Phase 2, Parallel Group, Rollover Study of AKR-501 in Patients With ChronicITP Who Completed 28 Days of Study Treatment in Protocol 501-CL-003

• ClinicalTrials.gov Identifier: NCT00625443
• Recruitment Status: Completed
• First Posted: February 28, 2008
• Results First Posted: March 16, 2018
• Last Update Posted: March 16, 2018
• Sponsor: Eisai Inc.
• Information provided by (Responsible Party): Eisai Inc.

Study Description

Brief Summary:

The purpose of this study is to determine the safety and efficacy of AKR-501 (avatrombopag) administered in participants with chronic Idiopathic Thrombocytopenic Purpura (ITP) who were enrolled into and completed 28 days of study treatment in Protocol 501-CL-003 (NCT00441090).

Condition or disease	Intervention/treatment	Phase
Idiopathic Thrombocytopenic Purpura	Drug: Blinded (placebo); Drug: Open Label (Avatrombopag tablets); Drug: Blinded (Avatrombopoag tablets)	Phase 2

Detailed Description:

Participants eligible to enroll into this rollover protocol will begin study treatment within 2-5 days of their Day 28 study termination visit in Protocol 501-CL-003 (NCT00441090). Participants who met the primary efficacy response criterion in Protocol 501-CL-003 will continue receiving the same study treatment to which they were assigned in the previous protocol in a double-blinded manner, these being one of the following 5 treatments:

• avatrombopag 2.5 mg daily
• avatrombopag 5 mg daily
• avatrombopag 10 mg daily
• avatrombopag 20 mg daily
• placebo

Participants who did not meet the primary efficacy response criterion in Protocol 501-CL-003 who otherwise meet the eligibility criteria for this rollover protocol will be offered open label avatrombopag 10 mg daily.

This is a parallel group, rollover study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 53 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Parallel Group, Rollover Study of AKR-501 in Patients With Chronic Idiopathic Thrombocytopenic Purpura (ITP) Who Completed 28 Days of Study Treatment in Protocol 501-CL-003
• Study Start Date: May 2007
• Actual Primary Completion Date: June 2009
• Actual Study Completion Date: October 2009

Arms and Interventions

Arm	Intervention/treatment
Experimental: Placebo (double-blind)	Drug: Blinded (placebo); Placebo Orally, once daily administered under fasting conditions (at least 1 hr prior to or at least 2 hours after a meal or snack) Duration - 6 months
Experimental: Avatrombopag tablets (open-label)	Drug: Open Label (Avatrombopag tablets); Dose 10 mg Orally, once daily administered under fasting conditions (at least 1 hr prior to or at least 2 hours after a meal or snack) Duration - 6 months; Other Names: AKR-501; E5501; YM477
Experimental: Avatrombopag tablets (double-blind)	Drug: Blinded (Avatrombopoag tablets); Dose: 2.5, 5, 10, or 20 mg Orally, once daily administered under fasting conditions (at least 1 hr prior to or at least 2 hours after a meal or snack) Duration - 6 months; Other Names: AKR-501; E5501; YM477

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Day 1 through Month 6 while receiving treatment and at Month 7 after discontinuation of treatment. ]
   A TEAE was defined as 1) the AE started on or after the date of first dose of study drug up to and including 30 days after the last dose of study drug, or 2) the AE started before the first dose of study drug but worsened in severity on or after the date of first dose of study drug up to and including 3 days after the last dose of study drug. For participants having a tapering period of study drug, the last dose day is the last day of study drug during the tapering period. Related AEs included those whose relationship was categorized as possible or probably by the investigator. Dose interruption includes dose decreased, dose previously stopped, permanently stopped, or temporarily stopped. The safety population was divided into three subgroups based on the mean daily dose of active study drug taken; lower 1/3 (less than 8.85 mg avatrombopag), middle 1/3 (greater than or equal to 8.85 mg but less than 13.5 mg avatrombopag), and upper 1/3 (greater than or equal to 13.5 mg avatrombopag).
2. Incidence of Severe (Grade 3 or 4) TEAEs [ Time Frame: Day 1 through Month 6 while receiving treatment and at Month 7 after discontinuation of treatment. ]
   A TEAE was defined as 1) the AE started on or after the date of first dose of study drug up to and including 30 days after the last dose of drug, or 2) the AE started before the first dose of study drug but worsened in severity on or after the date of first dose of study drug up to and including 3 days after the last dose of study drug. For participants having a tapering period of study drug, the last dose day is the last day of study drug during the tapering period. The safety population was divided into three subgroups based on the mean daily dose of active study drug taken; lower 1/3 (less than 8.85 mg avatrombopag), middle 1/3 (greater than or equal to 8.85 mg but less than 13.5 mg avatrombopag), and upper 1/3 (greater than or equal to 13.5 mg avatrombopag).
3. Incidence of Drug-Related TEAEs [ Time Frame: Day 1 through Month 6 while receiving treatment and at Month 7 after discontinuation of treatment. ]
   Drug-related TEAEs included those whose relationship was categorized as possible or probably by the investigator. A TEAE was defined as 1) the AE started on or after the date of first dose of study drug up to and including 30 days after the last dose of drug, or 2) the AE started before the first dose of study drug but worsened in severity on or after the date of first dose of study drug up to and including 3 days after the last dose of study drug. For participants having a tapering period of study drug, the last dose day is the last day of study drug during the tapering period. The safety population was divided into three subgroups based on the mean daily dose of active study drug taken; lower 1/3 (less than 8.85 mg avatrombopag), middle 1/3 (greater than or equal to 8.85 mg but less than 13.5 mg avatrombopag), and upper 1/3 (greater than or equal to 13.5 mg avatrombopag).

