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Trial record 2 of 17 for:    GSK1265744

A Randomized Study to Assess the Relative Bioavailability of New Formulations of GSK1265744 Long Acting Parental (LAP) in Healthy Adult Subjects

This study has been completed.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT01754116
First received: December 17, 2012
Last updated: April 17, 2014
Last verified: April 2014
  Purpose

This is a single-center, randomized, open-label, 3 parallel treatment study in healthy adult subjects to assess the relative bioavailability of new formulations of GSK1265744 LAP 400 mg intra muscular compared to the current GSK1265744 LAP 400 mg nanomilled formulation. This study will evaluate LAP formulations of GSK1265744 with different particle sizes.

Following a 14 day lead in period with oral GSK1265744, forty-five subjects will receive 400 mg of one of three GSK1265744 formulations which vary in particle size from 200 nm to 5 um by intramuscular injection. Samples for determination of GSK1265744 concentrations will be collected for 12 weeks post-injection. Safety will be evaluated by adverse event recording and laboratory values at frequent intervals throughout the trial. A subgroup of 12 subjects will receive a 3 mg dose of oral midazolam at baseline on Day-29 and then again on the last day of the oral GSK1265744 lead in period to evaluate the effect of GSK1265744 on CYP3A enzymes.

The subjects will undergo follow-up evaluations for a minimum of 12 weeks.


Condition Intervention Phase
Infection, Human Immunodeficiency Virus
Drug: GSK1265744 30 mg oral
Drug: Midazolam 3 mg oral + GSK1265744 30mg oral
Drug: GSK1265744 400 mg (200 nm)
Drug: GSK1265744 400 mg (1 micro m)
Drug: GSK1265744 400 mg (5 micro m)
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-availability Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Single-Center Randomized, Open-Label, Study to Assess the Relative Bioavailability of New Formulations of GSK1265744 LAP in Healthy Adult Subjects.

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • Plasma GSK1265744 area under the concentration-time curve for 12 weeks (AUC 0-wk12) [ Time Frame: Treatment Period: Day 1 pre-dose and 4 hour (h) post dose, 48 h (Day 3), 96 h (Day 5), 144 h (Day 7), Week 2, Week 3, Week 4, Week 6, Week 8, Week 12 ] [ Designated as safety issue: No ]
    To evaluate the relative bioavailability of two new formulations of GSK1265744 400 mg LAP given intramuscularly compared to the current formulation (200 nm particle size) the pharmacokinetic (PK) parameters will include AUC 0 - 12

  • Plasma GSK1265744 last observed quantifiable concentration at week 12 (Cwk12) [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    To evaluate the relative bioavailability of two new formulations of GSK1265744 400 mg LAP given intramuscularly compared to the current formulation (200 nm particle size) the PK parameters will include Cwk12

  • Plasma GSK1265744 maximum observed concentration (Cmax) [ Time Frame: Treatment period: Day 1 (pre-dose) and 4 hour (h) post dose, 48 h (Day 3), 96 h (Day 5), 144 h (Day 7), Week 2, Week 3, Week 4, Week 6, Week 8, Week 12, Week 14 (follow-up) ] [ Designated as safety issue: No ]
    To evaluate the relative bioavailability of two new formulations of GSK1265744 400 mg LAP given intramuscularly compared to the current formulation (200 nm particle size) the PK parameters will include the maximum observed concentration


Secondary Outcome Measures:
  • Plasma GSK1265744 AUC(0-infinity) following the long acting parenteral (LAP) dosing [ Time Frame: Day 1 (pre-dose) and 4 hour (h) post dose, 48 h (Day 3), 96 h (Day 5), 144 h (Day 7), Week 2, Week 3, Week 4, Week 6, Week 8, Week12 and Week 14 (follow-up) ] [ Designated as safety issue: No ]
    Plasma GSK1265744 AUC(0-infinity), AUC(0-wk4), Cwk4, AUC(0-wk8), Cwk8, t½, tmax, and CL/F following the LAP dosing

  • Plasma GSK1265744 AUC(0-wk4) and AUC(0-wk8) following the LAP dosing [ Time Frame: Day 1 (pre-dose) and 4 hour (h) post dose, 48 h (Day 3), 96 h (Day 5), 144 h (Day 7), Week 2, Week 3, Week 4, Week 6, Week 8 ] [ Designated as safety issue: No ]
    Plasma GSK1265744 AUC(0- infinity), AUC(0-wk4), Cwk4, AUC(0-wk8), Cwk8, t½, tmax, and CL/F following the LAP dosing

