Study to Determine the Bioequivalence of Two Fixed Dose Combination (FDC) Tablet Formulations of Amlodipine and Losartan FDC5/50 and FDC5/100 Under Fasting Conditions

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01797926
First received: February 21, 2013
Last updated: February 20, 2014
Last verified: February 2014
  Purpose

This is a three-period, three sequence, reference replicated, cross-over study to determine the bioequivalence of two amlodipine and losartan FDC tablet formulations FDC5/50 and FDC5/100 (GSK2944406; 5 mg amlodipine and 50 mg and 100 mg losartan) to reference amlodipine and losartan tablets co-administered in two groups enrolling 102 healthy adult male and female subjects under fasting conditions.

A description of each treatment is provided below:

A (Reference) = 1 x 5 mg amlodipine tablet and 1 x 50 mg losartan tablet. B (FDC5/50) = 1 x 5 mg amlodipine and 50 mg losartan tablet C (Reference) = 1 x 5 mg amlodipine tablet and 1 x 100 mg losartan tablet D (FDC5/100) = 1 x 5 mg amlodipine and100 mg losartan tablet The treatments will be administered in accordance with the randomisation schedule as.

Group 1: A → A → B or A → B → A or B → A → A Group 2: C → C → D or C → D → C or D → C → C All subjects will attend a screening visit within 28 days of their first dosing period (Day 1). The baseline assessments will be conducted the day before the first dosing.

In each treatment period, subjects will be admitted to the clinic in the evening before Day 1. All subjects will receive a single oral dose of amlodipine and losartan in the morning on Day 1. All the subjects will remain in the clinical unit until completion of all assessments at 24 hours post-dose on Day 2 including collection of the 24 hour post-dose PK sample. Subjects will return to the clinic for pharmacokinetic samples at 36, 48, 72 and 96 hours post-dose.

The three treatment periods will be separated by a washout period of 10-17 days. Upon completion of the last dosing period, or early withdrawal, subjects will return to the clinical unit within 14-21 days for a follow up visit.


Condition Intervention Phase
Hypertension
Drug: Reference Treatment: 5 mg amlodipine + 50 mg losartan
Drug: Reference Treatment:5 mg amlodipine + 100 mg losartan
Drug: FDC 5/50 amlodipine/ losartan
Drug: FDC 5/100 amlodipine /losartan
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-label, Randomised, Single Dose, Three-way Crossover, Parallel Groups Study to Determine the Bioequivalence of Two Fixed Dose Combination (FDC) Tablet Formulations of Amlodipine and Losartan FDC5/50 and FDC5/100 to Respective Reference Dosages in Healthy Adult Male and Female Subjects Under Fasting Conditions

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Plasma pharmacokinetic parameters for amlodipine and losartan in relevant treatments [ Time Frame: Up to 25 days at regular time points ] [ Designated as safety issue: No ]
    Pharmacokinetic (PK) parameters for amlodipine and losartan will include the 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), area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time exposure over the dosing and interval area under the plasma concentration time curve (AUC (0- infinity)), and maximum plasma concentration (Cmax)


Secondary Outcome Measures:
  • Plasma pharmacokinetic (PK) parameters tmax, Clast, percentage AUCex and t½ for amlodipine and losartan [ Time Frame: Up to 25 Days at regular time points ] [ Designated as safety issue: No ]
    The PK parameters: time of occurrence of Cmax (tmax), last observed quantifiable concentration (Clast), percentage AUCex and terminal phase half-life (t½) will be determined from the plasma concentration-time data

  • Plasma Pharmacokinetic parameters for carboxylic acid (active losartan metabolite) [ Time Frame: Up to 25 Days at regular time points ] [ Designated as safety issue: No ]
    The PK paramenters for carboxylic acid: AUC (0-t), AUC (0-infinity), Cmax, tmax, %AUCex, Clast and t½will be determined from the plasma concentration-time data

  • Measure of clinical laboratory test values to access safety and tolerability [ Time Frame: Up to 45 Days ] [ Designated as safety issue: No ]
    Clinical laboratory tests will include hematology, clinical chemistry and urinalysis

