Relative Bioavailability Study of a Fixed-dose Combination Dolutegravir/Abacavir/Lamivudine Dispersible Tablet

NCT02893488 | Completed Phase 1

• 1 other identifier: 200402
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, randomized, crossover study in healthy adult subjects with 5 treatment groups over 5 dosing periods. This study will evaluate pharmacokinetic parameters and relative bioavailability of a dispersible, fixed-dose combination (FDC) tablet of TRIUMEQ™ (\[abacavir, ABC\]/\[dolutegravir, DTG\]/\[lamivudine, 3TC\]) when dispersed and consumed under four different dosing conditions in comparison to an oral dose of TIVICAY™ (DTG) + EPZICOM™ (ABC/3TC) non-dispersible tablets administered in the fasted state. Approximately 20 subjects will be randomized, each to one of 5 treatment groups. The total duration of participation of a subject in this study will be approximately 10-11 weeks. It will include a screening visit within 30 days prior to the first dose of study drug, five treatment periods each with a single dose of study drug per treatment period and a follow up visit within 7 10 days after the last dose. There will also be a washout of at least 7 days between doses in each treatment period. TRIUMEQ, EPZICOM, and TIVICAY are trademarks of the GlaxoSmithKline group of companies.

Conditions

Infection, Human Immunodeficiency Virus

Keywords

dolutegravir; abacavir; relative bioavailability; palatability; GSK2619619; palatability questionnaire; lamivudine; pediatric; calcium; dispersible tablet

Outcome Measures

Primary Outcomes (2)

• Area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-infinity]) of DTG, ABC, and 3TC

  Blood samples will be collected at pre-dose and at specific post-dose time points for calculating AUC \[0- infinity\]

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 h post dose

• Maximum observed plasma concentration (Cmax) of DTG, ABC, and 3TC

  Blood samples will be collected at pre-dose and at specific post dose time points for calculating Cmax

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 h post dose

Secondary Outcomes (15)

• Area under the plasma concentration-time curve from time zero (pre-dose) to 24 hours (h) AUC(0-24) of DTG, ABC, and 3TC

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24h post dose in each of the 5 treatment periods.

• Area under the plasma concentration-time curve from time zero (pre-dose) to time of last measurable concentration (AUC[0 t]) of DTG, ABC, and 3TC

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 h post dose in each of the 5 treatment periods.

• Time to maximum plasma concentration (Tmax) of DTG, ABC, and 3TC

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 h post dose in each of the 5 treatment periods.

• Apparent clearance following oral dosing (CL/F) of DTG, ABC, and 3TC

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 h post dose in each of the 5 treatment periods.

• Concentration at 24 h after dose administration (C24) of DTG, ABC, and 3TC

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24h post dose in each of the 5 treatment periods.

Study Arms (5)

SEQUENCE ABCDE

EXPERIMENTAL

Participants will receive treatment A in period 1, treatment B in period 2, treatment C in period 3, treatment D in period 4 and treatment E in period 5 (one treatment per period). Where A=EPZICOM (ABC 600 milligrams (mg)/3TC 300 mg) plus four TIVICAY (DTG 10 mg) tablets with zero mineral content (ZMC) water. B=Four TRIUMEQ (ABC 150mg/DTG 10 mg/3TC 75 mg) tablets dispersed in 40 milliliter (mL) stock solution 1 and consumed immediately. C=Four TRIUMEQ tablets dispersed in 40 mL stock solution 1, held for 30 minutes(mins), re-dispersed, and then consumed. D=Four TRIUMEQ tablets dispersed in 40 mL stock solution 2 and consumed immediately. E=Four TRIUMEQ tablets dispersed in 40 mL stock solution 2, held for 30 mins, re-dispersed, and then consumed.

Drug: DTG/ABC/3TC FDC DISPERSIBLE TABLET; Drug: EPZICOM (ABC/3TC); Drug: TIVICAY (DTG)

SEQUENCE BCDEA

EXPERIMENTAL

Participants will receive treatment B in period 1, treatment C in period 2, treatment D in period 3, treatment E in period 4 and treatment A in period 5 (one treatment per period). Where A= EPZICOM (ABC 600 milligrams (mg)/3TC 300 mg) plus four TIVICAY (DTG 10 mg) tablets with ZMC water. B=Four TRIUMEQ (ABC 150mg/DTG 10 mg/3TC 75 mg) tablets dispersed in 40 mL stock solution 1 and consumed immediately. C=Four TRIUMEQ tablets dispersed in 40 mL stock solution 1, held for 30 mins, re-dispersed, and then consumed. D=Four TRIUMEQ tablets dispersed in 40 mL stock solution 2 and consumed immediately. E=Four TRIUMEQ tablets dispersed in 40 mL stock solution 2, held for 30 mins, re-dispersed, and then consumed.

Drug: DTG/ABC/3TC FDC DISPERSIBLE TABLET; Drug: EPZICOM (ABC/3TC); Drug: TIVICAY (DTG)

SEQUENCE CDEAB

EXPERIMENTAL

Participants will receive treatment C in period 1, treatment D in period 2, treatment E in period 3, treatment A in period 4 and treatment B in period 5 (one treatment per period). Where A=EPZICOM (ABC 600 milligrams (mg)/3TC 300 mg) plus four TIVICAY (DTG 10 mg) tablets with ZMC water. B=Four TRIUMEQ (ABC 150mg/DTG 10 mg/3TC 75 mg) tablets dispersed in 40 mL stock solution 1 and consumed immediately. C=Four TRIUMEQ tablets dispersed in 40 mL stock solution 1, held for 30 mins, re-dispersed, and then consumed. D=Four TRIUMEQ tablets dispersed in 40 mL stock solution 2 and consumed immediately. E=Four TRIUMEQ tablets dispersed in 40 mL stock solution 2, held for 30 mins, re-dispersed, and then consumed.

