Long Haul COVIDPhase 4COVIVANCT05481177
Ivabradine for Long-Term Effects of COVID-19 With POTS Cohort
A Phase 4 study testing Ivabradine in people with Long Haul COVID and Postural Orthostatic Tachycardia Syndrome, run by Uniformed Services University of the Health Sciences at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Long Haul COVID, Postural Orthostatic Tachycardia Syndrome
- What is being tested?
- Ivabradine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 250 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Jun 2023to 1 Sep 2024
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
- 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
Who cannot join
- 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.
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- 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
- -
Trial locations and contacts
1 site in 1 country.
United States1 site, 1 recruiting
- Recruiting
Uniformed Services University
Bethesda, Maryland, 20814
About this study
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.
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.
Read the 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.
- Being tested
- Ivabradine
- Medical subject headings
- Post-Acute COVID-19 Syndrome, Postural Orthostatic Tachycardia Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IvabradineDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Long Haul COVID | No intervention | Persistent signs and/or symptoms >12 weeks post Covid-infection N = 200 evaluable subjects. |
| Post COVID without LHC | No intervention | No persistent signs and/or symptoms >12 weeks N = 50 evaluable subjects. |
| Ivabradine RCT Arms | Placebo comparator | 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 Receives: Drug: Ivabradine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Aug 2022
- Study start14 Jun 2023
- Primary completion1 Sep 2024 (estimated)
- Study completion1 Sep 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Long Haul COVIDStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 250 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Uniformed Services University of the Health Sciences
- Sponsor type
- US federal agency
- Responsible party
- Principal investigator, David Saunders, Uniformed Services University of the Health Sciences
- Investigators
- David L Saunders, MD, MPH, Principal investigator, Uniformed Services University of the Health SciencesMark C Haigney, MD, FAHA, Study chair, Uniformed Services University of the Health Sciences
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05481177
- Sponsor's protocol ID
- USUHS.2022-094
- Acronym
- COVIVA
- Status last verified
- Nov 2023
- First submitted
- 28 Jul 2022
- Last updated
- 29 Nov 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Saunders D, Arnold TB, Lavender JM, Bi D, Alcover K, Hellwig LD, Leazer ST, Mohammed R, Markos B, Perera K, Shaw D, Kobi P, Evans M, Mains A, Tanofsky-Kraff M, Goguet E, Mitre E, Pratt KP, Dalgard CL, Haigney MC. Comparative cohort study of post-acute COVID-19 infection with a nested, randomized controlled trial of ivabradine for those with postural orthostatic tachycardia syndrome (the COVIVA study). Front Neurol. 2025 Jul 7;16:1550636. doi: 10.3389/fneur.2025.1550636. eCollection 2025.
PubMed 40692561
Study at a glance
From the registry record, last updated by the sponsor on 29 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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.
- ClinicalTrials.gov ID
- NCT05481177
- Acronym / sponsor ID
- COVIVA / USUHS.2022-094
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 250 participants (estimated)
- Lead sponsor
- Uniformed Services University of the Health SciencesUS federal agency
- Study start
- 14 Jun 2023 (actual)
- Primary completion
- 1 Sep 2024 (estimated)
- Study completion
- 1 Sep 2024 (estimated)
- First posted
- 1 Aug 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Long Haul COVID | No intervention | –Persistent signs and/or symptoms >12 weeks post Covid-infection N = 200 evaluable subjects. |
| Post COVID without LHC | No intervention | –No persistent signs and/or symptoms >12 weeks N = 50 evaluable subjects. |
| Ivabradine RCT Arms | Placebo comparator | Drug: IvabradineIf 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 |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- 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
Key exclusion criteria (24 listed)
- Resting heart rate <60 bpm
- Atrial fibrillation
- Supraventricular tachycardia
- Allergic reaction or known contraindications to study drug
- Pregnant/lactating females
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IvabradineIvabradine 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. | Drug | Ivabradine RCT Arms |
Primary outcome
Change in standing heart rate following 3 months treatment.
Time frame: 3 months
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.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Nov 2023.
- Derived from this study: PubMed 40692561Saunders D, Arnold TB, Lavender JM, Bi D, Alcover K, Hellwig LD, Leazer ST, Mohammed R, Markos B, Perera K, Shaw D, Kobi P, Evans M, Mains A, Tanofsky-Kraff M, Goguet E, Mitre E, Pratt KP, Dalgard CL, Haigney MC. Comparative cohort study of post-acute COVID-19 infection with a nested, randomized controlled trial of ivabradine for those with postural orthostatic tachycardia syndrome (the COVIVA study). Front Neurol. 2025 Jul 7;16:1550636. doi: 10.3389/fneur.2025.1550636. eCollection 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David L Saunders, MD, MPH principal investigator
Uniformed Services University of the Health Sciences
Mark C Haigney, MD, FAHA study chair
Uniformed Services University of the Health Sciences
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Ivabradine in people with Long Haul COVID and Postural Orthostatic Tachycardia Syndrome, run by Uniformed Services University of the Health Sciences at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 29 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Roshila Mohammed, MBBS ((301) 318-6024, clinical.research.unit.53-ggg@usuhs.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in standing heart rate following 3 months treatment. (time frame: 3 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05481177, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Nov 2023.