Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures - Full Text View

Sponsor:	GlaxoSmithKline
Information provided by:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT00678587

Purpose

The purpose of this study is to assess the ability of eltrombopag to elevate platelet counts thereby reducing the need for platelet transfusions in chronic liver disease patients with thrombocytopenia undergoing elective invasive procedures. The clinical benefit of eltrombopag will be measured by the proportion of subjects who avoid platelet transfusions, before, during and up to 7 days after undergoing an invasive procedure. In addition, bleeding events will be monitored during this time. The number of transfusions, safety events and medical resource utilisation will be monitored during this time and for up to 30 days after undergoing an invasive procedure to help further evaluate clinical benefit.

Condition	Intervention	Phase
Non-alcoholic Steatohepatitis Chronic Liver Disease HCV NASH. HIV Infection Thrombocytopenia Hepatitis C Virus HBV Human Immunodeficiency Virus Liver Diseases Hepatitis B Virus	Drug: Eltrombopag Drug: Placebo	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Randomised, Double-Blind, Placebo-Controlled, Multi-Centre Study to Evaluate the Safety and Efficacy of Eltrombopag to Reduce the Need for Platelet Transfusion in Thrombocytopenic Subjects With Chronic Liver Disease Undergoing Elective Invasive Procedures

Resource links provided by NLM:

Genetics Home Reference related topics: complement factor I deficiency MYH9-related disorder

MedlinePlus related topics: Blood Transfusion and Donation HIV/AIDS Hepatitis Hepatitis A Hepatitis B Hepatitis C Liver Diseases

Drug Information available for: Eltrombopag

U.S. FDA Resources

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:

Number of Participants With Chronic Liver Disease and Thrombocytopenia (Platelets <50 Gi/L) Who do Not Require a Platelet Transfusion Prior to, During, and up to 7 Days Following Elective Invasive Procedures [ Time Frame: Prior to, during, and up to seven days following elective invasive procedures (Study Days 16-19); therefore, this covers a time period from Baseline to Day 26 ] [ Designated as safety issue: No ]
A platelet transfusion was given if the platelet count was <50 giga (10^9) per liter (Gi/L) before the procedure. A platelet transfusion was not given if the platelet count was >80 Gi/L (based on a primary endpoint of success). For participants with platelet counts between 50 Gi/L and 80 Gi/L, platelet transfusions were administered at the discretion of the investigator and the physician performing the elective invasive procedure.

Secondary Outcome Measures:

