Safety, Tolerability, Pharmacokinetic (PK), and Pharmacodynamic Study of GSK2881078 and Study to Evaluate the Effect of CYP3A4 Inhibition on PK of GSK2881078

NCT ID: NCT02567773

Last Updated: 2017-03-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 108 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-09-30
• Study Completion Date: 2016-12-31

Brief Summary

GSK2881078 is a selective androgen receptor modulator (SARM) that is being evaluated for effects on muscle growth and strength in subjects with muscle wasting to improve their physical function. Part A of this study will evaluate the safety, efficacy and pharmacokinetics of GSK2881078 in healthy, older men and post-menopausal women who will take daily dosing for 28 days and be followed for a total of 70 days. Part B of this study will characterize the effect of Cytochrome P450 3A4 (CYP3A4) inhibition on the GSK2881078 pharmacokinetics. Part B will only be conducted if safe and efficacious dose is identified in Part A. Part A will include healthy older males and post-menopausal females; and randomize approximately 60 subjects (about 15 per cohort [4 cohorts]) to complete approximately 48 (about 12 per cohort). Part B will enroll one cohort of approximately 15 healthy male subjects to complete approximately 12. The study duration will be approximately 115 days for Part A and 122 days for Part B.

Conditions

Cachexia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Part A: GSK2881078

The first cohort subjects will receive GSK2881078 1.5 mg (for males) or 0.75 mg (for females) twice daily for 3 days followed by once daily for 25 days. The subsequent cohort subjects will receive GSK2881078 doses selected after reviewing the unblinded data from at least 2 weeks of dosing of at least 6 subjects in the first cohort. Each cohort subjects will receive GSK2881078 dose twice daily for the first 3 days followed by 25 days of once daily.

Group Type: EXPERIMENTAL

GSK2881078

Intervention Type: DRUG

GSK2881078 hot melt solutions, ranging in concentration from 0.05 mg/g to 50 mg/g, will be prepared by weighing drug substance directly into specific quantities of the hot melt vehicle solution. Subjects will be administered GSK2881078 (dose for Cohort 1: 0.75 mg for females and 1.5 mg for males) hot melt solution within capsule orally with water.

Part A: Placebo

Subjects will receive placebo twice daily for 3 days followed by once daily for 25 days.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Subjects will be administered as hot melt vehicle placebo within capsule orally with water.

Part B: GSK2881078-Itraconazole

Subjects will receive GSK2881078 (dose level will be determined based on the results from Part A) on Day 1 of Period-1 and Day 6 of Period-2. Subjects will also receive itraconazole 200 mg twice daily on Day1 of Period-2 and 200 mg once daily on Days 2-34 of Period-2.

Group Type: EXPERIMENTAL

GSK2881078

Intervention Type: DRUG

GSK2881078 hot melt solutions, ranging in concentration from 0.05 mg/g to 50 mg/g, will be prepared by weighing drug substance directly into specific quantities of the hot melt vehicle solution. Subjects will be administered GSK2881078 (dose for Cohort 1: 0.75 mg for females and 1.5 mg for males) hot melt solution within capsule orally with water.

Itraconazole

Intervention Type: DRUG

Subjects will be administered as two capsules of itraconazole 100 mg (200 mg) orally with water.

Interventions

GSK2881078

GSK2881078 hot melt solutions, ranging in concentration from 0.05 mg/g to 50 mg/g, will be prepared by weighing drug substance directly into specific quantities of the hot melt vehicle solution. Subjects will be administered GSK2881078 (dose for Cohort 1: 0.75 mg for females and 1.5 mg for males) hot melt solution within capsule orally with water.

Intervention Type: DRUG

Placebo

Subjects will be administered as hot melt vehicle placebo within capsule orally with water.

Intervention Type: DRUG

Itraconazole

Subjects will be administered as two capsules of itraconazole 100 mg (200 mg) orally with water.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age: Part A: Between 50 and 75 years of age inclusive, at the time of signing the informed consent form. Part B: Between 18 and 60 years of age inclusive, at the time of signing the informed consent form.
• Healthy as determined by the investigator. Subjects with hypertension, hyperlipidemia or hypothyroidism, well controlled and stable on a single medication, may also be included.
• Subject values for Hemoglobin (Hgb) must be within the normal range (plus or minus 10%).
• Estimated glomerular filtration rate (GFR) >=60 milliliter (mL)/minute (min)/1.73 square meter (m^2).
• Body Mass Index (BMI) within the range 19 - 32 kilogram (kg)/m^2 (inclusive).
• Sex: Part A: Male or Female; Part B: Male Males: Male subjects with female partners of child bearing potential must agree to use a condom from the time of first dose of study medication until the final follow-up visit.

Females: A female subject is eligible to participate if she is post-menopausal.

Exclusion Criteria

• Alanine transaminase (ALT) and bilirubin >1.1x upper limit of normal (ULN) (isolated bilirubin >1.1xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• Current or chronic history of liver disease including fatty liver, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Corrected QT interval (QTc) > 450 msec. Heart rate: <40 and >100 beats per minute, PR Interval: <120 and >210 millisecond (msec), QRS duration: <70 and >120 msec.
• Subjects with a history at any time in the past of coronary artery disease, congestive heart failure, angina, myocardial infarction, any cardiac surgery, valvular heart disease, clinically significant arrhythmia, dyspnea, pulmonary edema, stroke, or transient ischemic attack.
• Subjects with a history of clinically significant endocrine, gastrointestinal, hepatic, cardiovascular, neurological, haematological, immunological, renal, respiratory, or genitourinary abnormalities or diseases.
• Subjects with a history of malignancy that is not in complete remission for at least 5 years or 1 year for non-melanoma skin carcinoma.
• Male subjects with a family history of early onset (55 years of age or younger) prostate cancer or 2 or more direct family members with prostate cancer.
• Unable to refrain from prescription or non-prescription drugs as described in protocol.
• History of regular alcohol consumption within 6 months of the study.
• History of drug or alcohol abuse within 5 years prior to the Screening Period.
• Unable to refrain from consumption (whole fruit or juice) of seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, or grapefruit hybrids.
• Regular, strenuous exercise or weightlifting >2 times per week for at least 2 weeks prior to screening visit or intent to start a new exercise routine during the study.
• History of sensitivity to heparin or heparin-induced thrombocytopenia.
• History of sensitivity to any of the study medications, or components thereof.
• Metal implants (contraindicated for MRI and disrupt DXA imaging). These include intra-orbital metal fragments.
• Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. For potent immunosuppressive agents, subjects with presence of hepatitis B core antibody (HBcAb) should also be excluded.
• A positive pre-study drug/alcohol screen.
• A positive test for human immunodeficiency 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 the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Subjects who previously received GSK2881078 are allowed to participate in this trial, with the same timeline restrictions.
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
• Prostate Specific Antigen (PSA) >4.0 nanograms (ng)/mL.
• High-density lipoprotein cholesterol (HDL-C) <35 milligram (mg)/deciliter (dL).
• Thyroid stimulating hormone (TSH) >10 mIU/L, test may be repeated or thyroid panel discussed with Medical Monitor.
• Testosterone < 0.9 lower limit of normal range (LLNR) - 10%, test may be repeated, or free testosterone determined also <0.9 LLNR.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Overland Park, Kansas, United States

Countries

United States

Other Identifiers

204699

Identifier Type: -

Identifier Source: org_study_id