Propranolol vs Ivabradine for POTS

Overseen By Shahana Safdar

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Calgary

Must not be taking: Antiarrhythmics, Calcium channel blockers

Disqualifiers: Heart disease, Diabetes, Asthma, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

20 Participants Needed

Trial Summary

What is the purpose of this trial?

1.0 BACKGROUND Postural tachycardia syndrome (POTS) is a disorder of chronic orthostatic intolerance characterized by symptoms of palpitations, lightheadedness, chest discomfort, shortness of breath, blurred vision, and mental clouding. These symptoms occur during standing and are associated with a marked increase in heart rate (HR) in the absence of hypotension, which typically resolve when sitting or lying down. Most importantly, POTS is associated with a very poor quality of life and significant functional disability. POTS patients commonly experience mental clouding ("brain fog") even while lying down or seated, which poses significant limitations to daily activities . Unfortunately, there is a relative paucity in the literature assessing therapies for POTS patients. Given that excessive tachycardia on standing is a fundamental component of this syndrome, a handful of studies have evaluated medications that reduce HR. Ivabradine is newer drug that is a selective If channel blocker that reduces HR without affecting other cardiovascular functions. 2.0 RATIONALE / STUDY PURPOSE The investigators propose to compare the efficacy of propranolol and ivabradine on HR response to standing, and symptom burden in patients with POTS. 3.0 Study Design This will be a single-center double-blind placebo-controlled randomized crossover trial conducted in patients with POTS to compare effects of (1) oral ivabradine 5 mg bid plus placebo BID (to fill out a QID schedule); (2) oral propranolol 10 mg qid; and (3) oral placebo qid in POTS patients. After a baseline screening assessment following a washout period of 7 days, participants will be randomized to start with a 4-week course of either ivabradine, propranolol or placebo. The other two treatments will be given in separate 4-week courses with a 7-day washout period between phases, with each participant acting as his or her own control. At the end of each 4-week phase, participants will complete the symptom-rating and HRQOL questionnaires, and also undergo tilt table testing to assess the change in HR at 10 min with head up tilt. Participants will undergo POTS testing at baseline and at the end of each 4-week treatment course. This will involve a total of 4 separate study visits.

Will I have to stop taking my current medications?

Participants must stop taking certain medications before joining the trial. There is a 7-day washout period (time without taking certain medications) required before starting the study treatments. If you are currently on beta-blockers or ivabradine, you need to be able to safely stop them before the study.

What data supports the effectiveness of the drug propranolol for treating POTS?

Propranolol has been shown to effectively control blood pressure in patients with hypertension and has antiarrhythmic effects, which may suggest potential benefits for managing symptoms in POTS (a condition characterized by an abnormal increase in heart rate when standing). ^{1 2 3 4 5}

Is propranolol generally safe for human use?

Propranolol has been studied in various formulations and is generally considered safe for human use, as it has been used effectively for conditions like angina, hypertension, and hyperthyroidism. Studies have shown that different brands and formulations of propranolol do not significantly differ in their safety profiles. ^{2 3 6 7 8}

How does the drug propranolol differ from other treatments for POTS?

Propranolol is a beta-blocker that works by slowing down the heart rate, which can help manage symptoms of POTS (Postural Orthostatic Tachycardia Syndrome) by reducing the heart's workload. Unlike some other treatments, propranolol has been shown to have a consistent bioavailability across different brands, ensuring reliable effects in controlling heart rate. ^{1 2 4 9 10}

Research Team

Satish R Raj, MD

Principal Investigator

University of Calgary

Eligibility Criteria

This trial is for adults aged 18-60 with Postural Tachycardia Syndrome (POTS) who can consent to participate. Excluded are those with low heart rates or blood pressure, structural heart disease, diabetes, uncontrolled asthma, pregnancy, severe liver issues, certain medication use and specific heart rhythm problems.

Inclusion Criteria

I am either a man or a woman.

I have been diagnosed with Postural Tachycardia Syndrome.

Able and willing to provide informed consent

Exclusion Criteria

I am not taking specific heart rhythm or blood pressure medications.

I am not taking strong medications that affect liver enzyme CYP 3A4.

