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

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03226275
• Collaborator: (none)
• Enrollment: 32
• Location: 1
• Arms: 4
• Actual Duration (Months): 1
• Patients Per Site Per Month: 31.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Bisoprolol-Amlodipine FDC; Drug: Bisoprolol; Drug: Amlodipine	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• 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
• Actual Study Start Date: Aug 9, 2017
• Actual Primary Completion Date: Sep 9, 2017
• Actual Study Completion Date: Sep 9, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fasting: First Bisoprolol-Amlodipine FDC, Then Both Separately 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; 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.; Other Names: Concor AM® ; Drug: Bisoprolol; Participants received 5 mg bisoprolol tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions.; Drug: Amlodipine; Participants received 5 mg amlodipine tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions.
Experimental: Fasting: First Bisoprolol and Amlodipine Separately, Then FDC 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; 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.; Other Names: Concor AM® ; Drug: Bisoprolol; Participants received 5 mg bisoprolol tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions.; Drug: Amlodipine; Participants received 5 mg amlodipine tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions.
Experimental: Fed: First Bisoprolol-Amlodipine FDC, Then Both Separately 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; 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.; Other Names: Concor AM® ; Drug: Bisoprolol; Participants received 5 mg bisoprolol tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions.; Drug: Amlodipine; Participants received 5 mg amlodipine tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions.
Experimental: Fed: First Bisoprolol and Amlodipine Separately, Then FDC 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; 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.; Other Names: Concor AM® ; Drug: Bisoprolol; Participants received 5 mg bisoprolol tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions.; Drug: Amlodipine; Participants received 5 mg amlodipine tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions.

Outcome Measures

Primary Outcome Measures

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 [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 [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 Measures

1. 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]

2. 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]

   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.

3. 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]

4. 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]

   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.

5. 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]

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

6. Apparent Total Body Clearance From Plasma (CL/f) 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]

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

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

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

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

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Xuanwu Hospital	Beijing		China	100053

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible, Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

• Study Protocol - May 3, 2017
• Statistical Analysis Plan - Sep 18, 2017

More Information

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT03226275
• Other Study ID Numbers: EMR200006-001
• First Posted: Jul 21, 2017
• Last Update Posted: Feb 20, 2019
• Last Verified: Feb 1, 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Merck KGaA, Darmstadt, Germany: Concor AM®; Concor®; Norvasc®; Bisoprolol; Amlodipine; Bisoprolol-Amlodipine fixed dose combination; Chinese Participants
• Additional relevant MeSH terms: Amlodipine; Bisoprolol

Study Results

Participant Flow

Pre-assignment Detail	The study was designed to assess bioequivalence (BE) between a single oral dose of bisoprolol-amlodipine fixed-dose-combination (FDC) tablet and bisoprolol and amlodipine, each given concomitantly as a single dose in fasting or fed state.

Arm/Group Title	Fasting: First Bisoprolol-Amlodipine FDC, Then Both Separately	Fasting: First Bisoprolol and Amlodipine Separately, Then FDC	Fed: First Bisoprolol-Amlodipine FDC, Then Both Separately	Fed: First Bisoprolol and Amlodipine Separately, Then FDC
Arm/Group Description	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.	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.	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.	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.
Period Title: Treatment Period 1 (8 Days)
STARTED	8	8	8	8
COMPLETED	8	8	7	7
NOT COMPLETED	0	0	1	1
Period Title: Treatment Period 1 (8 Days)
STARTED	8	8	7	7
COMPLETED	8	8	7	7
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Fasting: First Bisoprolol-Amlodipine FDC, Then Both Separately	Fasting: First Bisoprolol and Amlodipine Separately, Then FDC	Fed: First Bisoprolol-Amlodipine FDC, Then Both Separately	Fed: First Bisoprolol and Amlodipine Separately, Then FDC	Total
Arm/Group Description	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.	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.	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.	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.	Total of all reporting groups
Overall Participants	8	8	7	7	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.9 (8.89)	29.3 (3.15)	31.0 (3.56)	32.4 (10.29)	31.6 (7.01)
Sex: Female, Male (Count of Participants)
Female	4 50%	2 25%	2 28.6%	3 42.9%	11 36.7%
Male	4 50%	6 75%	5 71.4%	4 57.1%	19 63.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	8 100%	8 100%	7 100%	7 100%	30 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) Analysis Set included all participants who completed the study with adequate study medication compliance, without any relevant protocol violations with respect to factors likely to affect comparability of PK results, and with sufficient evaluable data to determine primary endpoints (AUC0-t and Cmax ) for both treatments.

