Phase 2, Pharmacokinetics Study of Eltrombopag in Japanese Thrombocytopenic Subjects With Chronic Liver Disease

Study Overview
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Brief Summary
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This is an open label, multi-centre, dose ranging study to assess efficacy, safety and pharmacokinetics of eltrombopag in thrombocytopenic subjects with chronic liver disease.

Official Title
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TPL111913, a Multi-centre, Open Label, Dose Ranging Phase II Study to Assess Efficacy, Safety and Pharmacokinetics of Eltrombopag in Japanese Thrombocytopenic Subjects With Chronic Liver Disease

Conditions
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Liver Diseases

Intervention / Treatment
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* Drug: eltrombopag 12.5 milligrams (mg) tablet
* Drug: eltrombopag 25 mg tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject who agree to comply with protocol requirements and instructions and who provide signed and dated written informed consent. Male and female subjects, ≥20 years of age (at the time of informed consent) with chronic liver disease. Child-Pugh score <=9. A baseline platelet count <50,000/mcL. A baseline serum sodium level >130 mEq/L. Haemoglobin concentration >8 g/dL, stable for at least 4 weeks. A female is eligible to enter and participate in the study if she is of: Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) including any female who: Has had a hysterectomy Has had a bilateral oophorectomy (ovariectomy) Has had a bilateral tubal ligation Is post-menopausal (demonstrate total cessation of menses for longer than one year) Childbearing potential, has a negative urine and/or serum pregnancy test at screening, and within the 24 hour period prior to the first dose of investigational product and uses one of the following acceptable methods of contraception: Complete abstinence from intercourse. Any intrauterine device (IUD) with a documented failure rate of less than 1% per year. Double-barrier contraception (condom with spermicidal jelly, or diaphragm with spermicide). Male partner who is sterile (diagnosed by a qualified medical professional) prior to the female subject's study entry and is the sole sexual partner for that female. Oral contraceptive (combined). Subject has no physical limitation to ingest and retain oral medication. Exclusion Criteria: Subjects with known or suspected hypersensitivity, intolerance or allergy to any of the ingredients in eltrombopag tablets. Evidence of portal vein thrombosis on abdominal imaging (ultrasound with Doppler or appropriate magnetic resonance imaging/computed tomography (MRI/CT) imaging techniques) within 3 months before the start of the study. History of arterial or venous thrombosis (including Budd-Chiari Syndrome), AND ≥ two of the following risk factors: hereditary thrombophilic disorders (e.g. antithrombinIII (ATIII) deficiency, etc.) hormone replacement therapy systemic contraception therapy (containing oestrogen) smoking diabetes hypercholesterolemia medication for hypertension or cancer Human Immunodeficiency Virus (HIV) infection. History of drug/alcohol abuse or dependence within 1 year prior to screening. Any disease condition associated with current active World Health Organization (WHO) Grade 3 or 4 bleeding. Active infection requiring systemic antibiotic therapy. Pregnant, nursing mothers, women who may be pregnant, or women who plan to become pregnant during the time of study participation. Treatment with platelet transfusion within 2 weeks prior to Day 1. Treatment with interferon within 4 weeks prior to Day 1. Treatment with an investigational drug within 30 days or five half-lives (whichever is longer) preceding the first dose of study medication. History of platelet agglutination abnormality. History of porphyria. Subjects who are deemed unsuitable for the study by the investigator (or subinvestigator).

