Relative Bio-availability Study of Dolutegravir and Lamivudine Fixed Dose Combinations

NCT02738931 | Completed Phase 1

• 1 other identifier: 204993
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Dolutegravir (DTG) and lamivudine (3TC) are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Fixed dose combination (FDC) tablets of existing approved drugs are preferred by many patients and offer the potential for increased patient adherence and consequently a reduced likelihood of virological failure and viral resistance. The purpose of the present study is to evaluate the relative bioavailability of two experimental FDC tablets of DTG and 3TC relative to co-administration of the single entity products in healthy adult subjects. This study will be conducted as a randomized, open label three-way, crossover design with 6 treatment sequences in approximately 30 subjects. Each subject will have a screening visit within 30 days prior to the first dose of study drug, three treatment periods each with a single dose of study drug and a follow-up visit within 7-14 days after the last dose of study drug. There will be at least 7 days washout between dosing periods. The total duration of participation of a subject in this study will be approximately 9 weeks.

Conditions

Infection, Human Immunodeficiency Virus

Keywords

dolutegravir; lamivudine; Bioavailability; fixed dose combinations

Outcome Measures

Primary Outcomes (4)

• DTG: Area under the concentration-time curve from time 0 extrapolated to infinity (AUC[0-inf])

  Serial blood samples for pharmacokinetic (PK) analysis of DTG will be collected. From the plasma concentration-time data, the PK parameters will be determined.

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose

• DTG: maximum concentration observed (Cmax)

  Serial blood samples for PK analysis of DTG will be collected. From the plasma concentration-time data, the PK parameters will be determined.

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose

• 3TC: AUC(0-inf)

  Serial blood samples for PK analysis of 3TC will be collected. From the plasma concentration-time data, the PK parameters will be determined.

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose

• 3TC: Cmax

  Serial blood samples for PK analysis of 3TC will be collected. From the plasma concentration-time data, the PK parameters will be determined.

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose

Secondary Outcomes (19)

• DTG: Area under the concentration-time curve from time 0 to the last measurable timepoint (AUC[0-t])

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose

• DTG: Drug concentration at 24 hours post-dose (C24)

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose

• DTG: Half-life (t1/2)

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose

• DTG: Absorption lag time (tlag)

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose

• DTG: Time to observed maximal drug concentration (tmax)

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 9, 12, 16, 24, and 48 hours post-dose

Study Arms (6)

Treatment Sequence ABC

EXPERIMENTAL

Subject will receive reference treatment DTG 50mg and 3TC 300mg administered as single entity tablets (treatment A) in period 1, experimental Dolutegravir/Lamivudine 50 mg/300 mg FDC tablet (Product Code AA, treatment B) in period 2 and experimental Dolutegravir/Lamivudine 50 mg/300 mg FDC tablet (Product Code AB, treatment C) in period 3 in a fasted state. There will be at least 7 days washout between dosing periods.

Drug: Dolutegravir 50 mg tablet; Drug: Lamivudine 300 mg tablet; Drug: Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AA); Drug: Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AB)

Treatment Sequence BCA

EXPERIMENTAL

Subject will receive experimental Dolutegravir/Lamivudine 50 mg/300 mg FDC tablet (Product Code AA, treatment B) in period 1 and experimental Dolutegravir/Lamivudine 50 mg/300 mg FDC tablet (Product Code AB, treatment C) in period 2 and reference treatment DTG 50mg and 3TC 300mg administered as single entity tablets (treatment A) in period 3 in a fasted state. There will be at least 7 days washout between dosing periods.

Drug: Dolutegravir 50 mg tablet; Drug: Lamivudine 300 mg tablet; Drug: Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AA); Drug: Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AB)

Treatment Sequence CAB

EXPERIMENTAL

Subject will receive experimental Dolutegravir/Lamivudine 50 mg/300 mg FDC tablets (Product Code AB, treatment C) in period 1 and reference treatment DTG 50mg and 3TC 300mg administered as single entity tablets (treatment A) in period 2 and experimental Dolutegravir/Lamivudine 50 mg/300 mg FDC tablets (Product Code AA, treatment B) in period 3 in a fasted state. There will be at least 7 days washout between dosing periods.

