Trial record 17 of 28 for:    " December 05, 2012":" January 04, 2013"[FIRST-RECEIVED-DATE]AND HIV[CONDITION]

A Study to Evaluate the Effects of Calcium Carbonate and Ferrous Fumarate on Pharmacokinetics of Dolutegravir in Healthy Adult Subjects

This study has been completed.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT01762995
First received: December 19, 2012
Last updated: April 18, 2013
Last verified: March 2013
  Purpose

Human immune virus (HIV) infected subjects may take mineral supplements in combination with their antiretroviral medications. Calcium and Iron supplementations are commonly used and both of these have the potential to interact with Dolutegravir (DTG), this study will evaluate the potential of calcium and iron supplements to decrease DTG exposure. It will also evaluate two possible strategies for combined use; if an interaction is observed. The first strategy is a two hour separation. The second strategy involves the administration of DTG and the supplement with a meal since the presence of food modestly increases DTG exposure, and because mineral supplements can be administered with food.

This is an open label, randomized, two cohort, four-period cross-over study in healthy volunteers. One cohort will examine the effects of calcium carbonate and the other cohort will examine the effects of ferrous fumarate on the pharmacokinetic (PK) of DTG. Approximately 12 subjects will be enrolled into each of the two cohorts and receive each of four treatments in a randomized fashion: 1) A single dose of DTG 50 milligram (mg) administered under fasted conditions ; 2) A single dose of DTG 50 mg co-administered with a single dose of calcium carbonate or ferrous fumarate under fasted conditions ; 3) A single dose of DTG 50 mg co-administered with a single dose of calcium carbonate or ferrous fumarate with a moderate-fat meal; 4) A single dose of DTG 50 mg administered under fasted conditions 2 hours prior to administration of a single dose of calcium carbonate or ferrous fumarate. There will be a washout period of at least 7 days between treatments. Safety evaluations and serial PK samples will be collected during each treatment period. A follow-up visit will occur 7-14 days after the last dose of study drug. This study will be conducted at one center in the United States, with healthy adult male and female subjects.


Condition Intervention Phase
Infection, Human Immunodeficiency Virus
Drug: Dolutegravir 50 mg
Drug: Calcium Carbonate 1200 mg
Drug: Ferrous Fumarate 324 mg
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I, Open Label, Randomized, Four-Period Crossover Study to Evaluate the Effects of Calcium Carbonate 1200 mg and Ferrous Fumarate 324 mg on Pharmacokinetics of Dolutegravir 50 mg in Healthy Adult Subjects

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • Single dose plasma DTG PK assessed by AUC (0-t) and AUC (0-infinity) [ Time Frame: Blood samples (2 mililiter [mL]) for plasma PK parameters will be collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hrs post-dose), Day 2 (24 and 36 hrs post-dose) and Day 3 (48 hrs post- dose) in each of the four treatment periods ] [ Designated as safety issue: No ]
    To evaluate the single dose PK of DTG, area under the concentration-time curve from time zero to last time of quantifiable concentration (AUC [0-t]) and area under the concentration-time curve from time zero extrapolated to infinite time (AUC (0-infinity) will be assessed with DTG given alone and when given with Calcium Carbonate (co-administered in fed or fasted state or 2 hours (hrs) separation, fasted) or Ferrous Fumarate (co-administered in fed or fasted state or 2 hrs separation, fasted)

  • Single dose plasma DTG PK assessed by Cmax and C24 [ Time Frame: Blood samples (2 mL) for plasma PK parameters will be collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hrs post-dose), day 2 (24 and 36 hrs post-dose) and day 3 (48 hrs post dose) in each of the four ] [ Designated as safety issue: No ]
    To evaluate the single dose PK of DTG, maximum observed concentration (Cmax) and concentration at 24 hours post-dose (C24) will be assessed with DTG given alone and when given with Calcium Carbonate (co-administered in fed or fasted state or 2 hrs separation, fasted) or Ferrous Fumarate (co-administered in fed or fasted state or 2 hrs separation, fasted)


Secondary Outcome Measures:
  • Safety and tolerability assessed by change from baseline in electrocardiogram (ECG) [ Time Frame: Baseline and up to 36 days ] [ Designated as safety issue: No ]
    Single 12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.

