A Study to Investigate the Safety, Tolerability and Pharmacokinetics of Repeat Dose Administration of Long-Acting GSK1265744 and Long-Acting TMC278 Intramuscular and Subcutaneous Injections in Healthy Adult Subjects

This study has been completed.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT01593046
First received: May 3, 2012
Last updated: February 6, 2014
Last verified: January 2014
  Purpose

LAI115428 is a Phase I, randomized, repeat dose escalation study to determine the safety, tolerability, and PK profile of intramuscular and subcutaneous injections of GSK1265744 in a long acting parenteral (LAP) formulation in healthy subjects. Subjects will be randomized to 3 monthly dosing cohorts and 1 quarterly dosing cohort with either intramuscular or subcutaneous dosing. In the monthly dosing cohorts subjects will receive GSK1265744 alone for 2 months and then in combination with TMC278 long acting parenteral (LA) for 2 months. For the quarterly dosing cohort, 2 quarterly intramuscular doses of GSK1265744 LAP will be given alone. Three dose levels of GSK1265744 will be evaluated partly in combination with TMC278 LA to adequately characterize the GSK1265744 LAP and TMC278 LA safety, tolerability, and PK profile. A total enrolment of approximately 40 healthy subjects is planned for this study.


Condition Intervention Phase
Infection, Human Immunodeficiency Virus
Drug: GSK1265744 Oral
Drug: GSK1265744 LAP 800mg intramuscular injection
Drug: GSK1265744 LAP 200mg subcutaneous injection
Drug: GSK1265744 LAP 200mg intramuscular injection
Drug: GSK1265744 LAP 400mg intramuscular injection
Drug: TMC278 LA 1200mg intramuscular injection
Drug: TMC278 LA 600mg intramuscular injection
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: A Randomized, Open Label Study to Investigate the Safety, Tolerability and Pharmacokinetics of Repeat Dose Administration of Long-Acting GSK1265744 and Long-Acting TMC278 Intramuscular and Subcutaneous Injections in Healthy Adult Subjects

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • GSK1265744 LAP safety and tolerability parameters including the collection of adverse events [ Time Frame: approximately 25 weeks ] [ Designated as safety issue: No ]
  • GSK1265744 LAP safety and tolerability parameters including change from baseline in clinical laboratory safety assessments [ Time Frame: approximately 25 weeks ] [ Designated as safety issue: No ]
    Hematology, Clinical Chemistry and Urinalysis

  • GSK1265744 LAP safety and tolerability parameters including change from baseline in electrocardiogram (ECG) measurements [ Time Frame: approximately 25 weeks ] [ Designated as safety issue: No ]
  • GSK1265744 LAP safety and tolerability parameters including change from baseline in vital sign measurements [ Time Frame: approximately 25 weeks ] [ Designated as safety issue: No ]
    Blood pressure and heart rate

  • TMC278 LA safety and tolerability parameters including the collection of adverse events [ Time Frame: approximately 12 weeks ] [ Designated as safety issue: No ]
  • TMC278 LA safety and tolerability parameters including change from baseline in clinical laboratory safety assessments [ Time Frame: approximately 12 weeks ] [ Designated as safety issue: No ]
    Hematology, Clinical Chemistry and Urinalysis

  • TMC278 LA safety and tolerability parameters including change from baseline in ECG measurements [ Time Frame: approximately 12 weeks ] [ Designated as safety issue: No ]
  • TMC278 LA safety and tolerability parameters including change from baseline in vital sign measurements [ Time Frame: approximately 12 weeks ] [ Designated as safety issue: No ]
    Blood pressure and heart rate

  • Composite of PK parameters following single and repeat dose intramuscular or subcutaneous administration [ Time Frame: approximately 25 weeks ] [ Designated as safety issue: No ]
    Measurements include: area under the plasma concentration time curve over the dosing interval (AUC(0-t)), maximum observed concentration (Cmax), time to maximum observed concentration (tmax), concentration at the end of the dosing interval (Ct).