Arm/Group Title	Fasting: Bisoprolol-Amlodipine FDC	Fasting: Bisoprolol and Amlodipine Separately	Fed: Bisoprolol-Amlodipine FDC	Fed: Bisoprolol and Amlodipine Separately
Arm/Group Description	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fasting conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fasting conditions.	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fed conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fed conditions.
Measure Participants	16	16	13	14
Bisoprolol	294 (16.7)	295 (21.5)	270 (23.4)	275 (23.9)
Amlodipine	205 (32.1)	212 (34.7)	174 (29.9)	167 (33.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fasting: Bisoprolol-Amlodipine FDC, Fasting: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Bisoprolol in Fasting state
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Square Mean Percentage
	Estimated Value	99.46
	Confidence Interval	(2-Sided) 90%; 93.25 to 106.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fasting: Bisoprolol-Amlodipine FDC, Fasting: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Amlodipine in Fasting State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Square Mean Percentage
	Estimated Value	96.76
	Confidence Interval	(2-Sided) 90%; 92.95 to 100.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fed: Bisoprolol-Amlodipine FDC, Fed: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Bisoprolol in Fed State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Square Mean Percentage
	Estimated Value	98.95
	Confidence Interval	(2-Sided) 90%; 90.02 to 108.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Fed: Bisoprolol-Amlodipine FDC, Fed: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Amlodipine in Fed State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Square Mean Percentage
	Estimated Value	103.07
	Confidence Interval	(2-Sided) 90%; 95.53 to 111.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic analysis set.

Arm/Group Title	Fasting: Bisoprolol-Amlodipine FDC	Fasting: Bisoprolol and Amlodipine Separately	Fed: Bisoprolol-Amlodipine FDC	Fed: Bisoprolol and Amlodipine Separately
Arm/Group Description	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fasting conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fasting conditions.	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fed conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fed conditions.
Measure Participants	16	16	13	14
Bisoprolol	26.1 (20.1)	26.6 (21.2)	20.5 (18.6)	21.9 (27.2)
Amlodipine	4.17 (25.6)	4.17 (24.1)	3.34 (23.1)	3.19 (31.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fasting: Bisoprolol-Amlodipine FDC, Fasting: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Bisoprolol in Fasting State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Square Mean Percentage
	Estimated Value	97.85
	Confidence Interval	(2-Sided) 90%; 92.29 to 103.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fasting: Bisoprolol-Amlodipine FDC, Fasting: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Amlodipine in Fasting State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Square Mean Percentage
	Estimated Value	100.03
	Confidence Interval	(2-Sided) 90%; 94.37 to 106.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fed: Bisoprolol-Amlodipine FDC, Fed: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Bisoprolol in Fed State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Square Mean Percentage
	Estimated Value	93.87
	Confidence Interval	(2-Sided) 90%; 84.56 to 104.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Fed: Bisoprolol-Amlodipine FDC, Fed: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Amlodipine in Fed State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Square Mean Percentage
	Estimated Value	106.56
	Confidence Interval	(2-Sided) 90%; 97.82 to 116.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic analysis set.

Arm/Group Title	Fasting: Bisoprolol-Amlodipine FDC	Fasting: Bisoprolol and Amlodipine Separately	Fed: Bisoprolol-Amlodipine FDC	Fed: Bisoprolol and Amlodipine Separately
Arm/Group Description	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fasting conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fasting conditions.	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fed conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fed conditions.
Measure Participants	16	16	13	14
Bisoprolol	1.00	1.00	3.00	3.00
Amlodipine	6.00	6.00	6.00	6.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fasting: Bisoprolol-Amlodipine FDC, Fasting: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Bisoprolol in Fasting State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 90%; 0.00 to 0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fasting: Bisoprolol-Amlodipine FDC, Fasting: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Amlodipine in Fasting State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 90%; -1.00 to 0.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fed: Bisoprolol-Amlodipine FDC, Fed: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Bisoprolol in Fed State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 90%; -1.00 to 0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Fed: Bisoprolol-Amlodipine FDC, Fed: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Amlodipine in Fed State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 90%; -1.00 to 0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic analysis set. Here, "Number Analyzed" signified those participants who were evaluable for the specified category.

