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

NCT01438840 | Completed Phase 3 Results DMC

• 1 other identifier: E5501-G000-302
• Study Type: interventional
• Target: 49
• Locations: 11 countries
• Sites: 25

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).

Conditions

Chronic Thrombocytopenia; Immune Thrombocytopenia

Keywords

Chronic Immune Thrombocytopenia

Outcome Measures

Primary Outcomes (1)

• Number of Weeks With Platelet Count Greater Than or Equal to 50 x 10^9/L During 6-Month Treatment Period

  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.

  Week 1 to Week 26

Secondary Outcomes (2)

• Number of Participants With a Reduction in Use of Concomitant Immune/Idiopathic Thrombocytopenic Purpura (ITP) Medication

  Week 1 through Week 26

• Number of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Day 8

  Week 1 (Day 8)

Study Arms (3)

Avatrombopag (Core Study)

ACTIVE COMPARATOR

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.

Drug: Avatrombopag; Drug: Standard of care

Placebo (Core Study)

PLACEBO COMPARATOR

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.

Drug: Placebo; Drug: Standard of care

Avatrombopag (Open-Label Extension)

EXPERIMENTAL

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.

Drug: Avatrombopag; Drug: Standard of care

Interventions

Avatrombopag DRUG

Also known as: E5501, Avatrombopag maleate

Avatrombopag (Core Study); Avatrombopag (Open-Label Extension)

Placebo DRUG

Placebo (Core Study)

Standard of care 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 (Core Study); Avatrombopag (Open-Label Extension); Placebo (Core Study)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women greater than or equal to 18 years of age
• 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
• Participants who previously received one or more ITP therapies (including, but not limited to corticosteroids, immunoglobulins, azathioprine, danazol, cyclophosphamide and/or rituximab).
• 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
• 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

You may not qualify if:

• 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)
• 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)
• History of MDS
• History of gastric atrophy (added per Amendment 01)
• 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)
• 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
• 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)
• Participants with a history of cirrhosis, portal hypertension, and chronic active hepatitis
• Participants with concurrent malignant disease
• Use of immunoglobulins (IVIg and anti-D) within 1 week of randomization
• Splenectomy or use of rituximab within 12 weeks of randomization
• Use of romiplostim or eltrombopag within 4 weeks of randomization
• 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
• 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
• Use of cyclophosphamide or vinca alkaloid regimens within 4 weeks of randomization

Sponsors & Collaborators

• Eisai Inc.: lead

Study Sites (25)

Unknown Facility

Adelaide, Australia

Location

Unknown Facility

Bedford Park, Australia

Location

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Antwerp, Belgium

Location

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Plovdiv, Bulgaria

Location

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Sofia, Bulgaria

Location

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Brno, Czechia

Location

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Hradec Králové, Czechia

Location

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Prague, Czechia

Location

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Rotterdam, Netherlands

Location

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Christchurch, New Zealand

Location

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Palmerston North, New Zealand

Location

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Bialystok, Poland

Location

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Chorzów, Poland

Location

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Gdansk, Poland

Location

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Krakow, Poland

Location

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Lodz, Poland

Location

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Wroclaw, Poland

Location

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Singapore, Singapore

Location

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Bratislava, Slovakia

Location

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Johannesburg, South Africa

Location

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Dnipropetrovsk, Ukraine

Location

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Donetsk, Ukraine

Location

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Ivano-Frankivsk, Ukraine

Location

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Kyiv, Ukraine

Location

Unknown Facility

Lviv, Ukraine

Location

Related Publications (1)

• Jurczak W, Chojnowski K, Mayer J, Krawczyk K, Jamieson BD, Tian W, Allen LF. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018 Nov;183(3):479-490. doi: 10.1111/bjh.15573. Epub 2018 Sep 7.

  PMID: 30191972 DERIVED

MeSH Terms

Conditions

Purpura, Thrombocytopenic, Idiopathic

Interventions

avatrombopag; Standard of Care

Condition Hierarchy (Ancestors)

Purpura, Thrombocytopenic; Purpura; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Thrombotic Microangiopathies; Thrombocytopenia; Blood Platelet Disorders; Cytopenia; Hemorrhagic Disorders; Autoimmune Diseases; Immune System Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Skin Manifestations; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Results Point of Contact

• Title: Eisai Inc.
• Organization: Eisai Call Center

888-422-4743

Study Officials

• Joe McIntosh

  Eisai Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 19, 2011
• First Posted: September 22, 2011
• Study Start: February 16, 2012
• Primary Completion: November 1, 2013
• Study Completion: March 1, 2014
• Last Updated: February 5, 2018
• Results First Posted: January 5, 2018

Record last verified: 2018-01

Locations

NZ (2); SL (1); BU (2); ZA (1); UA (5); BE (1); AU (2); CZ (3); PL (6); SG (1); NL (1)