Clinical trial NCT03095638: Bioavailability Study of 10 Milligram (mg) and 5 mg Tablets Versus Conventional Tablets of Dolutegravir
Official title: A 2-Part, Phase I, Single Dose, Crossover Relative Bioavailability Study of Both TIVICAY 10 mg Conventional Tablets and 5 mg Dispersible Tablets Compared to Conventional TIVICAY Tablets in Fasted Healthy Adult Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Keywords: Dispersible tablets
Bioavailability
Dolutegravir
Healthy
Conventional tablets
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2017-03-29
Enrollment: 38
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: 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.


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 and 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 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) 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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Area Under the Plasma Concentration-time Curve From Time of Dose Extrapolated to Infinite Time (AUC[0-infinity]) of DTG for Part 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1
measure: Area Under the Plasma Concentration-time Curve From Time of Dose to Last Measurable Concentration AUC [0-t] of DTG for Part 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1
measure: Maximum Observed Concentration (Cmax) of DTG for Part 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1
measure: AUC (0-infinity) of DTG for Part 2
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2
Secondary outcomes:
measure: AUC (0-t) of DTG for Part 2
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2
measure: Cmax of DTG for Part 2
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2
measure: Plasma DTG Lag Time Before Observation of Drug Concentrations (Tlag) for Part 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1
measure: Time to First Occurrence of Cmax (Tmax) of DTG for Part 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1
measure: Terminal Phase Half-life (t1/2) of DTG for Part 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1
measure: Terminal-phase Rate Constant (Lambda z) of DTG for Part 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1
measure: Percentage of AUC (0-infinity) Obtained by Extrapolation (%AUCex) of DTG for Part 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1
measure: Area Under the Concentration-time Curve Over Time Zero (Pre-dose) to 24 Hours After Dose Administration (AUC[0-24]) of DTG for Part 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1
measure: Apparent Oral Clearance (CL/F) of DTG for Part 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1
measure: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of DTG for Part 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1
measure: Last Observed Quantifiable Concentration (Ct) of DTG for Part 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1
measure: Observed Concentration at 24 Hours After Dose Administration (C24) of DTG for Part 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 1
measure: Plasma DTG Tlag for Part 2
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2
measure: Tmax of DTG for Part 2
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2
measure: t1/2 of DTG for Part 2
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2
measure: Lambda Z of DTG for Part 2
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2
measure: %AUCex of DTG for Part 2
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2
measure: AUC (0-24) of DTG for Part 2
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2
measure: DTG CL/F for Part 2
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2
measure: Vz/F of DTG for Part 2
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2
measure: Ct of DTG for Part 2
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2
measure: C24 of DTG for Part 2
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours post-dose in Part 2
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) for Part 1
timeFrame: Up to 25 days in Part 1
measure: Number of Participants With Adverse Events AEs and Serious Adverse Events SAEs for Part 2
timeFrame: Up to 36 days in Part 2
measure: Change From Baseline in Clinical Laboratory Parameters Serum Glucose, Serum Calcium, Serum Potassium, Serum Sodium, Serum Urea for Part 1