  • Plasma GSK1265744 Cwk4 and Cwk8 following the LAP dosing [ Time Frame: Week 4 and Week 8 ] [ Designated as safety issue: No ]
    Plasma GSK1265744 AUC(0- infinity), AUC(0-wk4), Cwk4, AUC(0-wk8), Cwk8, t½, tmax, and CL/F following the LAP dosing

  • Plasma GSK1265744 terminal phase half-life (t½) and time of occurrence of Cmax (tmax) following the LAP dosing [ Time Frame: Day 1 (pre-dose) and 4 hour (h) post dose, 48 h (Day 3), 96 h (Day 5), 144 h (Day 7), Week 2, Week 3, Week 4, Week 6, Week 8, Week12 and Week 14 (Follow-up) ] [ Designated as safety issue: No ]
    Plasma GSK1265744 AUC(0- infinity), AUC(0-wk4), Cwk4, AUC(0-wk8), Cwk8, t½, tmax, and CL/F following the LAP dosing

  • Plasma GSK1265744 apparent clearance (CL/F) following oral dosing [ Time Frame: Day 1 (pre-dose) and 4 hour (h) post dose, 48 h (Day 3), 96 h (Day 5), 144 h (Day 7), Week 2, Week 3, Week 4, Week 6, Week 8, Week12 and Week 14 (Follow-up) ] [ Designated as safety issue: No ]
    Plasma GSK1265744 AUC(0- infinity), AUC(0-wk4), Cwk4, AUC(0-wk8), Cwk8, t½, tmax, and CL/F following the LAP dosing

  • Plasma GSK1265744 AUC(0-wk12) and AUC(0-wk4) following LAP administration of 400 mg IM (unsplit) in Cohorts 3 and 8 of LAI114433 (historical control) [ Time Frame: Day 1 (pre-dose) and 4 hour (h) post dose, 48 h (Day 3), 96 h (Day 5), 144 h (Day 7), Week 2, Week 3, Week 4, Week 6, Week 8, Week 12 ] [ Designated as safety issue: No ]
    Following LAP administration of 400 mg IM (unsplit) in Cohorts 3 and Cohort 8 of LAI114433 (ClinicalTrials.gov Identifier: NCT01215006) for historical control Route C material.the following PK parameters will be determined AUC(0-wk12) and AUC(0-wk4)

  • Plasma GSK1265744 Cwk12 following LAP administration of 400 mg IM (unsplit) in Cohorts 3 and 8 of LAI114433 (historical control) [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Following LAP administration of 400 mg IM (unsplit) in Cohorts 3 and Cohort 8 of LAI114433 (ClinicalTrials.gov Identifier: NCT01215006) for historical control Route C material.the following PK parameter will be determined Cwk12

  • Plasma GSK1265744 Cmax following LAP administration of 400 mg IM (unsplit) in Cohorts 3 and 8 of LAI114433 (historical control) [ Time Frame: Day 1 (pre-dose) and 4 hour (h) post dose, 48 h (Day 3), 96 h (Day 5), 144 h (Day 7), Week 2, Week 3, Week 4, Week 6, Week 8, Week12 and Week 14 (Follow-up) ] [ Designated as safety issue: No ]
    Following LAP administration of 400 mg IM (unsplit) in Cohorts 3 and Cohort 8 of LAI114433 (ClinicalTrials.gov Identifier: NCT01215006) for historical control Route C material.the following PK parameter will be determined Cmax

  • Plasma GSK1265744 area under the concentration-time curve over the dosing interval (AUC(0-tau)) following oral administration of GSK1265744 with midazolam [ Time Frame: During the oral lead in period: on Day -29, Day Day -28, Day -15, Day -14, Day -13 ] [ Designated as safety issue: No ]
    Following the LAP administration of the GSK 1265744 with midazolam the following PK parameter will be determined AUC(0-tau)

  • Plasma GSK1265744 Cmax following oral administration of GSK1265744 with midazolam [ Time Frame: During the oral lead in period: on Day -29, Day Day -28, Day -15, Day -14, Day -13 ] [ Designated as safety issue: No ]
    Following the LAP administration of the GSK 1265744 with midazolam the following PK parameter will be determined -Cmax

  • Plasma GSK1265744 t½ and tmax following oral administration of GSK1265744 with midazolam [ Time Frame: During the oral lead in period: on Day -29, Day Day -28, Day -15, Day -14, Day -13 ] [ Designated as safety issue: No ]
    Following the LAP administration of the GSK 1265744 with midazolam the following PK parameter will be determined t½ and tmax