Drug: Dolutegravir 50 mg tablet; Drug: Lamivudine 300 mg tablet; Drug: Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AA); Drug: Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AB)

Treatment Sequence ACB

EXPERIMENTAL

Subject will receive reference treatment DTG 50mg and 3TC 300mg administered as single entity tablets (treatment A) in period 1, experimental Dolutegravir/Lamivudine 50 mg/300 mg FDC tablets (Product Code AB, treatment C) in period 2 and experimental Dolutegravir/Lamivudine 50 mg/300 mg FDC tablets (Product Code AA, treatment B) in period 3 in a fasted state. There will be at least 7 days washout between dosing periods.

Drug: Dolutegravir 50 mg tablet; Drug: Lamivudine 300 mg tablet; Drug: Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AA); Drug: Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AB)

Treatment Sequence BAC

EXPERIMENTAL

Subject will receive experimental Dolutegravir/Lamivudine 50 mg/300 mg FDC tablets (Product Code AA, treatment B) in period 1 and reference treatment DTG 50mg and 3TC 300mg administered as single entity tablets (treatment A) in period 2 and experimental Dolutegravir/Lamivudine 50 mg/300 mg FDC tablets (Product Code AB, treatment C) in period 3 in a fasted state. There will be at least 7 days washout between dosing periods.

Drug: Dolutegravir 50 mg tablet; Drug: Lamivudine 300 mg tablet; Drug: Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AA); Drug: Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AB)

Treatment Sequence CBA

EXPERIMENTAL

Subject will receive experimental Dolutegravir/Lamivudine 50 mg/300 mg FDC tablets (Product Code AB, treatment C) in period 1 and experimental Dolutegravir/Lamivudine 50 mg/300 mg FDC tablets (Product Code AA, treatment B) in period 2 and reference treatment DTG 50mg and 3TC 300mg administered as single entity tablets (treatment A) in period 3 in a fasted state. There will be at least 7 days washout between dosing periods.

Drug: Dolutegravir 50 mg tablet; Drug: Lamivudine 300 mg tablet; Drug: Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AA); Drug: Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AB)

Interventions

Dolutegravir 50 mg tablet DRUG

A white, film-coated, round tablet debossed with SV 572 on one side and 50 on the other side. Single dose of one tablet will be administered with 240 mL of water.

Treatment Sequence ABC; Treatment Sequence ACB; Treatment Sequence BAC; Treatment Sequence BCA; Treatment Sequence CAB; Treatment Sequence CBA

Lamivudine 300 mg tablet DRUG

Gray, diamond-shaped tablet, engraved "GX EJ7" on one side and plain on the other side. Single dose of one tablet will be administered with 240 mL of water.

Treatment Sequence ABC; Treatment Sequence ACB; Treatment Sequence BAC; Treatment Sequence BCA; Treatment Sequence CAB; Treatment Sequence CBA

Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AA) DRUG

Immediate release oval tablet embossed 'gsk' on one face with white film coat. Single dose of one tablet will be administered with 240 mL of water.

Treatment Sequence ABC; Treatment Sequence ACB; Treatment Sequence BAC; Treatment Sequence BCA; Treatment Sequence CAB; Treatment Sequence CBA

Dolutegravir/Lamivudine 50 mg/300 mg Tablet (Product Code AB) DRUG

Immediate release oval tablet embossed 'gsk' on one face with white film coat. Single dose of one tablet will be administered with 240 mL of water.

Treatment Sequence ABC; Treatment Sequence ACB; Treatment Sequence BAC; Treatment Sequence BCA; Treatment Sequence CAB; Treatment Sequence CBA

Eligibility Criteria

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

You may qualify if:

• Between 18 and 65 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, electrocardiogram \[ECG\]).

You may not qualify if:

• Body weight \>= 50 kilogram (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/meter square (m\^2) (inclusive)
• Male or Female
• Female subject of non-reproductive potential: is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine 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; in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels). 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.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in protocol.
• Alanine transaminase (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).
• QT interval corrected for heart rate according to Fridericia's formula (QTcF) \> 450 millisecond (msec)
• 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 ViiV/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 gram (g) of alcohol: 12 ounces (360 milliliter \[mL\]) 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/minute (min)

Sponsors & Collaborators

• GlaxoSmithKline: collaborator
• ViiV Healthcare: lead

Study Sites (1)

GSK Investigational Site

Overland Park, Kansas, 66211, United States

Location

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome

Interventions

dolutegravir; Tablets; Lamivudine

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

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations; Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dideoxynucleosides

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 11, 2016
• First Posted: April 14, 2016
• Study Start: May 1, 2016
• Primary Completion: June 1, 2016
• Study Completion: June 1, 2016
• Last Updated: January 18, 2017

Record last verified: 2017-01

Locations

US (1)