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: low dose<br>eltrombopag 12.5 mg/day | Drug: eltrombopag 12.5 milligrams (mg) tablet<br>* eltrombopag 12.5 mg tablet once a day<br>|
| Experimental: middle dose<br>eltrombopag 25 mg/day | Drug: eltrombopag 25 mg tablet<br>* eltrombopag 25 mg tablet once a day<br>|
| Experimental: high dose<br>eltrombopag 37.5 mg/day | Drug: eltrombopag 12.5 milligrams (mg) tablet<br>* eltrombopag 12.5 mg tablet once a day<br>Drug: eltrombopag 25 mg tablet<br>* eltrombopag 25 mg tablet once a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Platelet Counts on Day 15 | Platelet counts were measured by blood draw. Change from Baseline was calculated as the Day 15 value minus the Baseline value. | Baseline, Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analysis of Covariance for Three Patterns of Dose Response Using the Change From Baseline in Platelet Counts (Baseline Platelet Counts as Covariate) | Exploratory analysis was conducted to see a dose response/trend when a dose goes high with the changes from baseline in platelet counts (12.5 mg, 25 mg, and 37.5 mg) on Day 15 of each subject. The data were analyzed with baseline of platelet counts as covariate for the following dose response pattern using contrast: (1) linearity, (2) saturation at the medium dose, (3) onset of response at the high dose. | Baseline, Day 15 | 
| Analysis of Covariance for Three Patterns of Dose Response Using the Change From Baseline in Platelet Counts (Baseline of Platelet Counts and Child-Pugh Class as Covariates) | Exploratory analysis was conducted to see a dose response/trend when a dose goes high with the changes from baseline in platelet counts (12.5 mg, 25 mg, and 37.5 mg) on Day 15 of each subject. The data were analyzed with baseline of platelet counts and Child-Pugh class as covariate for the following dose response pattern using contrast: (1) linearity, (2) saturation at the medium dose, (3) onset of response at the high dose. | Baseline, Day 15 | 
| Percent Change From Baseline in Platelet Counts on Day 15 | Platelet counts were measured by blood draw. Change from Baseline was calculated as the Day 15 value minus the Baseline value. | Baseline, Day 15 | 
| Platelet Counts by Treatment Visit | Platelet counts were measured by blood draw. The Final Assessment Point is the last visit during the treatment period, which is Day 15 or Day 22. | Day 1 (Baseline), Day 8, Day 15, and Final Assessment Point (Day 15 or Day 22) | 
| Platelet Counts by Post-Treatment Visit | Platelet counts were measured by blood draw. | 4 days post-treatment, 8 days post-treatment, and 15 days post-treatment | 
| Platelet Counts at Day 22 | Platelet counts were measured by blood draw. The Final Assessment Point is the last visit during the treatment period, which is Day 15 or Day 22. | Day 22 | 
| Change From Baseline in Platelet Counts by Treatment Visit | Platelet counts were measured by blood draw. The Final Assessment Point is the last visit during the treatment period, which is Day 15 or Day 22. Change from Baseline was calculated as the value at each visit minus the Baseline value. | Baseline, Day 8, Day 15, and Final Assessment Point (Day 15 or Day 22) | 
| Change From Baseline in Platelet Counts by Post-Treatment Visit | Platelet counts were measured by blood draw. Change from Baseline was calculated as the value at each visit minus the Baseline value. | 4 days post-treatment, 8 days post-treatment, and 15 days post-treatment | 
| Percentage of Responders on Day 15 | A responder was defined as a participant with a platelet count within the target range (>=80 x 10^9/Liter) on Day 15. | Day 15 | 
| Percentage of Responders on Day 22 | A responder was defined as a participant with a platelet count within the target range (>=80 x 10^9/Liter) on Day 22 after receiving eltrombopag for an additional week from Day 15, on which his or her platelet count was <80 x 10^9/Liter. | Day 22 | 
| Change From Baseline in Platelet Counts on Day 15 by Child-Pugh Class | Change from Baseline was calculated as the Day 15 value minus the Baseline value. The Child-Pugh (CP) score (ranging from 5 to 15, with 5 being mild and 15 being severe), calculated based on total bilirubin, serum albumin, international normalized ratio, ascites, and hepatic encephalopathy, is used to assess the severity of liver disease. A CP score of 5 or 6 is classified as Class A (mild), a score of 7-9 is classified as Class B (moderate), and a score >=10 is classified as Class C (severe). Participants with a CP score <10 were enrolled in the study. | Baseline, Day 15 | 
| Change From Baseline in Platelet Counts on Day 15 by Sex | Change from Baseline was calculated as the Day 15 value minus the Baseline value. The numbers of females and males in each treatment group are illustrated by the n's in the category titles. | Baseline, Day 15 | 
| Change From Baseline in Platelet Counts on Day 15 by Age | Change from Baseline was calculated as the Day 15 value minus the Baseline value. The numbers of participants in each age category are illustrated by the n's in the category titles. | Baseline, Day 15 | 
| Log-transformed Cmax on Days 14 and 15 in Participants Receiving Eltrombopag 12.5 mg | Serial PK samples were collected over a 24-hour (h) period on Days 14 and 15 in participants receiving eltrombopag 12.5 mg. A total of 8 blood samples (3 milliliters per sample) were collected at pre-dose, and at 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h post-dose. Cmax=maximum drug concentration. | Day 14, Day 15 | 
| Log-transformed Tmax on Days 14 and 15 in Participants Receiving Eltrombopag 12.5 mg | Serial PK samples were collected over a 24-hour (h) period on Days 14 and 15 in participants receiving eltrombopag 12.5 mg. A total of 8 blood samples (3 milliliters per sample) were collected at pre-dose, and at 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h post-dose. Tmax=maximum drug concentration time. | Day 14, Day 15 | 
| Log-transformed AUC(0-t) and AUC(0-24) on Days 14 and 15 in Participants Receiving Eltrombopag 12.5 mg | Serial PK samples were collected over a 24-hour (h) period on Days 14 and 15 in participants receiving eltrombopag 12.5 mg. A total of 8 blood samples (3 milliliters per sample) were collected at pre-dose, and at 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h post-dose. AUC(0-t)=area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration, and AUC(0-24)=area under the concentration-time curve from 0 (pre-dose) to 24 hours. | Day 14, Day 15 |