Bioequivalence Study Between GSK3542503 Hydrochlorothiazide + Amiloride Hydrochloride 50 mg: 5 mg Tablets and Reference Product in Healthy Adult Participants Under Fasting Conditions

NCT03031496 | Completed Phase 1 Results

• 1 other identifier: 205694
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Hypertension

Keywords

Cross-over; Hydrochlorothiazide; Amiloride hydrochloride; Phase I; GSK3542503; Bioequivalence; FTIH

Outcome Measures

Primary Outcomes (2)

• Area Under the Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration (AUC [0-t]) of Hydrochlorothiazide and Amiloride Hydrochloride

  Blood samples were collected at indicated time points under fasting conditions for pharmacokinetic (PK) analysis of hydrochlorothiazide and amiloride. Bioequivalence of test product and reference product was assessed based on the 90 percent confidence intervals (CIs) for estimates of the geometric mean ratios between the AUC (0-t) of the test and reference products in relation to the conventional bioequivalence range. An analysis of variance was used with sequence, subject (sequence), treatment and period as fixed effects.

  Pre-dose, 0.33, 0.67, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 10, 12,14, 16 hours post-dose on Day 1, 24 and 36 hours post dose on Day 2 and 48 hours post-dose on Day 3

• Maximum Observed Concentration (Cmax) of Hydrochlorothiazide and Amiloride Hydrochloride in Plasma

  Blood samples were collected at indicated time points under fasting conditions for pharmacokinetic (PK) analysis of hydrochlorothiazide and amiloride. Bioequivalence of test product and reference product was assessed based on the 90 percent CIs for estimates of the geometric mean ratios between the Cmax of the test and reference products in relation to the conventional bioequivalence range. An analysis of variance was used with sequence, subject (sequence), treatment and period as fixed effects.

  Pre-dose, 0.33, 0.67, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 10, 12,14, 16 hours post-dose on Day 1, 24 and 36 hours post dose on Day 2 and 48 hours post-dose on Day 3

Secondary Outcomes (14)

• AUC From Time Zero to Infinity (AUC[0-inf]) of Hydrochlorothiazide and Amiloride Hydrochloride in Plasma

  Pre-dose, 0.33, 0.67, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 10, 12,14, 16 hours post-dose on Day 1, 24 and 36 hours post dose on Day 2 and 48 hours post-dose on Day 3

• Time of Occurrence of Cmax (Tmax) of Hydrochlorothiazide and Amiloride Hydrochloride in Plasma

  Pre-dose, 0.33, 0.67, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 10, 12,14, 16 hours post-dose on Day 1, 24 and 36 hours post dose on Day 2 and 48 hours post-dose on Day 3

• Percentage of AUC(0-inf) Obtained by Extrapolation (Percent AUCex) of Hydrochlorothiazide and Amiloride Hydrochloride in Plasma

  Pre-dose, 0.33, 0.67, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 10, 12,14, 16 hours post-dose on Day 1, 24 and 36 hours post dose on Day 2 and 48 hours post-dose on Day 3

• Terminal Phase Half-life (T1/2) of Hydrochlorothiazide and Amiloride Hydrochloride in Plasma

  Pre-dose, 0.33, 0.67, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 10, 12,14, 16 hours post-dose on Day 1, 24 and 36 hours post dose on Day 2 and 48 hours post-dose on Day 3

• Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment Period

  Up to 25 days

Study Arms (2)

Test A followed by Ref B of HCTZ 50mg+ Amiloride HCl 5mg

EXPERIMENTAL

Eligible participants following an overnight fast of at least 10 hours, will be administered the study drug orally with 240 mL (8 fluid ounces) of water. No food will be allowed for at least 4 hours post-dose. Water will be allowed as desired except for one hour before and after drug administration.

Drug: GSK3542503 (HCTZ 50mg/Amiloride HCl 5mg tablets); Drug: Moduretic (HCTZ 50mg/Amiloride HCl 5mg tablets)

Ref B followed by test A of HCTZ 50mg + Amiloride HCl 5mg

EXPERIMENTAL

Eligible participants following an overnight fast of at least 10 hours, will be administered the study drug orally with 240 mL (8 fluid ounces) of water. No food will be allowed for at least 4 hours post-dose. Water will be allowed as desired except for one hour before and after drug administration.

Drug: GSK3542503 (HCTZ 50mg/Amiloride HCl 5mg tablets); Drug: Moduretic (HCTZ 50mg/Amiloride HCl 5mg tablets)

Interventions

GSK3542503 (HCTZ 50mg/Amiloride HCl 5mg tablets) DRUG

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.

Ref B followed by test A of HCTZ 50mg + Amiloride HCl 5mg; Test A followed by Ref B of HCTZ 50mg+ Amiloride HCl 5mg

Moduretic (HCTZ 50mg/Amiloride HCl 5mg tablets) DRUG

Moduretic (HCTZ 50mg/Amiloride HCl 5mg tablets) tablets are peach-colored, half scored, diamond shaped tablets marked "MSD917".

Ref B followed by test A of HCTZ 50mg + Amiloride HCl 5mg; Test A followed by Ref B of HCTZ 50mg+ Amiloride HCl 5mg

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Bloemfontein, 9301, South Africa

Location

MeSH Terms

Conditions

Hypertension

Interventions

Hydrochlorothiazide; Amiloride; amiloride, hydrochlorothiazide drug combination

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Chlorothiazide; Benzothiadiazines; Sulfonamides; Sulfones; Sulfur Compounds; Organic Chemicals; Thiazides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

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: January 23, 2017
• First Posted: January 25, 2017
• Study Start: March 17, 2017
• Primary Completion: April 10, 2017
• Study Completion: April 10, 2017
• Last Updated: May 7, 2021
• Results First Posted: August 31, 2018

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

ZA (1)