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Trial record 58 of 103 for:    "Kennedy disease"

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

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ClinicalTrials.gov Identifier: NCT02567773
Recruitment Status : Completed
First Posted : October 5, 2015
Last Update Posted : March 6, 2017
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Cachexia Drug: GSK2881078 Drug: Placebo Drug: Itraconazole Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 108 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Double-blind (Sponsor Unblind) Placebo Controlled Study in Healthy Subjects to Evaluate: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Repeat Doses of GSK2881078, the Selective Androgen Receptor Modulator With an Open Label Dosing Arm to Evaluate the Effect of CYP3A4 Inhibition on Pharmacokinetics of GSK2881078
Study Start Date : September 2015
Actual Primary Completion Date : December 2016
Actual Study Completion Date : December 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: 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.

Placebo Comparator: Part A: Placebo
Subjects will receive placebo twice daily for 3 days followed by once daily for 25 days.
Drug: Placebo
Subjects will be administered as hot melt vehicle placebo within capsule orally with water.

Experimental: 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.
Drug: 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.

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




Primary Outcome Measures :
  1. Part A: Blood pressure as a measure of safety and tolerability [ Time Frame: Up to Day 70 ]
    Blood pressure will be recorded whilst the subject is in a semi -supine position, having rested in this position for at least 10 minutes.

  2. Part A: Heart rate as a measure of safety and tolerability [ Time Frame: Up to Day 70 ]
    Heart rate will be recorded whilst the subject is in a semi -supine position, having rested in this position for at least 10 minutes.

  3. Part A: Cardiac telemetry as a measure of safety and tolerability [ Time Frame: Up to Day 28 ]
    Continuous cardiac telemetry will be performed for at least 8 hours post-dose.

  4. Part A: Electrocardiogram (ECG) as a measure of safety and tolerability [ Time Frame: Up to Day 70 ]
    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.

  5. Part A: Composite of clinical laboratory parameters including hematology, clinical chemistry, and lipid blood panel (fasting) as a measure of safety and tolerability [ Time Frame: Up to Day 70 ]
  6. Part A: Number of subjects with adverse events (AEs) [ Time Frame: Up to Day 70 ]
    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.

  7. 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 [ Time Frame: 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) ]
  8. 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 [ Time Frame: 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) ]
  9. Part A: maximum observed plasma drug concentration (Cmax) for GSK2881078 after 14 and 28 days of dosing [ Time Frame: 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) ]
  10. Part A: time to maximum observed plasma drug concentration (Tmax) for GSK2881078 after 14 and 28 days of dosing [ Time Frame: 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) ]
  11. Part A: terminal half-life (t1/2) for GSK2881078 after 14 and 28 days of dosing [ Time Frame: 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) ]
  12. Part B: area under the plasma drug concentration curve from time zero to infinity (AUC0- infinity) of GSK2881078 in absence and presence of itraconazole [ Time Frame: 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 ]
  13. Part B: Cmax of GSK2881078 in absence and presence of itraconazole [ Time Frame: 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 Outcome Measures :
  1. Part A: Change from baseline in appendicular mass as assessed by Dual-energy X-ray Absorptiometry (DXA) [ Time Frame: Baseline and up to Day 70 ]
    Appendicular lean mass will be calculated from the regional lean mass measurements of the arms and legs.

  2. Part A: Change from baseline in total lean mass as assessed by DXA [ Time Frame: Baseline and up to Day 70 ]
    Output from DXA will be used to measure total lean mass.

  3. Part A: Change from baseline in thigh muscle volume as assessed by MRI [ Time Frame: Baseline and up to Day 70 ]
    MRI cross-sectional thigh scans will be performed for each cohort in Part A of the study.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

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): NCT02567773


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

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02567773     History of Changes
Other Study ID Numbers: 204699
First Posted: October 5, 2015    Key Record Dates
Last Update Posted: March 6, 2017
Last Verified: March 2017

Keywords provided by GlaxoSmithKline:
Itraconazole
GSK2881078
CYP3A4
Selective Androgen Receptor Modulator
Safety
Pharmacokinetics
Tolerability

Additional relevant MeSH terms:
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Cachexia
Emaciation
Weight Loss
Body Weight Changes
Body Weight
Signs and Symptoms
Androgens
Itraconazole
Hydroxyitraconazole
GSK2881078
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Cytochrome P-450 CYP3A Inhibitors
Anabolic Agents