A Fixed Dose Combination Amlodipine + Enalapril Bioavailability Study

An Open-Label, Randomized, Single Dose, Two-Way Crossover Pilot Study to Evaluate the Relative Bioavailability of One Amlodipine 5 mg Tablet and One Enalapril Maleate 20mg Tablet to a Fixed Dose Combination Tablet Formulation of Amlodipine (5 mg) and Enalapril Maleate (20 mg), in Healthy Adult Male and Female Subjects Under Fasting Conditions

The study is designed to estimate the bioavailability of amlodipine and enalapril maleate fixed dose combination (FDC) relative to co-administration of amlodipine and enalapril maleate tablets. The rational for this study is to provide a more convenient dosing regimen for patients. This is an open-label, randomized, single dose, two-way crossover study, in which 16 healthy adult male and female subjects will be enrolled and dosed under fasting conditions. Each subject will participate in two treatment periods of 7 days each. There will be at least 14 days of wash out period between the two dosing periods and a follow-up period of up to 21 days after treatment period 2. The total duration of study will be approximately 35 days from the start of the first treatment.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: GSK2944404 FDC; Drug: Amlodipine 5 mg; Drug: Enalapril Maleate 20 mg

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Male or female aged between 18 and 65 years of age inclusive, at the time of signing the informed consent.
• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. 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 GlaxoSmithKline (GSK) 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 kilograms (kg) and Body Mass Index within the range 19 to 32 kg/meter squared (m^2) (inclusive).
• A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy [for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records]; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone > 40 milli international unit (MlU)/ milliliter (mL) and estradiol < 40 picogram/mL (<147 picomoles/liter) is confirmatory]. OR Child-bearing potential with negative pregnancy test as determined by serum human chorionic gonadotropin test at screening or prior to dosing. Agrees to use one of the contraception methods for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the follow-up contact visit. OR has only same-sex partners, when this is her preferred and usual lifestyle.
• Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods This criterion must be followed from the time of the first dose of study medication until the follow-up contact visit.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Alanine aminotransferase, alkaline phosphatase and bilirubin <=1.5 x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).
• Based on single or averaged QT duration corrected for heart rate (QTc) values of triplicate electrocardiograms (ECGs)obtained over a brief recording period: QTc by Fridericia's formula <450 millisecond (msec).

Exclusion Criteria Based Upon Medical Histories

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (With the exception of Gilbert's syndrome or asymptomatic gallstones).
• History of regular alcohol consumption within 6 months of the study defined as An average weekly intake of >21 units for males or >14 units for females. In Australia one unit (=standard drink) is equivalent to 10 grams of alcohol: 270 mL of full strength beer (4.8 percent), 375 mL of mid strength beer (3.5 percent), 470mL of light beer (2.7 percent), 250 mL pre-mix full strength spirit (5 percent), 100 mL of wine (13.5 percent) and 30 mL of spirit (40 percent).
• 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 GSK Medical Monitor, contraindicates their participation.

Exclusion Criteria Based Upon Diagnostic Assessments

• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
• Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
• A positive pre-study drug/alcohol screen.
• A positive test for human immuno virus antibody.
• Pregnant females as determined by positive serum hCG test at screening or at any other time points.
• Any subject with a systolic blood pressure <95 millimeter of mercury (mmHg) or with a recent history of postural symptoms.
• Orthostatic event at screening, defined as a symptomatic event (i.e. dizziness or any pre syncope or syncope) and a reduction in systolic blood pressure of 20mmHg or more and/or a reduction in diastolic blood pressure of 10 mmHg or more for standing versus supine measurement.

