Post-Acute Sequelae of Coronavirus-19 (COVID-19) With Dyspnea on Exertion And Associated TaChycardia TrEatment Study

COVID-19 Clinical Trial

— PEACE  

Official title:

Post-Acute Sequelae of Coronavirus-19 (COVID-19) With DysPnEA on ExertIon And Associated TaChycardia TrEatment Study

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT05096884
• Other study ID #: Pro2021-1100
• Status: Terminated
• Phase: Early Phase 1
• Start date: March 23, 2022
• Est. completion date: September 12, 2023

Study information

• Verified date: January 2024
• Source: Hackensack Meridian Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Most patients with acute COVID-19 (Coronavirus 19) recover within weeks, however a significant number of individuals will develop the post-acute COVID 19 syndrome (PASC). As of July 2021, the post COVID syndrome qualifies as a disability under the Americans with Disabilities Act. The symptoms which comprise this condition are highly variable and often extraordinarily debilitating. They may be distinct from the initial presentation or may mimic those which defined the initial infection. The post COVID syndrome can be diagnosed when symptoms persist longer than 3 months and may extend to beyond one year. There are risks for permanent levels of disability. Patients who seemingly did not have active COVID-19 symptoms in the days following infectious exposure may also develop post Covid syndromes. These syndromes are considered to constitute a distinct clinical entity which has of yet no clearly defined pathogenic mechanism or validated treatment algorithms.

International investigative efforts are now underway to determine who might develop the post COVID syndrome, it's long term consequences and how best to treat its many problematic symptoms.

Description:

Although the long Covid syndrome or PASC is a well recognized syndrome, its pathogenesis is poorly understood. Hypotheses have included persistent viral remnants with consequent provocation of the generalized symptoms characteristic of systemic inflammation. The virus may continue to infect heart, lung or neurologic tissue rendering various organs dysfunctional. Alternatively there could be persistently infected or damaged endothelial cells which line blood vessels and thereby create perturbations of blood flow.

The altered blood flow might then explain the many reported symptoms. However the pathogenesis can be distinguished and studied independently from the physiological disturbance. Existing and accepted therapies for tachycardia and shortness of breath, although they might not reverse the virus caused injury, could be used to reduce the resultant physiologic abnormalities which in turn produce the symptoms of the long Covid syndrome. Beta blockers are standard therapies in sinus tachycardias, (1,2) and postural orthostatic tachycardia syndrome (POTS) (3,4) which are often characterized by high levels of sympathetic drive which beta blockers are designed to modulate.

Thus it is reasonable to hypothesize that that treatment with beta blockers may be an effective intervention as Covid-19 directly infects the nerve and vascular tissues which regulate sympathetic excess which in turn may produce the cardiovascular symptoms of PASC. Moreover it is important to specifically study beta blockers in PASC because they are currently actively in use for this indication. Yet the possibility remains that although the symptoms are similar to those in which beta blockers have been effective, the pathologic processes in PASC will not be responsive to beta blocker therapy. If this were to be true, beta blockers would prove ineffective and might carry a risk of harm. Equally as important is to properly determine the effective dose as the therapeutic window for these agents is wide.

Metoprolol which is a widely used agent in cardiovascular disease is approved in doses ranging from 25 to 400 mg per day. The proposed study will compare 6 minute walk distances (pre and post the treatment), the echocardiographic measurement of the impact of sympathetic excess on the heart's ability to empty effectively and a quality of life survey. Each of these study elements will be measured before and after progressively increased doses of beta blocker.

Our study is thus designed to study two issues:

1. Whether beta blockers which have been utilized to treat tachycardias, POTS (postural orthostatic tachycardia syndrome), and hypertension will have similar effectiveness in PASC

2. To determine appropriate dosing which may be different than those used on non PASC conditions.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 14
• Est. completion date: September 12, 2023
• Est. primary completion date: September 12, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 40 Years

Eligibility

Inclusion Criteria:

1. Subject should be between the ages of 18 and 40 with DOE (dyspnea on exertion) for 3 - 12 months

2. Subjects recovered from acute, polymerase chain reaction (PCR) positive, COVID-19 infection

3. Recovery from COVID-19 will be defined as substantial improvement in or essential resolution of initial clinical symptoms

4. Demonstration of tachycardia and/or dyspnea with minimal activity (subjectively different than pre-COVID 19 infection state)

5. Abnormal HUTT (heads up tilt test)

6. Normal chest x-ray

7. Left ventricular ejection fraction (LVEF) >50% by transthoracic echocardiography

8. Zva >3.5 as calculated from TTE (transthoracic echocardiogram).

9. Hemoglobin/Hematocrit within normal laboratory standards

10. Thyroid-stimulating hormone (TSH) within normal laboratory standards

Exclusion Criteria:

