Back to resultsPhase 2, Pharmacokinetics Study of Eltrombopag in Japanese Thrombocytopenic Subjects With Chronic Liver Disease
Primary Purpose
Liver Diseases
Status
Completed
Phase
Phase 2
Locations
Japan
Study Type
Interventional
Intervention
eltrombopag 12.5 milligrams (mg) tablet
eltrombopag 25 mg tablet
Sponsored by
About this trial
This is an interventional treatment trial for Liver Diseases
Eligibility Criteria
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).
Sites / Locations
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
low dose
middle dose
high dose
Arm Description
eltrombopag 12.5 mg/day
eltrombopag 25 mg/day
eltrombopag 37.5 mg/day
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
Platelet Counts by Post-Treatment Visit
Platelet counts were measured by blood draw.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00861601
Brief Title
Phase 2, Pharmacokinetics Study of Eltrombopag in Japanese Thrombocytopenic Subjects With Chronic Liver Disease
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
February 2011
Overall Recruitment Status
Completed
Study Start Date
January 2009 (undefined)
Primary Completion Date
August 2009 (Actual)
Study Completion Date
August 2009 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline
4. Oversight
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Liver Diseases
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
38 (Actual)
8. Arms, Groups, and Interventions
Arm Title
low dose
Arm Type
Experimental
Arm Description
eltrombopag 12.5 mg/day
Arm Title
middle dose
Arm Type
Experimental
Arm Description
eltrombopag 25 mg/day
Arm Title
high dose
Arm Type
Experimental
Arm Description
eltrombopag 37.5 mg/day
Intervention Type
Drug
Intervention Name(s)
eltrombopag 12.5 milligrams (mg) tablet
Intervention Description
eltrombopag 12.5 mg tablet once a day
Intervention Type
Drug
Intervention Name(s)
eltrombopag 25 mg tablet
Intervention Description
eltrombopag 25 mg tablet once a day
Primary Outcome Measure Information:
Title
Change From Baseline in Platelet Counts on Day 15
Description
Platelet counts were measured by blood draw. Change from Baseline was calculated as the Day 15 value minus the Baseline value.
Time Frame
Baseline, Day 15
Secondary Outcome Measure Information:
Title
Analysis of Covariance for Three Patterns of Dose Response Using the Change From Baseline in Platelet Counts (Baseline Platelet Counts as Covariate)
Description
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.
Time Frame
Baseline, Day 15
Title
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)
Description
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.
Time Frame
Baseline, Day 15
Title
Percent Change From Baseline in Platelet Counts on Day 15
Description
Platelet counts were measured by blood draw. Change from Baseline was calculated as the Day 15 value minus the Baseline value.
Time Frame
Baseline, Day 15
Title
Platelet Counts by Treatment Visit
Description
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.
Time Frame
Day 1 (Baseline), Day 8, Day 15, and Final Assessment Point (Day 15 or Day 22)
Title
Platelet Counts by Post-Treatment Visit
Description
Platelet counts were measured by blood draw.
Time Frame
4 days post-treatment, 8 days post-treatment, and 15 days post-treatment
Title
Platelet Counts at Day 22
Description
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.
Time Frame
Day 22
Title
Change From Baseline in Platelet Counts by Treatment Visit
Description
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.
Time Frame
Baseline, Day 8, Day 15, and Final Assessment Point (Day 15 or Day 22)
Title
Change From Baseline in Platelet Counts by Post-Treatment Visit
Description
Platelet counts were measured by blood draw. Change from Baseline was calculated as the value at each visit minus the Baseline value.
Time Frame
4 days post-treatment, 8 days post-treatment, and 15 days post-treatment
Title
Percentage of Responders on Day 15
Description
A responder was defined as a participant with a platelet count within the target range (>=80 x 10^9/Liter) on Day 15.
Time Frame
Day 15
Title
Percentage of Responders on Day 22
Description
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.
Time Frame
Day 22
Title
Change From Baseline in Platelet Counts on Day 15 by Child-Pugh Class
Description
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.
Time Frame
Baseline, Day 15
Title
Change From Baseline in Platelet Counts on Day 15 by Sex
Description
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.
Time Frame
Baseline, Day 15
Title
Change From Baseline in Platelet Counts on Day 15 by Age
Description
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.
Time Frame
Baseline, Day 15
Title
Log-transformed Cmax on Days 14 and 15 in Participants Receiving Eltrombopag 12.5 mg
Description
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.
Time Frame
Day 14, Day 15
Title
Log-transformed Tmax on Days 14 and 15 in Participants Receiving Eltrombopag 12.5 mg
Description
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.
Time Frame
Day 14, Day 15
Title
Log-transformed AUC(0-t) and AUC(0-24) on Days 14 and 15 in Participants Receiving Eltrombopag 12.5 mg
Description
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.
Time Frame
Day 14, Day 15
10. Eligibility
Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline
Official's Role
Study Director
Facility Information:
Facility Name
GSK Investigational Site
City
Fukuoka
ZIP/Postal Code
810-8563
Country
Japan
Facility Name
GSK Investigational Site
City
Fukuoka
ZIP/Postal Code
814-0180
Country
Japan
Facility Name
GSK Investigational Site
City
Fukuoka
ZIP/Postal Code
815-8555
Country
Japan
Facility Name
GSK Investigational Site
City
Fukuoka
ZIP/Postal Code
830-0011
Country
Japan
Facility Name
GSK Investigational Site
City
Fukuoka
ZIP/Postal Code
839-0863
Country
Japan
Facility Name
GSK Investigational Site
City
Kagoshima
ZIP/Postal Code
890-8520
Country
Japan
Facility Name
GSK Investigational Site
City
Kumamoto
ZIP/Postal Code
860-8556
Country
Japan
Facility Name
GSK Investigational Site
City
Kumamoto
ZIP/Postal Code
862-8655
Country
Japan
Facility Name
GSK Investigational Site
City
Nagasaki
ZIP/Postal Code
856-8562
Country
Japan
Facility Name
GSK Investigational Site
City
Oita
ZIP/Postal Code
879-5593
Country
Japan
12. IPD Sharing Statement
Citations:
PubMed Identifier
22674141
Citation
Kawaguchi T, Komori A, Seike M, Fujiyama S, Watanabe H, Tanaka M, Sakisaka S, Nakamuta M, Sasaki Y, Oketani M, Hattori T, Katsura K, Sata M. Efficacy and safety of eltrombopag in Japanese patients with chronic liver disease and thrombocytopenia: a randomized, open-label, phase II study. J Gastroenterol. 2012 Dec;47(12):1342-51. doi: 10.1007/s00535-012-0600-5. Epub 2012 Jun 8.
Results Reference
background
Learn more about this trial
Phase 2, Pharmacokinetics Study of Eltrombopag in Japanese Thrombocytopenic Subjects With Chronic Liver Disease
We'll reach out to this number within 24 hrs