POTS: Effect of Ivabradine on Patients With Postural Orthostatic Tachycardia Syndrome

• Sponsor: University of California, San Diego (Other)
• Overall Status: Completed
• CT.gov ID: NCT03182725
• Collaborator: Amgen (Industry)
• Enrollment: 37
• Location: 1
• Arms: 2
• Actual Duration (Months): 27
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

Postural orthostatic tachycardia syndrome (POTS) occurs in approximately 500,000 Americans, but predominates in women with a 5:1 ratio. Patients with POTS experience debilitating tachycardia upon postural changes such as standing that impairs their quality of life. Tachycardia is clinically defined as a heart rate greater than 100 beats/min; and in POTS patients, the prolonged heart rate increase is greater than 30 beats/min or increases to 120 beats/min within the first ten minutes of a diagnostic tilt table test without postural hypotension. There are currently no effective treatment methods for POTS. However, several studies suggest Ivabradine could be a main treatment option for POTS because Ivabradine specifically inhibits the f-channels (If) within the sinoatrial (SA) node, which slows the heart rate. Currently in the US, Ivabradine is mainly prescribed to treat chronic heart failure. It is well tolerated in patients, but it is not commonly prescribed for POTS. It has been also used for treatment of inappropriate sinus tachycardia with good benefit. The hypothesis for this experiment is that Ivabradine will reduce tachycardia and improve functional status in patients with POTS.

Condition or Disease	Intervention/Treatment	Phase
Postural Orthostatic Tachycardia Syndrome	Drug: Ivabradine; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: 20 patients with POTS will receive Ivabradine treatment vs placebo for one month. Then there will be a one-month wash out period prior to the cross over in which patients who received Ivabradine will receive the placebo, and patients who initially were on placebo will now receive Ivabradine.20 patients with POTS will receive Ivabradine treatment vs placebo for one month. Then there will be a one-month wash out period prior to the cross over in which patients who received Ivabradine will receive the placebo, and patients who initially were on placebo will now receive Ivabradine.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of Ivabradine on Patients With Postural Orthostatic Tachycardia Syndrome (a Double-blind Placebo-parallel Group Trial)
• Actual Study Start Date: Feb 6, 2018
• Actual Primary Completion Date: May 8, 2020
• Actual Study Completion Date: May 8, 2020

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Patient will consume one placebo pill twice a day for one month.	Drug: Placebo; A substance that has no therapeutic effect and will act as a control.
Experimental: Ivabradine Patient will consume one dose of Ivabradine twice a day for one month.	Drug: Ivabradine; Ivabradine is prescribed for treatment of chronic heart failure through inhibition of the f-channels (If) within the sinoatrial node.

Outcome Measures

Primary Outcome Measures

1. Change in Heart Rate [Baseline and one month post-treatment]

   Orthostatic heart rate monitoring will be used to gauge heart rate changes.

Secondary Outcome Measures

1. Change in Quality of Life Via SF-36 Survey [Baseline and one month post-treatment]

   Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) The SF-36 has 36 questions and is an indicator of overall health status and is well-validated. The SF-36 has eight scaled scores; the scores are weighted sums of the questions in each section. The total score on the SF-36 ranges from 0 - 100 Lower scores = more disability, higher scores = less disability Sections: Vitality Physical functioning Bodily pain General health perceptions Physical role functioning Emotional role functioning Social role functioning Mental health

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects aged 18-65.

