Clinical trial NCT02738931: Relative Bio-availability Study of Dolutegravir and Lamivudine Fixed Dose Combinations
Official title: A Phase I, Relative Oral Bioavailability Study of Different Fixed Dose Combinations of Dolutegravir and Lamivudine in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Infection, Human Immunodeficiency Virus
Keywords: dolutegravir
lamivudine
Bioavailability
fixed dose combinations
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2016-04-14
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria

* 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 \[ECG\]).
* 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 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.

Exclusion Criteria

* 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)
* A positive hepatitis B surface antigen (HBsAg) or a 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 immunodeficiency 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.

Primary outcomes:
measure: DTG: Area under the concentration-time curve from time 0 extrapolated to infinity (AUC[0-inf])
timeFrame: 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
measure: DTG: maximum concentration observed (Cmax)
timeFrame: 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
measure: 3TC: AUC(0-inf)
timeFrame: 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
measure: 3TC: Cmax
timeFrame: 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:
measure: DTG: Area under the concentration-time curve from time 0 to the last measurable timepoint (AUC[0-t])
timeFrame: 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
measure: DTG: Drug concentration at 24 hours post-dose (C24)
timeFrame: 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
measure: DTG: Half-life (t1/2)
timeFrame: 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
measure: DTG: Absorption lag time (tlag)
timeFrame: 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
measure: DTG: Time to observed maximal drug concentration (tmax)
timeFrame: 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
measure: DTG: Apparent oral clearance (CL/F)
timeFrame: 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
measure: 3TC:AUC(0-t)
timeFrame: 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
measure: 3TC: C24
timeFrame: 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
measure: 3TC:t1/2
timeFrame: 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
measure: 3TC: tlag
timeFrame: 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
measure: 3TC: tmax
timeFrame: 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
measure: 3TC: CL/F
timeFrame: 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
measure: Change from baseline in temperature
timeFrame: Baseline and up to 9 weeks
measure: Change from baseline in systolic and diastolic blood pressure (BP)
timeFrame: Baseline and up to 9 weeks
measure: Change from baseline in pulse rate
timeFrame: Baseline and up to 9 weeks
measure: Number of subjects with adverse events
timeFrame: Up to 9 weeks
measure: Number of subjects with the Toxicity Grade and Change from baseline summary for the Indicated Hematology Parameters
timeFrame: Up to 9 weeks
measure: Number of subjects with the Toxicity Grade and Change from baseline summary for the Indicated Clinical Chemistry Parameters
timeFrame: Up to 9 weeks
measure: Number of subjects with urinalysis abnormalities
timeFrame: Up to 9 weeks
Other outcomes:
Locations:
city: Overland Park
country: United States
facility: GSK Investigational Site
state: Kansas
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: