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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| 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. |
|
| Fed: First Bisoprolol and Amlodipine Separately, Then FDC |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | Merck KGaA, Darmstadt, Germany | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Xuanwu Hospital | Beijing | 100053 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30232699 | Derived | 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. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| FG002 | 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. |
| FG003 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 1 (8 Days) |
|
| ||||||||||||||||||
| Treatment Period 2 (8 Days) |
|
The safety analysis set included all participants who received at least 1 dose of study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram hour per milliliter (ng*h/mL) | 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 |
|
Baseline up to Day 29
The Safety Analysis Set included all participants who received at least 1 dose of study drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Fasting: Bisoprolol-Amlodipine FDC | 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. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Communication Center | Merck KGaA Darmstadt, Germany | +49-6151-72-5200 | service@emdgroup.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 3, 2017 | Sep 4, 2018 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 18, 2017 | Sep 4, 2018 | SAP_001.pdf |
| ID | Term |
|---|---|
| D017298 | Bisoprolol |
| D017311 | Amlodipine |
| ID | Term |
|---|---|
| D050198 | Phenoxypropanolamines |
| D011412 | Propanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
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| 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. |
|
|
| 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. |
|
| 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. |
|
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.
| 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 | 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. | 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 | λz was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. | 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 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. | 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 | Vz/f is defined as the distribution of a study drug between plasma and the rest of the body after oral dosing. | 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 | 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. | Baseline up to Day 29 |
| Protocol non-compliance |
|
| COMPLETED |
|
| NOT COMPLETED |
|
| BG001 | 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. |
| BG002 | 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. |
| BG003 | 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. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 | Fasting: Bisoprolol and Amlodipine Separately | 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. |
| OG002 | Fed: Bisoprolol-Amlodipine FDC | 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. |
| OG003 | Fed: Bisoprolol and Amlodipine Separately | 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. |
|
|
|
| Primary | Maximum Observed Plasma Concentration (Cmax) of Bisoprolol and Amlodipine | The Pharmacokinetic analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 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 | Time to Reach Maximum Plasma Concentration (Tmax) of Bisoprolol and Amlodipine | The Pharmacokinetic analysis set. | Posted | Median | Full Range | hours | 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 | 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. | The Pharmacokinetic analysis set. Here, "Number Analyzed" signified those participants who were evaluable for the specified category. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | 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 | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC 0-inf) of Bisoprolol and Amlodipine | The Pharmacokinetic analysis set. Here, "Number Analyzed" signified those participants who were evaluable for the specified category. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | 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 | 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. | The Pharmacokinetic analysis set. | Posted | Geometric Mean | Geometric Coefficient of Variation | percentage of AUC0-inf | 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 | 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. | The Pharmacokinetic analysis set. Here, "Number Analyzed" signified those participants who were evaluable for the specified category. | Posted | Geometric Mean | Geometric Coefficient of Variation | 1 per hour | 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 | 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. | The Pharmacokinetic analysis set. Here, "Number Analyzed" signified those participants who were evaluable for the specified category. | Posted | Geometric Mean | Geometric Coefficient of Variation | liter per hour | 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 | 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. | The Pharmacokinetic analysis set. Here, "Number Analyzed" signified those participants who were evaluable for the specified category. | Posted | Geometric Mean | Geometric Coefficient of Variation | liter | 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 | 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. | The Safety Analysis Set included all participants who received at least 1 dose of study drug. | Posted | Count of Participants | Participants | Baseline up to Day 29 |
|
|
|
| 0 |
| 16 |
| 0 |
| 16 |
| 0 |
| 16 |
| EG001 | Fasting: Bisoprolol and Amlodipine Separately | 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. | 0 | 16 | 0 | 16 | 0 | 16 |
| EG002 | Fed: Bisoprolol-Amlodipine FDC | 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. | 0 | 14 | 0 | 14 | 0 | 14 |
| EG003 | Fed: Bisoprolol and Amlodipine Separately | 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. | 0 | 14 | 0 | 14 | 0 | 14 |
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| D009930 |
| Organic Chemicals |
| D020005 | Propanols |
| D000588 | Amines |
| D004095 | Dihydropyridines |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| Amlodipine |
|
Statistical Comparison of Amlodipine in Fasting State |
| Geometric Least Square Mean Percentage |
| 100.03 |
| 2-Sided |
| 90 |
| 94.37 |
| 106.03 |
| Equivalence |
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 Comparison of Bisoprolol in Fed State | Geometric Least Square Mean Percentage | 93.87 | 2-Sided | 90 | 84.56 | 104.20 | Equivalence | 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 Comparison of Amlodipine in Fed State | Geometric Least Square Mean Percentage | 106.56 | 2-Sided | 90 | 97.82 | 116.08 | Equivalence | Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect. |
| Amlodipine |
|
Statistical Comparison of Amlodipine in Fasting State |
| Median Difference |
| 0.00 |
| 2-Sided |
| 90 |
| -1.00 |
| 0.00 |
| Equivalence |
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 Comparison of Bisoprolol in Fed State | Median Difference | 0.00 | 2-Sided | 90 | -1.00 | 0.50 | Equivalence | 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 Comparison of Amlodipine in Fed State | Median Difference | 0.00 | 2-Sided | 90 | -1.00 | 0.50 | Equivalence | Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect. |
|
| Amlodipine |
|
|
|
| Amlodipine |
|
|
Statistical Comparison of Amlodipine in Fasting State |
| Geometric Least Square Mean Percentage |
| 98.68 |
| 2-Sided |
| 90 |
| 93.38 |
| 104.28 |
| Equivalence |
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 Comparison of Bisoprolol in Fed State | Geometric Least Square Mean Percentage | 98.52 | 2-Sided | 90 | 89.75 | 108.15 | Equivalence | 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 Comparison of Amlodipine in Fed State | Geometric Least Square Mean Percentage | 104.06 | 2-Sided | 90 | 96.11 | 112.66 | Equivalence | Results based on a mixed-effects model with sequence, treatment, and period as fixed effects and participant nested within sequence as a random effect. |
| Amlodipine |
|
|
| Amlodipine |
|
|
|
| Amlodipine |
|
|
|
| Amlodipine |
|
|
| Serious TEAEs |
|
| AEs Leading to Death |
|
| AEs Leading to Discontinuation |
|