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| ID | Type | Description | Link |
|---|---|---|---|
| FD14-024 | Other Grant/Funding Number | US FOOD AND DRUG ADMN | |
| OCR15985 | Other Identifier | Universiy of Florida |
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| Name | Class |
|---|---|
| Food and Drug Administration (FDA) | FED |
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Recently, the quality of generic metoprolol extended-release (ER) products has been called into question with reports of inconsistent effects when switching from the brand name product to a generic formulation. Problems with how the body processes these drugs could have serious and widespread consequences given the high frequency of metoprolol ER use in the management of various cardiovascular disorders, including high blood pressure, coronary heart disease, heart failure, and cardiac arrhythmias. Investigators hypothesize that both product- and subject-specific factors lead to variability in the way the body breaks down the drug (pharmacokinetics) and clinical response to generic versus name brand metoprolol ER formulations. Investigators will study the brand name and generic metoprolol ER formulations in subjects with high blood pressure to compare the pharmacokinetics and cardiovascular responses among equivalent labeled doses of each product (brand name and two approved generics).
The study objective is to provide information on how the body breaks down generic and brand name metoprolol ER products (pharmacokinetics) and how the body responds to generic and brand name metoprolol ER products (pharmacodynamics) to better understand if generic metoprolol ER products are as good as the brand name product.
As a participant in this study the following will happen.
A study nurse will draw 3 teaspoonfuls (15 ml) of blood. Two teaspoons (10ml) will be drawn for basic blood work and one teaspoon (5ml) will be drawn for genotyping. The study physician will perform a physical exam and discuss all medical history.
The study will be randomized to one of two groups like flipping a coin.
Each study sequence will consist of treatment with brand name metoprolol ER for 2 periods, treatment with Generic A metoprolol ER for one period, and treatment with Generic B metoprolol ER for one period. The generic drug periods will be in a different order for each study group. During the times the switch will take place the following tests will be performed: 24-hour pharmacokinetic parameter assessment, 24-hour heart rate monitoring, 24-hour blood pressure monitoring, 24-hour holter monitoring, exercise treadmill to induce heart rate, and a 24-hour gastric potential hydrogen (pH) monitoring via a wireless capsule.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Study Sequence A | Active Comparator | Start with brand name metoprolol ER, switch to Generic B metoprolol, switch back to brand name metoprolol ER, then switch to Generic A metoprolol |
|
| Study Sequence B | Active Comparator | Start with brand name metoprolol ER, switch to Generic A metoprolol, switch back to brand name metoprolol ER, then switch to Generic B metoprolol. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| brand name metoprolol ER | Drug | This medication will be taken for 7 to 28 days |
|
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve (AUC) | The AUC of Brand name metoprolol ER will be compared against each generic for determination of bioequivalence. The mean and standard deviation (SD) values of AUC are entered separately for the 50mg, 100mg and 150mg doses. Results are reported for brand name metoprolol ER, Generic B and Generic A. | 0.0, 0.30, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0, 24.0 hours post dose |
| Peak Plasma Concentration (Cmax) of Metoprolol Succinate | The Peak Plasma Concentration (Cmax) of Brand name metoprolol ER will be compared against each generic for determination of bioequivalence. The mean and SD values of Cmax are entered separately for the 50mg, 100mg and 150mg doses. Results are reported for brand name metoprolol ER, Generic B and Generic A. | 0.0, 0.30, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0, 24.0 hours post dose |
| Measure | Description | Time Frame |
|---|---|---|
| The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | 24-h digital heart rate monitor analyses were obtained after Phase 1 (brand name metoprolol ER ), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B). Data were analyzed by quartiles. One 5-minute epoch from each hour of each quartile was selected based on absence of a significant number of ectopic beats and artifact from which spectral measures were calculated: high-frequency variability (measure of parasympathetic activity), low-frequency variability (measure of sympathetic activity). The ratio of low-to-high frequency variability was calculated for each quartile. The averages of values obtained for each hour of each quartile constituted the final quartile measures that were used for analysis. The low to high frequency ratio obtained for each quartile represents the balance between sympathetic and parasympathetic nervous system activity and was the primary variable for heart rate variability analysis. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Larisa Cavallari, PharmD | University of Florida | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Family Medicine at Hampton Oaks Medical Plaza | Gainesville | Florida | 32607 | United States | ||
| Oak Hammock at the University of Florida |
61 participants were consented with 10 participants as screen fails, 2 declining to further participate, and 1 unable to fit standard monitoring equipment.
