Back to resultsIvabradine for Long-Term Effects of COVID-19 With POTS Cohort (COVIVA)
Primary Purpose
Long Haul COVID, Postural Orthostatic Tachycardia Syndrome
Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Ivabradine
Sponsored by
About this trial
This is an interventional treatment trial for Long Haul COVID
Eligibility Criteria
Inclusion Criteria:
- Age 18-80
- History of documented COVID-19 infection of any severity to include a positive COVID-19 PCR, or antibody test
- Meets criteria for 'long-haul' COVID-19 with symptoms >12 weeks following acute illness
- Able and willing to provide informed consent and participate for study duration
- Willing to participate in the nested randomized controlled trial of ivabradine if RCT enrollment criteria are met
- Access to a primary healthcare provider and proof of health insurance
Inclusion Criteria for non-LHC Cohort
- Age 18-80
- History of documented COVID-19 infection of any severity to include a positive COVID-19 PCR, or antibody test
- Does not meet criteria for 'long-haul' COVID-19
- Able and willing to provide informed consent and participate for study duration
- Willing to participate in the nested randomized controlled trial of ivabradine if RCT enrollment criteria are met
- Access to a primary healthcare provider and proof of health insurance
Inclusion Criteria for POTS RCT:
Age 18-80; Meets criteria for 'long-haul' COVID-19
- Documented history of COVID-19 infection made available to study team 1914
- Lack of documented history, but evidence of infection from sensitive antibody tests
- Able and willing to provide informed consent and participate for study duration
- Volunteers with or without LHC combined with POTS based on an increase in comparing the supine heart rate to standing heart rate >20 beats per minute with a drop in systolic blood pressure less than 20 mm Hg or a drop in diastolic blood pressure less than 10 mm Hg will be included, OR additionally, volunteers with or without LHC and a 24-hour mean heart rate of 90 beats per minute or more (in sinus rhythm) will be diagnosed with IST and be included.
- For females of childbearing age - willing to use a highly effective form of contraceptive with <1% failure rate or practice abstinence for the duration of the study
Exclusion Criteria:
- Resting heart rate <60 bpm
- Atrial fibrillation
- Supraventricular tachycardia
Allergic reaction or known contraindications to study drug
- Acute decompensated heart failure
- Clinically significant hypotension, defined as a drop in systolic BP >20 mmHg or drop in diastolic >10 mmHg during orthostatic vital signs testing.
- Sick sinus syndrome, sinoatrial block or 3rd degree AV block, unless a functioning demand pacemaker is present
- Clinically significant bradycardia
- Severe hepatic impairment
- Pacemaker dependence (heart rate maintained exclusively by the pacemaker)
- Concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors or inducers
- Pregnant/lactating females
- Impaired gastrointestinal absorption that would preclude oral drug administration
Taking any of the following without discontinuation in consultation with the volunteer's healthcare provider and a one-week washout period:
- ivabradine
- beta-blockers
- calcium- channel blockers
- cholinesterase inhibitors (pyridostigmine),
- vasoconstrictors (midodrine, octreotide, droxidopa, stimulants)
- sympatholytics (clonidine, methyldopa)
- blood volume enhancers (fludrocortisone, desmopressin, salt supplementation)
- oral ketoconazole (contraindicated)
Acute suicidality identified at screening
-
Sites / Locations
- Uniformed Services UniversityRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
No Intervention
No Intervention
Placebo Comparator
Arm Label
Long Haul COVID
Post COVID without LHC
Ivabradine RCT Arms
Arm Description
Persistent signs and/or symptoms >12 weeks post Covid-infection N = 200 evaluable subjects.
No persistent signs and/or symptoms >12 weeks N = 50 evaluable subjects.
If POTS or IST is present for participants within either of these cohorts, then they will be assigned to one of two arms of the Ivabradine RCT [2:1 treatment:control]. RCT Arms: at least 36 evaluable subjects will be enrolled to two arms in a 2:1 ratio. More may be enrolled, depending on the number from the overall COVID-19 cohort who qualify. IVA (Ivabradine) - at least 24 evaluable subjects Placebo - at least 12 evaluable subjects
Outcomes
Primary Outcome Measures
Change in standing heart rate following 3 months treatment.
The primary endpoint will be a reduction in standing heart rate at 3 months. Up to 200 evaluable subjects will be enrolled in the general LHC cohort with the expectation that at least 20% of those recruited will have POTS or otherwise IST causing symptoms appropriate for enrollment to the nested RCT (ivabradine vs. placebo). This will yield an RCT study population of at least 40 evaluable subjects. Study recruiting will be aimed at volunteers with features of POTS. Drop-outs in all cohorts may be replaced.
