Effect of Dolutegravir on Metformin Pharmacokinetics in Healthy Adult Subjects

This study has been completed.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT02064374
First received: February 13, 2014
Last updated: May 22, 2014
Last verified: May 2014
  Purpose

This study will be a phase 1, open label, parallel group, three period crossover study to evaluate the effect of dolutegravir (DTG) on the steady state pharmacokinetics of metformin and on the safety and tolerability of dolutegravir and metformin. Subjects will have a screening visit within 30 days prior to the first dose of study drug, three treatment periods, and a follow up visit 7-14 days after the last dose of study drug. Eligible subjects will be assigned to one of the two treatment cohorts. Subjects will receive metformin 500 milligram (mg) after every 12 hours (q12h) for 5 days in Period 1; metformin 500 mg q12h plus dolutegravir 50 mg after every 24 hours (q24h) (Cohort 1) or 50 mg q12h (Cohort 2) for 7 days in Period 2; and metformin 500 mg q12h for 10 days in Period 3. There will be no washout periods between treatments. All doses of study drug will be taken following a meal. Safety evaluations will be collected during each period. Serial pharmacokinetic (PK) samples will be collected for metformin on the last day of each period and for dolutegravir on the last day of Period 2.


Condition Intervention Phase
Infection, Human Immunodeficiency Virus
Drug: Metformin 500 mg q12h
Drug: Dolutegravir 50 mg q24h
Drug: Dolutegravir 50 mg q12h
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I, Open Label, Parallel Group, Three Period, Fixed Sequence Crossover Study to Evaluate the Effect of Dolutegravir on Metformin Pharmacokinetics in Healthy Adult Subjects

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • Steady state plasma metformin pharmacokinetics (PK) parameters [ Time Frame: Day 5 to Day 22 ] [ Designated as safety issue: No ]
    PK parameters will include: maximum concentration (Cmax), area under the time-concentration curve over the dosing interval [AUC(0-tau)]

  • Steady state plasma DTG PK parameters [ Time Frame: Day 12 and Day 13 ] [ Designated as safety issue: No ]
    PK parameters will include: Area under the time-concentration curve over the dosing interval [AUC(0-tau)], apparent clearance following oral dosing (CL/F), concentration at time zero (C0) and maximum concentration (Cmax)

  • Steady-state plasma metformin PK parameters in Period 2 as compared to those in Period 1 [ Time Frame: Day 5 to Day 12 ] [ Designated as safety issue: No ]
    PK parameters will include: Terminal phase half-life (t1/2) and Apparent clearance following oral dosing (CL/F)


Secondary Outcome Measures:
  • Change from baseline in vital signs [ Time Frame: Upto Day 22 ] [ Designated as safety issue: No ]
    Vital signs will include systolic and diastolic blood pressure and pulse rate.

  • Number of subjects with adverse events (AEs) [ Time Frame: Upto Day 22 ] [ Designated as safety issue: No ]
    AEs will be assessed throughout the study.

  • Toxicity grading of clinical laboratory tests [ Time Frame: Upto Day 22 ] [ Designated as safety issue: No ]
    Laboratory assessments will include haematology, clinical chemistry and urinalysis parameters.

  • Steady-state plasma metformin PK parameters in Period 3 for each cohort [ Time Frame: Upto Day 22 ] [ Designated as safety issue: No ]
    PK parameters will include: Cmax, concentration curve over the dosing interval [AUC(0-tau)], Terminal phase half-life (t1/2) and apparent clearance following oral dosing (CL/F)

  • Changes in serum creatinine upon dosing and discontinuation of DTG [ Time Frame: Upto Day 22 ] [ Designated as safety issue: No ]
    Serum creatinine change will be calculated from baseline over time in each period


