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Drug-drug Interaction Study of Eltrombopag and Cyclosporine in Healthy Subjects

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02281370
First Posted: November 3, 2014
Last Update Posted: November 10, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
GlaxoSmithKline
  Purpose
A drug-drug interaction study between eltrombopag and cyclosporine is being conducted to support the use of these drugs together in subjects, such as those with severe aplastic anemia or immune thrombocytopenia purpura. The primary objective of the study is to evaluate the effect of cyclosporine on the pharmacokinetics of eltrombopag. This is a Phase I, open-label, randomized, three-period cross-over study in healthy adult subjects. The study consists of a screening visit and three treatment periods. All subjects will be randomized to receive one of the three treatments in each treatment period separated by washout periods of 3-10 days. The total duration of a subject's participation in the study from screening to final discharge is up to approximately 6 weeks (assuming 3 day washouts between treatment periods). Approximately 39 healthy subjects will be enrolled with the goal of completing at least 10 subjects per sequence (total 30).

Condition Intervention Phase
Purpura, Thrombocytopenic, Idiopathic Drug: Eltrombopag Drug: Cyclosporine Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Phase I, Open-label, Randomized, Three-period Cross-over Study Evaluating the Effect of Cyclosporine on the Pharmacokinetics of Eltrombopag in Healthy Adult Subjects

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Plasma eltrombopag area under time-concentration curve from time zero to infinity (AUC[0-inf]) [ Time Frame: Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, and 72 hours post-dose in each treatment period ]
  • Plasma eltrombopag maximum observed concentration (Cmax) [ Time Frame: Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, and 72 hours post-dose in each treatment period ]

Secondary Outcome Measures:
  • Composite of plasma eltrombopag pharmacokinetic (PK) parameters [ Time Frame: Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, and 72 hours post-dose in each treatment period ]
    PK parameters include: area under time-concentration curve from time zero to the time of last quantifiable concentration (AUC[0-t]), the percentage of AUC(0-inf) obtained by extrapolation (%AUCex), time to occurrence of Cmax (tmax), terminal phase half-life (t1/2), and apparent oral clearance (CL/F)

  • Vital signs assessment [ Time Frame: Up to 6 weeks ]
    Vital signs will include temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate

  • Composite clinical laboratory assessments including hematology, clinical chemistry and urinalysis parameters [ Time Frame: Up to 6 weeks ]
  • Number of participants with adverse events (AEs) [ Time Frame: From the start of study treatment until the end of treatment period 3 (assessed up to 18 days) ]
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product

  • Electrocardiogram (ECG) assessment [ Time Frame: Up to 6 weeks ]
    Single 12-lead ECG will be obtained following eltrombopag dosing using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT interval (QTc)


Enrollment: 39
Actual Study Start Date: November 5, 2014
Study Completion Date: December 24, 2014
Primary Completion Date: December 24, 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: SEQUENCE D0, D1, D2
Participants will receive treatment D0 in treatment period 1, D1 in treatment period 2 and D2 in treatment period 3 (one treatment per period). Where D0=eltrombopag 50 milligram (mg), D1= cyclosporine 200 mg + eltrombopag 50 mg, and D2= cyclosporine 600 mg + eltrombopag 50 mg. Treatment periods will be separated by washout periods of 3-10 days
Drug: Eltrombopag
White to off white bi-convex round tablets containing eltrombopag 50 mg for oral administration
Drug: Cyclosporine
Soft gelatine capsule containing cyclosporine 100 mg for oral administration. Cyclosporine will be administered at the doses of 200 mg (2 x 100 mg capsules) or 600 mg (6 x 100 mg capsules)
Experimental: SEQUENCE D1, D0, D2
Participants will receive treatment D1 in treatment period 1, D0 in treatment period 2 and D2 in treatment period 3 (one treatment per period). Where D0=eltrombopag 50 mg, D1= cyclosporine 200 mg + eltrombopag 50 mg, and D2= cyclosporine 600 mg + eltrombopag 50 mg. Treatment periods will be separated by washout periods of 3-10 days
Drug: Eltrombopag
White to off white bi-convex round tablets containing eltrombopag 50 mg for oral administration
Drug: Cyclosporine
Soft gelatine capsule containing cyclosporine 100 mg for oral administration. Cyclosporine will be administered at the doses of 200 mg (2 x 100 mg capsules) or 600 mg (6 x 100 mg capsules)
Experimental: SEQUENCE D1, D2, D0
Participants will receive treatment D1 in treatment period 1, D2 in treatment period 2 and D0 in treatment period 3 (one treatment per period). Where D0=eltrombopag 50 mg, D1= cyclosporine 200 mg + eltrombopag 50 mg, and D2= cyclosporine 600 mg + eltrombopag 50 mg. Treatment periods will be separated by washout periods of 3-10 days
Drug: Eltrombopag
White to off white bi-convex round tablets containing eltrombopag 50 mg for oral administration
Drug: Cyclosporine
Soft gelatine capsule containing cyclosporine 100 mg for oral administration. Cyclosporine will be administered at the doses of 200 mg (2 x 100 mg capsules) or 600 mg (6 x 100 mg capsules)

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Between 18 and 64 years of age inclusive.
  • Healthy subjects.
  • Body weight >=60 kilograms (kg) for men and women and body mass index (BMI) within the range 24.7-32.0 kg/meter squared (m^2) inclusive.
  • Male: Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception during the study.
  • Female of non-child bearing potential.
  • Female of child-bearing potential who has a negative serum or urine pregnancy test and is willing to practice acceptable methods of birth control during the study.
  • Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

Exclusion Criteria:

  • Alanine aminotransferase (ALT) and bilirubin >1.5x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • QT interval corrected (QTc) > 450 millisecond (msec): The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB), Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read.

For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used.

  • Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St. John's Wort) within 7 days.
  • Requiring the use of oral or injectable strong Cytochrome P3A4 (CYP3A4) and Breast cancer resistance protein (BRCP) inhibitors or use of other CYP3A4 and BCRP inhibitors/inducers within 14 days prior to dosing.
  • History of regular alcohol consumption within 1 month of the study.
  • Urinary cotinine levels indicative of smoking or history of regular use of tobacco- or nicotine-containing products within 30 days prior to screening.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
  • Platelet counts or creatinine levels that exceed the upper limit of the normal range.
  • Presence of hepatitis B surface antigen (HBsAg) or presence of hepatitis B core antibody (HBcAb), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment - A positive pre-study drug/alcohol screen.
  • A positive test for human immune virus (HIV) antibody.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56-day period.
  • The subject has participated in a clinical trial and has received an investigational product within 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02281370


Locations
United States, Kansas
GSK Investigational Site
Overland Park, Kansas, United States, 66211
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02281370     History of Changes
Other Study ID Numbers: 201583
First Submitted: October 30, 2014
First Posted: November 3, 2014
Last Update Posted: November 10, 2017
Last Verified: November 2017

Keywords provided by GlaxoSmithKline:
cyclosporine
drug-drug interaction
pharmacokinetics
eltrombopag
SB-497115

Additional relevant MeSH terms:
Purpura
Purpura, Thrombocytopenic
Purpura, Thrombocytopenic, Idiopathic
Blood Coagulation Disorders
Hematologic Diseases
Hemorrhage
Pathologic Processes
Skin Manifestations
Signs and Symptoms
Thrombotic Microangiopathies
Thrombocytopenia
Blood Platelet Disorders
Immune System Diseases
Hemorrhagic Disorders
Autoimmune Diseases
Cyclosporins
Cyclosporine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Calcineurin Inhibitors