Arm/Group Title	Fasting: Bisoprolol-Amlodipine FDC	Fasting: Bisoprolol and Amlodipine Separately	Fed: Bisoprolol-Amlodipine FDC	Fed: Bisoprolol and Amlodipine Separately
Arm/Group Description	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fasting conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fasting conditions.	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fed conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fed conditions.
Measure Participants	16	16	13	14
Bisoprolol	8.87 (18.1)	8.84 (15.4)	9.49 (30.2)	8.86 (20.6)
Amlodipine	51.8 (16.1)	49.7 (23.5)	46.7 (16.5)	43.2 (26.1)

5. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic analysis set. Here, "Number Analyzed" signified those participants who were evaluable for the specified category.

Arm/Group Title	Fasting: Bisoprolol-Amlodipine FDC	Fasting: Bisoprolol and Amlodipine Separately	Fed: Bisoprolol-Amlodipine FDC	Fed: Bisoprolol and Amlodipine Separately
Arm/Group Description	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fasting conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fasting conditions.	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fed conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fed conditions.
Measure Participants	16	16	13	14
Bisoprolol	306 (16.6)	306 (21.5)	281 (23.4)	287 (23.2)
Amlodipine	235 (34.4)	216 (31.7)	192 (31.4)	182 (34.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fasting: Bisoprolol-Amlodipine FDC, Fasting: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Bisoprolol in Fasting State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Square Mean Percentage
	Estimated Value	99.98
	Confidence Interval	(2-Sided) 90%; 93.61 to 106.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fasting: Bisoprolol-Amlodipine FDC, Fasting: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Amlodipine in Fasting State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Square Mean Percentage
	Estimated Value	98.68
	Confidence Interval	(2-Sided) 90%; 93.38 to 104.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fed: Bisoprolol-Amlodipine FDC, Fed: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Bisoprolol in Fed State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Square Mean Percentage
	Estimated Value	98.52
	Confidence Interval	(2-Sided) 90%; 89.75 to 108.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Fed: Bisoprolol-Amlodipine FDC, Fed: Bisoprolol and Amlodipine Separately
	Comments	Statistical Comparison of Amlodipine in Fed State
	Type of Statistical Test	Equivalence
	Comments	Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Square Mean Percentage
	Estimated Value	104.06
	Confidence Interval	(2-Sided) 90%; 96.11 to 112.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic analysis set.

Arm/Group Title	Fasting: Bisoprolol-Amlodipine FDC	Fasting: Bisoprolol and Amlodipine Separately	Fed: Bisoprolol-Amlodipine FDC	Fed: Bisoprolol and Amlodipine Separately
Arm/Group Description	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fasting conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fasting conditions.	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fed conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fed conditions.
Measure Participants	16	16	13	14
Bisoprolol	3.60 (36.1)	3.24 (25.5)	3.83 (21.9)	3.94 (48.2)
Amlodipine	10.9 (40.1)	10.8 (52.0)	8.58 (44.7)	6.81 (64.3)

7. Secondary Outcome

Title	Apparent Terminal Elimination Rate Constant (λz) of Bisoprolol and Amlodipine
Description	λz was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
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

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic analysis set. Here, "Number Analyzed" signified those participants who were evaluable for the specified category.

