RECOVER-VITAL: Platform Protocol to Measure the Effects of Antiviral Therapies on Long COVID Symptoms

Inclusion Criteria:

1. ≥ 18 years of age at the time of enrollment

2. Previous suspected, probably or confirmed SARS-CoV-2 infection, as defined by thePan American Health Organization*

*Suspected and probable cases will only be allowed if it occurred before May 1, 2021, and will be limited to 10% of the study population. Otherwise, confirmed casesare required. Suspected case of SARS-CoV-2 infection - Three options, A through C: A. A person who meets the clinical OR epidemiological criteria. Clinical criteria:Acute onset of fever AND cough (influenza-like illness) OR Acute onset of ANY THREEOR MORE of the following signs or symptoms: fever, cough, general, weakness/fatigue,headache, myalgia, sore throat, coryza, dyspnea, nausea, diarrhea, anorexia.Epidemiological criteria: Contact of a probable or confirmed case or linked to aCOVID-19 cluster; or B. Acute respiratory infection with history of fever or measured fever of ≥ 38°C;and cough; with onset within the last 10 days; and who requires hospitalization); or C. With no clinical signs or symptoms, NOR meeting epidemiologic criteria with apositive professional use or self-test SARS-CoV-2 antigen-Rapid Diagnostic Test. Probable case of SARS-CoV-2 infection: A. A patient who meets clinical criteria above AND is a contact of a probable orconfirmed case or is linked to a COVID-19 cluster. Confirmed case of SARS-CoV-2 infection - Two options, A through B: A. A person with a positive nucleic acid amplification test, regardless of clinicalcriteria OR epidemiological criteria; or B. Meeting clinical criteria AND/OR epidemiological criteria (See suspect case A).With a positive professional use or self-test SARS-CoV-2 Antigen-Rapid DiagnosticTest.

3. At least two moderate symptoms from the same symptom cluster or one severecluster-associated symptom identified via the Cluster Targeted COVID-19 SymptomQuestions (CTCSQ), with participant identifying new symptoms since COVID-19 illnessand having persisted for at least 12 weeks

4. Meeting PRO Symptom Cluster criteria for at least one Symptom Cluster

5. Willing and able to provide informed consent, complete the surveys, clinicalassessments, and return for all of the necessary follow-up visits

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study. Refer to appendices for additional appendix-level criteria:

1. Known active acute SARS-CoV-2 infection ≤ 4 weeks from consent

2. Known severe anemia, defined as < 8 g/dL

3. Meeting the following symptom cluster exclusion for all eligible clusters*: a. Cognitive dysfunction: known stroke that resulted in cognitive impairment within 3 months of enrollment b. Autonomic dysfunction: atrial fibrillation or significantcardiac arrhythmia, more than moderate alcohol consumption**, pre-existing sustainedsevere hypertension (BP> 180/110 mmHg in the sitting position) c. Exerciseintolerance: i. any of the following within 4 weeks of consent - an acute myocardialinfarction or unstable angina, uncontrolled arrhythmias causing symptoms orhemodynamic compromise, acute myocarditis or pericarditis, uncontrolled acutelydecompensated heart failure (acute pulmonary edema), acute pulmonary embolism,suspected dissecting aneurysm, severe hypoxemia at rest, any acute or chronicdisorder that may affect exercise performance ii. if the participant is aggravatedby exercise (e.g., infection, thyrotoxicosis, unable to cooperate)

*Participants who are eligible for > 1 cluster must meet all inclusion and noexclusion criteria for an individual symptom cluster. If not, the participant willbe excluded from that individual symptom cluster.

** Defined as greater than 2 drinks a day for men and 1 drink a day for women. Adrink is equivalent to 12 ounces of beer (5% alcohol content), 8 ounces of maltliquor (7% alcohol content), 5 ounces of wine (12% alcohol content), 1.5 ounces or a "shot" of 80-proof (40% alcohol content) distilled spirits or liquor (e.g., gin,rum, vodka, whiskey). 21

4. Known diagnosis of chronic Lyme disease with persistent symptoms, sequelae, orrelated therapy

5. Any non-marijuana illicit drug use within 30 days of informed consent

6. Current or recent use (within the last 14 days) of study intervention*

7. Known allergy/sensitivity or any hypersensitivity to components of the studyintervention (s) or control*

8. Known contraindication(s) to study intervention(s),

9. Inability to discontinue symptomatic medications for the identified time periods

10. Moderate or severe immunocompromised patients, such as those described in the NIHCOVID-19 Treatment Guidelines (https://www.covid19treatmentguidelines.nih.gov/special populations/immunocompromised/)

11. Currently enrolled in another clinical trial outside this platform protocol oranother study intervention appendix in this platform protocol***

***Participants may re-enroll in the trial for a different study interventionappendix if the participant has completed an appropriate washout period and efficacyhas been determined for the appendix in which the participant was previouslyenrolled.

12. Any condition that would make the participant, in the opinion of the investigator,unsuitable for the study

• If only one study intervention appendix is open at the time of enrollment. Ifmultiple study intervention appendices are open, a participant may be excludedfrom any study intervention appendix based on contraindications listed in thestudy intervention appendix, current use of study intervention, or knownallergy/sensitivity/hypersensitivity and still remain eligible for theremaining study intervention appendices.