Infection, Human Immunodeficiency Virus, HIV Infections
Conditions
Keywords
Fixed-dose Combination (FDC), Bioequivalence, Dolutegravir, Rilpivirine
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.
Interventions
DRUGDTG
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.
DRUGRPV
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.
DRUGDTG/RPV FDC
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.
Sponsors
GlaxoSmithKline
ViiV Healthcare
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* 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). * 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 in consultation with the Medical Monitor if required agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. | — |
| Percentage of AUC(0-inf) resulting from extrapolation (%AUCex) 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 24 hours (AUC[0-24]) 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 oral clearance (CL/F) 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 oral volume of distribution (Vz/F) 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. | — |
| Last quantifiable concentration (Ct) 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. | — |
| Change from baseline in 12-lead electrocardiogram (ECG) | Baseline and up to 8 weeks | — |
| Change from baseline in blood pressure (BP) | Baseline and up to 8 weeks | — |
| Change from baseline in heart rate (HR) | Baseline and up to 8 weeks | — |
| Number of subjects with any adverse events (AEs) and any serious adverse events (SAEs) | Up to 4 weeks | An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is associated with liver injury and impaired liver function. |
| Number of subjects with Grade 3/4 hematology parameters | Up to 8 weeks | — |
| Number of subjects with Grade 3/4 clinical chemistry parameters | Up to 8 weeks | — |
| Concentration at 24 hours post-dose (C24) 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. | — |
| 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. | — |
Countries
United States
Outcome results
None listed