1. Active pregnancy (negative pregnancy test is the standard of care prior to HUTT)

2. Demonstrate a primary cause of appropriate DOE and sinus tachycardia

1. Fevers/infection

2. Hypovolemia

3. Anemia

4. Hyperthyroidism

5. Alcohol/drug/medication withdrawal

3. Currently taking beta blocker medications

4. Currently being treated for pre-existing neurally mediated hypotension/syncope or known dysautonomia.

5. Medical history of chronic lung disease or reactive airway syndrome.

Related Conditions & MeSH terms

• COVID-19
• Dyspnea
• Tachycardia

Intervention

Drug:
• Metoprolol Succinate
The beta blocker metoprolol succinate will be initiated at a starting low dose of 25 mg daily for two weeks and will be escalated if well tolerated every 2 weeks to a maximum dose of 400 mg po daily.

Locations

Country	Name	City	State
United States	Hackensack Univeristy Medical Center	Hackensack	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
Hackensack Meridian Health

Country where clinical trial is conducted

United States, 

References & Publications (4)

Brugada J, Katritsis DG, Arbelo E, Arribas F, Bax JJ, Blomstrom-Lundqvist C, Calkins H, Corrado D, Deftereos SG, Diller GP, Gomez-Doblas JJ, Gorenek B, Grace A, Ho SY, Kaski JC, Kuck KH, Lambiase PD, Sacher F, Sarquella-Brugada G, Suwalski P, Zaza A; ESC Scientific Document Group. 2019 ESC Guidelines for the management of patients with supraventricular tachycardiaThe Task Force for the management of patients with supraventricular tachycardia of the European Society of Cardiology (ESC). Eur Heart J. 2020 Feb 1;41(5):655-720. doi: 10.1093/eurheartj/ehz467. No abstract available. Erratum In: Eur Heart J. 2020 Nov 21;41(44):4258. — View Citation

Deng X, Zhang Y, Liao Y, Du J. Efficacy of beta-Blockers on Postural Tachycardia Syndrome in Children and Adolescents: A Systematic Review and Meta-Analysis. Front Pediatr. 2019 Nov 7;7:460. doi: 10.3389/fped.2019.00460. eCollection 2019. — View Citation

Page RL, Joglar JA, Caldwell MA, Calkins H, Conti JB, Deal BJ, Estes NA 3rd, Field ME, Goldberger ZD, Hammill SC, Indik JH, Lindsay BD, Olshansky B, Russo AM, Shen WK, Tracy CM, Al-Khatib SM; Evidence Review Committee Chairdouble dagger. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2016 Apr 5;133(14):e506-74. doi: 10.1161/CIR.0000000000000311. Epub 2015 Sep 23. No abstract available. Erratum In: Circulation. 2016 Sep 13;134(11):e234-5. — View Citation

Raj SR, Black BK, Biaggioni I, Paranjape SY, Ramirez M, Dupont WD, Robertson D. Propranolol decreases tachycardia and improves symptoms in the postural tachycardia syndrome: less is more. Circulation. 2009 Sep 1;120(9):725-34. doi: 10.1161/CIRCULATIONAHA.108.846501. Epub 2009 Aug 17. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in 6 minute walk test at the end of treatment period	To assess the reduction of symptoms in patients with PASC Dyspnea on Exertion (DOE) and associated tachycardia when treated with beta blockers as captured in patients walk test. Walk test will be performed at day 1 (baseline) and at 2-4 weeks post treatment completion which consists of 8 weeks metoprolol succinate (approximately 12 weeks from baseline).	12 weeks from baseline walk test
Primary	Change in Zva measurement at the end of treatment period	To assess the reduction of symptoms in patients with PASC Dyspnea on Exertion (DOE) and associated tachycardia when treated with beta blockers as captured in Zva measurement calculated from patient's TTE (transthoracic echocardiogram).; TTE (and Zva) will be performed at day 1 (baseline) and at 2-4 weeks post treatment completion which consists of 8 weeks metoprolol succinate (approximately 12 weeks from baseline).	12 weeks from baseline transthoracic echocardiogram (TTE).
Secondary	Change in Minnesota Living with Heart Failure score at the end of treatment period	Subjective improvement in Dyspnea on Exertion (DOE), tachycardia and well being score as measured by the Minnesota Living with Heart Failure.; The Minnesota Living with Heart Failure questionnaire will be administered at day 1 (baseline) and at 2-4 weeks post treatment completion which consists of 8 weeks metoprolol succinate (approximately 12 weeks from baseline).	12 weeks from baseline