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

HIV Infection Clinical Trial

— ELEVATE  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00678587
• Other study ID #: TPL104054
• Status: Terminated
• Phase: Phase 3
• Start date: June 2008
• Est. completion date: October 2009

Study information

• Verified date: January 2013
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 292
• Est. completion date: October 2009
• Est. primary completion date: October 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• Chronic Liver Disease
• Fatty Liver
• HBV
• HCV
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B Virus
• Hepatitis C
• Hepatitis C Virus
• HIV Infection
• HIV Infections
• Human Immunodeficiency Virus
• Immunologic Deficiency Syndromes
• Liver Diseases
• NASH - Nonalcoholic Steatohepatitis
• Non-alcoholic Fatty Liver Disease
• Non-alcoholic Steatohepatitis
• Thrombocytopenia

Intervention

Drug:
• Eltrombopag
75 mg, once daily, oral
• Placebo
placebo, once daily, oral

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Capital Fefderal	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autonoma de Buenos Aires
Argentina	GSK Investigational Site	Derqui, Pilar	Buenos Aires
Argentina	GSK Investigational Site	Rosario	Santa Fe
Belgium	GSK Investigational Site	Brussels
Belgium	GSK Investigational Site	Edegem
Belgium	GSK Investigational Site	Gent
Canada	GSK Investigational Site	Calgary	Alberta
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Ottawa	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
France	GSK Investigational Site	Clermont Ferrand Cédex 1
France	GSK Investigational Site	Lyon
France	GSK Investigational Site	Lyon Cedex 02
France	GSK Investigational Site	Marseille
France	GSK Investigational Site	Montpellier
France	GSK Investigational Site	Nice
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Paris Cedex 12
France	GSK Investigational Site	Paris Cedex 13
France	GSK Investigational Site	Villejuif
India	GSK Investigational Site	Jaipur
India	GSK Investigational Site	Mumbai
India	GSK Investigational Site	Mumbai
Italy	GSK Investigational Site	Avellino	Campania
Italy	GSK Investigational Site	Bari	Puglia
Italy	GSK Investigational Site	Bologna	Emilia-Romagna
Italy	GSK Investigational Site	Genova	Liguria
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Napoli	Campania
Italy	GSK Investigational Site	Padova	Veneto
Italy	GSK Investigational Site	Palermo	Sicilia
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	San Giovanni Rotondo (FG)	Puglia
Italy	GSK Investigational Site	Torino	Piemonte
Korea, Republic of	GSK Investigational Site	Busan
Korea, Republic of	GSK Investigational Site	Incheon
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Pakistan	GSK Investigational Site	Lahore
Pakistan	GSK Investigational Site	Lahore
Poland	GSK Investigational Site	Chorzow
Poland	GSK Investigational Site	Lubin
Poland	GSK Investigational Site	Slupsk
Poland	GSK Investigational Site	Warszawa
Poland	GSK Investigational Site	Wroclaw
Russian Federation	GSK Investigational Site	Ekaterinburg
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	Samara
Russian Federation	GSK Investigational Site	Smolensk
Spain	GSK Investigational Site	Barakaldo
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Hospitalet de Llobregat
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Málaga
Spain	GSK Investigational Site	Oviedo
Spain	GSK Investigational Site	Sevilla
Spain	GSK Investigational Site	Valencia
Spain	GSK Investigational Site	Valencia
Spain	GSK Investigational Site	Valladolid
Taiwan	GSK Investigational Site	Douliou
Taiwan	GSK Investigational Site	Kaohsiung
Taiwan	GSK Investigational Site	Taipei
Taiwan	GSK Investigational Site	Taipei
Taiwan	GSK Investigational Site	Taoyuan
United States	GSK Investigational Site	Ann Arbor	Michigan
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Burlington	Massachusetts
United States	GSK Investigational Site	Charleston	South Carolina
United States	GSK Investigational Site	Charlotte	North Carolina
United States	GSK Investigational Site	Charlottesville	Virginia
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Denver	Colorado
United States	GSK Investigational Site	Detroit	Michigan
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Falls Church	Virginia
United States	GSK Investigational Site	Hershey	Pennsylvania
United States	GSK Investigational Site	Indianapolis	Indiana
United States	GSK Investigational Site	Jacksonville	Florida
United States	GSK Investigational Site	Little Rock	Arkansas
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	New Orleans	Louisiana
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Portland	Oregon
United States	GSK Investigational Site	Richmond	Virginia
United States	GSK Investigational Site	Richmond	Virginia
United States	GSK Investigational Site	San Diego	California
United States	GSK Investigational Site	San Francisco	California
United States	GSK Investigational Site	Scottsdale	Arizona
United States	GSK Investigational Site	Valhalla	New York
United States	GSK Investigational Site	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Canada,  France,  India,  Italy,  Korea, Republic of,  Pakistan,  Poland,  Russian Federation,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	Pharmacokinetics (PK) of Eltrombopag, Cmax	Cmax is the steady state peak plasma concentration of a drug observed after its administration.	Day 14
Secondary	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
Secondary	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
Secondary	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
Secondary	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