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Open-Labeled PK-PD Studies of Metoprolol ER

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ClinicalTrials.gov Identifier: NCT02417246
Recruitment Status : Active, not recruiting
First Posted : April 15, 2015
Last Update Posted : December 28, 2018
Sponsor:
Collaborator:
Food and Drug Administration (FDA)
Information provided by (Responsible Party):
University of Florida

Brief Summary:

Recently, the quality of generic metoprolol extended-release (ER) (Toprol XL, Activas,Wockhardt) 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 formulation. 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.

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.


Condition or disease Intervention/treatment Phase
Blood Pressure Drug: Toprol XL Device: SmartPill Capsule Procedure: Exercise Treadmill Procedure: 24 hour holter monitor Other: 24-hour pharmacokinetic parameters Drug: Wockhardt metoprolol Drug: Activas metoprolol Phase 4

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, Dr. Sigfried Schmidt 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 Group A- start with Toprol XL, switch to Wockhardt metoprolol, switch back to Toprol XL, then switch to Activas metoprolol
  • Study Group B- start with Toprol XL, switch to Activas metoprolol, switch back to Toprol XL, then switch to Wockhardt metoprolol.

Each study group will consist of treatment with Toprol XL for 2 periods, treatment with Wockhardt metoprolol for one period, and treatment with Activas metoprolol 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 parameters, 24-hour heart rate, 24-hour blood pressure, 24-hour holter monitor, exercise treadmill to induced heart rate, and a 24-hour gastric pH through SmartPill Capsule.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Open-Labeled Pharmacokinetic and Pharmacodynamic (PK-PD) Studies of Metoprolol ER
Study Start Date : August 2015
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : March 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Study Group A
This group will start with the brand name Toprol XL for 7 to 28 days, and then switch to Wockhardt metoprolol for 7 days, then they will switch back to Toprol XL for 7 to 28 days, and then they will be switch to Activas metoprolol for 7 days. During the times the switch will take place the following tests will be performed: 24-hour pharmacokinetic parameters, 24-hour heart rate, 24-hour blood pressure, 24-hour holter monitor, exercise treadmill to induced heart rate, and a 24-hour gastric pH through SmartPill Capsule.
Drug: Toprol XL
Both groups will receive this to compare if there is a difference in the clinical response.
Other Names:
  • Metoprolol extended-release (ER)
  • Wockhardt metoprolol
  • Activas metoprolol

Device: SmartPill Capsule
Both groups will have a continuous measure of pH by a SmartPill Capsule as it moves through the gastrointestinal tract.

Procedure: Exercise Treadmill
Both groups will have a treadmill exercise test performed.

Procedure: 24 hour holter monitor
Both groups will have a 24 hour holter monitor performed.

Other: 24-hour pharmacokinetic parameters
Both groups will have this test performed.
Other Name: Blood test

Drug: Wockhardt metoprolol
Both groups will receive this to compare if there is a difference in the clinical response.
Other Names:
  • Activas metoprolol
  • Metoprolol extended-release (ER)
  • Toprol XL

Drug: Activas metoprolol
Both groups will receive this to compare if there is a difference in the clinical response.
Other Names:
  • Metoprolol extended-release (ER)
  • Toprol XL
  • Wockhardt metoprolol

Active Comparator: Study Group B
This group will start with the brand name Toprol XL for 7 to 28 days, and then switch to Activas metoprolol for 7 days, then they will switch back to Toprol XL for 7 to 28 days, and then they will be switch to Wockhardt metoprolol for 7 days. During the times the switch will take place the following tests will be performed: 24-hour pharmacokinetic parameters, 24-hour heart rate, 24-hour blood pressure, 24-hour holter monitor, exercise treadmill to induced heart rate, and a 24-hour gastric pH through SmartPill Capsule.
Drug: Toprol XL
Both groups will receive this to compare if there is a difference in the clinical response.
Other Names:
  • Metoprolol extended-release (ER)
  • Wockhardt metoprolol
  • Activas metoprolol

Device: SmartPill Capsule
Both groups will have a continuous measure of pH by a SmartPill Capsule as it moves through the gastrointestinal tract.

