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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT03226275
• Date of registration: 20/07/2017
• Prospective Registration: Yes
• Primary sponsor: Merck KGaA, Darmstadt, Germany
• Public title: Bioequivalence Trial of Concor AM® vs Bisoprolol and Amlodipine in Chinese Participants
• Scientific title: A Randomized, Two-period Crossover Trial Examining Bioequivalence of Bisoprolol-Amlodipine 5 mg/5 mg Combination Tablets Versus Bisoprolol 5 mg Tablets and Amlodipine 5 mg Tablets Given Concomitantly in Healthy Subjects in Fasting and Fed State
• Date of first enrolment: August 9, 2017
• Target sample size: 32
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03226275
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Crossover Assignment. Primary purpose: Other. Masking: None (Open Label).
• Phase: Phase 1

Countries of recruitment

China, Germany

Contacts

• Name: Medical Responsible
• Affiliation: Merck KGaA, Darmstadt, Germany

Key inclusion & exclusion criteria

Inclusion Criteria:

- 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

Exclusion Criteria:

- 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

- Positive results to HIV antibody, hepatitis B surface antigen (HBsAg), hepatitis C
virus (HCV) antibody, or treponema pallidum (TP) antibody tests

- Donation of 50 milliliter (mL) or more of blood within 28 days before Day 1 of the
trial; donation of 500 mL or more of blood within 56 days before Day 1 of the trial

- History of suicidal tendency, history of or disposition to seizures, state of
confusion, clinically relevant psychiatric diseases

- Poor motivation, intellectual problems likely to limit the validity of consent to
participate in the trial or limit the ability to comply with the protocol requirements
or inability to cooperate adequately, inability to understand and to observe the
instructions of the physician

- Maintenance therapy with any drug, or significant history of drug dependency or
alcohol abuse (> 3 × 14 gram (g) alcohol per day, intake of excessive alcohol, acute
or chronic use)

- Positive urine screening of drugs of abuse (cannabis, benzodiazepines, barbiturates,
opiates, cocaine, and methyl amphetamine), or positive breath test of alcohol

- Positive pregnancy test (only for females of child-bearing potential) or females
breast feeding a child

- Consumption of large quantities of methylxanthine-containing beverages (more than 600
mg caffeine/day: 1 cup (250 mL) of coffee contains approximately 100 mg of caffeine, 1
cup of black or green tea contains approximately 30 mg and 1 glass of cola contains
approximately 20 mg caffeine)

- Volunteers who took an investigational product (in another clinical trial) by
prescription within 2 weeks or an over-the-counter medication taken within 1 week
before drug administration



Age minimum: 18 Years
Age maximum: 55 Years
Gender: All

Health Condition(s) or Problem(s) studied

Healthy

Intervention(s)

Drug: Bisoprolol-Amlodipine FDC

Drug: Bisoprolol

Drug: Amlodipine

Primary Outcome(s)

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 [Time Frame: 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 [Time Frame: 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 Outcome(s)

Apparent Terminal Half-life (t1/2) of Bisoprolol and Amlodipine [Time Frame: 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 Total Body Clearance From Plasma (CL/f) of Bisoprolol and Amlodipine [Time Frame: 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 [Time Frame: 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]

Time to Reach Maximum Plasma Concentration (Tmax) of Bisoprolol and Amlodipine [Time Frame: 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 (?z) of Bisoprolol and Amlodipine [Time Frame: 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 Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Bisoprolol and Amlodipine [Time Frame: 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]

Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation [Time Frame: Baseline up to Day 29]

Extrapolated Part of Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUCextra%) of Bisoprolol and Amlodipine [Time Frame: 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 ID(s)

EMR200006-001

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 20/02/2019
• URL: https://clinicaltrials.gov/ct2/show/results/NCT03226275