  • Safety and tolerability assessed by number of subjects with adverse events (AEs) [ Time Frame: up to 36 days ] [ Designated as safety issue: No ]
    AEs will be collected from the start of Study Treatment and until the follow-up contact

  • Safety and tolerability assessed by toxicity grading of clinical laboratory tests [ Time Frame: up to 36 days ] [ Designated as safety issue: No ]
    Clinical laboratory tests include hematology, clinical chemistry, pregnancy test, alcohol and drug of abuse screen, and other additional parameters

  • Single dose plasma DTG PK assessed by AUC (0-24) [ Time Frame: Blood samples (2 mL) for plasma PK parameter will be collected on day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hrs post-dose), Day 2 (24 and 36 hrs post-dose) and Day 3 (48 hrs post- dose) in each of the four treatment periods. ] [ Designated as safety issue: No ]
    To evaluate the single dose PK of DTG, area under the concentration-time curve from time zero to 24 hrs post dose (AUC [0-24]) will be assessed when DTG will be given alone and when given with Calcium Carbonate (co-administered in fed or fasted state or 2 hrs separation, fasted) or Ferrous Fumarate (co-administered in fed or fasted state or 2 hrs separation, fasted)

  • Single dose plasma DTG PK assessed by tlag, tmax, and t1/2 [ Time Frame: Blood samples (2 mL) for plasma PK parameter will be collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hrs post-dose), Day 2 (24 and 36 hrs post-dose) and Day 3 (48 hrs post- dose) in each of the four treatment periods. ] [ Designated as safety issue: No ]
    To evaluate the single dose PK of DTG, lag time before observation of drug concentrations in sampled matrix (tlag), time of occurrence of Cmax (tmax), and terminal phase half-life (t1/2) will be assessed when DTG will be given alone and when given with Calcium Carbonate (co-administered in fed or fasted state or 2 hrs separation, fasted) or Ferrous Fumarate (co-administered in fed or fasted state or 2 hrs separation, fasted).

  • Single dose plasma DTG PK assessed by CL/F [ Time Frame: Blood samples (2 mL) for plasma PK parameter will be collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hrs post-dose), Day 2 (24 and 36 hrs post-dose) and Day 3 (48 hrs post- dose) in each of the four treatment periods. ] [ Designated as safety issue: No ]
    To evaluate the single dose PK of DTG, apparent clearance following oral dosing (CL/F) will be assessed when DTG will be given alone and when given with Calcium Carbonate (co-administered in fed or fasted state or 2 hrs separation, fasted) or Ferrous Fumarate (co-administered in fed or fasted state or 2 hrs separation, fasted).

  • Safety and tolerability assessed by change from baseline in blood pressure [ Time Frame: Baseline and up to 36 days ] [ Designated as safety issue: No ]
    Blood pressure (BP) measurement will include systolic and diastolic BP measurement. BP will be measured after resting in a semi-supine position for 5 minutes

  • Safety and tolerability assessed by change from baseline in Pulse rate [ Time Frame: Baseline and up to 36 days ] [ Designated as safety issue: No ]
    Pulse rate will be measured after resting in a semi-supine position for 5 minutes