Secondary Outcome Measures :

1. Median Platelet Counts at Selected Analysis Timepoints [ Time Frame: Day 1, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and Follow-up Weeks (after last dose of study drug in this study) 1, 2, 3, 4 ]
   Platelet count (PC) was measured from blood draws. Based on avatrombopag response in study 501-CL-003, participants were divided into two subgroups; 1) "Responders", participants who met the primary efficacy response; pretreatment PC was less than 30,000/mm^3 and increased to greater than or equal to 50,000/mm^3 after treatment with avatrombopag, and for participants on steroids, pretreatment PC was greater than or equal to 30,000/mm3 but less than 50,000/mm^3 and increased to a PC greater than or equal to 20,000/mm^3 above their pretreatment values and 2) "Nonresponders", participants who did not meet the primary efficacy response and those who were in the placebo arm. Open-label dose escalation of avatrombopag, as well as reductions in ITP-directed concomitant therapy (e.g. steroids) was allowed for all participants. During the periods of avatrombopag dose escalation and/or ITP-directed concomitant medication reduction, platelet sampling was done weekly.
2. Percentage of Participants Who Achieved a Platelet Count of 100,000/mm^3 or Higher by Response Status and Selected Study Visit [ Time Frame: Baseline (last PC before first dose of study drug in previous study), Weeks 2, 4, 8, 12, 16, 20, 24, and Follow-up Weeks (after last dose of study drug in this study) 1, 2, 3, 4 ]
   Platelet count (PC) was measured from blood draws. Based on avatrombopag response in study 501-CL-003, participants were divided into two subgroups; 1) "Responders", participants who met the primary efficacy response; pretreatment PC was less than 30,000/mm^3 and increased to greater than or equal to 50,000/mm^3 after treatment with avatrombopag, and for participants on steroids, pretreatment PC was greater than or equal to 30,000/mm^3 but less than 50,000/mm^3 and increased to a PC greater than or equal to 20,000/mm^3 above their pretreatment values and 2) "Nonresponders", participants who did not meet the primary efficacy response and those who were in the placebo arm. Open-label dose escalation of avatrombopag, as well as reductions in ITP-directed concomitant therapy (e.g. steroids) was allowed for all participants. During the periods of avatrombopag dose escalation and/or ITP-directed concomitant medication reduction, platelet sampling was done weekly.
3. Percentage of Participants Who Maintained a Platelet Count of 100,000/mm^3 or Higher by Response Status [ Time Frame: Baseline (last PC before first dose of study drug in previous study), Weeks 2, 4, 8, 12, 16, 20, 24, and Follow-up Weeks (after last dose of study drug in this study) 1, 2, 3, 4 ]
   Platelet count (PC) was measured from blood draws. Based on avatrombopag response in study 501-CL-003, participants were divided into two subgroups; 1) "Responders", participants who met the primary efficacy response; pretreatment PC was less than 30,000/mm^3 and increased to greater than or equal to 50,000/mm^3 after treatment with avatrombopag, and for participants on steroids, pretreatment PC was greater than or equal to 30,000/mm^3 but less than 50,000/mm^3 and increased to a PC greater than or equal to 20,000/mm^3 above their pretreatment values and 2) "Nonresponders", participants who did not meet the primary efficacy response and those who were in the placebo arm. Open-label dose escalation of avatrombopag, as well as reductions in ITP-directed concomitant therapy (e.g. steroids) was allowed for all participants. During the periods of avatrombopag dose escalation and/or ITP-directed concomitant medication reduction, platelet sampling was done weekly.
4. Percentage of Participants Who Achieved Response-Level Platelet Count by Selected Study Visit [ Time Frame: Baseline (last PC before first dose of study drug in previous study), Weeks 2, 4, 8, 12, 16, 20, 24, and Follow-up Weeks (after last dose of study drug in this study) 1, 2, 3, 4 ]
   Platelet count (PC) was measured from blood draws. Based on avatrombopag response in study 501-CL-003, participants were divided into two subgroups; 1) "Responders", participants who met the primary efficacy response; pretreatment PC was less than 30,000/mm^3 and increased to greater than or equal to 50,000/mm^3 after treatment with avatrombopag, and for participants on steroids, pretreatment PC was greater than or equal to 30,000/mm^3 but less than 50,000/mm^3 and increased to a PC greater than or equal to 20,000/mm^3 above their pretreatment values and 2) "Nonresponders", participants who did not meet the primary efficacy response and those who were in the placebo arm. Open-label dose escalation of avatrombopag, as well as reductions in ITP-directed concomitant therapy (e.g. steroids) was allowed for all participants. During the periods of avatrombopag dose escalation and/or ITP-directed concomitant medication reduction, platelet sampling was done weekly.