Procedure: Exercise Treadmill
Both groups will have a treadmill exercise test performed.

Procedure: 24 hour holter monitor
Both groups will have a 24 hour holter monitor performed.

Other: 24-hour pharmacokinetic parameters
Both groups will have this test performed.
Other Name: Blood test

Drug: Wockhardt metoprolol
Both groups will receive this to compare if there is a difference in the clinical response.
Other Names:
  • Activas metoprolol
  • Metoprolol extended-release (ER)
  • Toprol XL

Drug: Activas metoprolol
Both groups will receive this to compare if there is a difference in the clinical response.
Other Names:
  • Metoprolol extended-release (ER)
  • Toprol XL
  • Wockhardt metoprolol




Primary Outcome Measures :
  1. Area under the plasma concentration versus time curve (AUC) of Toprol XL compared to Wockhardt metoprolol. [ Time Frame: 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 ]
  2. Area under the plasma concentration versus time curve (AUC) of Toprol XL compared to Activas metoprolol. [ Time Frame: 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 ]
  3. Peak Plasma Concentration (Cmax) of Toprol XL compared to Wockhardt metoprolol. [ Time Frame: 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 ]
  4. Peak Plasma Concentration (Cmax) of of Toprol XL compared to Activas metoprolol. [ Time Frame: 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 Outcome Measures :
  1. Changes at day 14, day 49, and day 84 for 24-hour Holter monitor for heart rate between different drug formulations. [ Time Frame: Changes at day 14, day 49, and day 84 ]
    The heart rate variability response to brand name versus generic formulations of metoprolol.

  2. Changes at day 14, day 49, and day 84 in blood pressure between the different drug formulations. [ Time Frame: Changes at day 14, day 49, and day 84 ]
    The blood pressure response to brand name versus generic formulations of metoprolol.

  3. Changes at day 14, day 49, and day 84 for exercise-induced heart rate. [ Time Frame: Changesatn day 14, day 49, and day 84 ]
    Exercise-induced heart rate with brand name versus generic formulations of metoprolol.

  4. Changes at day 14, day 49, and day 84 in gastrointestinal pH and proton pump inhibitors used. [ Time Frame: Changes at day 14, day 49, and day 84 ]
    The impact of gastric pH variation and proton pump inhibitors on drug concentration and response to brand name versus generic formulations of metoprolol.

  5. CYP2D6 genotype on drug concentration [ Time Frame: Day 1 ]
    Determine the impact of genotype on drug concentration of name brand versus generic formulations of metoprolol.

  6. CYP2D6 genotype on the response to different drug formulations. [ Time Frame: Day 1 ]
    Determine the impact of genotype on response to name brand versus generic formulations of metoprolol.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 UF Health Family Medicine clinic

Exclusion Criteria:

  • Documented secondary forms of HTN
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02417246


Locations
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United States, Florida
Family Medicine at Hampton Oaks Medical Plaza
Gainesville, Florida, United States, 32607
Oak Hammock at the University of Florida
Gainesville, Florida, United States, 32608
Sponsors and Collaborators
University of Florida
Food and Drug Administration (FDA)
Investigators
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Principal Investigator: Larisa Cavallari, PharmD University of Florida

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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT02417246     History of Changes
Other Study ID Numbers: IRB201500092
FD14-024 ( Other Grant/Funding Number: US FOOD AND DRUG ADMN )
OCR15985 ( Other Identifier: Universiy of Florida )
First Posted: April 15, 2015    Key Record Dates
Last Update Posted: December 28, 2018
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Florida:
pharmacokinetics
pharmacodynamics
pharmacogenetics
Additional relevant MeSH terms:
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Metoprolol
Anti-Arrhythmia Agents
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action