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| ID | Title | Description |
|---|---|---|
| FG000 | Sequence A | Brand name metoprolol ER for 7 to 28 days, and then switch to generic B metoprolol for 7 days, Brand name metoprolol ER for 7 to 28 days, generic A metoprolol for 7 days |
| FG001 | Sequence B | Brand name metoprolol ER for 7 to 28 days, and then switch to generic A metoprolol for 7 days, Brand name metoprolol ER for 7 to 28 days, generic B metoprolol for 7 days |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1 Brand Name Metoprolol ER |
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| Phase 2 1st Generic Administered |
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| Phase 3 Brand Name Metoprolol ER #2 |
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| Phase 4 2nd Generic Administered |
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18 participants who were administered both brand name metoprolol ER and Generic B and 18 participants who were administered both brand name metoprolol ER and Generic A were analyzed
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| ID | Title | Description |
|---|---|---|
| BG000 | Sequence A: Brand Name Metoprolol ER and Generic B | This group will start with the brand name metoprolol ER for 7 to 28 days, and then switch to Generic B metoprolol for 7 days. Brand name metoprolol ER: This medication will be taken for 7 to 28 days Generic B metoprolol: This medication will be taken for 7 days Generic A metoprolol: This medication will be taken for 7 days |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 18 subjects who were administered both brand name metoprolol ER and Generic A; and 18 subjects who were administered both brand name metoprolol ER and Generic B were analyzed |
| 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 Versus Time Curve (AUC) | The AUC of Brand name metoprolol ER will be compared against each generic for determination of bioequivalence. The mean and standard deviation (SD) values of AUC are entered separately for the 50mg, 100mg and 150mg doses. Results are reported for brand name metoprolol ER, Generic B and Generic A. | This is a 2-way crossover analysis | Posted | Mean | Standard Deviation | ng.hr/ml | 0.0, 0.30, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0, 24.0 hours post dose | Plasma | Plasma |
|
Up to 12 weeks since the start of phase one (patients starting their first dose of brand name metoprolol ER)
Safety population included all patients who took at least one dose of study drug (i.e. one dose of brand name metoprolol ER in Phase 1)
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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 | Brand Name | Brand Name Metoprolol ER | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| ECG signs of myocardia ischemia | Investigations | MedDRA | Systematic Assessment | ECG changes observed during stress test. Patient received medical attention and was withdrawn from study. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Urinary tract infections | Renal and urinary disorders | MedDRA 19.0 | Systematic Assessment |
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Larisa H Cavallari | UF | 352-273-8245 | lcavallari@cop.ufl.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP_ICF | Yes | Yes | Yes | Study Protocol, Statistical Analysis Plan, and Informed Consent Form | Jul 13, 2018 | Jul 3, 2019 | Prot_SAP_ICF_000.pdf |
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| Generic A | Drug | This medication will be taken for 7 days |
|
|
| Generic B | Drug | This medication will be taken for 7 days |
|
|
| Heart rate variability (Low-to-High Frequency Ratio) over each quartile of 6 hours in the 24-hr period |
| Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | 24-hr ambulatory blood pressure (BP) recordings taken 4 times per hour (every 15 minutes) between 6AM and 11PM and 2 times per hour (every 30 minutes) 11PM and 6AM were obtained after Phase 1 (Brand name metoprolol ER), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B). | Average value over each quartile of 6 hours in the 24-hr period |
| Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | 24-h ambulatory heart rate recordings taken 4 times per hour (every 15 minutes) between 6AM and 11PM and 2 times per hour (every 30 minutes) 11PM and 6AM were obtained after Phase 1 (brand name metoprolol ER), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B) | Average value over each quartile of 6 hours in the 24-hr period |
| Gainesville |
| Florida |
| 32608 |
| United States |
| Withdrawal by Subject |
|
| NOT COMPLETED |
|
|
| NOT COMPLETED |
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| NOT COMPLETED |
|
| BG001 | Sequence B: Brand Name Metoprolol ER and Generic A | This group will start with the brand name metoprolol ER for 7 to 28 days, and then switch to Generic A metoprolol for 7 days. Brand name metoprolol ER: This medication will be taken for 7 to 28 days Generic A metoprolol: This medication will be taken for 7 days Generic B metoprolol: This medication will be taken for 7 days |
| BG002 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | 18 subjects who were administered both brand name metoprolol ER and Generic B and 18 subjects who were administered both brand name metoprolol ER and Generic A were analyzed | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| BMI | Mean | Standard Deviation | kg/m^2 |
|
| Weight | Mean | Standard Deviation | kg |
|
| Height | Mean | Standard Deviation | cm |
|
Generic B received in Phase 2 or Phase 4
| OG002 | Generic A | Generic A received in Phase 2 or Phase 4 |
|
|
|
| Primary | Peak Plasma Concentration (Cmax) of Metoprolol Succinate | The Peak Plasma Concentration (Cmax) of Brand name metoprolol ER will be compared against each generic for determination of bioequivalence. The mean and SD values of Cmax are entered separately for the 50mg, 100mg and 150mg doses. Results are reported for brand name metoprolol ER, Generic B and Generic A. | A two-way cross over study in which patients are administered brand name metoprolol ER and Generic B or Generic A | Posted | Mean | Standard Deviation | ng/mL | 0.0, 0.30, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0, 24.0 hours post dose |
|
|
|
|
| Secondary | The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | 24-h digital heart rate monitor analyses were obtained after Phase 1 (brand name metoprolol ER ), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B). Data were analyzed by quartiles. One 5-minute epoch from each hour of each quartile was selected based on absence of a significant number of ectopic beats and artifact from which spectral measures were calculated: high-frequency variability (measure of parasympathetic activity), low-frequency variability (measure of sympathetic activity). The ratio of low-to-high frequency variability was calculated for each quartile. The averages of values obtained for each hour of each quartile constituted the final quartile measures that were used for analysis. The low to high frequency ratio obtained for each quartile represents the balance between sympathetic and parasympathetic nervous system activity and was the primary variable for heart rate variability analysis. | The analysis aimed to compare HRV (Low-to-High Frequency Ratio) for patients who took Brand name metoprolol ER and a generic formulation (Generic B or Generic A). Low to High Frequency Ratio values are entered for each quartile for Brand name metoprolol ER, Generic B and Generic A | Posted | Mean | Standard Deviation | no units | Heart rate variability (Low-to-High Frequency Ratio) over each quartile of 6 hours in the 24-hr period |
|
|
|
|
| Secondary | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | 24-hr ambulatory blood pressure (BP) recordings taken 4 times per hour (every 15 minutes) between 6AM and 11PM and 2 times per hour (every 30 minutes) 11PM and 6AM were obtained after Phase 1 (Brand name metoprolol ER), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B). | The analysis aimed to compare mean BP values in Hg mm between the brand name and each of the generic (Generic B or Generic A) formulation of metoprolol succinate. Patients were included in the analysis if they took brand name metoprolol ER and at least one generic. | Posted | Mean | Standard Deviation | mm Hg | Average value over each quartile of 6 hours in the 24-hr period |
|
|
|
|
| Secondary | Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | 24-h ambulatory heart rate recordings taken 4 times per hour (every 15 minutes) between 6AM and 11PM and 2 times per hour (every 30 minutes) 11PM and 6AM were obtained after Phase 1 (brand name metoprolol ER), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B) | The analysis aimed to compare 24-hr HR between the brand name and each generic (generic B or generic A) formulation of metoprolol succinate. Mean and SD values for HR entered for each medication by quartile | Posted | Mean | Standard Deviation | bpm | Average value over each quartile of 6 hours in the 24-hr period |
|
|
|
|
| 48 |
| 1 |
| 48 |
| 33 |
| 48 |
| EG001 | Generic A | Generic Metoprolol ER type A | 0 | 38 | 0 | 38 | 21 | 38 |
| EG002 | Generic B | Generic Metoprolol ER type B | 0 | 40 | 0 | 40 | 16 | 40 |
|
| Dyspepsia | General disorders | MedDRA 19.0 | Systematic Assessment |
|
| Bradycardia | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
|
| Oedema peripheral | Metabolism and nutrition disorders | MedDRA 19.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 19.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 19.0 | Systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA 19.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 19.0 | Systematic Assessment |
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| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 19.0 | Systematic Assessment |
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| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 19.0 | Systematic Assessment | Lower extremity itching and burning |
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| Anxiety | Psychiatric disorders | MedDRA 19.0 | Systematic Assessment |
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| Sluggishness | General disorders | MedDRA 19.0 | Systematic Assessment |
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| Hyperhidrosis | General disorders | MedDRA 19.0 | Systematic Assessment |
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| Syncope | Vascular disorders | MedDRA 19.0 | Systematic Assessment |
