Bioequivalence Study of a Fixed-dose Combination (FDC) of Dolutegravir (DTG) and Rilpivirine (RPV)

NCT02741557 | Completed Phase 1

• 1 other identifier: 201676
• Study Type: interventional
• Target: 118
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of the study is to evaluate the bioequivalence between Fixed-dose Combination (FDC) tablet formulation of Dolutegravir (DTG) 50 milligrams (mg) and Rilpivirine (RPV) 25 mg versus co-administration of the separate tablet formulations of DTG 50 mg plus RPV 25 mg, in the fed state. This pivotal bioequivalence study, is to serve as a pharmacokinetic (PK) bridge to the ongoing Phase 3 trials with the separate agents. This study will be conducted under fed conditions to appropriately mimic the conditions in the Phase 3 trials. This is a single-center, randomized, open-label, 2-period, single-dose, crossover study. A minimum of 86 healthy adult subjects will be randomized such that a minimum of approximately 82 evaluable subjects complete the study. The total duration of participation of a subject in this study will be approximately 8 weeks which includes a screening visit within 30 days prior to the first dose of study drug, two treatment periods each with a single dose of study drug and a follow-up visit within 12-17 days after the last dose of study drug. There will be a washout of at least 21 days between each dose of study drug. A blinded (for treatment) review of DTG and RPV plasma concentration data for approximately the first 40 subjects will be conducted. If the within-subject coefficients of variation (CVw%) for either DTG or RPV maximal drug concentration (Cmax) values are \>=31%; a sample size re-estimation will be employed and additional subjects (beyond the 86 planned) will be randomized for treatment in the study. Following the re-estimation, it is possible that up to approximately 154 healthy adult subjects (68 new subjects in addition to the planned 86 subjects above) will be randomized such that a maximum of approximately 146 evaluable subjects could complete the study.

Conditions

Infection, Human Immunodeficiency Virus; HIV Infections

Keywords

Fixed-dose Combination (FDC); Bioequivalence; Dolutegravir; Rilpivirine

Outcome Measures

Primary Outcomes (3)

• Area under the concentration-time curve (AUC) from time 0 extrapolated to infinity (AUC[0-inf]) of DTG and RPV in plasma

  Blood samples will be collected at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose during the 2 treatment periods.

• AUC from time 0 to the last measurable timepoint (AUC[0-t]) of DTG and RPV in plasma

  Blood samples will be collected at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose during the 2 treatment periods.

• Maximal drug concentration (Cmax) of DTG and RPV in plasma

  Blood samples will be collected at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose during the 2 treatment periods.

Secondary Outcomes (17)

• Absorption lag time (tlag) of DTG and RPV in plasma

  Blood samples will be collected at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose during the 2 treatment periods.

• Time to observed maximal drug concentration (tmax) of DTG and RPV in plasma

  Blood samples will be collected at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose during the 2 treatment periods.

• Time of last quantifiable concentration (t) of DTG and RPV in plasma

  Blood samples will be collected at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose during the 2 treatment periods.

• Half-life (t1/2) of DTG and RPV in plasma

  Blood samples will be collected at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose during the 2 treatment periods.

• Apparent terminal elimination phase rate constant (lambda z) of DTG and RPV in plasma

  Blood samples will be collected at pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose during the 2 treatment periods.

Study Arms (2)

DTG/RPV FDC-DTG plus RPV

EXPERIMENTAL

Subjects will receive a single oral dose of DTG/RPV 50 mg/25 mg FDC tablet in Period 1 under fed state. After a washout period of at least 21 days, subjects will receive a single oral dose of separate tablet formulations of DTG 50 mg and RPV 25 mg together in Period 2 under fed state.

Drug: DTG; Drug: RPV; Drug: DTG/RPV FDC

DTG plus RPV-DTG/RPV FDC

EXPERIMENTAL

Subjects will receive a single oral dose of separate tablet formulations of DTG 50 mg and RPV 25 mg together in Period 1 under fed state. After a washout period of at least 21 days, subjects will receive a single oral dose of DTG/RPV 50 mg/25 mg FDC tablet in Period 2 under fed state.

Drug: DTG; Drug: RPV; Drug: DTG/RPV FDC

Interventions

DTG DRUG

DTG is provided as a white, film-coated, round tablet containing DTG 50 mg, debossed with SV 572 on one side and 50 on the other side. Subjects will receive a single oral dose of DTG 50 mg tablet with 240 mL of water.

DTG plus RPV-DTG/RPV FDC; DTG/RPV FDC-DTG plus RPV

RPV DRUG

RPV is provided as a white to off-white, film-coated, round, biconvex tablet containing RPV 25 mg, debossed with TMC on one side and 25 on the other side. Subjects will receive a single oral dose of RPV 25 mg tablet with 240 mL of water.

DTG plus RPV-DTG/RPV FDC; DTG/RPV FDC-DTG plus RPV

DTG/RPV FDC DRUG

DTG/RPV FDC is provided as a pink, film coated, oval biconvex tablet containing FDC of DTG 50 mg and RPV 25 mg, debossed with SV J3T on one face. Subjects will receive a single oral dose of DTG/RPV 50 mg/25 mg FDC tablet with 240 mL of water.

DTG plus RPV-DTG/RPV FDC; DTG/RPV FDC-DTG plus RPV

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age: Between 18 and 55 years of age inclusive, at the time of signing the informed consent.
• Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac evaluation (history, ECG).

You may not qualify if:

• Body weight \>=50 kilograms (kg) (110 pounds \[lbs\]) for men and \>=45 kg (99 lbs) for women and body mass index (BMI) within the range 18.5-31.0 kg/square meter (m\^2) (inclusive)
• Male or Female.
• Females: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative \[serum or urine according to site standard procedure\] human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies:
• Non-reproductive potential defined as: Pre-menopausal females with one of the following: 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. 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 enrollment.
• 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 (at least five terminal half-lives OR until any continuing pharmacologic effect has ended, whichever is longer) after the last dose of study medication and completion of the follow-up visit.
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.
• ALT and bilirubin \>1.5xupper limit of normal (ULN) (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).
• 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 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.
• Positive results for drugs of abuse.
• Cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 30 days 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.
• Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
• A positive pre-study drug/alcohol screen.

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

GSK Investigational Site

Overland Park, Kansas, 66211, United States

Location

Related Publications (1)

• Mehta R, Wolstenholme A, Di Lullo K, Fu C, Joshi S, Crauwels H, Givens N, Vanveggel S, Wynne B, Adkison K. Bioequivalence of a Fixed-Dose Combination Tablet of the Complete Two-Drug Regimen of Dolutegravir and Rilpivirine for Treatment of HIV-1 Infection. Antimicrob Agents Chemother. 2018 Aug 27;62(9):e00748-18. doi: 10.1128/AAC.00748-18. Print 2018 Sep.

  PMID: 29987139 BACKGROUND

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome; HIV Infections

Condition Hierarchy (Ancestors)

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: April 14, 2016
• First Posted: April 18, 2016
• Study Start: May 11, 2016
• Primary Completion: October 24, 2016
• Study Completion: October 24, 2016
• Last Updated: July 15, 2019

Record last verified: 2019-06

Locations

US (1)