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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of GSK2881078 in Single and Repeat Doses

Primary Purpose

Cachexia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
GSK2881078
Placebo
Sponsored by
GlaxoSmithKline
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cachexia focused on measuring FTIH, pharmacokinetics, SARM, safety

Eligibility Criteria

18 Years - 50 Years (Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria:

  • Males between 18 and 50 years of age (inclusive), at the time of signing the informed consent form
  • Body weight >= 50 kilogram (kg) and Body Mass Index (BMI) within the range 19 - 32 kg/meter square (m^2) (inclusive), where BMI= weight in kg/ height in m^2
  • Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
  • Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in the Lifestyle Section of the protocol. This criterion must be followed through the completion of the follow-up visit.
  • Average QTcF <450millisecond (msec); or QTcF <480msec in subjects with Bundle Branch Block.
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

  • 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 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. ECG exclusion criteria: Heart rate-<40 and >100 beats per minute, PR Interval-<120 and >200msec, QRS duration-<70 and >110msec.
  • 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
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • History of drug or alcohol abuse within 5 years prior to the Screening Period.
  • History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 milliliter [mL]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
  • 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 GSK Medical Monitor, contraindicates their participation.
  • Subjects with a family history of early onset prostate cancer or multiple members with prostate cancer.
  • A positive pre-study drug or alcohol screen.
  • Cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
  • Subjects with values outside the specified ranges for the following Key Clinical Laboratory Tests must be excluded from the study:

Liver function tests - Alanine aminotransferase, Direct Bilirubin, or Albumin more than 10% outside the normal reference range (<0.9 x lower limit of normal [LLN] or >1.1 x upper limit of normal [ULN]) Renal function - Creatinine >1.6milligrams (mg)/deciliter (dL) with an age appropriate glomerular filtration rate<=60 (mL/minute/1.73 m^2).

Electrolytes - Sodium more than ± 5milliequivalents/Liter outside the normal reference range, Potassium or Calcium more than 10% outside the normal reference range (<0.9 x LLN or >1.1 x ULN) Metabolic - Glucose more than 10% outside the normal reference range (<0.9 x LLN or >1.1 x ULN) and Total Cholesterol > 240mg/dL Muscle - creatine phosphokinase >2.0 x ULN Hematology - Hemoglobin, white blood cells, Neutrophils, or Platelets more than 10% outside the normal reference range (<0.9 x LLN or >1.1 x ULN) Prostate Specific Antigen >2.5nanogram/mL

  • A positive test for human immuno virus antibody
  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day
  • Unable to refrain from prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication and throughout the study, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  • 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: 3 months (12 weeks), 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Where participation in the study would result in donation of blood or blood products in excess of 500mL within a 56-day period.
  • Unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication

Sites / Locations

  • GSK Investigational Site
  • GSK Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Cohort 5

Arm Description

Participants will receive one of the following four treatment sequences in four study period (one treatment per period). Sequence 1=Placebo, dose level (DL) 2, DL3, and DL4. Sequence 2=DL1, placebo, DL2, and DL4. Sequence 3=DL1, DL2, placebo, and DL4. Sequence 4=DL1, DL2, DL3, and placebo

Participants will receive one of the following four treatment sequences in four study period (one treatment per period). Sequence 5=Placebo, DL5, DL6, and DL7. Sequence 6=DL4, placebo, DL6, and DL7. Sequence 7=DL4, DL5, placebo, and DL7. Sequence 8=DL4, DL5, DL6, and placebo

Participants will receive repeat doses of GSK2881078 or placebo in a 3:1 randomization ratio for 14 days. The dose level will depend upon results from Part A

Participants will receive repeat doses of GSK2881078 or placebo in a 3:1 randomization ratio for 14 days. The dose level will depend upon results from Part A and preceding repeat dose Cohort

Participants will receive repeat doses of GSK2881078 or placebo in a 3:1 randomization ratio for 14 days. The dose level will depend upon results from Part A and preceding repeat dose Cohorts

Outcomes

Primary Outcome Measures

Vital sign assessment following single doses as a measure of safety and tolerability
Vital signs include: systolic blood pressure, diastolic blood pressure and heart rate
Vital sign assessment following repeat doses as a measure of safety and tolerability
Vital signs include: systolic blood pressure, diastolic blood pressure and heart rate
Cardiac telemetry following single doses as a measure of safety and tolerability
Continuous cardiac telemetry will be performed for at least 12 hours post dose in each treatment period in Part A.
Cardiac telemetry following repeat doses as a measure of safety and tolerability
Continuous cardiac telemetry will be performed for at least 8 hours post dose in Days 1, 4, 7, 10, and 14 in Part B
Electrocardiogram (ECG) assessment following single doses as a measure of safety and tolerability
12-lead ECGs will be obtained during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT duration corrected for heart rate by Fridericia's formula (QTcF intervals) at each timepoint
ECG assessment following repeat doses as a measure of safety and tolerability
12-lead ECGs will be obtained during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT duration corrected for heart rate by Fridericia's formula (QTcF intervals) at each timepoint
Laboratory parameters assessment following single doses as a measure of safety and tolerability
Laboratory parameters include: hematology, clinical chemistry, and urinalysis
Laboratory parameters following repeat doses as measure of safety and tolerability
Laboratory parameters include: hematology, clinical chemistry, and urinalysis
Number of participants with adverse events following single doses as a measure of safety and tolerability
AEs will be collected from the start of Study Treatment and until the follow-up contact
Number of participants with adverse events following repeat doses as a measure of safety and tolerability
AEs will be collected from the start of Study Treatment and until the follow-up contact