  • Composite of GSK1265744 pharmacokinetic parameters following repeat dose oral administration [ Time Frame: approximately 25 weeks ] [ Designated as safety issue: No ]
    Measurements include: area under the plasma concentration time curve over the dosing interval (AUC(0-t)), maximum observed concentration (Cmax), time to maximum observed concentration (tmax), concentration at the end of the dosing interval (Ct).

  • Composite of TMC278 LA pharmacokinetic parameters following single and repeat dose intramuscular administration [ Time Frame: approximately 12 weeks ] [ Designated as safety issue: No ]
    Measurements include: area under the plasma concentration time curve over the dosing interval (AUC(0-t)), maximum observed concentration (Cmax), time to maximum observed concentration (tmax), concentration at the end of the dosing interval (Ct).

  • GSK1265744 LAP safety and tolerability parameters including change from baseline for clinical chemistry assessments (ALT, AST, ALP, Total and Direct Bilirubin). [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • GSK1265744 oral formulation safety and tolerability parameters including the collection of adverse events [ Time Frame: 21 days ] [ Designated as safety issue: No ]
  • GSK1265744 oral formulation safety and tolerability parameters including change from baseline in clinical laboratory safety assessments [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    Hematology, Clinical Chemistry and Urinalysis

  • GSK1265744 oral formulation safety and tolerability parameters including change from baseline in ECG measurements [ Time Frame: 21 days ] [ Designated as safety issue: No ]
  • GSK1265744 oral formulation safety and tolerability parameters including change from baseline in vital sign measurements [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    Blood pressure and heart rate

  • Composite of PK parameters of GSK1265744 LAP and TMC278 LA [ Time Frame: approximately 12 weeks ] [ Designated as safety issue: No ]
    Measurements include: apparent clearance (CL/FLAP) following single and repeat dose administration.

  • Composite of PK parameters following each dose administration at different dose levels for the assessment of dose proportionality and relative exposure [ Time Frame: approximately 25 weeks ] [ Designated as safety issue: No ]
    Measurements include: GSK1265744 LAP AUC(0-t), Cmax, and Ct

  • Composite of PK parameters for GSK1265744 LAP [ Time Frame: approximately 25 weeks ] [ Designated as safety issue: No ]
    Measurements include: apparent terminal phase half-life for LAP administration (t½), lambda z as a measure of absorption rate constant if data allow

  • Composite of PK parameters of TMC278 LA [ Time Frame: approximately 12 weeks ] [ Designated as safety issue: No ]
    Measurements include: AUC(0-t), Cmax, and Ct in cohort 2 and 3


Enrollment: 43
Study Start Date: May 2012
Study Completion Date: November 2013
Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Run-in Period
Oral GSK1265744 30mg once daily for 14 days
Drug: GSK1265744 Oral
30mg tablet
Other Name: GSK1265744
Experimental: Cohort 1
GSK1265744 LAP injection given subcutaneously once a month for 4 months
Drug: GSK1265744 LAP 800mg intramuscular injection
800mg Loading dose given at month 1 dose
Other Name: GSK1265744
Drug: GSK1265744 LAP 200mg subcutaneous injection
200mg maintenance dose give at months 2 - 4
Other Name: GSK1265744
Experimental: Cohort 2
GSK1265744 LAP injection given intramuscularly once a month for 4 months. TMC278 LA + GSK1265744 given in Month 3 and 4.
Drug: GSK1265744 LAP 800mg intramuscular injection
800mg Loading dose given at month 1 dose
Other Name: GSK1265744
Drug: GSK1265744 LAP 200mg intramuscular injection
200mg maintenance dose given at months 2 - 4
Other Name: GSK1265744
Drug: TMC278 LA 1200mg intramuscular injection
1200mg Loading dose given at month 3
Other Name: TMC278 LA
Drug: TMC278 LA 600mg intramuscular injection
600mg Loading dose given at month 4
Other Name: TMC278 LA
Experimental: Cohort 3
GSK1265744 LAP injection given intramuscularly once a month for 4 months. TMC278 LA + GSK1265744 given in Month 3 and 4.
Drug: GSK1265744 LAP 800mg intramuscular injection
800mg Loading dose given at month 1 dose
Other Name: GSK1265744
Drug: GSK1265744 LAP 400mg intramuscular injection
400mg maintenance dose given at month 2 - 4
Other Name: GSK1265744
Drug: TMC278 LA 1200mg intramuscular injection
1200mg Loading dose given at month 3
Other Name: TMC278 LA
Drug: TMC278 LA 600mg intramuscular injection
600mg Loading dose given at month 4
Other Name: TMC278 LA
Experimental: Cohort 4
GSK1265744 LAP injection given intramuscularly once every 12 weeks.
Drug: GSK1265744 LAP 800mg intramuscular injection
800mg dose given quarterly (once every) 12 weeks
Other Name: GSK1265744

  Eligibility

Ages Eligible for Study:   18 Years to 64 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • AST, ALT, alkaline phosphatase and bilirubin greater than or equal to 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • 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 clinically significant 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 or female between 18 and 64 years of age inclusive, at the time of signing the informed consent.
  • Females of childbearing potential with a negative pregnancy test (serum or urine) at screen and at Day -21, and agrees to use one of the contraception methods listed in the protocol for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception for six months after the final dose of study drug.
  • Body weight greater than or equal to 50 kg for men and greater than or equal to 45 kg for women and body mass index (BMI) within the range 18.5-31.0 kg/m2 (inclusive).
  • All Study subjects should be counseled on the practice of safer sexual practices including the use of effective barrier methods (e.g. male condom/spermicide).

Exclusion Criteria:

  • History of bleeding or clotting disorders including disseminated intravascular coagulation, hemophilia Henoch-Schönlein purpura (allergic purpura), hereditary hemorrhagic telangiectasia, thrombocytopenia, thrombophilia or Von Willebrand's disease.
  • High-risk behavior for HIV infection including one of the following risk factors within six months before entering the study (day 1): Unprotected vaginal or anal sex with a known HIV infected person or a casual partner, engaged in sex work for money or drugs, acquired a sexually transmitted disease, high risk partner currently or in the previous six months.
  • 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 (screening and Day -21) drug/alcohol screen.
  • History of regular alcohol consumption within 6 months of the study as defined in the protocol.
  • 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.
  • Refrain from use of prescription or non-prescription drugs, 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, 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. If heparin is used during PK sampling, subjects with a history or sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
  • The subject has an underlying skin disease or disorder (i.e. infection, inflammation, dermatitis, eczema, drug rash, drug allergy, psoriasis, food allergy, urticaria. Mild cases of localized acne or folliculitis are not exclusionary.)
  • The subject has a tattoo or other dermatological condition overlying the gluteus and/or abdominal region which may interfere with interpretation of injection site reactions.
  • 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.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Subject is mentally or legally incapacitated.
  • The subject's systolic blood pressure is outside the range of 90-140mmHg, or diastolic blood pressure is outside the range of 45-90mmHg or heart rate is outside the range of 50-100bpm for female subjects or 45-100 bpm for male subjects.
  • History of clinically significant cardiovascular disease.
  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: NCT01593046

Locations
United States, Florida
GSK Investigational Site
Daytona Beach, Florida, United States, 32117
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: NCT01593046     History of Changes
Other Study ID Numbers: 115428
Study First Received: May 3, 2012
Last Updated: February 6, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by ViiV Healthcare:
GSK1265744 LAP
integrase inhibitor
healthy subjects
TMC278 LA
GSK1265744LAP
long acting retroviral
HIV-1 infection

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immune System Diseases
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 18, 2014