Your blood pressure while lying down is lower than 90/60 mmHg.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment Phase 1

Participants receive a 4-week course of either ivabradine, propranolol, or placebo, followed by a 7-day washout period.

5 weeks

1 visit (in-person) at the end of the phase

Treatment Phase 2

Participants receive a 4-week course of the second treatment (ivabradine, propranolol, or placebo), followed by a 7-day washout period.

5 weeks

1 visit (in-person) at the end of the phase

Treatment Phase 3

Participants receive a 4-week course of the final treatment (ivabradine, propranolol, or placebo).

4 weeks

1 visit (in-person) at the end of the phase

Follow-up

Participants are monitored for safety and effectiveness after treatment.

4 weeks

Treatment Details

Interventions

• Ivabradine
• Propranolol

Trial Overview The study tests the effectiveness of Ivabradine versus Propranolol in managing POTS symptoms and heart rate upon standing. It's a double-blind placebo-controlled crossover trial where participants try each treatment for 4 weeks with breaks in between.

Participant Groups

Group I: 1st drug Ivabradine Active Control 3 Interventions

Patients will take Ivabradine first followed by Propranolol and Placebo

Group II: 2nd drug Ivabradine Active Control 3 Interventions

Patients will take either Propranolol or placebo first and then Ivabradine

Group III: 3rd drug Ivabradine Active Control 3 Interventions

Patients will take Propranolol and placebo first and then Ivabradine

Ivabradine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Corlanor for:

• Heart failure
• Angina

Approved in European Union as Procoralan for:

• Angina
• Heart failure

Approved in Canada as Lancora for:

• Angina
• Heart failure

Who Is Running the Clinical Trial?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

Dysautonomia International

Collaborator

Trials

6

Recruited

420+

Findings from Research

In a single-blind study involving 13 patients with mild to moderately severe hypertension, the combination of propranolol (80 mg) and bendrofluazide (2.5 mg) effectively controlled blood pressure in 12 patients over a 12-week period.

The treatment did not result in significant changes in biochemical parameters or ECG readings, and no serious side effects were reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fixed ratio combination of propranolol and bendrofluazide in the treatment of hypertension. Pandhi, P., Sharma, BK., Sharma, PL., et al.[2013]

A study involving six healthy adult volunteers tested four different brands of propranolol (Inderal, Ciplar, Corbeta, and Propal) to assess variations in how the body absorbs and responds to the medication.

The results showed no significant differences in the pharmacokinetic (how the drug is processed in the body) and pharmacodynamic (the drug's effects on the body) parameters among the brands, indicating they are likely interchangeable in terms of efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative pharmacokinetic and pharmacodynamic study of four different brands of propranolol in normal volunteers. Biswas, NR., Garg, SK., Kumar, N., et al.[2013]

In a study of 181 patients with organic heart disease, sotalol demonstrated a significantly greater reduction in ventricular premature complexes (VPCs) per hour compared to propranolol, achieving an 80% reduction versus 50%.

Sotalol was also more effective in suppressing ventricular tachycardia events, with an 89% reduction compared to 78% for propranolol, highlighting its superior antiarrhythmic efficacy due to its combined type II and type III properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sotalol Is More Powerful Than Propranolol in Suppressing Complex Ventricular Arrhythmias. Deedwania, PC.[2019]

In a study of 37 patients with a history of heart issues and inducible ventricular tachycardia (VT), adding propranolol to conventional antiarrhythmic drugs significantly increased the ventricular effective refractory period and VT cycle length, enhancing the antiarrhythmic effects.

Propranolol alone or in combination with type I antiarrhythmic drugs rendered 10 patients noninducible for VT, demonstrating its potential as an effective treatment option, with a follow-up showing only one sudden death and manageable recurrence rates over 20 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of propranolol added to a type I antiarrhythmic agent for sustained ventricular tachycardia secondary to coronary artery disease. Friehling, TD., Lipshutz, H., Marinchak, RA., et al.[2019]

Inderex, a combination of bendrofluazide and sustained-release propranolol, was found to be more effective in lowering blood pressure compared to either medication alone in a study of 21 patients.