• Subjects must have POTS diagnosis (Hyperadrenergic Subtype with NE> 600pg/ml))

• Subjects with no structural heart disease

• Subject with no arrhythmias

• Subjects with norepinephrine levels greater than 600 pg/ml

• Subjects with normal CBC, Metabolic, and thyroid levels

Exclusion Criteria:

• Thyroid or adrenal disorders

• Drugs that interfere with Ivabradine (example: Cytochrome P450 drugs)

• Presentation of peripheral edema and discolored toes with peripheral autonomic neuropathy. Symptoms include: legs (reduced hair growth, cramps), toes (blue color), legs/feet (wounds, ulcers that do not heal), and muscles (numbness, heaviness)

• Subjects who have had a history of systemic illnesses (acute or chronic infectious); autoimmune/ inflammatory disease, cancer, COPD, anemia, diabetes, or psychiatric illness

• Subjects with resting heart rate< 60beats/min, atrial fibrillation, advanced AV blocks, sinus disease, and acute decompensated heart failure and severe hepatic impairment.

• Smokers or alcohol abuse

• Pregnant or breastfeeding mothers

• Woman of childbearing potential who are unwilling to use highly effective contraception during treatment and for an additional one month after discontinuing the study drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	La Jolla	California	United States	92093

Sponsors and Collaborators

• University of California, San Diego
• Amgen

Investigators

• Principal Investigator: Pam Taub, M.D., University of California, San Diego

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 7, 2020
• Informed Consent Form - Mar 7, 2020

More Information

Publications

None provided.

• Responsible Party: Pam Taub, MD, Associate Professor of Medicine, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT03182725
• Other Study ID Numbers: 170694
• First Posted: Jun 9, 2017
• Last Update Posted: Jun 29, 2021
• Last Verified: Jun 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Pam Taub, MD, Associate Professor of Medicine, University of California, San Diego: POTS; tachycardia; ivabradine
• Additional relevant MeSH terms: Postural Orthostatic Tachycardia Syndrome; Tachycardia; Syndrome

Study Results

Participant Flow

Pre-assignment Detail	10 participants signed the consent form but did not pass the screening assessments. 1 participant signed the consent form and then withdrew prior to randomization.

Arm/Group Title	Placebo in Arm A, Ivabradine in Arm B	Ivabradine in Arm A, Placebo in Arm B
Arm/Group Description	In the first Arm, Patient will consume one placebo pill twice a day for one month. After the first arm, there will be a one-week washout. After washout, the patient will commence Arm B where they consume ne dose of ivabradine twice a day for one month. Placebo: A substance that has no therapeutic effect and will act as a control. In the second arm, patient will consume one dose of Ivabradine twice a day for one month. Ivabradine: Ivabradine is prescribed for treatment of chronic heart failure through inhibition of the f-channels (If) within the sinoatrial node.	Patient will consume one dose of Ivabradine twice a day for one month. In the first Arm, Patient will consume one dose of ivabradine twice a day for one month. After the first arm, there will be a one-week washout. After washout, the patient will commence Arm B where they consume one placebo pill twice a day for one month Placebo: A substance that has no therapeutic effect and will act as a control. In the second arm, patient will consume one dose of Ivabradine twice a day for one month. Ivabradine: Ivabradine is prescribed for treatment of chronic heart failure through inhibition of the f-channels (If) within the sinoatrial node.
Period Title: Treatment Arm 1 (First Half of Study)
STARTED	16	10
COMPLETED	16	7
NOT COMPLETED	0	3
Period Title: Treatment Arm 1 (First Half of Study)
STARTED	16	6
COMPLETED	16	6
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Placebo in Arm A, Ivabradine in Arm B	Ivabradine in Arm A, Placebo in Arm B	Total
Arm/Group Description	In the first Arm, Patient will consume one placebo pill twice a day for one month. Placebo: A substance that has no therapeutic effect and will act as a control. In the second arm, patient will consume one dose of Ivabradine twice a day for one month. Ivabradine: Ivabradine is prescribed for treatment of chronic heart failure through inhibition of the f-channels (If) within the sinoatrial node.	In the first arm of the study, patient will consume one dose of Ivabradine twice a day for one month. Ivabradine: Ivabradine is prescribed for treatment of chronic heart failure through inhibition of the f-channels (If) within the sinoatrial node. In the second arm, patient will consume one placebo pill twice a day for one month. Placebo: A substance that has no therapeutic effect and will act as a control.	Total of all reporting groups
Overall Participants	16	10	26
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	16 100%	10 100%	26 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.75 (10.7)	27.8 (11.15)	34.8 (11.5)
Sex: Female, Male (Count of Participants)
Female	15 93.8%	10 100%	25 96.2%
Male	1 6.3%	0 0%	1 3.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 6.3%	0 0%	1 3.8%
Not Hispanic or Latino	15 93.8%	10 100%	25 96.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	13 81.3%	10 100%	23 88.5%
More than one race	2 12.5%	0 0%	2 7.7%
Unknown or Not Reported	1 6.3%	0 0%	1 3.8%
Region of Enrollment (participants) [Number]
United States	16 100%	10 100%	26 100%

