Bioequivalence Study Between GSK3542503 Hydrochlorothiazide + Amiloride Hydrochloride 50 mg: 5 mg Tablets and Reference Product in Healthy Adult Participants Under Fasting Conditions
Condition: Hypertension
MeSH terms: Hypertension
Intervention: GSK3542503 (HCTZ 50mg/Amiloride HCl 5mg tablets); Moduretic (HCTZ 50mg/Amiloride HCl 5mg tablets)
Intervention description: GSK3542503 (HCTZ 50mg/Amiloride HCl 5mg tablets) are cream-colored, circular, flat faced uncoated tablets with beveled edges having break line on one side and "BD" embossed on the other side.; Moduretic (HCTZ 50mg/Amiloride HCl 5mg tablets) tablets are peach-colored, half scored, diamond shaped tablets marked "MSD917".
Intervention MeSH terms: Hydrochlorothiazide; Amiloride; Amiloride, hydrochlorothiazide drug combination
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 42.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Cross-over; Hydrochlorothiazide; Amiloride hydrochloride; Phase I; GSK3542503; Bioequivalence; FTIH

Summary:

      The combination of the diuretics amiloride hydrochloride (HCl) and hydrochlorothiazide (HCTZ)
      (GSK3542503) is indicated for the treatment of hypertension, congestive heart failure and
      hepatic cirrhosis with ascites and edema. This first time in human (FTIH) study is aimed to
      determine whether the test product GSK3542503 is bioequivalent to the reference (ref)
      hydrochlorothiazide 50 milligram (mg)/amiloride hydrochlorothiazide 5 mg in healthy adult
      participants under fasting conditions based on pharmacokinetic (PK) endpoints. This is a
      phase I, open label, balanced, randomized, single dose, two-way crossover study, enroling
      approximately 42 healthy participants at a single center. Study participants will be
      randomized to one of two treatment sequences (A-B or B-A) in accordance with the
      randomization schedule. A single dose of one of the two treatments A (Test: GSK3542503, a
      hydrochlorothiazide 50 mg and amiloride hydrochloride 5 mg fixed dose combination) or B
      (Reference: Moduretic, a hydrochlorothiazide 50 mg and amiloride hydrochloride 5 mg fixed
      dose combination), will be administered on Day 1, in each treatment period. Each participant
      will participate in both treatment periods and receive a single dose of each treatment. The
      treatment periods will be separated by a washout period of at least 7 days and no more than
      14 days. The total duration in the study for each participant is expected to be 5 to 7 weeks,
      from screening to his or her last visit. A maximum of 42 participants will be randomized such
      that at least 32 evaluable participants complete the study.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants must be between18 and 65 years of age inclusive, at the time of signing
             the informed consent.

          -  Healthy, non-smoker, as determined by the investigator or medically qualified designee
             based on a medical evaluation including medical history, physical examination,
             laboratory tests, and cardiac monitoring.

          -  A participant with a clinical abnormality or laboratory parameter(s) which is/are not
             specifically listed in the inclusion or exclusion criteria, outside the normal
             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) and body mass index (BMI) within the range 19-30
             kg/meter^2(inclusive).

          -  Healthy male or female participants

               -  Male participants must agree to use contraception for 3 days after each dose of
                  study treatment and refrain from donating sperm during that period.

               -  A female participant is eligible to participate if she is not pregnant, not
                  breastfeeding, and at least one of the following conditions applies: not a woman
                  of childbearing potential (WOCBP), or a WOCBP who agrees to follow the
                  contraceptive guidance during the treatment period and for at least 30 days after
                  the last dose of study treatment.

        The investigator is responsible for ensuring that male and female study participants
        understand how to correctly use the methods of contraception.

        - Capable of giving signed informed consent, which includes compliance with the
        requirements and restrictions.

        Exclusion Criteria:

          -  History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal,
             endocrine, hematological, or neurological disorders capable of significantly altering
             the absorption, metabolism, or elimination of drugs; constituting a risk when taking
             the study treatment; or interfering with the interpretation of data.

          -  Abnormal renal function measured by creatinine clearance.

          -  Presence of hyperkalemia where the serum potassium is greater than upper limit of
             normal (ULN).

          -  History or known acute angle closure glaucoma or ocular complaints, which could
             increase the risk of ophthalmic reactions as deemed by the investigator.

          -  Abnormal BP as determined by the investigator.

          -  Alanine transaminase (ALT) >1.5 times ULN.

          -  Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN 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 Bazett's formula (QTcB) >450
             milliseconds (msec). For purposes of data analysis, only QTcB, will be used.

          -  Past or intended use of over-the-counter or prescription medication including herbal
             medications, within 14 days prior to dosing. Specific medications listed in protocol
             of this study may be allowed.

          -  Where participation in the study would result in loss of blood or blood products in
             excess of 500 milliliter (mL) within 90 days.

          -  Exposure to more than 4 new chemical entities within 12 months prior to the first
             dosing day.

          -  Current enrolment or past participation within the last 90 days before signing of
             consent in this or any other clinical study involving an investigational study
             treatment.

          -  Presence of hepatitis B surface antigen (HBsAg) at screening, or a positive hepatitis
             C antibody test result at screening. Participants with positive hepatitis C antibody
             due to prior resolved disease can be enrolled, only if a confirmatory negative
             hepatitis C ribonucleic acid (RNA) test is obtained.

          -  Positive pre-study drug/alcohol screen.

          -  Positive human immunodeficiency virus (HIV) antibody test.

          -  Regular use of known drugs of abuse.

          -  Sensitivity to heparin or heparin-induced thrombocytopenia.

          -  Sensitivity to any of the study treatments, or components thereof, or drug or other
             allergy including allergy to penicillin and sulfonamides that, in the opinion of the
             investigator or medical monitor, contraindicates participation in the study.

          -  Regular alcohol consumption within 6 months prior to the study defined as an average
             weekly intake of >21 units for males or > 14 units for females. One unit is equivalent
             to 8 gram of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of
             wine or 1 (25 mL) measure of spirits.

          -  Urinary cotinine levels indicative of smoking or history of regular use of tobacco- or
             nicotine-containing products within 6 months prior to screening.

          -  Participants with any risk as defined in protocol of this study should be excluded
             from participation in this study.