5. Percentage of Participants Who Maintained Response-Level Platelet Count [ Time Frame: Baseline (last PC before first dose of study drug in previous study), Weeks 2, 4, 8, 12, 16, 20, 24, and Follow-up Weeks (after last dose of study drug in this study) 1, 2, 3, 4 ]
   Platelet count (PC) was measured from blood draws. Based on avatrombopag response in study 501-CL-003, participants were divided into two subgroups; 1) "Responders", participants who met the primary efficacy response; pretreatment PC was less than 30,000/mm^3 and increased to greater than or equal to 50,000/mm^3 after treatment with avatrombopag, and for participants on steroids, pretreatment PC was greater than or equal to 30,000/mm^3 but less than 50,000/mm^3 and increased to a PC greater than or equal to 20,000/mm^3 above their pretreatment values and 2) "Nonresponders", participants who did not meet the primary efficacy response and those who were in the placebo arm. Open-label dose escalation of avatrombopag, as well as reductions in ITP-directed concomitant therapy (e.g. steroids) was allowed for all participants. During the periods of avatrombopag dose escalation and/or ITP-directed concomitant medication reduction, platelet sampling was done weekly.
6. Percentage of Participants Who Achieved a Durable, Transient, or Overall Platelet Response [ Time Frame: Baseline (last PC before first dose of study drug in previous study), Weeks 2, 4, 8, 12, 16, 20, 24, and Follow-up Weeks (after last dose of study drug in this study) 1, 2, 3, 4 ]
   Platelet count (PC) was measured from blood draws. Based on avatrombopag response in study 501-CL-003, participants were divided into two subgroups; 1) "Responders", participants who met the primary efficacy response; pretreatment PC was less than 30,000/mm^3 and increased to greater than or equal to 50,000/mm^3 after treatment with avatrombopag, and for participants on steroids, pretreatment PC was greater than or equal to 30,000/mm^3 but less than 50,000/mm^3 and increased to a PC greater than or equal to 20,000/mm^3 above their pretreatment values and 2) "Nonresponders", participants who did not meet the primary efficacy response and those who were in the placebo arm. Open-label dose escalation of avatrombopag, as well as reductions in ITP-directed concomitant therapy (e.g. steroids) was allowed for all participants. During the periods of avatrombopag dose escalation and/or ITP-directed concomitant medication reduction, platelet sampling was done weekly.
7. Number of Participants With Changes in Concomitant Steroid Use [ Time Frame: Day 1 through last 8 weeks of the Treatment Period ]
   A participant who used steroids at study entry was considered to have permanently discontinued steroid use if they had no steroid use during the last 8 weeks of the study Treatment Period. A participant who used steroids at study entry was considered to have decreased concomitant steroid medication by at least 50% if they permanently discontinued steroids, or in no dose of steroid was higher than 50% of their baseline steroid dose during the last 8 weeks of the study Treatment Period.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patients who completed 28 days of study treatment in Protocol 501-CL-003.
2. No significant safety or tolerability concerns from the patient's participation of Protocol 501-CL-003 as determined by the Investigator.
3. Received medical monitor approval for enrollment into this study.
4. Patients receiving maintenance corticosteroids may be enrolled, as long as the corticosteroids have been administered at a stable dose and the Investigator does not foresee the need to change the steroid dose during study participation. Patients should remain on this stable corticosteroid dose during study participation.
5. Women of child-bearing potential must have a negative serum pregnancy test at the Day 28 assessment in Protocol 501-CL-003. (Childbearing potential is defined as any woman who has not been surgically sterilized and is pre-menopausal or peri-menopausal i.e., any menstrual flow within 12 months of Screening Visit A for Protocol 501-CL-003).
6. Women of child-bearing potential must agree to practice a medically approved form of contraception (one of the following must be used: condoms (male or female) with a spermicidal agent, diaphragm or cervical cap with a spermicidal agent, IUD,hormonal contraception, abstinence).
7. Willing and able to provide written informed consent.