timeFrame: Baseline and up to 25 days in Part 1
measure: Change From Baseline in Clinical Chemistry Parameters Serum Alanine Amino Transferase (ALT), Serum Alkaline Phosphatase, Serum Aspartate Amino Transferase (AST), Serum Creatine Kinase for Part 1
timeFrame: Baseline and up to 25 days in Part 1
measure: Change From Baseline in Clinical Chemistry Parameters Serum Albumin and Serum Protein for Part 1
timeFrame: Baseline and up to 25 days in Part 1
measure: Change From Baseline in Clinical Chemistry Parameters Serum Bilirubin, Serum Creatinine and Serum Direct Bilirubin for Part 1
timeFrame: Baseline and up to 25 days in Part 1
measure: Change From Baseline in Clinical Chemistry Parameters Serum Glucose, Serum Calcium, Serum Potassium, Serum Sodium, Serum Urea for Part 2
timeFrame: Baseline and up to 36 days in Part 2
measure: Change From Baseline in Clinical Chemistry Parameters Serum ALT, Serum Alkaline Phosphate, Serum AST, Serum Creatine Kinase for Part 2
timeFrame: Baseline and up to 36 days in Part 2
measure: Change From Baseline in Clinical Chemistry Parameters Serum Albumin and Serum Protein for Part 2
timeFrame: Baseline and up to 36 days in Part 2
measure: Change From Baseline in Clinical Chemistry Parameters Serum Bilirubin, Serum Creatine and Serum Direct Bilirubin for Part 2
timeFrame: Baseline and up to 36 days in Part 2
measure: Change From Baseline in Hematology Parameter Blood Erythrocyte Mean Corpuscular Hemoglobin (MCH) for Part 1
timeFrame: Baseline and up to 25 days in Part 1
measure: Change From Baseline in Hematology Parameter Blood Erythrocyte Mean Corpuscular Volume (MCV) for Part 1
timeFrame: Baseline and up to 25 days in Part 1
measure: Change From Baseline in Hematology Parameters Blood Basophils, Blood Eosinophils, Blood Leukocytes, Blood Lymphocytes, Blood Monocytes, Blood Neutrophils, Blood Platelets for Part 1
timeFrame: Baseline and up to 25 days in Part 1
measure: Change From Baseline in Hematology Parameter Blood Hemoglobin for Part 1
timeFrame: Baseline and up to 25 days in Part 1
measure: Change From Baseline in Hematology Parameter Blood Hematocrit for Part 1
timeFrame: Baseline and up to 25 days in Part 1
measure: Change From Baseline in Hematology Parameter Blood Erythrocytes for Part 1
timeFrame: Baseline and up to 25 days in Part 1
measure: Change From Baseline in Hematology Parameter Blood Erythrocyte MCH for Part 2
timeFrame: Baseline and up to 36 days in Part 2
measure: Change From Baseline in Hematology Parameter Blood Erythrocyte MCV for Part 2
timeFrame: Baseline and up to 36 days in Part 2
measure: Change From Baseline in Hematology Parameters Blood Basophils, Blood Eosinophils,, Blood Leukocytes, Blood Lymphocytes, Blood Monocytes, Blood Neutrophils, Blood Platelets for Part 2
timeFrame: Baseline and up to 36 days in Part 2
measure: Change From Baseline in Hematology Parameter Blood Hemoglobin for Part 2
timeFrame: Baseline and up to 36 days in Part 2
measure: Change From Baseline in Hematology Parameter Blood Hematocrit for Part 2
timeFrame: Baseline and up to 36 days in Part 2
measure: Change From Baseline in Hematology Parameter Blood Erythrocytes for Part 2
timeFrame: Baseline and up to 36 days in Part 2
measure: Number of Participants With Abnormal Values on Urinalysis by Dipstick Method for Part 1
timeFrame: Up to 25 days in Part 1
measure: Urine Potential of Hydrogen (pH) Analysis by Dipstick Method for Part 1
timeFrame: Up to 25 days in Part 1
measure: Urine Specific Gravity Analysis by Dipstick Method for Part 1
timeFrame: Up to 25 days in Part 1
measure: Number of Participants With Abnormal Values on Urinalysis by Dipstick Method for Part 2
timeFrame: Up to 36 days in Part 2
measure: Urine pH Analysis by Dipstick Method for Part 2
timeFrame: Up to 36 days in Part 2
measure: Urine Specific Gravity Analysis by Dipstick Method for Part 2
timeFrame: Up to 36 days in Part 2
measure: Number of Participants With Chemistry Toxicities of Grade 2 as Defined by Division of Acquired Immunodeficiency Syndrome (DAIDS) for Part 1
timeFrame: Up to 25 days in Part 1
measure: Number of Participants With Urinalysis Toxicities of Grade 2 as Defined by DAIDS for Part 1
timeFrame: Up to 25 days in Part 1
Other outcomes:
Locations:
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.