Enrollment: 30
Study Start Date: February 2014
Study Completion Date: May 2014
Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
All subjects will be assigned to a single-sequence of three treatment periods without washout. Subjects will receive Metformin immediate release (IR) 500 mg q12h following a moderate fat meal for 5 days (Period 1), followed by Metformin IR 500 mg q12h plus DTG 50 mg q24h following a moderate fat meal for 7 days (Days 1-7 of Period 2), followed by Metformin IR 500 mg q12h following a moderate fat meal (Days 1-10 of period 3).
Drug: Metformin 500 mg q12h
Metformin will be supplied as 500 mg tablet to be administered orally.
Drug: Dolutegravir 50 mg q24h
Dolutegravir will be supplied as 50 mg tablet to be administered orally. To be taken once a day in the morning in Period 2 (Total daily dose 50 mg per day for Cohort 1 only)
Experimental: Cohort 2
All subjects will be assigned to a single-sequence of three treatment periods without washout. Subjects will receive Metformin IR 500 mg q12h following a moderate fat meal (Day 1-5 of Period 1), followed by Metformin IR 500 mg q12h plus DTG 50 mg q12h following a moderate fat meal for 7 days (Days 1-7 of Period 2), followed by Metformin IR 500 mg q12h following a moderate fat meal (Days 1-10 of period 3).
Drug: Metformin 500 mg q12h
Metformin will be supplied as 500 mg tablet to be administered orally.
Drug: Dolutegravir 50 mg q12h
Dolutegravir will be supplied as 50 mg tablet to be administered orally. To be taken 50 mg tablets every 12 hours in Period 2 (Total daily dose 100 mg per day for Cohort 2 only).

  Eligibility

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

Inclusion Criteria:

  • Male/females aged 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 subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator agrees and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
  • Body weight >=50 kilograms (Kg) for males and >=45 Kg for females and body mass index (BMI) within the range 18.5 - 31.0 Kg/m^2 (square meters) (inclusive).
  • A female subject is eligible to participate if she is of: non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy [for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records]; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli international units per milliliter (MIU/mL) and estradiol <40 picograms (pg)/mL (<147 picomole per liter (pmol/L) is confirmatory]; Child-bearing potential with negative pregnancy test as determined by [serum or urine] human chorionic gonadotropin (hCG) test at screening or prior to dosing AND Agrees to use one of the contraception methods 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 until 5 days post-last dose. OR has only same-sex partners, when this is her preferred and usual lifestyle.
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
  • Alanine aminotransferase, alkaline phosphatase and bilirubin <= 1.5x Upper Limit of Normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). A single repeat is allowed for eligibility determination.

Exclusion Criteria:

  • A positive pre-study drug/alcohol screen.
  • A positive test for human immunodeficiency virus (HIV) antibody.
  • Pregnant females as determined by positive [serum or urine] hCG test at screening or prior to dosing.
  • 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 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 GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation. Subjects will allergy to tricyclic antidepressants should not be enrolled.
  • 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).
  • Lactating females.
  • 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).
  • Regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
  • 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.
  • The subject's systolic blood pressure is outside the range of 90-140 millimeters of mercury (mmHg), or diastolic pressure is outside the range of 45-90 mmHg, or heart rate is outside the range of 50-100 beats per minute (bpm) for female subjects or 45-100 bpm for male subjects. A single repeat is allowed for eligibility determination.
  • Exclusion criteria for screening electrocardiogram (ECG) (a single repeat is allowed for eligibility determination): Heart rate for males <45 and >110 bpm and females <50 and >100 bpm; PR interval <120 and >220 msec, QRS duration <70 and >120 msec, QTc interval (Bazett) >450 msec. Evidence of previous myocardial infarction (Does not include ST segment changes associated with repolarization); any clinically significant arrhythmia which, in the opinion of the investigator and GSK Medical Monitor, will interfere with the safety for the individual subject; any conduction abnormality (including but not specific to left or right incomplete bundle branch block, atrioventricular block [2nd degree or higher], Wolf Parkinson White [WPW] syndrome), sinus pauses>3 seconds, and non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular ectopic beats).
  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: NCT02064374

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: NCT02064374     History of Changes
Other Study ID Numbers: 201167
Study First Received: February 13, 2014
Last Updated: May 22, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by ViiV Healthcare:
Dolutegravir
drug interaction
metformin
pharmacokinetics
healthy volunteers

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
HIV Infections
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Metformin
Dolutegravir
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
HIV Integrase Inhibitors
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 30, 2014