Number of Participants With a World Health Organization (WHO) Bleeding Score >=2 During and up to 7 Days Following Elective Invasive Procedures [ Time Frame: Prior to, during, and up to 7 days following elective invasive procedures (Study Days 16-19); therefore, this covers a time period from Baseline to Day 26 ] [ Designated as safety issue: No ]
The WHO Bleeding Scale was used to assess bleeding during the study. The range of possible scores is 0 to 4. Grade 0 is no bleeding; Grade 1 is petechiae (small [1-2 millimeter] red or purple spot on the body, caused by a minor hemorrhage); Grade 2 is mild blood loss; Grade 3 is gross blood loss (requiring a transfusion; and Grade 4 is debilitating blood loss (retinal or cerebral associated with fatality).
Number of Participants With the Indicated Number of Platelet Transfusions Administered [ Time Frame: Prior to, during, and up to 4 weeks (30 days) following elective invasive procedures (Days 16-19); therefore, this covers a time period from Baseline to Day 26 ] [ Designated as safety issue: No ]
Platelet transfusion use was documented at every visit throughout the study from screening until the 4-week (30-day) post-procedure follow-up visit or at the time of participant withdrawal from the study.
Median Platelet Count at Screening; Days 1, 8, 15, 16-19; Procedure + 7, 14, 21, 30 Day Follow-up; Early Withdrawal; and Maximum Post-baseline [ Time Frame: Screening; Days 1, 8, 15, 16-19; Procedure + 7, 14, 21, 30 day follow-up; early withdrawal; and maximum post-baseline ] [ Designated as safety issue: No ]
Procedure +7 = Days 23-26; +14 = Days 30-33; +21 = Days 37-40; +30 = Days 46-49. Early withdrawal can occur at any time. Maximum post-baseline refers to any time point listed above for which the maximum value was reached (therefore this time point is variable).
Number of Participants With the Indicated Platelet Count at Screening; Days 8 and 15; Procedure + 7, 14, 21, 30 Day Follow-up (FU); and Maximum Post-baseline [ Time Frame: Screening; Days 8 and 15; Procedure + 7, 14, 21, 30 day follow-up; and maximum post-baseline ] [ Designated as safety issue: No ]
Procedure +7 = Days 23-26; +14 = Days 30-33; +21 = Days 37-40; +30 = Days 46-49. Early withdrawal can occur at any time. Maximum post-baseline refers to any time point listed above for which the maximum value was reached (therefore this time point is variable).
Number of Participants Experiencing an Adverse Event (AEs) and Serious Adverse Event (SAEs) Within the Indicated Category [ Time Frame: Screening to Procedure +30 day follow-up or early withdrawal ] [ Designated as safety issue: No ]
An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect or an ocular event of clinical concern. Medical or scientific judgement is exercised in deciding whether reporting is appropriate in other situations.
Number of Participants With a Serious Adverse Event That Occurred in Greater Than One Participant [ Time Frame: Screening to Procedure +30 day follow-up or early withdrawal ] [ Designated as safety issue: No ]
Number of Participants With the Indicated Event Relating to Vision [ Time Frame: Screening or Baseline and at End of Study (Procedure +30 day follow-up or withdrawal visit) ] [ Designated as safety issue: No ]
The progression of pre-existing cataracts was measured by the use of slit lamp examination. Decrease in visual acuity is defined as the loss of 3 or more lines of visual acuity in either eye (0.3 log minimal angle of resolution [logMAR], 15 letters on the standard Early Treatment Diabetic Retinopathy Study chart).
Number of Participants With Renal Function Abnormality [ Time Frame: Screening to Procedure +30 day follow-up or early withdrawal ] [ Designated as safety issue: No ]
Renal function abnormality was defined by threshold values for: serum creatinine: change from baseline of >=0.3 and <0.5 milligrams (mg)/deciliter (dL) (>=26.6 and <44.3 micromoles [umol]/L) or change from baseline of >=0.5 mg/dL (>=44.3 umol/L); microscopic urine analysis: cellular casts pathologic (as defined by local standards of microscopic urine analysis); urine protein/creatinine ratio (UP/CR): >0.5 mg/mg; Glomerular Filtration Rate (GFR) as determined by the Cockcroft-Gault formula and urine dipstick test.
Number of Participants With a Clinically Significant Change in Electrocardiogram (ECG) Results [ Time Frame: Screening, Baseline, Day 15, and Withdrawal ] [ Designated as safety issue: No ]
A 12-lead ECG was obtained in duplicate at screening, baseline, Day 15, and withdrawal from the study. Participants rested supine for 5 minutes before the 12-lead ECG was recorded. A 30 second rhythm strip was obtained, and the ECG was calibrated, labelled, and initialled by the person performing the recording. A written, interpretive assessment detailing clinical significance was produced, dated, and signed off by the physician at the site.
Pharmacokinetics (PK) of Eltrombopag, Steady State AUC(0-tau) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
AUC(0-tau) is the area under a concentration versus time curve between dose interval following repeat dosing. It is a measure of systemic drug exposure.
Pharmacokinetics (PK) of Eltrombopag, Cmax [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
Cmax is the steady state peak plasma concentration of a drug observed after its administration.
Pharmacokinetics (PK) of Eltrombopag, t1/2 [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
t1/2 is the half life of a drug based on its terminal phase. Half life is defined as the time necessary to halve the plasma concentration.
Pharmacokinetics (PK) of Eltrombopag, CL/F [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
CL/F is the apparent plasma clearance, where CL is an estimate of the total body clearance, and F is the fraction of dose absorbed. Total clearance is the volume of blood cleared of the drug by the various elimination processes (metabolism and excretion) per unit time.
Mean Number of Days Spent in the Hospital [ Time Frame: Prior to, during, and up to 4 weeks (30 days) following elective invasive procedures (Days 16-19); therefore, this covers a time period from Baseline to Day 26 ] [ Designated as safety issue: No ]
The number of days spent in the hospital was analyzed as an indication of medical resource utilization throughout the study.
Mean Number of Unscheduled Office Visits, Unscheduled Laboratory Tests, and Unscheduled Procedures [ Time Frame: Prior to, during, and up to 4 weeks (30 days) following elective invasive procedures (Days 16-19); therefore, this covers a time period from Baseline to Day 26 ] [ Designated as safety issue: No ]
The number of unscheduled events was analyzed as an indication of medical resource utilization throughout the study.

