Bioavailability Study of 10 Milligram (mg) and 5 mg Tablets Versus Conventional Tablets of Dolutegravir

NCT ID: NCT03095638

Last Updated: 2019-07-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 38 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-05-03
• Study Completion Date: 2017-06-23

Brief Summary

The aim of this cross-over study is to compare the relative bioavailability and pharmacokinetic parameters of both 10 mg conventional tablets and 5 mg dispersible tablets of dolutegravir (DTG) with that of 25 mg or 50 mg conventional DTG tablets. The study will be carried out in 2 parts. Part 1 of the study will be open-label, 2 period designs with a wash out period of at least 7 days between the dosing periods. Subjects will be randomized to receive either single dose of five 10 mg DTG tablets or one 50 mg DTG tablet in a crossover manner in the fasting state. Part 2 of the study will be a 3 period crossover design with a wash out period of at least 7 days between the dosing periods. Subjects will be randomized to receive either single dose of five 5 mg DTG tablets (administered as dispersed with water or directly to mouth) or one 25 mg DTG tablet in a crossover manner in the fasting state. Subjects will have a follow-up visit 7-10 days post last dose of study treatment. Approximately 14 healthy subjects will participate in Part 1 and approximately 24 healthy subjects will participate in Part 2 of the study. The total duration of Part 1 will be approximately 7 to 8 weeks and that of part 2 will be approximately 8 to 9 weeks.

TIVICAY® is a trademark of the GlaxoSmithKline group of companies.

Conditions

HIV Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment sequence A/B: Part 1

Eligible subjects will be randomized in sequence A/B in Part 1 and will receive A: conventional 10 mg DTG tablet (5 tablets) in Period 1 and B: conventional 50 mg DTG tablet in Period 2, administered directly to mouth.

Group Type: EXPERIMENTAL

Conventional dolutegravir 10 mg tablet

Intervention Type: DRUG

Single dose of five 10 mg DTG tablets will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 1. DTG will be a white, round shaped, biconvex tablet.

Conventional dolutegravir 50 mg tablet

Intervention Type: DRUG

Single dose of one 50 mg tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 1. DTG will be a white, round shaped, biconvex tablet.

Treatment sequence B/A: Part 1

Eligible subjects will be randomized in sequence B/A in Part 1 and will receive B: conventional 50 mg DTG tablet in Period 1 and A: conventional 10 mg DTG tablet (5 tablets) in Period 2, administered directly to mouth.

Group Type: EXPERIMENTAL

Conventional dolutegravir 10 mg tablet

Intervention Type: DRUG

Single dose of five 10 mg DTG tablets will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 1. DTG will be a white, round shaped, biconvex tablet.

Conventional dolutegravir 50 mg tablet

Intervention Type: DRUG

Single dose of one 50 mg tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 1. DTG will be a white, round shaped, biconvex tablet.

Treatment sequence C/D/E: Part 2

Eligible subjects will be randomized in sequence C/D/E in Part 2 and will receive C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 1, D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 2 and E: conventional 25 mg DTG tablet administered as direct to mouth in Period 3.

Group Type: EXPERIMENTAL

Dispersible dolutegravir 5 mg tablet

Intervention Type: DRUG

Single dose of five 5 mg DTG tablets will be administered as dispersed in water or direct to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Conventional dolutegravir 25 mg tablet

Intervention Type: DRUG

Single dose of one 25 mg DTG tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Treatment sequence D/E/C: Part 2

Eligible subjects will be randomized in sequence D/E/C in Part 2 and will receive D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 1, E: conventional 25 mg DTG tablet administered as direct to mouth in Period 2 and C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 3.

Group Type: EXPERIMENTAL

Dispersible dolutegravir 5 mg tablet

Intervention Type: DRUG

Single dose of five 5 mg DTG tablets will be administered as dispersed in water or direct to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Conventional dolutegravir 25 mg tablet

Intervention Type: DRUG

Single dose of one 25 mg DTG tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Treatment sequence E/C/D: Part 2

Eligible subjects will be randomized in sequence E/C/D in Part 2 and will receive E: conventional 25 mg DTG tablet administered as direct to mouth in Period 1, C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 2 and D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 3.