Secondary Outcome Measures

Composite of PK parameters following single doses
PK parameters include: area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-infinite]), area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration (AUC[0-t]), maximum observed concentration (Cmax), time of occurrence of Cmax (tmax), terminal phase half-life (t1/2)
Composite of PK parameters following repeat doses
PK parameters include: AUC (0-infinite), area under the concentration-time curve over the dosing interval (AUC [0-tau]), AUC (0-t), Cmax, tmax, t1/2 and accumulation ratio

Full Information

First Posted
January 23, 2014
Last Updated
July 20, 2018
Sponsor
GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT02045940
Brief Title
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of GSK2881078 in Single and Repeat Doses
Official Title
A Randomized Double Blinded (Sponsor Unblind), Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Selective Androgen Receptor Modulator (SARM) in Single and Repeat Doses in Healthy Male Subjects
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
January 20, 2014 (Actual)
Primary Completion Date
March 26, 2015 (Actual)
Study Completion Date
March 26, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This study is the first administration of GSK2881078 to humans. The intention of this study is to provide sufficient confidence in the safety of the molecule to inform progression to further repeat dose and proof of concept studies. This study will include approximately 52 subjects and consist of 2 parts. Part A will consist of two cohorts of 8 subjects to assess the safety, tolerability, and pharmacokinetic (PK) of ascending single oral doses of GSK2881078. Cohorts 1 and 2 will include healthy male subjects. Part B (Cohorts 3, 4 and 5) will include three cohorts of 12 healthy male subjects to examine the safety, tolerability, PK, and pharmacodynamic (PD) of repeated doses of GSK2881078 over 14 days. The total duration of the study including screening and follow-up, is not expected to exceed 70 days.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cachexia
Keywords
FTIH, pharmacokinetics, SARM, safety

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
99 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
Participants will receive one of the following four treatment sequences in four study period (one treatment per period). Sequence 1=Placebo, dose level (DL) 2, DL3, and DL4. Sequence 2=DL1, placebo, DL2, and DL4. Sequence 3=DL1, DL2, placebo, and DL4. Sequence 4=DL1, DL2, DL3, and placebo
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
Participants will receive one of the following four treatment sequences in four study period (one treatment per period). Sequence 5=Placebo, DL5, DL6, and DL7. Sequence 6=DL4, placebo, DL6, and DL7. Sequence 7=DL4, DL5, placebo, and DL7. Sequence 8=DL4, DL5, DL6, and placebo
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
Participants will receive repeat doses of GSK2881078 or placebo in a 3:1 randomization ratio for 14 days. The dose level will depend upon results from Part A
Arm Title
Cohort 4
Arm Type
Experimental
Arm Description
Participants will receive repeat doses of GSK2881078 or placebo in a 3:1 randomization ratio for 14 days. The dose level will depend upon results from Part A and preceding repeat dose Cohort
Arm Title
Cohort 5
Arm Type
Experimental
Arm Description
Participants will receive repeat doses of GSK2881078 or placebo in a 3:1 randomization ratio for 14 days. The dose level will depend upon results from Part A and preceding repeat dose Cohorts
Intervention Type
Drug
Intervention Name(s)
GSK2881078
Intervention Description
Hot melt solution within Capsule for oral single ascending doses or repeat dose administration with planned dose level and strength of 0.1, 0.3, 1.0, 2.0, 4.0, 8.0, and 10.0 mg
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Hot melt solution within Capsule for oral single ascending doses or repeat doses administration.
Primary Outcome Measure Information:
Title
Vital sign assessment following single doses as a measure of safety and tolerability
Description
Vital signs include: systolic blood pressure, diastolic blood pressure and heart rate
Time Frame
Up to 61 days
Title
Vital sign assessment following repeat doses as a measure of safety and tolerability
Description
Vital signs include: systolic blood pressure, diastolic blood pressure and heart rate
Time Frame
Up to 56 days
Title
Cardiac telemetry following single doses as a measure of safety and tolerability
Description
Continuous cardiac telemetry will be performed for at least 12 hours post dose in each treatment period in Part A.
Time Frame
Up to 19 days
Title
Cardiac telemetry following repeat doses as a measure of safety and tolerability
Description
Continuous cardiac telemetry will be performed for at least 8 hours post dose in Days 1, 4, 7, 10, and 14 in Part B
Time Frame
14 days
Title
Electrocardiogram (ECG) assessment following single doses as a measure of safety and tolerability
Description
12-lead ECGs will be obtained during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT duration corrected for heart rate by Fridericia's formula (QTcF intervals) at each timepoint
Time Frame
Up to 61 days
Title
ECG assessment following repeat doses as a measure of safety and tolerability
Description
12-lead ECGs will be obtained during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT duration corrected for heart rate by Fridericia's formula (QTcF intervals) at each timepoint
Time Frame
Up to 56 days
Title
Laboratory parameters assessment following single doses as a measure of safety and tolerability
Description
Laboratory parameters include: hematology, clinical chemistry, and urinalysis
Time Frame
Up to 61 days
Title
Laboratory parameters following repeat doses as measure of safety and tolerability
Description
Laboratory parameters include: hematology, clinical chemistry, and urinalysis
Time Frame
Up to 56 days
Title
Number of participants with adverse events following single doses as a measure of safety and tolerability
Description
AEs will be collected from the start of Study Treatment and until the follow-up contact
Time Frame
33 days
Title
Number of participants with adverse events following repeat doses as a measure of safety and tolerability
Description
AEs will be collected from the start of Study Treatment and until the follow-up contact
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Composite of PK parameters following single doses
Description
PK parameters include: area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-infinite]), area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration (AUC[0-t]), maximum observed concentration (Cmax), time of occurrence of Cmax (tmax), terminal phase half-life (t1/2)
Time Frame
PK samples will be collected at pre-dose and 0.2, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48 hours post dose in each of the four dosing session
Title
Composite of PK parameters following repeat doses
Description
PK parameters include: AUC (0-infinite), area under the concentration-time curve over the dosing interval (AUC [0-tau]), AUC (0-t), Cmax, tmax, t1/2 and accumulation ratio
Time Frame
Up to 17 days