Exclusion Criteria:

1. Women who are pregnant and/or lactating.

2. Use of the following drugs or treatments:

   • Rituximab
   • Azathioprine, Cyclosporine A, or other immunosuppressant therapy
   • Aspirin, Aspirin-containing compounds, Salicylates,Anticoagulants, Non-steroidal anti-inflammatory drugs(NSAIDs)(including Cyclooxygenase-2 [COX-2] specific NSAIDs), clopidogrel; ticlopidine; and any drugs that affect platelet function.
   • Danazol
   • Rh0(D) immune globulin (WinRho®) or intravenous immunoglobulin (IVIG).
3. Inability to comply with protocol requirements or give informed consent, as determined by the Investigator.

For more information regarding inclusion/exclusion criteria, please see record for AKR 501-CL-003 Protocol.

Contacts and Locations

Locations

United States, California

Pacific Cancer Medical Center, Inc

Anaheim, California, United States, 92801

Comprehensive Blood and Cancer Center

Bakersfield, California, United States, 93309

United States, Connecticut

Davis, Posteraro and Wasser, MDs, LLP

Manchester, Connecticut, United States, 06105

United States, Florida

Florida Cancer Institute

New Port Richey, Florida, United States, 34655

United States, Illinois

John H. Stroger, Jr. Hospital of Cook County, Div. of Hematology and Oncology

Chicago, Illinois, United States, 60612

United States, Indiana

Cancer Care Center, Inc.

New Albany, Indiana, United States, 47150

United States, Missouri

Capitol Comprehensive Cancer Care Clinic

Jefferson City, Missouri, United States, 65109

Kansas City Cancer Center, LLC

Kansas City, Missouri, United States, 64131

United States, New York

Mount Sinai Medical Center

New York, New York, United States, 10029

New York Presbyterian Hospital, Weill Medical College of Cornell University

New York, New York, United States, 10032

United States, North Carolina

Emerywood Oncology and Hematology

High Point, North Carolina, United States, 27262

United States, Ohio

Mid Ohio Oncology/Hematology, Inc., dba The Mark H. Zangmeister Center

Columbus, Ohio, United States, 43219

Sponsors and Collaborators

Eisai Inc.

Investigators

• Study Director: Pei-Ran Ho, MD; Eisai Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bussel JB, Kuter DJ, Aledort LM, Kessler CM, Cuker A, Pendergrass KB, Tang S, McIntosh J. A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia. Blood. 2014 Jun 19;123(25):3887-94. doi: 10.1182/blood-2013-07-514398. Epub 2014 May 6.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT00625443
• Other Study ID Numbers: AKR-501-CL-004
• First Posted: February 28, 2008
• Results First Posted: March 16, 2018
• Last Update Posted: March 16, 2018
• Last Verified: March 2018

Keywords provided by Eisai Inc.:

Idiopathic Thrombocytopenic Purpura; ITP; Chronic Idiopathic Thrombocytopenic Purpura

Additional relevant MeSH terms:

Purpura; Purpura, Thrombocytopenic; Purpura, Thrombocytopenic, Idiopathic; Blood Coagulation Disorders; Hematologic Diseases; Hemorrhage; Pathologic Processes; Skin Manifestations; Thrombotic Microangiopathies; Thrombocytopenia; Blood Platelet Disorders; Immune System Diseases; Hemorrhagic Disorders; Autoimmune Diseases