Secondary Outcome Measures
Full Information
NCT ID
NCT05481177
First Posted
July 28, 2022
Last Updated
March 21, 2023
Sponsor
Uniformed Services University of the Health Sciences
1. Study Identification
Unique Protocol Identification Number
NCT05481177
Brief Title
Ivabradine for Long-Term Effects of COVID-19 With POTS Cohort
Acronym
COVIVA
Official Title
Comparative Cohort Study of Post-acute COVID-19 Infection With a Nested, Randomized Controlled Trial of Ivabradine for Those With Postural Orthostatic Tachycardia Syndrome.
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 2, 2023 (Anticipated)
Primary Completion Date
September 1, 2024 (Anticipated)
Study Completion Date
September 1, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Uniformed Services University of the Health Sciences
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of the study is three-fold. The primary aim is to identify the proportion of Long-Haul COVID (LHC) and non-LHC volunteers with relevant symptoms actually have postural orthostatic tachycardia syndrome (POTS). The second is to determine benefit of ivabradine treatment. Ivabradine is a drug approved to treat tachycardia in persons with heart failure. The third is to characterize risk factors and outcomes among volunteers with and without LHC. This will include comparison with COVID-19-positive individuals who did not develop long-COVID symptoms.
The study will improve basic and applied knowledge of LHC and its associated cardiovascular and autonomic consequences. Cellular and molecular characterization of LHC and non-LHC participants will be performed with a nested clinical trial for Ivabradine responsiveness on reduction of tachycardia. It is hoped that a greater understanding of LHC, and related autonomic dysfunction in particular will help to identify treatment paradigms and therapeutic targets for improving recovery and enhancing health for those affected.
Detailed Description
The study will first attempt to address the frequency of clinically confirmed POTS in those with persistent COVID-19 symptoms, particularly those symptoms suggestive of autonomic dysfunction.
Those with confirmed POTS or Inappropriate sinus tachycardia (IST) will be randomized to ivabradine or placebo to determine efficacy in reducing heart rate as a putative surrogate for POTS disease as well as effects on POTS symptoms. The biopsychosocial mechanisms of LHC and POTS will also be explored. Specific objectives will be:
To assess the frequency and severity of fatigue, dyspnea, headache, and confusion and other suggestive symptoms among volunteers with and without LHC and measure the occurrence of clinically confirmed POTS or IST-in relation to these symptoms.
To assess whether treatment with ivabradine will significantly reduce heart rate and improve symptoms and quality of life among subjects manifesting typical POTS or similar autonomic dysregulation.
To characterize the immunoinflammatory and genomic factors associated with LHC and POTS among those with LHC. In particular, to determine whether those with POTS have differential expression of genes and/or proteins associated with autonomic nervous system function. To determine whether these factors reflect a genetic predisposition.
To determine whether wearable automated ambulatory monitoring with existing FDA-approved devices will permit improved diagnostic accuracy for POTS.
To determine the degree to which LHC induced autonomic instability and whether it is associated with induced inflammation and/or dysregulation
To evaluate potential contribution of psychological symptoms and the interplay between psychosocial symptoms, quality of life, cognitive symptoms, and physiologic responses induced by LHC.
To determine whether LHC improves following vaccination (in the limited number of cases where late vaccination occurs) and/or "breakthrough" clinical COVID-19 infection.
Assess whether individuals with LHC have different antibody and/or cellular immune responses to SARS-CoV-2 antigens compared to infected individuals who did not develop LHC.
Assess whether specific plasma protein markers of dysregulated blood coagulation, which were significantly correlated with immunothrombosis in severe COVID-19, persist in individuals with LHC.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Long Haul COVID, Postural Orthostatic Tachycardia Syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
250 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Long Haul COVID
Arm Type
No Intervention
Arm Description
Persistent signs and/or symptoms >12 weeks post Covid-infection N = 200 evaluable subjects.
Arm Title
Post COVID without LHC
Arm Type
No Intervention
Arm Description
No persistent signs and/or symptoms >12 weeks N = 50 evaluable subjects.
Arm Title
Ivabradine RCT Arms
Arm Type
Placebo Comparator
Arm Description
If POTS or IST is present for participants within either of these cohorts, then they will be assigned to one of two arms of the Ivabradine RCT [2:1 treatment:control].
RCT Arms: at least 36 evaluable subjects will be enrolled to two arms in a 2:1 ratio. More may be enrolled, depending on the number from the overall COVID-19 cohort who qualify.
IVA (Ivabradine) - at least 24 evaluable subjects Placebo - at least 12 evaluable subjects
Intervention Type
Drug
Intervention Name(s)
Ivabradine
Intervention Description
Ivabradine is a drug approved to treat tachycardia in volunteers with heart failure. This study is to determine benefit of ivabradine treatment in postural orthostatic tachycardia syndrome (POTS) in participants with Long haul Covid.
Primary Outcome Measure Information:
Title
Change in standing heart rate following 3 months treatment.
Description
The primary endpoint will be a reduction in standing heart rate at 3 months. Up to 200 evaluable subjects will be enrolled in the general LHC cohort with the expectation that at least 20% of those recruited will have POTS or otherwise IST causing symptoms appropriate for enrollment to the nested RCT (ivabradine vs. placebo). This will yield an RCT study population of at least 40 evaluable subjects. Study recruiting will be aimed at volunteers with features of POTS. Drop-outs in all cohorts may be replaced.
Time Frame
3 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age 18-80
History of documented COVID-19 infection of any severity to include a positive COVID-19 PCR, or antibody test
Meets criteria for 'long-haul' COVID-19 with symptoms >12 weeks following acute illness
Able and willing to provide informed consent and participate for study duration
Willing to participate in the nested randomized controlled trial of ivabradine if RCT enrollment criteria are met
Access to a primary healthcare provider and proof of health insurance
Inclusion Criteria for non-LHC Cohort
Age 18-80
History of documented COVID-19 infection of any severity to include a positive COVID-19 PCR, or antibody test
Does not meet criteria for 'long-haul' COVID-19
Able and willing to provide informed consent and participate for study duration
Willing to participate in the nested randomized controlled trial of ivabradine if RCT enrollment criteria are met
Access to a primary healthcare provider and proof of health insurance
Inclusion Criteria for POTS RCT:
Age 18-80; Meets criteria for 'long-haul' COVID-19
Documented history of COVID-19 infection made available to study team 1914
Lack of documented history, but evidence of infection from sensitive antibody tests
Able and willing to provide informed consent and participate for study duration
Volunteers with or without LHC combined with POTS based on an increase in comparing the supine heart rate to standing heart rate >20 beats per minute with a drop in systolic blood pressure less than 20 mm Hg or a drop in diastolic blood pressure less than 10 mm Hg will be included, OR additionally, volunteers with or without LHC and a 24-hour mean heart rate of 90 beats per minute or more (in sinus rhythm) will be diagnosed with IST and be included.
For females of childbearing age - willing to use a highly effective form of contraceptive with <1% failure rate or practice abstinence for the duration of the study
Exclusion Criteria:
Resting heart rate <60 bpm
Atrial fibrillation
Supraventricular tachycardia
Allergic reaction or known contraindications to study drug
Acute decompensated heart failure
Clinically significant hypotension, defined as a drop in systolic BP >20 mmHg or drop in diastolic >10 mmHg during orthostatic vital signs testing.
Sick sinus syndrome, sinoatrial block or 3rd degree AV block, unless a functioning demand pacemaker is present
Clinically significant bradycardia
Severe hepatic impairment
Pacemaker dependence (heart rate maintained exclusively by the pacemaker)
Concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors or inducers
Pregnant/lactating females
Impaired gastrointestinal absorption that would preclude oral drug administration
Taking any of the following without discontinuation in consultation with the volunteer's healthcare provider and a one-week washout period:
ivabradine
beta-blockers
calcium- channel blockers
cholinesterase inhibitors (pyridostigmine),
vasoconstrictors (midodrine, octreotide, droxidopa, stimulants)
sympatholytics (clonidine, methyldopa)
blood volume enhancers (fludrocortisone, desmopressin, salt supplementation)
oral ketoconazole (contraindicated)
Acute suicidality identified at screening
-
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Roshila Mohammed, MBBS
Phone
(301) 318-6024
Email
clinical.research.unit.53-ggg@usuhs.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David L Saunders, MD, MPH
Organizational Affiliation
Uniformed Services University of the Health Sciences
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Mark C Haigney, MD, FAHA
Organizational Affiliation
Uniformed Services University of the Health Sciences
Official's Role
Study Chair
Facility Information:
Facility Name
Uniformed Services University
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20814
Country
United States
Individual Site Status
Recruiting
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Ivabradine for Long-Term Effects of COVID-19 With POTS Cohort
We'll reach out to this number within 24 hrs