Enrollment: 24
Study Start Date: December 2012
Study Completion Date: March 2013
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
Subjects in this cohort will take part in 4 treatment periods with one of the following treatments in each period. Subjects will receive all four treatments (one per period) in a random order. Treatment A = single dose DTG 50 mg fasted. Treatment B = single dose DTG 50 mg + Calcium Carbonate 1200 mg fasted. Treatment C = single dose of DTG 50 mg + Calcium Carbonate 1200 mg fed. Treatment D = single dose DTG 50 mg 2 hours prior to single dose Calcium Carbonate 1200 mg fasted
Drug: Dolutegravir 50 mg
One tablet ( 50 mg) will be administered orally as a single dose in each period per the random code
Drug: Calcium Carbonate 1200 mg
Two tablets (2 X 600 mg) will be administered orally as a single dose in three out of four periods to Cohort 1 only per the random code. Calcium carbonate will be given in fasted state, fed state and 2 hours before dolutegravir administration.
Experimental: Cohort 2
Subjects in this cohort will take part in 4 treatment periods with one of the following treatments in each period. Subjects will receive all four treatments (one per period) in a random order. Treatment A = single dose DTG 50 mg fasted. Treatment E = single dose DTG 50 mg + Ferrous Fumarate 324 mg fasted. Treatment F = single dose of DTG 50 mg + Ferrous Fumarate 324 mg fed. Treatment G = single dose DTG 50 mg 2 hours prior to single dose Ferrous Fumarate 324 mg fasted
Drug: Dolutegravir 50 mg
One tablet ( 50 mg) will be administered orally as a single dose in each period per the random code
Drug: Ferrous Fumarate 324 mg
One tablet (324 mg) will be administered orally as a single dose in three out of four periods to Cohort 2 only per the random code. Ferrous fumarate will be given in fasted state, fed state and 2 hours before dolutegravir administration.

  Eligibility

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

Inclusion Criteria:

  • Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and ECG.
  • Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
  • A female subject is eligible to participate if she is of: non-childbearing potential, or child-bearing potential and agrees to use one of the contraception methods for an appropriate period of time prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the follow-up visit.
  • Body weight >= 50 kilogram (kg) for males and >=45 kg for females and body mass index (BMI) within the range 18.5 to 31.0 kg/meter^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 QT interval corrected using Fredericia's formula (QTcF) <450 millisecond (msec)
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
  • The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
  • A positive test for 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.
  • Pregnant females as determined by positive serum or urine human chorionic gonadotropin test at screening or prior to dosing.
  • Lactating females.
  • 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 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 gram 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.
  • 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).
  • 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 GlaxoSmithKline (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.
  • Unwillingness or inability to follow the procedures outlined in the protocol
  • Subject is mentally or legally incapacitated.
  • If heparin is used during PK sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
  • Consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication.
  • Unwillingness or inability to follow the procedures in the protocol.
  • The subject's systolic blood pressure is outside the range of 90-140 millimeter mercury (mmHg, or diastolic blood pressure is outside the range of 45 to 90 mmHg or heart rate is outside the range of 50-100 beats per minutes (bpm) for female subjects or 45 to 100 bpm for male subjects. A single repeat is allowed for eligibility determination.
  • Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): Male subjects with Heart rate <45 and >110 bpm and female subjects with heart rate <50 and >100 bpm, PR <120 and >220 milliseconds (msec), QRS duration <70 and >120 msec, QTc (Bazett) >450 msec.
  • Evidence of previous myocardial infarction (does not include ST segment changes associated with repolarization).
  • Any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block [2nd degree or higher], Wolf Parkinson White [WPW] syndrome), non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular ectopic beats), and sinus pauses > 3 seconds.
  • Any significant arrhythmia which, in the opinion of the principal investigator and GSK medical monitor, will interfere with the safety for the individual subject.
  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: NCT01762995

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: NCT01762995     History of Changes
Other Study ID Numbers: 116898
Study First Received: December 19, 2012
Last Updated: April 18, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by ViiV Healthcare:
Dolutegravir, pharmacokinetics, calcium, iron, drug interaction, healthy volunteers

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
Calcium, Dietary
Calcium Carbonate
Ferrous fumarate
Bone Density Conservation Agents
Physiological Effects of Drugs
Pharmacologic Actions
Antacids
Molecular Mechanisms of Pharmacological Action
Trace Elements
Micronutrients
Growth Substances

ClinicalTrials.gov processed this record on July 26, 2014