Open-Labeled PK-PD Studies of Metoprolol ER

Phase 4

Completed

• Conditions: Blood Pressure
• Interventions: Drug: brand name metoprolol ER; Drug: Generic A; Drug: Generic B

• Registration Number: NCT02417246
• Lead Sponsor: University of Florida

Brief Summary

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.

Detailed Description

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.

* Study Sequence A- 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- start with brand name metoprolol ER, switch to Generic A metoprolol, switch back to brand name metoprolol ER, then switch to Generic B metoprolol.

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.

Study Timeline

• Study First Submitted: 2015-04-01
• Study First Submitted QC: 2015-04-10
• Study First Posted: 2015-04-15
• Study Start: 2015-08
• Primary Completion: 2018-06-06
• Study Completion: 2018-06-06
• Results First Submitted: 2019-07-29
• Results First Submitted QC: 2019-10-19
• Results First Posted: 2019-11-08
• Status Verified: 2020-02
• Last Update Submitted: 2020-02-06
• Last Update Posted: 2020-02-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 61

Inclusion Criteria

• Subjects will be targeted for enrollment based on current treatment of their hypertension with a beta-blocker or known tolerability to a beta-blocker based on their previous participation in the Pharmacogenomic Evaluation of Antihypertensive Responses studies (PEAR-1 and PEAR-2). If necessary to meet enrollment targets, additional patients will be recruited from the existing patient population in the University of Florida Health Family Medicine clinic or through other means.

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Exclusion Criteria

• Documented secondary forms of hypertension
• Known cardiovascular disease (including history of angina pectoris, myocardial infarction, coronary revascularization procedure, heart failure, or presence of a cardiac pacemaker)
• Known cerebrovascular disease (including stroke and TIA)
• Known peripheral vascular disease
• Diabetes mellitus (Type 1 or 2) (defined as a diabetes diagnosis in the medical record or fasting blood glucose greater than or equal to 126 mg per dl or nonfasting blood glucose greater than or equal to 200 mg per dl on screening laboratories)
• Systolic blood pressure (SBP) greater than180 mm Hg on screening visit
• Heart rate less than 55 bpm on screening visit (in the absence of treatment with a beta-blocker)
• Renal insufficiency (serum creatinine greater than 1.5 in men or greater than 1.4 in women on screening laboratories)
• Liver enzymes (ALT and or AST) greater than 3 times the upper limit of normal on screening laboratories.
• Known Raynaud's phenomenon
• Known asthma or chronic obstructive pulmonary disease
• Pregnancy or lactation
• Gastric bezoar
• Swallowing disorders
• Strictures
• Fistulas
• GI obstruction
• Severe dysphagia
• Crohn's disease
• Diverticulitis
• Any implantable electromedical device
• Use of non-dihydropyridine calcium channel blockers (diltiazem or verapamil)
• Use of digoxin to avoid additive effects on heart rate

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Study Sequence B	brand name metoprolol ER	Start with brand name metoprolol ER, switch to Generic A metoprolol, switch back to brand name metoprolol ER, then switch to Generic B metoprolol.
Study Sequence A	brand name metoprolol ER	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 A	Generic A	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 A	Generic B	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	Generic A	Start with brand name metoprolol ER, switch to Generic A metoprolol, switch back to brand name metoprolol ER, then switch to Generic B metoprolol.
Study Sequence B	Generic B	Start with brand name metoprolol ER, switch to Generic A metoprolol, switch back to brand name metoprolol ER, then switch to Generic B metoprolol.

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration Versus Time Curve (AUC)	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	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.
Peak Plasma Concentration (Cmax) of Metoprolol Succinate	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	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.

Secondary Outcome Measures

Name	Time	Method
The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate.	Heart rate variability (Low-to-High Frequency Ratio) over each quartile of 6 hours in the 24-hr period	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.
Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A)	Average value over each quartile of 6 hours in the 24-hr period	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).
Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate	Average value over each quartile of 6 hours in the 24-hr period	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)

Trial Locations

Locations (2)

Family Medicine at Hampton Oaks Medical Plaza; 🇺🇸 Gainesville, Florida, United States

Oak Hammock at the University of Florida; 🇺🇸 Gainesville, Florida, United States