Outcome Measures

1. Primary Outcome

Title	Change in Heart Rate
Description	Orthostatic heart rate monitoring will be used to gauge heart rate changes.
Time Frame	Baseline and one month post-treatment

Outcome Measure Data

Analysis Population Description

In total, 22 patients with hyperadrenergic POTS as the predominant subtype completed a randomized, double-blinded, placebo-controlled, crossover trial with ivabradine. Patients were randomized to start either ivabradine or placebo for 1 month, and then were crossed over to the other treatment for 1 month. Heart rate, QOL, and plasma NE levels were measured at baseline and at the end of each treatment month.

Arm/Group Title	Placebo	Ivabradine
Arm/Group Description	In the first Arm, Patient will consume one placebo pill twice a day for one month. Placebo: A substance that has no therapeutic effect and will act as a control.	Patient will consume one dose of Ivabradine twice a day for one month. Ivabradine: Ivabradine is prescribed for treatment of chronic heart failure through inhibition of the f-channels (If) within the sinoatrial node.
Measure Participants	22	22
Mean (Standard Deviation) [beats per minute]	17.0 (10.4)	13.1 (8.6)

2. Secondary Outcome

Title	Change in Quality of Life Via SF-36 Survey
Description	Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) The SF-36 has 36 questions and is an indicator of overall health status and is well-validated. The SF-36 has eight scaled scores; the scores are weighted sums of the questions in each section. The total score on the SF-36 ranges from 0 - 100 Lower scores = more disability, higher scores = less disability Sections: Vitality Physical functioning Bodily pain General health perceptions Physical role functioning Emotional role functioning Social role functioning Mental health
Time Frame	Baseline and one month post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ivabradine
Arm/Group Description	In the first Arm, Patient will consume one placebo pill twice a day for one month. Placebo: A substance that has no therapeutic effect and will act as a control.	Patient will consume one dose of Ivabradine twice a day for one month. Ivabradine: Ivabradine is prescribed for treatment of chronic heart failure through inhibition of the f-channels (If) within the sinoatrial node.
Measure Participants	22	22
Mean (Standard Deviation) [units on a scale]	44.1 (22.4)	53.4 (27)

Adverse Events

Time Frame	3 months
Adverse Event Reporting Description	Adverse events were monitored in all enrolled participants over a period of 3 months.
Arm/Group Title	Placebo		Ivabradine
Arm/Group Description	Patient will consume one placebo pill twice a day for one month. Placebo: A substance that has no therapeutic effect and will act as a control.		Patient will consume one dose of Ivabradine twice a day for one month. Ivabradine: Ivabradine is prescribed for treatment of chronic heart failure through inhibition of the f-channels (If) within the sinoatrial node.
All Cause Mortality
	Placebo		Ivabradine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/37 (0%)
Serious Adverse Events
	Placebo		Ivabradine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/37 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Ivabradine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/37 (0%)

Limitations/Caveats

smaller sample size many patients suspected they were on ivabradine patients were only on 1 month of ivabradine; longer study duration may be warranted to assess potential long term effects

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.