Bioequivalence Trial of Concor AM® vs Bisoprolol and Amlodipine in Chinese Participants

NCT03226275 | Completed Phase 1 Results

• 1 other identifier: EMR200006-001
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase I, open-label, randomized, 2-period, 2-sequence, crossover study to demonstrate bioequivalence (BE) between the bisoprolol-amlodipine fixed-dose-combination (FDC) tablet (investigational product) and bisoprolol and amlodipine tablets administered concomitantly (comparators) given as a single oral dose in fasting and fed state.

Conditions

Healthy

Keywords

Concor AM®; Concor®; Norvasc®; Bisoprolol; Amlodipine; Bisoprolol-Amlodipine fixed dose combination; Chinese Participants

Outcome Measures

Primary Outcomes (2)

• Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Bisoprolol and Amlodipine

  Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period

• Maximum Observed Plasma Concentration (Cmax) of Bisoprolol and Amlodipine

  Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period

Secondary Outcomes (8)

• Time to Reach Maximum Plasma Concentration (Tmax) of Bisoprolol and Amlodipine

  Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period

• Apparent Terminal Half-life (t1/2) of Bisoprolol and Amlodipine

  Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period

• Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC 0-inf) of Bisoprolol and Amlodipine

  Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period

• Extrapolated Part of Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUCextra%) of Bisoprolol and Amlodipine

  Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period

• Apparent Terminal Elimination Rate Constant (λz) of Bisoprolol and Amlodipine

  Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period

Study Arms (4)

Fasting: First Bisoprolol-Amlodipine FDC, Then Both Separately

EXPERIMENTAL

Participants received a single oral dose of 5 milligram(mg)/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) on Day 1 in treatment period 1 followed by a single oral dose of 5 mg bisoprolol and a single oral dose of 5 mg amlodipine given concomitantly on Day 15 in treatment period 2 under fasting conditions. The two periods were separated by a washout period of 14 days.

Drug: Bisoprolol-Amlodipine FDC; Drug: Bisoprolol; Drug: Amlodipine

Fasting: First Bisoprolol and Amlodipine Separately, Then FDC

EXPERIMENTAL

Participants received a single oral dose of 5 mg bisoprolol and a single oral dose of 5 mg amlodipine given concomitantly on Day 1 in treatment period 1 followed by a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) on Day 15 in treatment period 2 under fasting conditions. The two periods were separated by a washout period of 14 days.

Drug: Bisoprolol-Amlodipine FDC; Drug: Bisoprolol; Drug: Amlodipine

Fed: First Bisoprolol-Amlodipine FDC, Then Both Separately

EXPERIMENTAL

Participants received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) on Day 1 in treatment period 1 followed by a single oral dose of 5 mg bisoprolol and a single oral dose of 5 mg amlodipine given concomitantly on Day 15 in treatment period 2 under fed conditions. The two periods were separated by a washout period of 14 days.

Drug: Bisoprolol-Amlodipine FDC; Drug: Bisoprolol; Drug: Amlodipine

Fed: First Bisoprolol and Amlodipine Separately, Then FDC

EXPERIMENTAL

Participants received a single oral dose of 5 mg bisoprolol and a single oral dose of 5 mg amlodipine given concomitantly on Day 1 in treatment period 1 followed by a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) on Day 15 in treatment period 2 under fed conditions. The two periods were separated by a washout period of 14 days.

Drug: Bisoprolol-Amlodipine FDC; Drug: Bisoprolol; Drug: Amlodipine

Interventions

Bisoprolol-Amlodipine FDC DRUG

Participants received a single oral dose of 5 milligram(mg)/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) either on Day 1 or Day 15 under fasting or fed conditions.

Also known as: Concor AM®

Fasting: First Bisoprolol and Amlodipine Separately, Then FDC; Fasting: First Bisoprolol-Amlodipine FDC, Then Both Separately; Fed: First Bisoprolol and Amlodipine Separately, Then FDC; Fed: First Bisoprolol-Amlodipine FDC, Then Both Separately

Bisoprolol DRUG

Participants received 5 mg bisoprolol tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions.

Fasting: First Bisoprolol and Amlodipine Separately, Then FDC; Fasting: First Bisoprolol-Amlodipine FDC, Then Both Separately; Fed: First Bisoprolol and Amlodipine Separately, Then FDC; Fed: First Bisoprolol-Amlodipine FDC, Then Both Separately

Amlodipine DRUG

Participants received 5 mg amlodipine tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions.

