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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Non-alcoholic Steatohepatitis, Chronic Liver Disease, HCV, NASH - Nonalcoholic Steatohepatitis, HIV Infection, Thrombocytopenia, Hepatitis C Virus, HBV, Human Immunodeficiency Virus, Liver Diseases, Hepatitis B Virus

Intervention / Treatment
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* Drug: Eltrombopag
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>placebo, once daily, oral | Drug: Placebo<br>* placebo, once daily, oral<br>|
| Active Comparator: Active<br>75 mg, once daily, oral | Drug: Eltrombopag<br>* 75 mg, once daily, oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a World Health Organization (WHO) Bleeding Score >=2 During and up to 7 Days Following Elective Invasive Procedures | 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). | 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 | 
| Number of Participants With the Indicated Number of Platelet Transfusions Administered | 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. | 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 | 
| 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 | 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). | Screening; Days 1, 8, 15, 16-19; Procedure + 7, 14, 21, 30 day follow-up; early withdrawal; and maximum post-baseline | 
| 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 | 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). | Screening; Days 8 and 15; Procedure + 7, 14, 21, 30 day follow-up; and maximum post-baseline | 
| Number of Participants Experiencing an Adverse Event (AEs) and Serious Adverse Event (SAEs) Within the Indicated Category | 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. | Screening to Procedure +30 day follow-up or early withdrawal | 
| Number of Participants With a Serious Adverse Event That Occurred in Greater Than One Participant |  | Screening to Procedure +30 day follow-up or early withdrawal | 
| Number of Participants With the Indicated Event Relating to Vision | 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). | Screening or Baseline and at End of Study (Procedure +30 day follow-up or withdrawal visit) | 
| Number of Participants With Renal Function Abnormality | 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. | Screening to Procedure +30 day follow-up or early withdrawal | 
| Number of Participants With a Clinically Significant Change in Electrocardiogram (ECG) Results | 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. | Screening, Baseline, Day 15, and Withdrawal | 
| Pharmacokinetics (PK) of Eltrombopag, Steady State AUC(0-tau) | 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. | Day 14 | 
| Pharmacokinetics (PK) of Eltrombopag, Cmax | Cmax is the steady state peak plasma concentration of a drug observed after its administration. | Day 14 | 
| Pharmacokinetics (PK) of Eltrombopag, t1/2 | 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. | Day 14 | 
| Pharmacokinetics (PK) of Eltrombopag, CL/F | 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. | Day 14 | 
| Mean Number of Days Spent in the Hospital | The number of days spent in the hospital was analyzed as an indication of medical resource utilization throughout the study. | 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 | 
| Mean Number of Unscheduled Office Visits, Unscheduled Laboratory Tests, and Unscheduled Procedures | The number of unscheduled events was analyzed as an indication of medical resource utilization throughout the study. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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platelets, elective invasive procedure., platelet transfusion, chronic liver disease-related thrombocytopenia, thrombopoietin