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

NCT02567773 | Completed Phase 1

• 1 other identifier: 204699
• Study Type: interventional
• Target: 108
• Locations: 1 country
• Sites: 1

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

Keywords

Itraconazole; GSK2881078; CYP3A4; Selective Androgen Receptor Modulator; Safety; Pharmacokinetics; Tolerability

Outcome Measures

Primary Outcomes (13)

• Part A: Blood pressure as a measure of safety and tolerability

  Blood pressure will be recorded whilst the subject is in a semi -supine position, having rested in this position for at least 10 minutes.

  Up to Day 70

• Part A: Heart rate as a measure of safety and tolerability

  Heart rate will be recorded whilst the subject is in a semi -supine position, having rested in this position for at least 10 minutes.

  Up to Day 70

• Part A: Cardiac telemetry as a measure of safety and tolerability

  Continuous cardiac telemetry will be performed for at least 8 hours post-dose.

  Up to Day 28

• Part A: Electrocardiogram (ECG) as a measure of safety and tolerability

  Triplicate or single 12-lead ECGs will be obtained at each timepoint and will be recorded whilst the subject is in a semi-supine position, having rested in this position for at least 10 minutes.

  Up to Day 70

• Part A: Composite of clinical laboratory parameters including hematology, clinical chemistry, and lipid blood panel (fasting) as a measure of safety and tolerability

  Up to Day 70

• Part A: Number of subjects with adverse events (AEs)

  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 AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.

  Up to Day 70

• Part A: area under the plasma drug concentration curve from time zero to the time of last quantifiable concentration (AUC0-t) for GSK2881078 after 14 and 28 days of dosing

  Day 14-15 (Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose) and Day 28-30 (Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 36, and 48 hours post-dose)

• Part A: area under the plasma drug concentration curve from time zero to end of dosing interval (AUC0-tau) for GSK2881078 after 14 and 28 days of dosing

  Day 14-15 (Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose) and Day 28-30 (Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 36, and 48 hours post-dose)

• Part A: maximum observed plasma drug concentration (Cmax) for GSK2881078 after 14 and 28 days of dosing

  Day 14-15 (Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose) and Day 28-30 (Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 36, and 48 hours post-dose)

• Part A: time to maximum observed plasma drug concentration (Tmax) for GSK2881078 after 14 and 28 days of dosing

  Day 14-15 (Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose) and Day 28-30 (Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 36, and 48 hours post-dose)

• Part A: terminal half-life (t1/2) for GSK2881078 after 14 and 28 days of dosing

  Day 14-15 (Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose) and Day 28-30 (Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 36, and 48 hours post-dose)

• Part B: area under the plasma drug concentration curve from time zero to infinity (AUC0- infinity) of GSK2881078 in absence and presence of itraconazole

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 216, 336, 504 and 672 hours post dose in both periods

• Part B: Cmax of GSK2881078 in absence and presence of itraconazole

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 216, 336, 504 and 672 hours post dose in both periods

Secondary Outcomes (3)

• Part A: Change from baseline in appendicular mass as assessed by Dual-energy X-ray Absorptiometry (DXA)

  Baseline and up to Day 70

• Part A: Change from baseline in total lean mass as assessed by DXA

  Baseline and up to Day 70

• Part A: Change from baseline in thigh muscle volume as assessed by MRI

  Baseline and up to Day 70

Study Arms (3)

Part A: GSK2881078

EXPERIMENTAL

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.

Drug: GSK2881078

Part A: Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Part B: GSK2881078-Itraconazole

EXPERIMENTAL

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.

Drug: GSK2881078; Drug: Itraconazole

Interventions

GSK2881078 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: GSK2881078; Part B: GSK2881078-Itraconazole

Placebo DRUG

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

Part A: Placebo

Itraconazole DRUG

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

Part B: GSK2881078-Itraconazole

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Overland Park, Kansas, 66211, United States

Location

MeSH Terms

Conditions

Cachexia

Interventions

GSK2881078; Itraconazole

Condition Hierarchy (Ancestors)

Weight Loss; Body Weight Changes; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Thinness

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 3, 2015
• First Posted: October 5, 2015
• Study Start: September 1, 2015
• Primary Completion: December 1, 2016
• Study Completion: December 1, 2016
• Last Updated: March 6, 2017

Record last verified: 2017-03

Locations

US (1)