Drug: DTG/ABC/3TC FDC DISPERSIBLE TABLET; Drug: EPZICOM (ABC/3TC); Drug: TIVICAY (DTG)

SEQUENCE DEABC

EXPERIMENTAL

Participants will receive treatment D in period 1, treatment E in period 2, treatment A in period 3, treatment B in period 4 and treatment C in period 5 (one treatment per period). Where A=EPZICOM (ABC 600 milligrams (mg)/3TC 300 mg) plus four TIVICAY (DTG 10 mg) tablets with ZMC water. B=Four TRIUMEQ (ABC 150mg/DTG 10 mg/3TC 75 mg) tablets dispersed in 40 mL stock solution 1 and consumed immediately. C=Four TRIUMEQ tablets dispersed in 40 mL stock solution 1, held for 30 mins, re-dispersed, and then consumed. D=Four TRIUMEQ tablets dispersed in 40 mL stock solution 2 and consumed immediately. E=Four TRIUMEQ tablets dispersed in 40 mL stock solution 2, held for 30 mins, re-dispersed, and then consumed.

Drug: DTG/ABC/3TC FDC DISPERSIBLE TABLET; Drug: EPZICOM (ABC/3TC); Drug: TIVICAY (DTG)

SEQUENCE EABCD

EXPERIMENTAL

Participants will receive treatment E in period 1, treatment A in period 2, treatment B in period 3, treatment C in period 4 and treatment D in period 5 (one treatment per period). Where A=EPZICOM (ABC 600 milligrams (mg)/3TC 300 mg) plus four TIVICAY (DTG 10 mg) tablets with ZMC water. B=Four TRIUMEQ (ABC 150mg/DTG 10 mg/3TC 75 mg) tablets dispersed in 40 mL stock solution 1 and consumed immediately. C=Four TRIUMEQ tablets dispersed in 40 mL stock solution 1, held for 30 mins, re-dispersed, and then consumed. D=Four TRIUMEQ tablets dispersed in 40 mL stock solution 2 and consumed immediately. E=Four TRIUMEQ tablets dispersed in 40 mL stock solution 2, held for 30 mins, re-dispersed, and then consumed.

Drug: DTG/ABC/3TC FDC DISPERSIBLE TABLET; Drug: EPZICOM (ABC/3TC); Drug: TIVICAY (DTG)

Interventions

DTG/ABC/3TC FDC DISPERSIBLE TABLET DRUG

DTG/ABC/3TC FDC dispersible tablet

SEQUENCE ABCDE; SEQUENCE BCDEA; SEQUENCE CDEAB; SEQUENCE DEABC; SEQUENCE EABCD

EPZICOM (ABC/3TC) DRUG

EPZICOM will be available as orange, film coated, modified capsule shaped tablets, debossed with "GS FC2" on one side.

SEQUENCE ABCDE; SEQUENCE BCDEA; SEQUENCE CDEAB; SEQUENCE DEABC; SEQUENCE EABCD

TIVICAY (DTG) DRUG

TIVICAY will be available as white, round, biconvex tablets

SEQUENCE ABCDE; SEQUENCE BCDEA; SEQUENCE CDEAB; SEQUENCE DEABC; SEQUENCE EABCD

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female aged between 18 and 65 years of age inclusive, at the time of signing the informed consent.

You may not qualify if:

• Body weight \>=50 kilogram (kg) for males and \>=45 kg for females and body mass index (BMI) within the range 18.5-31.0 kg/m\^2 (inclusive).
• Male or female
• Females of non-reproductive potential defined as pre-menopausal females with documented tubal ligation, documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, hysterectomy, documented bilateral oophorectomy, postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone \[FSH\] and estradiol levels consistent with menopause). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
• Female of reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and until 2 weeks after dosing with study medication and completion of the follow-up visit. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
• Documentation that the subject is negative for the human leukocyte antigen (HLA)-B\*5701 allele.
• ALT and bilirubin \>1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• QT interval corrected for heart rate according to Fridericia's formula (QTcF) \>450 milliseconds (msec). The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial.
• Unable to refrain from the use of prescription (i.e., dofetilide) 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 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.
• Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 1 month prior to screening.
• 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 Medical Monitor, contraindicates their participation.
• Creatinine clearance (CrCL) \<60 mL/min
• Presence of HBsAg, positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.

Sponsors & Collaborators

• ViiV Healthcare: lead

Study Sites (1)

GSK Investigational Site

Overland Park, Kansas, 66211, United States

Location

Related Publications (1)

• Singh RP, Shaik JSB, Skoura N, Joshi S, Shreeves T, Casillas L, Buchanan AM. Effects of Low- and High-Mineral Content Water on the Relative Bioavailability of a Coformulated Abacavir/Dolutegravir/Lamivudine Dispersible Tablet in Healthy Adults. J Acquir Immune Defic Syndr. 2018 Dec 15;79(5):631-638. doi: 10.1097/QAI.0000000000001859.

  PMID: 30239425 DERIVED

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome

Interventions

abacavir, lamivudine drug combination; dolutegravir

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 2, 2016
• First Posted: September 8, 2016
• Study Start: September 1, 2016
• Primary Completion: November 1, 2016
• Study Completion: November 25, 2016
• Last Updated: August 4, 2017

Record last verified: 2017-08

Locations

US (1)