  • Plasma GSK1265744 CL/F following oral administration of GSK1265744 with midazolam [ Time Frame: During the oral lead in period: on Day -29, Day Day -28, Day -15, Day -14, Day -13 ] [ Designated as safety issue: No ]
    Following the LAP administration of the GSK 1265744 with midazolam the following PK parameter will be determined CL/F

  • Plasma AUC(0-infinity) and last time of quantifiable concentration within a subject across all treatments (AUC(0-t)) of midazolam following oral administration of midazolam alone and in combination with oral GSK1265744 [ Time Frame: During the oral lead in period: on Day -29, Day Day -28, Day -15, Day -14, Day -13 ] [ Designated as safety issue: No ]
    Following oral administration of midazolam alone and in combination with oral GSK1265744 the following PK parameters will be determined: AUC(0-infinity) and (AUC(0-t))

  • Plasma Percentage of AUC(0-infinity) obtained by extrapolation (%AUCex )of midazolam following oral administration of midazolam alone and in combination with oral GSK1265744 [ Time Frame: During the oral lead in period: on Day -29, Day Day -28, Day -15, Day -14, Day -13 ] [ Designated as safety issue: No ]
    Following oral administration of midazolam alone and in combination with oral GSK1265744 the following PK parameters will be determined: %AUCex

  • Plasma Cmax of midazolam following oral administration of midazolam alone and in combination with oral GSK1265744 [ Time Frame: During the oral lead in period: on Day -29, Day Day -28, Day -15, Day -14, Day -13 ] [ Designated as safety issue: No ]
    Following oral administration of midazolam alone and in combination with oral GSK1265744 the following PK parameters will be determined Cmax

  • Plasma t1/2, tlag and tmax of midazolam following oral administration of midazolam alone and in combination with oral GSK1265744 [ Time Frame: During the oral lead in period: on Day -29, Day Day -28, Day -15, Day -14, Day -13 ] [ Designated as safety issue: No ]
    Following oral administration of midazolam alone and in combination with oral GSK1265744 the following PK parameters will be determined t1/2, Lag time before observation of drug concentrations in sampled matrix (tlag)and tmax

  • Plasma CL/F of midazolam following oral administration of midazolam alone and in combination with oral GSK1265744 [ Time Frame: During the oral lead in period: on Day -29, Day Day -28, Day -15, Day -14, Day -13 ] [ Designated as safety issue: No ]
    Following oral administration of midazolam alone and in combination with oral GSK1265744 the following PK parameters will be determined CL/F

  • Safety and tolerability assessed by the collection of all adverse events [ Time Frame: Upto Week 14 ] [ Designated as safety issue: No ]
    Following administration of the study treatment safety and tolerability which includes adverse events (AEs) will be assessed. AEs will be collected from the start of study treatment and until the follow-up contact

  • Safety and tolerability assessed by the collection of any use of concurrent medications [ Time Frame: Upto Week 14 ] [ Designated as safety issue: No ]
    Following administration of the study treatment safety and tolerability which includes concurrent medications taken by the subjects will be assessed

  • Safety and tolerability assessed by clinical laboratory screens [ Time Frame: Day -1, Week 2, Week 4, Week 8, Week12 and Week 14 (Follow-up) ] [ Designated as safety issue: No ]
    Following administration of the study treatment safety and tolerability which includes clinical laboratory screens will be assessed. Hematology, clinical chemistry, urinalysis

  • Safety and tolerability assessed by electrocardiograph (ECG) [ Time Frame: Upto Week 14 ] [ Designated as safety issue: No ]
    Following administration of the study treatment safety and tolerability which includes ECG readings will be assessed. ECGs will be obtained at each timepoint during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcB intervals

  • Safety and tolerability assessed by vital signs (blood pressure and pulse rate) [ Time Frame: Upto Week 14 ] [ Designated as safety issue: No ]
    Following administration of the study treatment safety and tolerability which includes vital signs will be assessed. Vital sign measurements will include systolic and diastolic blood pressure and pulse rate