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Males between 18 and 50 years of age (inclusive), at the time of signing the informed consent form Body weight >= 50 kilogram (kg) and Body Mass Index (BMI) within the range 19 - 32 kg/meter square (m^2) (inclusive), where BMI= weight in kg/ height in m^2 Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in the Lifestyle Section of the protocol. This criterion must be followed through the completion of the follow-up visit. Average QTcF <450millisecond (msec); or QTcF <480msec in subjects with Bundle Branch Block. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Exclusion Criteria: 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 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. ECG exclusion criteria: Heart rate-<40 and >100 beats per minute, PR Interval-<120 and >200msec, QRS duration-<70 and >110msec. 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 Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). History of drug or alcohol abuse within 5 years prior to the Screening Period. History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 milliliter [mL]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. 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 GSK Medical Monitor, contraindicates their participation. Subjects with a family history of early onset prostate cancer or multiple members with prostate cancer. A positive pre-study drug or alcohol screen. Cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening. Subjects with values outside the specified ranges for the following Key Clinical Laboratory Tests must be excluded from the study: Liver function tests - Alanine aminotransferase, Direct Bilirubin, or Albumin more than 10% outside the normal reference range (<0.9 x lower limit of normal [LLN] or >1.1 x upper limit of normal [ULN]) Renal function - Creatinine >1.6milligrams (mg)/deciliter (dL) with an age appropriate glomerular filtration rate<=60 (mL/minute/1.73 m^2). Electrolytes - Sodium more than ± 5milliequivalents/Liter outside the normal reference range, Potassium or Calcium more than 10% outside the normal reference range (<0.9 x LLN or >1.1 x ULN) Metabolic - Glucose more than 10% outside the normal reference range (<0.9 x LLN or >1.1 x ULN) and Total Cholesterol > 240mg/dL Muscle - creatine phosphokinase >2.0 x ULN Hematology - Hemoglobin, white blood cells, Neutrophils, or Platelets more than 10% outside the normal reference range (<0.9 x LLN or >1.1 x ULN) Prostate Specific Antigen >2.5nanogram/mL A positive test for human immuno virus antibody A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. Exposure to more than four new chemical entities within 12 months prior to the first dosing day Unable to refrain from prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication and throughout the study, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. 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: 3 months (12 weeks), 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Where participation in the study would result in donation of blood or blood products in excess of 500mL within a 56-day period. Unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline
Official's Role
Study Director
Facility Information:
Facility Name
GSK Investigational Site
City
Overland Park
State/Province
Kansas
ZIP/Postal Code
66211
Country
United States
Facility Name
GSK Investigational Site
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21225
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
IPD for this study will be made available via the Clinical Study Data Request site.
IPD Sharing Time Frame
IPD is available via the Clinical Study Data Request site (click on the link provided below)
IPD Sharing Access Criteria
Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
IPD Sharing URL
https://clinicalstudydatarequest.com

Learn more about this trial

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of GSK2881078 in Single and Repeat Doses

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