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HealthyPhase 1NCT03226275

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

A Phase 1 study testing Bisoprolol-Amlodipine FDC, Bisoprolol and Amlodipine in people with Healthy, run by Merck KGaA, Darmstadt, Germany at 1 site in China.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 55 yearsHealthy volunteers can take part
Conditions the study is for
Healthy
What is being tested?
Bisoprolol-Amlodipine FDC, Bisoprolol and Amlodipine
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
32 participants
Where
1 siteChina
Study dates
9 Aug 2017to 9 Sep 2017
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 55 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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)
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

1 site in 1 country.

China1 site

  • Xuanwu Hospital

    Beijing, 100053

Other trials in China

About this study

Official 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

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
Being tested
Bisoprolol-Amlodipine FDC, Bisoprolol, Amlodipine
Keywords
Concor AM®, Concor®, Norvasc®, Bisoprolol, Amlodipine, Bisoprolol-Amlodipine fixed dose combination, Chinese Participants

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Bisoprolol-Amlodipine FDCDrug

    Also called Concor AM®

    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.

  • BisoprololDrug

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

  • AmlodipineDrug

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

Study groups in NCT03226275
Study groupRoleWhat they receive
Fasting: First Bisoprolol-Amlodipine FDC, Then Both SeparatelyExperimentalParticipants 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.
Receives: Drug: Bisoprolol-Amlodipine FDC; Drug: Bisoprolol; Drug: Amlodipine
Fasting: First Bisoprolol and Amlodipine Separately, Then FDCExperimentalParticipants 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.
Receives: Drug: Bisoprolol-Amlodipine FDC; Drug: Bisoprolol; Drug: Amlodipine
Fed: First Bisoprolol-Amlodipine FDC, Then Both SeparatelyExperimentalParticipants 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.
Receives: Drug: Bisoprolol-Amlodipine FDC; Drug: Bisoprolol; Drug: Amlodipine
Fed: First Bisoprolol and Amlodipine Separately, Then FDCExperimentalParticipants 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.
Receives: Drug: Bisoprolol-Amlodipine FDC; Drug: Bisoprolol; Drug: Amlodipine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: 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

  2. Maximum Observed Plasma Concentration (Cmax) of Bisoprolol and Amlodipine

    Measured: 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)

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

    Measured: 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

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

    Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination. Terminal half-life was calculated as ln(2)/λz, where λz is a terminal rate constant, which was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.

    Measured: 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

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

    Measured: 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

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

    AUCextra% was calculated as area under the curve from time tlast extrapolated to infinity given as percentage of AUC 0-infinity. Here, tlast is the last sampling time at which the concentration is at or above the lower limit of quantification.

    Measured: 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

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

    λz was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.

    Measured: 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

  6. Apparent Total Body Clearance From Plasma (CL/f) of Bisoprolol and Amlodipine

    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

    Measured: 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

  7. Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Bisoprolol and Amlodipine

    Vz/f is defined as the distribution of a study drug between plasma and the rest of the body after oral dosing.

    Measured: 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

  8. Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation

    An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration. TEAEs included both Serious TEAEs and non-serious TEAEs.

    Measured: Baseline up to Day 29

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Jul 2017
  2. Study start9 Aug 2017
  3. Primary completion9 Sep 2017
  4. Study completion9 Sep 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Other
Allocation
Randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
32 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03226275
Sponsor's protocol ID
EMR200006-001
Status last verified
Feb 2019
First submitted
20 Jul 2017
Last updated
20 Feb 2019
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • 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.

    PubMed 30232699

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Bisoprolol-Amlodipine FDC, Bisoprolol and Amlodipine in people with Healthy, run by Merck KGaA, Darmstadt, Germany at 1 site in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 20 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 20 Feb 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03226275, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Feb 2019.

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