Other Exclusion Criteria

• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• Lactating females.
• 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.
• 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 GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
• Subject is mentally or legally incapacitated.
• Positive carbon monoxide on admission to the Unit.
• Unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice (and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices) from 7 days prior to the first dose of study medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence 1; Subjects in this arm will receive Treatment A in period 1 and Treatment B in period 2. Treatment A is co-administration of 5mg amlodipine tablet and 20 mg enalapril maleate tablet. Treatment B (GSK2944404) is fixed dose combination tablet of 5 mg amlodipine and 20 mg enalapril.	Drug: GSK2944404 FDC; Uncoated, round, yellow white bilayer fixed dose combination tablet containing 5 mg amlodipine and 20 mg enalapril for single dose oral administration in each period.; Drug: Amlodipine 5 mg; Emerald-shaped white 5 mg amlodipine table for single dose oral co-administration with enalapril maleate tablet in each period.; Drug: Enalapril Maleate 20 mg; Peach triangle shaped 20 mg enalapril maleate tablet for single dose oral co-administration with amlodipine in each period.
Experimental: Sequence 2; Subjects in this arm will receive Treatment B in period 1 and Treatment A in period 2. Treatment A is co-administration of 5mg amlodipine tablet and 20 mg enalapril maleate tablet. Treatment B (GSK2944404) is fixed dose combination tablet of 5 mg amlodipine and 20 mg enalapril.	Drug: GSK2944404 FDC; Uncoated, round, yellow white bilayer fixed dose combination tablet containing 5 mg amlodipine and 20 mg enalapril for single dose oral administration in each period.; Drug: Amlodipine 5 mg; Emerald-shaped white 5 mg amlodipine table for single dose oral co-administration with enalapril maleate tablet in each period.; Drug: Enalapril Maleate 20 mg; Peach triangle shaped 20 mg enalapril maleate tablet for single dose oral co-administration with amlodipine in each period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative oral bioavailability of GSK2944404 FDC to amlodipine and enalapril maleate tablets co-administered as assessed by composite of pharmacokinetic (PK) parameters.	PK parameters include: maximum observed concentration (Cmax) of amlodipine and enalapril in all treatments, area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments (AUC[0-t]), and area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC [0-infinity]. Bioavailability is defined as the amount of drug available at the site of action after administration.	PK samples will be collected at Pre-dose, 0.25, 0.5, 0.75, 1, 1.33, 1.66, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 36, 48, 72, 96, 120, and 144 hours post dose at each dosing session.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of PK parameters for enalaprilat following administration of GSK2944404 and co-administration of amlodipine and enalapril maleate as data permit.	PK parameters include: AUC (0-infinity), AUC (0-t), Cmax, time of occurrence of Cmax (tmax), percentage of AUC (0-infinity) obtained by extrapolation (percentage AUCex), last observed quantifiable concentration (Clast), and terminal phase half-life (t1/2).	PK samples will be collected at Pre-dose, 0.25, 0.5, 0.75, 1, 1.33, 1.66, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post dose at each dosing session.
Composite of PK parameters for amlodipine and enalapril maleate following administration of GSK2944404 and co-administration of amlodipine and enalapril maleate as data permit.	PK parameters include: tmax, Clast, percentage AUCex, and t1/2.	PK samples will be collected at Pre-dose, 0.25, 0.5, 0.75, 1, 1.33, 1.66, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 36, 48, 72, 96, 120, and 144 hours post dose at each dosing session.
Number of participants with adverse events (AEs) as a measure of safety and tolerability.	AEs will be collected from the start of Study Treatment and until the follow-up contact visit.	Up to 35 days.
Vital signs measurements to assess safety and tolerability.	Vital signs include blood pressure and pulse rate measurement. Orthostatic (sitting in upright position) as well as supine vitals will be measured.	Up to 35 days.
Absolute values and change over time of Clinical laboratory parameters to assess safety and tolerability.	Clinical laboratory parameters include: hematology, clinical chemistry, urinalysis and additional parameters.	Up to 35 days.

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2013
• Primary Completion (Actual): May 24, 2013
• Study Completion (Actual): May 24, 2013

Study Registration Dates

• First Submitted: March 28, 2013
• First Submitted That Met QC Criteria: March 28, 2013
• First Posted (Estimate): April 2, 2013

Study Record Updates

• Last Update Posted (Actual): June 5, 2017
• Last Update Submitted That Met QC Criteria: June 2, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Hypertension; pharmacokinetics; amlodipine; healthy volunteers; enalapril maleate
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Enzyme Inhibitors; Protease Inhibitors; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin-Converting Enzyme Inhibitors; Amlodipine; Enalaprilat; Enalapril
• Other Study ID Numbers: 116798

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Dataset Specification
   Information identifier: 116798
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Statistical Analysis Plan
   Information identifier: 116798
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Study Protocol
   Information identifier: 116798
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Clinical Study Report
   Information identifier: 116798
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Informed Consent Form
   Information identifier: 116798
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Individual Participant Data Set
   Information identifier: 116798
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Annotated Case Report Form
   Information identifier: 116798
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No