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

Phase 2

Completed

Conditions: Liver Diseases

Interventions: Drug: eltrombopag 12.5 milligrams (mg) tablet
Drug: eltrombopag 25 mg tablet

Registration Number: NCT00861601

Lead Sponsor: GlaxoSmithKline

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 38

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
high dose	eltrombopag 25 mg tablet	eltrombopag 37.5 mg/day
low dose	eltrombopag 12.5 milligrams (mg) tablet	eltrombopag 12.5 mg/day
middle dose	eltrombopag 25 mg tablet	eltrombopag 25 mg/day
high dose	eltrombopag 12.5 milligrams (mg) tablet	eltrombopag 37.5 mg/day

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Platelet Counts on Day 15	Baseline, Day 15	Platelet counts were measured by blood draw. Change from Baseline was calculated as the Day 15 value minus the Baseline value.

Secondary Outcome Measures

Name	Time	Method
Platelet Counts by Post-Treatment Visit	4 days post-treatment, 8 days post-treatment, and 15 days post-treatment	Platelet counts were measured by blood draw.
Analysis of Covariance for Three Patterns of Dose Response Using the Change From Baseline in Platelet Counts (Baseline Platelet Counts as Covariate)	Baseline, Day 15	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.
Change From Baseline in Platelet Counts by Post-Treatment Visit	4 days post-treatment, 8 days post-treatment, and 15 days post-treatment	Platelet counts were measured by blood draw. Change from Baseline was calculated as the value at each visit minus the Baseline value.
Percentage of Responders on Day 22	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.
Log-transformed Cmax on Days 14 and 15 in Participants Receiving Eltrombopag 12.5 mg	Day 14, Day 15	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.
Log-transformed Tmax on Days 14 and 15 in Participants Receiving Eltrombopag 12.5 mg	Day 14, Day 15	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.
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)	Baseline, Day 15	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.
Platelet Counts at Day 22	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.
Percent Change From Baseline in Platelet Counts on Day 15	Baseline, Day 15	Platelet counts were measured by blood draw. Change from Baseline was calculated as the Day 15 value minus the Baseline value.
Platelet Counts by Treatment Visit	Day 1 (Baseline), Day 8, Day 15, and Final Assessment Point (Day 15 or 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.
Log-transformed AUC(0-t) and AUC(0-24) on Days 14 and 15 in Participants Receiving Eltrombopag 12.5 mg	Day 14, Day 15	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.
Change From Baseline in Platelet Counts by Treatment Visit	Baseline, Day 8, Day 15, and Final Assessment Point (Day 15 or 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. Change from Baseline was calculated as the value at each visit minus the Baseline value.
Percentage of Responders on Day 15	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.
Change From Baseline in Platelet Counts on Day 15 by Sex	Baseline, Day 15	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.
Change From Baseline in Platelet Counts on Day 15 by Age	Baseline, Day 15	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.
Change From Baseline in Platelet Counts on Day 15 by Child-Pugh Class	Baseline, Day 15	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.