Fasting: First Bisoprolol and Amlodipine Separately, Then FDC; Fasting: First Bisoprolol-Amlodipine FDC, Then Both Separately; Fed: First Bisoprolol and Amlodipine Separately, Then FDC; Fed: First Bisoprolol-Amlodipine FDC, Then Both Separately

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Availability for the entire trial period and willingness to adhere to the protocol requirements as evidenced by the informed consent form (ICF) duly read, signed and dated by the volunteer
• Chinese male and female volunteer
• Volunteer with a body mass index greater than or equal to 18 and below 28 kilogram/meter\^2 (kg/m\^2)
• Systolic blood pressure (in supine position) within 100 to 139 mmHg (inclusive) and diastolic blood pressure (in supine position) within 65 to 90 millimeter of mercury (mmHg) (inclusive) at Screening, during Admission to the Clinical Research Unit (CRU) (12 hour predose) and before each dosing
• Clinical laboratory values (within 1 month before screening) within the laboratory's stated normal range; if not within this range, they must lack clinical significance
• Healthy according to assessment of the medical history, Electrocardiogram, vital signs, physical examination,laboratory results, negative drug screening, and negative serology tests (except results after vaccination)
• Non-smoker or ex-smoker, not using any nicotine product; an ex-smoker being defined as someone who completely stopped smoking for at least 12 months before Day 1 of the trial
• Each participant has to be capable of understanding the trial procedures and sign the Informed consent form prior to their participation in the trial
• Participants must consent to adhere to the recommended contraceptive methods

You may not qualify if:

• Significant history of hypersensitivity to bisoprolol, amlodipine, other dihydropyridines, or any related products (including excipients of the formulations)
• Significant history of severe hypersensitivity reactions (eg, angioedema) to any drugs
• Pulse rate (in supine position) less than (\<) 60 beats per minute (bpm) or more than 100 bpm at screening
• Presence of significant arrhythmia: QTc interval prolongation (QTc greater than 430 milliseconds (msec), severe sinus node dysfunction, or second or third atrioventricular block
• History of low blood pressure (\< 100/65 mmHg) or vegetative dystonia
• History or presence of peripheral arterial occlusion or Raynaud's syndrome
• Presence of diabetes mellitus
• History or presence of asthma
• Presence of significant gastrointestinal, liver, kidney disease, surgery, or any other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs or known to potentiate or predispose to undesired effects
• Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome P450 (CYP) enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem, and human immunodeficiency virus \[HIV\] antivirals) and strong inducers of CYP enzymes (such as barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin, St. John's wort or other herbal medicine known with effect on CYP enzymes) within 28 days before Day 1 of this trial
• Presence or history of significant cardiovascular, pulmonary, hematologic, neurologic, endocrine, immunologic, or dermatological disease
• Presence or history of significant angina pectoris, acute myocardial infarction or ST segment and T wave changes other than non-clinically significant minor changes
• Presence or history of ventricular arrhythmia (such as ventricular tachycardia or ventricular fibrillation) or of congestive heart failure Acute conditions which might alter the renal function (eg, dehydration, severe infection)
• Surgery in the previous 28 days before Day 1 of this trial
• Any history of tuberculosis and/or prophylaxis for tuberculosis within 10 years of Day 1 of the trial

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead

Study Sites (1)

Xuanwu Hospital

Beijing, 100053, China

Location

Related Publications (1)

• Hu C, Hu X, Wang C, Zhao Z, Gao D, Chen X, Zhou D, Huang Y, Li L, Zhang L. Bioequivalence and Pharmacokinetics of Bisoprolol-Amlodipine 5 mg/5 mg Combination Tablet versus Bisoprolol 5 mg Tablet and Amlodipine 5 mg Tablet: An Open-Label, Randomized, Two-Sequence Crossover Study in Healthy Chinese Subjects. Clin Drug Investig. 2018 Dec;38(12):1145-1154. doi: 10.1007/s40261-018-0700-y.

  PMID: 30232699 DERIVED

MeSH Terms

Interventions

Bisoprolol; Amlodipine

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Communication Center
• Organization: Merck KGaA Darmstadt, Germany

service@emdgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 20, 2017
• First Posted: July 21, 2017
• Study Start: August 9, 2017
• Primary Completion: September 9, 2017
• Study Completion: September 9, 2017
• Last Updated: February 20, 2019
• Results First Posted: February 20, 2019

Record last verified: 2019-02

Locations

CN (1)