Enrollment: 43
Study Start Date: January 2013
Study Completion Date: April 2014
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lead In Period GSK1265744 30 mg + midazolam 3mg
During the lead-in period, a group of 12 subjects will receive a midazolam probe (on Day -29 and Day -14) to examine the potential of GSK265744 to inhibit or induce cytochrome P450 (CYP)3A activity. On Day -28, subjects will begin a 14 day oral dose of GSK265744 30 mg. to be taken once daily from Day-28 to Day -14. Subjects will begin a wash out period from Day -14 to Day -1 and be randomized to GSK1265744 LAP on Day 1
Drug: Midazolam 3 mg oral + GSK1265744 30mg oral
Midazolam Syrup 3mg each mL Oral/single dose administer by oral syringe on Day -29 and Day -14
Experimental: Lead in Period GSK1265744 30mg
On Day -28, subjects will begin a 14 day oral dose lead-in period. Subjects will be dispensed a 14 day supply of 30mg oral GSK1265744 to be taken once daily from Day-28 to Day -15. Subjects will begin a wash out period from Day -14 to Day -1 and be randomized to GSK1265744 LAP on Day 1
Drug: GSK1265744 30 mg oral
GSK1265744B 30 mg Tablet taken orally, once a day in the morning with or without a meal
Experimental: Treatment A
Approximately 15 subjects will be enrolled and randomized on Day 1 to receive a single dose of 400 mg GSK1265744 (Nanomilled 200 nm) LAP intramuscular suspension injection
Drug: GSK1265744 400 mg (200 nm)
A single dose of GSK1265744 400 mg Intra Muscular (IM) injection (Nanomilled 200 nm)
Experimental: Treatment B
Approximately 15 subjects will be enrolled and randomized on Day 1 to receive a single dose of 400mg GSK1265744 (Nanomilled 1 micro m) LAP intramuscular suspension injection
Drug: GSK1265744 400 mg (1 micro m)
A single dose of GSK1265744 400 mg IM injection (Nanomilled 1 micrometer)
Experimental: Treatment C
Approximately 15 subjects will be enrolled and randomized on Day 1 to receive a single dose of 400 mg GSK1265744 (Dry milling and homogenization 5 micro m) LAP intramuscular suspension injection
Drug: GSK1265744 400 mg (5 micro m)
A single dose of GSK1265744 400 mg IM injection (Dry milling and homogenization 5 micrometer)

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria

  • Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
  • 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 female subject is eligible to participate if she is of: non-childbearing potential. Female subjects of child bearing potential must agree to use contraception for at least 6 months after the final dose of study drug and should understand that drug concentrations may be measurable for up to one year after final dose.
  • Male subjects with female partners of child-bearing potential must agree to use one of the required contraception methods noted in the protocol.
  • Body weight >=50 Kilograms (kg) for men and >=45 kg for women and body mass index (BMI) within the range 18.5-31.0 kg/m^2 (inclusive).
  • Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin <= 1.5xupper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Single QTcB <450 msec.

Exclusion Criteria:

  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • A positive pre-study drug/alcohol screen.
  • A positive test for Human Immunodeficiency Virus (HIV) antibody.
  • 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 grams (g) of alcohol: 12 ounces (360 milliliters [mL]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

  • History or regular use of tobacco-or nicotine-containing products within 3 months prior to screening.
  • 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).
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  • 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 (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, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  • History of sensitivity to any of the study medications, including midazolam and flumazenil, 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.
  • History or presence of allergy or intolerance to the study drugs or their components or drugs of their class.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
  • Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.
  • Lactating females.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Subject is mentally or legally incapacitated.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • 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.
  • The subject's systolic blood pressure is outside the range of 90-140mmHg, or diastolic blood pressure is outside the range of 45-90mmHg.
  • History of clinically significant cardiovascular disease.
  • Any significant arrhythmia which, in the opinion of the principal Investigator and GSK Medical Monitor, will interfere with the safety for the individual subject. Non-sustained (>=3 consecutive ventricular ectopic beats) or sustained ventricular tachycardia.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01754116

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

No publications provided

Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT01754116     History of Changes
Other Study ID Numbers: 116815
Study First Received: December 17, 2012
Last Updated: April 17, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by ViiV Healthcare:
healthy subjects
GSK1265744 LAP
integrase inhibitor
HIV-1 infection
long acting retroviral
relative bioavailability

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Infection
Immune System Diseases
Lentivirus Infections
RNA Virus Infections
Retroviridae Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Midazolam
Adjuvants, Anesthesia
Anesthetics
Anesthetics, General
Anesthetics, Intravenous
Anti-Anxiety Agents
Central Nervous System Agents
Central Nervous System Depressants
GABA Agents
GABA Modulators
Hypnotics and Sedatives
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs
Therapeutic Uses
Tranquilizing Agents

ClinicalTrials.gov processed this record on November 20, 2014