Bioequivalence Study of Fixed Dose Versus Single Entities of Dolutegravir and Lamivudine
Condition: Infection, Human Immunodeficiency Virus
MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections
Intervention: Dolutegravir; Lamivudine; Dolutegravir + Lamivudine FDC Formulation 1; Dolutegravir + Lamivudine FDC Formulation 2
Intervention description: Single dose of DTG 50 mg tablet along with 3TC (EPIVIR) tablet will be given to randomized subjects in parts 1 and 2 with 240 mL of room temperature water. DTG will be a white, film coated, round tablet engraved with SV 572 on one side and 50 on the other side.; Single dose 3TC (commercial name: EPIVIR) 300 mg tablet along with DTG tablet will be given to randomized subjects in parts 1 and 2 with 240 mL of room temperature water.<br>3TC will be gray, diamond shaped tablet, engraved "GX EJ7" on one side and plain on the other side.; Single dose of DTG 50 mg combined with 3TC 300 mg in a FDC formulation 1 tablet will be administered to randomized subjects in treatment periods 1 and 2 (under fasted state) of Part 1 and the first 16 subjects in treatment period 3 (under fed) of Part 1 with 240 mL of room temperature water. &lt;br&gt;FDC formulation 1 tablets will be oval, biconvex, white, film coated tablet engraved 'SV H7I' on one face.; Single dose of DTG 50 mg combined with 3TC 300 mg in a FDC formulation 2 tablet will be administered to randomized subjects in treatment periods 1 and 2 (under fasted state) and the first 16 subjects in treatment period 3 (under fed) of Part 2 with 240 mL of room temperature water. &lt;br&gt;FDC formulation 2 tablets will be oval, biconvex, white, film coated tablet engraved 'SV 13N' on one face.
Intervention MeSH terms: Lamivudine; Dolutegravir
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 154.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: FDC; Lamivudine; Bio-equivalence; Dolutegravir; HIV

Summary:

      This study aims to compare the bioequivalence of two experimental fixed dose combination
      (FDC) tablets versus single entity products of dolutegravir (DTG) and lamivudine (3TC) in
      healthy adult subjects. The study will be carried out in two parts. Part 1 of the study will
      be open label, up to 3 periods design with a wash out period of at least 7 days between
      treatment periods. Subjects will be randomized to receive either single entities or
      formulation 1 FDC of DTG and 3TC in a crossover manner in first 2 periods. The first 16
      subjects who complete the first two treatment periods and consent to continue will receive a
      single dose of FDC formulation 1 tablet administered with a high fat meal for a third
      treatment period. In Part 2 of the study, subjects will be randomized to receive either
      single entities or formulation 2 FDC of DTG and 3TC in a crossover manner in first 2 periods.
      Similarly the first 16 subjects will then receive FDC formulation 2 tablets with high fat
      meal in treatment period 3. Subjects will have a follow-up visit within 7-14 days after the
      last dose of study drug. Approximately 76 healthy subjects will be included in Part 1 of the
      study and if Part 2 of the study is conducted, another 76 healthy subjects will be included.
      The total duration will be approximately 11 weeks.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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, 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.

          -  Subject must be able to swallow 2 tablets at the same time (Reference tablets only).

          -  Body weight >=50 kilogram (kg) for men and >=45 kg for women and body mass index (BMI)
             within the range 18.5-31.0 kg per meter square (kg/m^2).

          -  Male or Female. Female subject: 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: 1. 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. 2. 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.

        Exclusion Criteria:

          -  Alanine aminotransferase (ALT) and bilirubin >1.5x upper limit of normal (ULN)
             (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct
             bilirubin <35 percentage).

          -  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
             milliseconds (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 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) <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 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.