Arm/Group Title	Fasting: Bisoprolol-Amlodipine FDC	Fasting: Bisoprolol and Amlodipine Separately	Fed: Bisoprolol-Amlodipine FDC	Fed: Bisoprolol and Amlodipine Separately
Arm/Group Description	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fasting conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fasting conditions.	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fed conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fed conditions.
Measure Participants	16	16	13	14
Bisoprolol	0.0781 (18.1)	0.0784 (15.4)	0.0731 (30.2)	0.0783 (20.6)
Amlodipine	0.0134 (16.1)	0.0139 (23.5)	0.0148 (16.5)	0.0160 (26.1)

8. Secondary Outcome

Title	Apparent Total Body Clearance From Plasma (CL/f) of Bisoprolol and Amlodipine
Description	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
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

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic analysis set. Here, "Number Analyzed" signified those participants who were evaluable for the specified category.

Arm/Group Title	Fasting: Bisoprolol-Amlodipine FDC	Fasting: Bisoprolol and Amlodipine Separately	Fed: Bisoprolol-Amlodipine FDC	Fed: Bisoprolol and Amlodipine Separately
Arm/Group Description	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fasting conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fasting conditions.	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fed conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fed conditions.
Measure Participants	16	16	13	14
Bisoprolol	16.4 (16.6)	16.4 (21.5)	17.8 (23.4)	17.4 (23.2)
Amlodipine	21.3 (34.4)	23.1 (31.7)	26.0 (31.4)	27.4 (34.8)

9. Secondary Outcome

Title	Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Bisoprolol and Amlodipine
Description	Vz/f is defined as the distribution of a study drug between plasma and the rest of the body after oral dosing.
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

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic analysis set. Here, "Number Analyzed" signified those participants who were evaluable for the specified category.

Arm/Group Title	Fasting: Bisoprolol-Amlodipine FDC	Fasting: Bisoprolol and Amlodipine Separately	Fed: Bisoprolol-Amlodipine FDC	Fed: Bisoprolol and Amlodipine Separately
Arm/Group Description	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fasting conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fasting conditions.	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fed conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fed conditions.
Measure Participants	16	16	13	14
Bisoprolol	209 (17.0)	209 (15.5)	243 (31.3)	223 (19.6)
Amlodipine	1590 (31.0)	1660 (40.6)	1750 (30.9)	1710 (40.5)

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of study drug.

Arm/Group Title	Fasting: Bisoprolol-Amlodipine FDC	Fasting: Bisoprolol and Amlodipine Separately	Fed: Bisoprolol-Amlodipine FDC	Fed: Bisoprolol and Amlodipine Separately
Arm/Group Description	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fasting conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fasting conditions.	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fed conditions.	All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fed conditions.
Measure Participants	16	16	14	14
TEAEs	0 0%	0 0%	0 0%	0 0%
Serious TEAEs	0 0%	0 0%	0 0%	0 0%
AEs Leading to Death	0 0%	0 0%	0 0%	0 0%
AEs Leading to Discontinuation	0 0%	0 0%	0 0%	0 0%

Adverse Events

Time Frame	Baseline up to Day 29
Adverse Event Reporting Description	The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Arm/Group Title	Fasting: Bisoprolol-Amlodipine FDC		Fasting: Bisoprolol and Amlodipine Separately		Fed: Bisoprolol-Amlodipine FDC		Fed: Bisoprolol and Amlodipine Separately
Arm/Group Description	All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fasting conditions.		All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fasting conditions.		All participants who received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet as a single oral dose on Day 1 or Day 15 under fed conditions.		All participants who received a single dose of 5 mg bisoprolol and a single dose of 5 mg amlodipine given concomitantly on Day 1 or Day 15 under fed conditions.
All Cause Mortality
	Fasting: Bisoprolol-Amlodipine FDC		Fasting: Bisoprolol and Amlodipine Separately		Fed: Bisoprolol-Amlodipine FDC		Fed: Bisoprolol and Amlodipine Separately
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/14 (0%)		0/14 (0%)
Serious Adverse Events
	Fasting: Bisoprolol-Amlodipine FDC		Fasting: Bisoprolol and Amlodipine Separately		Fed: Bisoprolol-Amlodipine FDC		Fed: Bisoprolol and Amlodipine Separately
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/14 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Fasting: Bisoprolol-Amlodipine FDC		Fasting: Bisoprolol and Amlodipine Separately		Fed: Bisoprolol-Amlodipine FDC		Fed: Bisoprolol and Amlodipine Separately
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/14 (0%)		0/14 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.