A Study to Investigate the Efficacy and Safety of Lusutrombopag (S-888711) Tablets Administered to Adults With Immune Thrombocytopenia (ITP)

Phase 2

Terminated

Conditions: Immune Thrombocytopenia (ITP)

Interventions: Drug: Placebo
Drug: Lusutrombopag

Registration Number: NCT01054443

Lead Sponsor: Shionogi

Brief Summary: The primary objective of this study was to assess the efficacy of 3 dose levels of lusutrombopag (0.5 mg, 0.75 mg, and 1.0 mg) and placebo on platelet count.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 20

Inclusion Criteria

A signed and dated written informed consent
Males and females ≥ 18 years of age
All subjects must agree to use barrier contraception
Diagnosis of ITP
Subjects > 60 years must have had a diagnostic bone marrow aspiration
Relapsed persistent or chronic ITP status, with or without prior splenectomy (exception: in Hungary only splenectomized subjects will be enrolled), after having failed at least 1 prior ITP therapy (excluding TPO agonists) and have a platelet count < 30,000/μL if not taking medications or < 50,000/μL despite concomitant steroids or other ITP therapies, such as danazol or immunosuppressive drugs
Subjects receiving steroid therapy must be on a stable dose
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) within 20% of the upper limit of normal (ULN)
Subjects receiving stable dosages of cyclosporine A, mycophenolate mofetil, azathioprine, or danazol are allowed. The dosages of all these medications must be stable for at least 4 weeks prior to Visit 1 (Day 1)

Exclusion Criteria

History of clinically important hemorrhagic clotting disorder
Females who are pregnant, lactating, or taking oral contraceptives
History of alcohol/drug abuse or dependence within 1 year
Use of the following drugs or treatment prior to Visit 1 (Day 1):
- Within 12 weeks - alemtuzumab, multi-drug systemic chemotherapy, stem cell therapy;
- Within 8 weeks - rituximab
- Within 2 weeks - platelet transfusions or plasmapheresis treatment
- Within 4 weeks - use of anti-platelet or anti-coagulant drugs
- Within 1 week - Rho(D) immune globulin or intravenous immunoglobulin
History of clinically significant cardiovascular or thromboembolic disease within 26 weeks prior to Screening
Splenectomy within 4 weeks prior to Screening
Clinically significant laboratory abnormalities
- Hemoglobin < 10.0 g/dL for men or women, not clearly related to ITP
- Absolute neutrophil count < 1000/mm^3
- Abnormal peripheral blood smear
- Total bilirubin > 1.5 x upper limit of normal
- Alanine aminotransferase (ALT) > 1.5 x upper limit of normal
- Aspartate aminotransferase (AST) > 1.5 x upper limit of normal
- Creatinine > 1.5 x upper limit of normal
- Human immunodeficiency virus (HIV) positive
- Hepatitis A immunoglobulin M antibody (IgM HAV) positive, hepatitis B surface antigen (HbsAg) or hepatitis C antibody (HCV) positive
- Thyroid stimulating hormone (TSH) > 1.5 x upper limit of normal
- Free thyroxine (T4) > 1.5 x upper limit of normal
Exposure to previous thrombopoietin (TPO) mimetics/agonists (e.g., eltrombopag,romiplostim, E5501 [AKR-501] or LGD-4665) within 4 weeks prior to Screening
Subjects unresponsive to previous TPO mimetics/agonists (e.g., eltrombopag, romiplostim, E5501 [AKR-501] or LGD-4665)
Exposure to an investigative medication within the past 30 days

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants received placebo tablets orally once a day for 42 days.
Lusutrombopag 0.5 mg	Lusutrombopag	Participants received 0.5 mg lusutrombopag orally once a day for 42 days.
Lusutrombopag 1.0 mg	Lusutrombopag	Participants received 1.0 mg lusutrombopag orally once a day for 42 days.
Lusutrombopag 0.75 mg	Lusutrombopag	Participants received 0.75 mg lusutrombopag orally once a day for 42 days.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With a Response	Week 6	Responders were participants with one of the following: 1. achieved a platelet count of ≥ 50,000 cells/µL after 6 weeks of dosing; or 2. prematurely withdrawn due to a platelet count \> 400,000 cells/µL prior to Day 42. Participants were counted as non-responders if any of the following conditions held: * The above conditions were not satisfied; * They received rescue medications; * They satisfied the above conditions after receiving restricted medications during the treatment period; * They had achieved a platelet count of ≥ 50,000 cells/µL before Week 6 but not after Week 6; or * They withdrew for any reason other than a platelet count \> 400,000 cells/µL.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Received Rescue Medication During the Treatment Period	6 weeks
Percentage of Participants Who Achieved a Platelet Count of ≥ 30,000 Cells/µL and Doubled the Baseline Platelet Count After 6 Weeks of Dosing	Week 6
Percentage of Participants Who Achieved a Platelet Count of ≥ 50,000 Cells/µL and Doubled the Baseline Platelet Count After 6 Weeks of Dosing	Week 6
Number of Participants With Worst Severity of Bleeding Associated With ITP During the Treatment Period,	6 weeks	Bleeding assessments were performed by the Investigator according to the World Health Organization (WHO) criteria bleeding scale: Grade 0: no bleeding; Grade 1: petechial bleeding; Grade 2: mild blood loss (clinically significant); Grade 3: gross blood loss, requires transfusion (severe); Grade 4: debilitating blood loss, retinal or cerebral associated with fatality. For each participant, the most severe WHO bleeding grade observed during the 6-week treatment period is reported.
Change From Baseline in Platelet Count at Week 6	Baseline and Week 6
Duration of Response	6 weeks	Duration of response was defined as the percentage of the cumulative time a platelet count was ≥ 50,000 cells/µL during the treatment period.
Number of Participants With Adverse Events (AEs)	6 weeks	An AE is defined as any untoward medical occurrence in a subject administered a pharmaceutical product during the course of a clinical investigation, including any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product (IP), whether or not thought to be related to the IP. AEs reported after initial study drug administration were considered treatment-emergent. A serious adverse event is defined as any AE that resulted in death, was life-threatening, hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect or an important medical event that, based upon medical judgment, may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed above. A treatment-related AE is any AE determined by the investigator to be possibly related, probably related, or definitely related to study drug.
Lusutrombopag Plasma Concentration	Days 8, 22, and 36, after dosing	Plasma concentrations of lusutrombopag were determined using a validated liquid chromatography mass spectrometry method. The lower limit of quantification (LOQ) for the plasma assay for lusutrombopag was 0.1 ng/mL.
Plasma Concentration of Metabolite S-888711 Deshexyl	Days 8, 22, and 36, after dosing	Plasma concentrations of the major metabolite S-888711 deshexyl were determined using a validated liquid chromatography mass spectrometry method. The lower limit of quantification (LOQ) for the plasma assay for S-888711 deshexyl was 0.1 ng/mL.