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| Bronchitis | Infections and infestations | MedDRA 19.0 | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | MedDRA 19.0 | Systematic Assessment |
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| Palpitations | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Nervousness | Psychiatric disorders | MedDRA 19.0 | Systematic Assessment |
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| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 19.0 | Systematic Assessment |
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| Flushing | Vascular disorders | MedDRA 19.0 | Systematic Assessment |
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| Dyspnoea | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 19.0 | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 19.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
|
| Gastroenteritis | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
|
| Electrocardiogram ST-T segment abnormal | Investigations | MedDRA 19.0 | Systematic Assessment | 1 mm ST segment depression with quick recovery |
|
| Influenza like illness | General disorders | MedDRA 19.0 | Systematic Assessment |
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| Nasopharyngitis | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 19.0 | Systematic Assessment |
|
| Puncture site reaction | Injury, poisoning and procedural complications | MedDRA 19.0 | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA 19.0 | Systematic Assessment |
|
| Fluid retention | Metabolism and nutrition disorders | MedDRA 19.0 | Systematic Assessment |
|
| Pre syncope | Nervous system disorders | MedDRA 19.0 | Systematic Assessment |
|
| Skin burning sensation | Nervous system disorders | MedDRA 19.0 | Systematic Assessment |
|
| Sneezing | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
|
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|
| 150mg |
|
| The analysis included a total of 29 patients on Generic B and brand name metoprolol ER, which is less than the initial plan of including 38 patients | Geometric mean ratio | 0.87 | 2-Sided | 90 | 0.79 | 0.95 | Equivalence | A bioequivalence (BE) test was performed for patients who were administered the 50mg dose. BE was declared if the 90% confidence interval for the ratio of the population geometric means of Cmax for Generic B to brand name metoprolol ER fell within 0.8 to 1.25 |
| t-test, 2 sided | Average Cmax for patients on the 50mg dose who were administered brand name metoprolol ER and Generic A were compared using a paired t-test (n=29) | 0.3 | Mean Difference (Final Values) | -2.5 | Standard Deviation | 12.6 | 2-Sided | 95 | -7.3 | 2.3 | Equivalence | A paired t-test was used to compare the mean values of Cmax for brand name metoprolol ER and Generic A at the 50mg dose. With a sample size of 38, at an alpha level of 0.025 (0.05/2 comparisons), using a 2-sided paired t-test, we would have >80% power to detect a 11% difference in Cmax. |
| The analysis included a total of 29 patients on Generic A and brand name metoprolol ER, which is less than a pre-planned sample size of 38. | Geometric mean ratio | 1.12 | 2-Sided | 90 | 1.02 | 1.23 | Equivalence | A bioequivalence (BE) test was performed for patients who were administered the 50mg dose. BE was declared if the 90% confidence interval for the ratio of the population geometric means of Cmax for Generic A to brand name metoprolol ER fell within 0.8 to 1.25 |
|
| Low to High Frequency Ratio: Quartile 3 |
|
| Low to High Frequency Ratio: Quartile 4 |
|
| Mixed Models Analysis |
| 0.0168 |
| Slope |
| -0.6 |
| Standard Error of the Mean |
| 0.3 |
| 2-Sided |
p for medication*quartile interaction considered significant if p<0.025. |
| Equivalence |
A mixed effect model for repeated measures was used to model medication effect on HRV comparing brand name metoprolol ER to Generic A, adjusting for quartile,(quartile*med) interaction, and treatment assignment. |
|
| Systolic Blood Pressure: quartile 3 |
|
| Systolic Blood Pressure: quartile 4 |
|
| Diastolic Blood Pressure: quartile 1 |
|
| Diastolic Blood Pressure: quartile 2 |
|
| Diastolic Blood Pressure: quartile 3 |
|
| Diastolic Blood Pressure: quartile 4 |
|
| Mixed Models Analysis |
| 0.671 |
| Slope |
| -0.543 |
| 2-Sided |
| Equivalence |
A mixed effect model for repeated measures was performed to model the 24-hour ambulatory diastolic blood pressure (DBP) by quartile for 35 patients receiving brand name metoprolol ER and Generic B. |
| Mixed Models Analysis | 0.200 | Slope | -2.371 | 2-Sided | Equivalence | A mixed effect model for repeated measures was performed to model the 24-hour ambulatory SBP by quartile for 35 patients receiving brand name metoprolol ER and Generic A. |
| Mixed Models Analysis | 0.068 | Slope | -2.3290 | 2-Sided | Equivalence | A mixed effect model for repeated measures was performed to model the 24-hour ambulatory DBP by quartile for 35 patients receiving brand name metoprolol ER and Generic A. |
|
| HR (beats per minute) Quartile three |
|
| HR (beats per minute) Quartile four |
|
| 0.368 |
| Slope |
| 1.1340 |
| 2-Sided |
| Equivalence |
A mixed effect model for repeated measures was performed to model the 24-hour HR by quartile for 35 patients receiving brand name metoprolol ER and Generic A. |