The study indicated that there were no significant differences in treatment responses across different age groups, suggesting that Inderex is a suitable option for a wide range of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of hypertension with a fixed ratio combination of long-acting propranolol and bendrofluazide, and influence of age of the subject. Herrick, AL., Davis, JM., Weir, RJ.[2013]

In a study involving anesthetized dogs, four beta-adrenergic receptor antagonists (sotalol, nadolol, atenolol, and propranolol) were found to equally increase the electrical threshold for inducing ventricular fibrillation, indicating their potential effectiveness in preventing dangerous heart rhythms.

The antifibrillatory effects of these drugs were not linked to their beta-blocking abilities or changes in heart conduction and excitability, suggesting that their mechanism of action may involve other cardiac properties beyond just beta-adrenergic blockade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antifibrillatory properties of the beta-adrenergic receptor antagonists, nadolol, sotalol, atenolol and propranolol, in the anesthetized dog. Patterson, E., Lucchesi, BR.[2018]

Long-acting propranolol (Inderal LA) provides a controlled release of the medication, maintaining higher plasma concentrations over 24 hours compared to conventional tablets, which helps ensure consistent beta-adrenoceptor blockade.

This formulation is equally effective for treating conditions like angina pectoris, hypertension, and hyperthyroidism, while potentially improving patient adherence to treatment due to simplified dosing regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-acting propranolol (Inderal LA): pharmacokinetics, pharmacodynamics and therapeutic use. Mishriki, AA., Weidler, DJ.[2019]

Controlled-release formulations of propranolol, specifically Elanol and Inderal LA, provide smoother serum level profiles and delayed peak times compared to conventional propranolol, indicating a potentially more stable therapeutic effect.

Elanol showed greater bioavailability than Inderal LA, suggesting that long-acting formulations can be effective without the drawbacks of reduced bioavailability due to first-pass metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and pharmacodynamic studies with a new controlled-release formulation of propranolol in normal volunteers: a comparison with other commercially available formulations. Perucca, E., Grimaldi, R., Gatti, G., et al.[2019]

In two pharmacokinetic studies involving 48 healthy volunteers, newly formulated generic propranolol HCl tablets were found to have the same rate and extent of absorption as the brand Inderal tablets, indicating bioequivalence.

Both studies showed no statistically significant differences in key pharmacokinetic parameters (AUC, Cmax, tmax, and Cmin) between the test and reference tablets, confirming that the generic formulation is as effective as the branded version.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioavailability of propranolol hydrochloride tablet formulations: application of multiple dose crossover studies. Eldon, MA., Kinkel, AW., Daniel, JE., et al.[2019]

The long-acting propranolol hydrochloride (LA 60 mg) formulation shows sustained-release characteristics, with a longer half-life and delayed peak concentration compared to conventional propranolol (20 mg tid), indicating it may provide more stable drug levels over time.

Pharmacodynamic effects, such as heart rate and blood pressure response, were similar between LA 60 mg and the conventional 20 mg dosing, suggesting that LA 60 mg can effectively replace the more frequent dosing without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of long-acting propranolol 60-mg capsules: a comparative evaluation. Marino, MR., Dey, M., Garg, DC., et al.[2019]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Fixed ratio combination of propranolol and bendrofluazide in the treatment of hypertension. [2013]

2. Germany pubmed.ncbi.nlm.nih.gov

Comparative pharmacokinetic and pharmacodynamic study of four different brands of propranolol in normal volunteers. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Sotalol Is More Powerful Than Propranolol in Suppressing Complex Ventricular Arrhythmias. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Effectiveness of propranolol added to a type I antiarrhythmic agent for sustained ventricular tachycardia secondary to coronary artery disease. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Treatment of hypertension with a fixed ratio combination of long-acting propranolol and bendrofluazide, and influence of age of the subject. [2013]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Antifibrillatory properties of the beta-adrenergic receptor antagonists, nadolol, sotalol, atenolol and propranolol, in the anesthetized dog. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Long-acting propranolol (Inderal LA): pharmacokinetics, pharmacodynamics and therapeutic use. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and pharmacodynamic studies with a new controlled-release formulation of propranolol in normal volunteers: a comparison with other commercially available formulations. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Bioavailability of propranolol hydrochloride tablet formulations: application of multiple dose crossover studies. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of long-acting propranolol 60-mg capsules: a comparative evaluation. [2019]