  • Safety assessed by vital sign measurements [ Time Frame: Up to 45 Days ] [ Designated as safety issue: No ]
    Vital sign measurements will include pulse rate and blood pressure

  • Number of subjects with adverse events (AE)s [ Time Frame: Up to 45 Days ] [ Designated as safety issue: No ]
    Safety and tolerability parameters will include recording of AEs


Enrollment: 102
Study Start Date: May 2013
Study Completion Date: July 2013
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1 (5 mg amlodipine and 50 mg losartan)
Subjects in Group 1 will be randomized to receive a single dose FDC 5/50 mg tablet and also separate single tablets each of reference treatment 5 mg amlodipine and 50 mg losartan. The reference treatment will be replicated in a three sequence, three period design
Drug: Reference Treatment: 5 mg amlodipine + 50 mg losartan
Subjects will receive 1 x 5 mg amlodipine tablet with 1 x 50 mg losartan tablet administered orally in fasted state as a single dose
Drug: FDC 5/50 amlodipine/ losartan
Subjects will receive single oral dose of 1 tablet containing 5 mg amlodipine and 50 mg losartan in fasted state
Experimental: Group 2 (5 mg amlodipine and 100 mg losartan)
Subjects in Group 2 will be randomized to receive a single dose FDC 5/100 mg; and also separate single tablets each of reference treatment 5 mg amlodipine and 100 mg losartan. The reference treatment will be replicated in a three sequence, three period design
Drug: Reference Treatment:5 mg amlodipine + 100 mg losartan
Subjects will receive 1 x 5 mg amlodipine tablet with 1 x 100 mg losartan tablet administered orally in fasted state as a single dose
Drug: FDC 5/100 amlodipine /losartan
Subjects will receive single oral dose of 1 tablet containing 5 mg amlodipine and 100 mg losartan in fasted state

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age & Gender: Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
  • Body weight >= 50 kg and body mass index (BMI) within the range 18.5 to 24.9 kilogram/meter squared.
  • Alanine aminotransferase (ALT) alkaline phosphatase and bilirubin <or=1.5x upper limit of normal (ULN).
  • Normal electrocardiogram (ECG) measurements. Average QT duration corrected for heart rate by Fridericia's formula (QTcF) <450 millisecond (msec) or QTcF <480 msec in subjects with Bundle Branch Block based on an average from three ECGs obtained over a brief recording period.
  • Female subjects of non-child bearing potential. Females of child bearing potential are eligible to enter if they are not pregnant and willing to use protocol-specified methods of contraception to prevent pregnancy.
  • Healthy as determined by a responsible and experienced physician, based on a medical Evaluation.
  • Capable of giving written informed consent.

Exclusion Criteria:

  • The subject has a positive: drug/alcohol screen, Hepatitis, human immunodeficiency virus(HIV) screen
  • Subject with systolic blood pressure less than 90 mmHg or diastolic less than 60 mm Hg irrespective of associated symptoms at the time of admission
  • If there is a drop in 20 mmHg of systolic pressure (and a 10 mmHg drop in diastolic) and a 20 beats per minute increase in heart rate between supine measurement and after two minutes standing at the time of admission.
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • A positive pre-study drug/alcohol at the time of admission.
  • Abuse of alcohol
  • 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 GlaxoSmithKline (GSK) Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  • 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.
  • Donation of more than 500 milliliter (mL) blood within a 56 day period.
  • Pregnant or lactating females.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Subject is mentally or legally incapacitated.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • Subject having positive urinary cotinine levels indicative of use of tobacco or nicotine-containing products within 6 months prior to screening.
  • Subjects who have asthma or a history of asthma including childhood asthma.
  • Unable to refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01797926

Locations
South Africa
GSK Investigational Site
Bloemfontein,, South Africa, 9301
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01797926     History of Changes
Other Study ID Numbers: 116799
Study First Received: February 21, 2013
Last Updated: February 20, 2014
Health Authority: South Africa: Medicines Control Council
India: Drugs Controller General of India

Keywords provided by GlaxoSmithKline:
pharmacokinetics
Hypertension
losartan
healthy volunteers
amlodipine

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Amlodipine
Losartan
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Anti-Arrhythmia Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists

ClinicalTrials.gov processed this record on August 18, 2014