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

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ClinicalTrials.gov Identifier: NCT03031496
Recruitment Status : Completed
First Posted : January 25, 2017
Results First Posted : August 31, 2018
Last Update Posted : August 31, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Hypertension Drug: GSK3542503 (HCTZ 50mg/Amiloride HCl 5mg tablets) Drug: Moduretic (HCTZ 50mg/Amiloride HCl 5mg tablets) Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Randomized, Single-dose, Two-period Cross-over Study to Evaluate Bioequivalence of GSK3542503 Hydrochlorothiazide + Amiloride Hydrochloride 50 mg: 5 mg Fixed Dose Combination Tablets Versus Reference Product in Healthy Adult Participants Under Fasting Conditions
Actual Study Start Date : March 17, 2017
Actual Primary Completion Date : April 10, 2017
Actual Study Completion Date : April 10, 2017


Arm Intervention/treatment
Experimental: Test A followed by Ref B of HCTZ 50mg+ Amiloride HCl 5mg
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)
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.

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

Experimental: Ref B followed by test A of HCTZ 50mg + Amiloride HCl 5mg
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)
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.

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




Primary Outcome Measures :
  1. Area Under the Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration (AUC [0-t]) of Hydrochlorothiazide and Amiloride Hydrochloride [ Time Frame: 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 ]
    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.

  2. Maximum Observed Concentration (Cmax) of Hydrochlorothiazide and Amiloride Hydrochloride in Plasma [ Time Frame: 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 ]
    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.


Secondary Outcome Measures :
  1. AUC From Time Zero to Infinity (AUC[0-inf]) of Hydrochlorothiazide and Amiloride Hydrochloride in Plasma [ Time Frame: 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 ]
    Blood samples were collected at indicated time points under fasting conditions for 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 AUC (0-inf) 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. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

  2. Time of Occurrence of Cmax (Tmax) of Hydrochlorothiazide and Amiloride Hydrochloride in Plasma [ Time Frame: 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 ]
    Blood samples were collected at indicated time points under fasting conditions for PK analysis of hydrochlorothiazide and amiloride. Median and full range has been presented.

  3. Percentage of AUC(0-inf) Obtained by Extrapolation (Percent AUCex) of Hydrochlorothiazide and Amiloride Hydrochloride in Plasma [ Time Frame: 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 ]
    Blood samples were collected at indicated time points under fasting conditions for 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 percent AUCex of the test and reference products in relation to the conventional bioequivalence range. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

  4. Terminal Phase Half-life (T1/2) of Hydrochlorothiazide and Amiloride Hydrochloride in Plasma [ Time Frame: 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 ]
    Blood samples were collected at indicated time points under fasting conditions for PK analysis of hydrochlorothiazide and amiloride. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

  5. Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment Period [ Time Frame: Up to 25 days ]
    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth effect, other situations and is associated with liver injury or impaired liver function. Only those participants with data available at the specified time points were analyzed

  6. Alanine Aminotransferase (ALT), Alkaline Phosphatase (Alk.Phosph.) and Aspartate Aminotransferase (AST) Levels at Indicated Time Points [ Time Frame: Day -1 and Day 3 of each treatment period ]
    Serum ALT, alk. phosph. and AST levels were assessed as a clinical chemistry laboratory parameter at Day -1 and Day 3 in each treatment period. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

  7. Blood Urea Nitrogen (BUN) Levels at Indicated Time Points [ Time Frame: Day -1 and Day 3 of each treatment period ]
    Serum BUN levels were assessed as a clinical chemistry laboratory parameter at Day -1 and Day 3 in each treatment period. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

  8. Calcium, Chloride, Glucose, Magnesium, Potassium and Sodium Levels at Indicated Time Points [ Time Frame: Day -1 and Day 3 of each treatment period ]
    Serum calcium, chloride, glucose, magnesium, potassium and sodium levels were assessed as a clinical chemistry laboratory parameter at Day -1 and Day 3 in each treatment period. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

  9. Creatinine, Direct Bilirubin and Total Bilirubin Levels at Indicated Time Points [ Time Frame: Day -1 and Day 3 of each treatment period ]
    Serum creatinine, direct bilirubin and total bilirubin levels were assessed as a clinical chemistry laboratory parameter at Day -1 and Day 3 in each treatment period. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

  10. Total Protein Levels at Indicated Time Points [ Time Frame: Day -1 and Day 3 of each treatment period ]
    Serum total protein levels were assessed as a clinical chemistry laboratory parameter at Day -1 and Day 3 in each treatment period. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

  11. Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Values at Indicated Time Points [ Time Frame: Day -1 and Day 3 of each treatment period ]
    Vital sign measurements including SBP and DBP were taken in a supine position after at least 5 minutes of rest at Day -1, Day 1, Day 2 and Day 3 in each treatment period. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

  12. Respiratory Rate Values at Indicated Time Points [ Time Frame: Day -1 and Day 3 of each treatment period ]
    Vital sign measurements including respiratory rate were taken in a supine position after at least 5 minutes of rest at Day -1, Day 1, Day 2 and Day 3 in each treatment period. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

  13. Pulse Rate Values at Indicated Time Points [ Time Frame: Day -1 and Day 3 of each treatment period ]
    Vital sign measurements including pulse rate were taken in a supine position after at least 5 minutes of rest at Day -1, Day 1, Day 2 and Day 3 in each treatment period. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

  14. Body Temperature Values at Indicated Time Points [ Time Frame: Day -1 and Day 3 of each treatment period ]
    Vital sign measurements including body temperature were taken in a supine position after at least 5 minutes of rest at Day -1, Day 1, Day 2 and Day 3 in each treatment period. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03031496


Locations
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South Africa
GSK Investigational Site
Bloemfontein, South Africa, 9301
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03031496    
Other Study ID Numbers: 205694
First Posted: January 25, 2017    Key Record Dates
Results First Posted: August 31, 2018
Last Update Posted: August 31, 2018
Last Verified: April 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
Cross-over
Hydrochlorothiazide
Amiloride hydrochloride
Phase I
GSK3542503
Bioequivalence
FTIH
Additional relevant MeSH terms:
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Hypertension
Vascular Diseases
Cardiovascular Diseases
Hydrochlorothiazide
Amiloride
Amiloride, hydrochlorothiazide drug combination
Antihypertensive Agents
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Acid Sensing Ion Channel Blockers
Sodium Channel Blockers
Epithelial Sodium Channel Blockers
Diuretics, Potassium Sparing