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).


Condition Intervention Phase
Chronic Thrombocytopenia
Immune Thrombocytopenia
Drug: Avatrombopag
Drug: Placebo
Drug: Standard of care
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official 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 Thrombocytopenia Purpura)

Resource links provided by NLM:


Further study details as provided by Eisai Inc.:

Primary Outcome Measures:
  • Cumulative Number Of Weeks Of Platelet Response Over 6 Months of Treatment [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Proportion of Participants with a Platelet Response At Day 8 [ Time Frame: 8 days ] [ Designated as safety issue: No ]
    Platelet response rate at Day 8 defined by the proportion of participants with a platelet response >= 50 X 10^9/L (liter) 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.


Enrollment: 49
Study Start Date: February 2012
Study Completion Date: March 2014
Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Avatrombopag (Core Study)
Avatrombopag was administered orally as 5 mg, 10 mg, 20 mg, 30 mg, or 40 mg in a flexible dose design for 26 weeks. Participants received blinded therapy at a starting dose of 20 mg avatrombopag, one daily and they were 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.
Drug: Avatrombopag
Other Names:
  • E5501
  • Avatrombopag maleate
Drug: Standard of care
Placebo Comparator: Placebo (Core Study)
Placebo was administered as 5 mg, 10 mg, 20 mg, 30 mg or 40 mg in a flexible dose design for 26 weeks. Placebo was administered orally at a starting dose of 20 mg, once daily. Afterwards the dose could 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 was used to maintain the blind.
Drug: Placebo Drug: Standard of care
Experimental: Avatrombopag (Open-Label Extension)
Participants who met all eligibility criteria requirements of extension phase and who discontinued the core study because of lack of treatment effect continued into the extension phase. Avatrombopag was administered to participants who entered extension phase, with a starting dose of 20 mg avatrombopag, once daily for 76 weeks and underwent dose titration.
Drug: Avatrombopag
Other Names:
  • E5501
  • Avatrombopag maleate
Drug: Standard of care

Detailed Description:
This study consisted of three phases: Prerandomization, Randomization (Core Study) and Extension study. The overall duration of treatment (Core and Extension) was 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 were randomized. No single platelet count should be greater than 35x10^9/L (liter). Participants were centrally stratified at randomization by splenectomy status, baseline platelet count, and use of concomitant ITP medication at baseline, and were randomized to receive either double-blind avatrombopag or placebo in a 2:1 ratio. Participants received blinded therapy at a starting dose of 20 mg avatrombopag or placebo once daily. Participants were 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 was 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.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01438840

Locations
Australia
Adelaide, Australia, ����
Bedford Park, Australia
Belgium
Antwerpen, Belgium, ����
Bulgaria
Plovdiv, Bulgaria, ����
Sofia, Bulgaria, ����
Czech Republic
Brno, Czech Republic, ����
Hradec Kralove, Czech Republic
Praha, Czech Republic
Praha, Czech Republic, ����
Netherlands
Rotterdam, Netherlands, ����
New Zealand
Christchurch, New Zealand
Palmerston North, New Zealand, ����
Poland
Bialystok, Poland
Chorzow, Poland, ����
Gdansk, Poland
Krakow, Poland, ����
Lodz, Poland
Wroclaw, Poland, ����
Singapore
Singapore, Singapore, ����
Slovakia
Bratislava, Slovakia
South Africa
Johannesburg, South Africa
Johannesburg, South Africa, ����
Ukraine
Dnipropetrovsk, Ukraine, ����
Donetsk, Ukraine
Ivano-Frankivsk, Ukraine, ����
Kyiv, Ukraine
Lviv, Ukraine, ����
Sponsors and Collaborators
Eisai Inc.
Investigators
Study Director: Joe McIntosh Eisai Inc.
  More Information

Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT01438840     History of Changes
Other Study ID Numbers: E5501-G000-302 
Study First Received: September 19, 2011
Last Updated: March 10, 2016
Health Authority: European Union: European Medicines Agency
United States: Food and Drug Administration

Keywords provided by Eisai Inc.:
Chronic Immune Thrombocytopenia

Additional relevant MeSH terms:
Thrombocytopenia
Purpura, Thrombocytopenic, Idiopathic
Blood Platelet Disorders
Hematologic Diseases
Purpura, Thrombocytopenic
Purpura
Blood Coagulation Disorders
Thrombotic Microangiopathies
Hemorrhagic Disorders
Autoimmune Diseases
Immune System Diseases
Hemorrhage
Pathologic Processes
Skin Manifestations
Signs and Symptoms

ClinicalTrials.gov processed this record on August 23, 2016