Enrollment:	292
Study Start Date:	June 2008
Study Completion Date:	October 2009
Primary Completion Date:	October 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: Placebo placebo, once daily, oral	Drug: Placebo placebo, once daily, oral
Active Comparator: Active 75 mg, once daily, oral	Drug: Eltrombopag 75 mg, once daily, oral Other Name: Eltrombopag

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Male and female subjects, 18 years of age or more with chronic liver disease.
Child-Pugh score of 12 or less.
Model of End Stage Liver Disease (MELD) score of 24 or less.
Subjects who, in the opinion of the investigator, are appropriate candidates to undergo an elective invasive procedure and who require a platelet transfusion to manage the risk of bleeding associated with the procedure.
A baseline platelet count <50,000/µL.
A baseline serum sodium level >130mEq/L.
Haemoglobin concentration >8g/dL stable for at least one month.
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 greater 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 for two weeks before exposure to the study drug, throughout the clinical study, and for 28 days after completion or premature discontinuation from the study to account for the elimination of the study drug (minimum of 5 half-lives).
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 (either combined or progesterone only).
Any other contraceptive method with a documented failure rate of <1% per year.
Subject has no physical limitation to ingest and retain oral medication.
Subject is able to understand and comply with protocol requirements and instructions and is likely to complete the study as planned.
Subject is able to provide signed and dated written informed consent.
In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

Subjects with a known 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 MRI/CT imaging techniques) within 3 months of study start.
History of arterial or venous thrombosis, including Budd-Chiari Syndrome, AND ≥ two of the following risk factors: hereditary thrombophilic disorders (e.g. Factor V Leiden, ATIII deficiency, etc.), hormone replacement therapy, systemic contraception therapy (containing oestrogen), smoking, diabetes, hypercholesterolemia, medication for hypertension or cancer.
Any disease condition associated with current active WHO Grade 3 or 4 bleeding.
Active infection requiring systemic antibiotic therapy. Prophylactic use of antibiotics is permitted.
Pregnant or nursing women.
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 that prevents reliable measurement of platelet counts.
History of porphyria.
Previous participation in TPL104054.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00678587

Show 77 Study Locations

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director:

GSK Clinical Trials

GlaxoSmithKline

More Information

No publications provided

Responsible Party:	Cheri Hudson; Clinical Disclosure Advisor, GSK Clinical Disclosure
ClinicalTrials.gov Identifier:	NCT00678587 History of Changes
Other Study ID Numbers:	TPL104054
Study First Received:	May 13, 2008
Results First Received:	October 10, 2010
Last Updated:	February 9, 2012
Health Authority:	European Union: European Medicines Agency United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:

elective invasive procedure.
platelet transfusion
chronic liver disease-related thrombocytopenia
platelets
thrombopoietin

Additional relevant MeSH terms:

Acquired Immunodeficiency Syndrome
HIV Infections
Hepatitis
Hepatitis A
Hepatitis B
Hepatitis C
Immunologic Deficiency Syndromes
Liver Diseases
Thrombocytopenia
Virus Diseases
Fatty Liver
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections

Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immune System Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Enterovirus Infections
Picornaviridae Infections
Hepadnaviridae Infections
DNA Virus Infections
Flaviviridae Infections
Blood Platelet Disorders
Hematologic Diseases

ClinicalTrials.gov processed this record on May 23, 2012