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

• ClinicalTrials.gov Identifier: NCT05096884
• Recruitment Status: Terminated
• First Posted: October 27, 2021
• Last Update Posted: January 11, 2024
• Sponsor: Hackensack Meridian Health
• Information provided by (Responsible Party): Hackensack Meridian Health

Tracking Information

• First Submitted Date: October 25, 2021
• First Posted Date: October 27, 2021
• Last Update Posted Date: January 11, 2024
• Actual Study Start Date: March 23, 2022
• Actual Primary Completion Date: September 12, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 27, 2021)

• Change in 6 minute walk test at the end of treatment period [ Time Frame: 12 weeks from baseline walk test ]
  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).
• Change in Zva measurement at the end of treatment period [ Time Frame: 12 weeks from baseline transthoracic echocardiogram (TTE). ]
  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).

Original Primary Outcome Measures (submitted: October 25, 2021)

• Change in 6 minute walk test at the end of treatment period [ Time Frame: 12 weeks from baseline walk test ]
  To assess the reduction of symptoms in patients with PASC 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).
• Change in Zva measurement at the end of treatment period [ Time Frame: 12 weeks from baseline TTE (transthoracic echocardiogram). ]
  To assess the reduction of symptoms in patients with PASC 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).

Current Secondary Outcome Measures (submitted: October 27, 2021)

Change in Minnesota Living with Heart Failure score at the end of treatment period [ Time Frame: 12 weeks from baseline ]

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).

Original Secondary Outcome Measures (submitted: October 25, 2021)

Change in Minnesota Living with Heart Failure score at the end of treatment period [ Time Frame: 12 weeks from baseline ]

Subjective improvement in 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).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Post-Acute Sequelae of Coronavirus-19 (COVID-19) With Dyspnea on Exertion And Associated TaChycardia TrEatment Study
• Official Title: Post-Acute Sequelae of Coronavirus-19 (COVID-19) With DysPnEA on ExertIon And Associated TaChycardia TrEatment Study

Brief 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.

Detailed 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.

• Study Type: Interventional
• Study Phase: Early Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Tachycardia
• Dyspnea
• COVID-19

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.

Study Arms

Experimental: Study arm - 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.

Intervention: Drug: Metoprolol Succinate

Publications *

• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 10, 2024): 14
• Original Estimated Enrollment (submitted: October 25, 2021): 20
• Actual Study Completion Date: September 12, 2023
• Actual Primary Completion Date: September 12, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 40 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05096884
• Other Study ID Numbers: Pro2021-1100
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Hackensack Meridian Health
• Original Responsible Party: Same as current
• Current Study Sponsor: Hackensack Meridian Health
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: David Landers, MD; Hackensack Meridian Health

• PRS Account: Hackensack Meridian Health
• Verification Date: January 2024