Group Type: EXPERIMENTAL

Dispersible dolutegravir 5 mg tablet

Intervention Type: DRUG

Single dose of five 5 mg DTG tablets will be administered as dispersed in water or direct to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Conventional dolutegravir 25 mg tablet

Intervention Type: DRUG

Single dose of one 25 mg DTG tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Treatment sequence C/E/D: Part 2

Eligible subjects will be randomized in sequence C/E/D in Part 2 and will receive C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 1, E: conventional 25 mg DTG tablet administered as direct to mouth in Period 2 and D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 3.

Group Type: EXPERIMENTAL

Dispersible dolutegravir 5 mg tablet

Intervention Type: DRUG

Single dose of five 5 mg DTG tablets will be administered as dispersed in water or direct to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Conventional dolutegravir 25 mg tablet

Intervention Type: DRUG

Single dose of one 25 mg DTG tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Treatment sequence D/C/E: Part 2

Eligible subjects will be randomized in sequence D/C/E in Part 2 and will receive D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 1, C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 2 and E: conventional 25 mg DTG tablet administered as direct to mouth in Period 3.

Group Type: EXPERIMENTAL

Dispersible dolutegravir 5 mg tablet

Intervention Type: DRUG

Single dose of five 5 mg DTG tablets will be administered as dispersed in water or direct to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Conventional dolutegravir 25 mg tablet

Intervention Type: DRUG

Single dose of one 25 mg DTG tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Treatment sequence E/D/C: Part 2

Eligible subjects will be randomized in sequence E/D/C in Part 2 and will receive E: conventional 25 mg DTG tablet administered as direct to mouth in Period 1, D: 5 mg dispersible DTG tablet (5 tablets) administered as direct to mouth in Period 2 and C: 5 mg dispersible DTG tablet (5 tablets) administered as a dispersion and immediately taken in Period 3.

Group Type: EXPERIMENTAL

Dispersible dolutegravir 5 mg tablet

Intervention Type: DRUG

Single dose of five 5 mg DTG tablets will be administered as dispersed in water or direct to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Conventional dolutegravir 25 mg tablet

Intervention Type: DRUG

Single dose of one 25 mg DTG tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Interventions

Conventional dolutegravir 10 mg tablet

Single dose of five 10 mg DTG tablets will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 1. DTG will be a white, round shaped, biconvex tablet.

Intervention Type: DRUG

Conventional dolutegravir 50 mg tablet

Single dose of one 50 mg tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 1. DTG will be a white, round shaped, biconvex tablet.

Intervention Type: DRUG

Dispersible dolutegravir 5 mg tablet

Single dose of five 5 mg DTG tablets will be administered as dispersed in water or direct to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Intervention Type: DRUG

Conventional dolutegravir 25 mg tablet

Single dose of one 25 mg DTG tablet will be administered directly to mouth with 240 mL of water in the morning to randomized subjects in fasting state present in Part 2. DTG will be a white, round shaped, biconvex tablet.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Between 18 and 65 years of age inclusive, at the time of signing the informed consent.

Exclusion Criteria

• 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 per meter square (kg/m^2) (inclusive).
• Male or female. 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 [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. 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.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions.

• Alanine amino transferase (ALT) and bilirubin >1.5x Upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• QT correction using Fridericia Formula (QTcF) >450 Milliseconds (msec).
• Unable to refrain from the use of prescription [that is (i.e. 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 ViiV 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 (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.
• 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) <90 mL/minute.
• A positive hepatitis B surface antigen (HBsAg) or a positive hepatitis B core antibody with a negative hepatitis B surface antibody, 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.
• A positive test for Human Immuno-deficiency Virus (HIV) antibody.
• Where participation in the study would result in donation of blood or blood product in excess of 500 mL within 56 days.
• 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).
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: collaborator

ViiV Healthcare

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

ViiV Healthcare

Locations

GSK Investigational Site

Austin, Texas, United States

Countries

United States

References

Singh RP, Adkison KK, Baker M, Parasrampuria R, Wolstenholme A, Davies M, Sewell N, Brothers C, Buchanan AM. Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children. Pediatr Infect Dis J. 2022 Mar 1;41(3):230-237. doi: 10.1097/INF.0000000000003366.

Reference Type: DERIVED

PMID: 34817414 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

205893

Identifier Type: -

Identifier Source: org_study_id