Valacyclovir Plus Celecoxib for Post-Acute Sequelae of SARS-CoV-2

Inclusion Criteria:

1. Willing and able to read, understand, and sign the informed consent.

2. Female at birth, 18-65 years of age at the time of study entry.

3. Must have smartphone with internet access to complete surveys online.

4. Diagnosis of Long COVID according to any of the following definitions Infectedindividuals will have a history of suspected, probable, or confirmed SARS-CoV-2infection as defined by WHO criteria and at least three months of persistent fatigueand muscle weakness, functional impairment, and cognitive impairment since the acuteinfection.

Adults with suspected SARS-CoV-2 infection. An adult qualifies as having suspected SARS-CoV-2 infection if meeting at least one of the following criteria (a-e) below:

a. Clinical criteria: Acute onset of fever and cough OR acute onset of any three or more of the following signs or symptoms: fever, cough, general weakness /fatigue, headache, myalgia, sore throat, coryza, dyspnea, anorexia/nausea/vomiting, diarrhea, altered mental status. These patients should also meet one of the following epidemiological criteria: i. Epidemiological criteria:

1. Residing or working in an area with a high risk of transmission of virus: closedresidential settings, humanitarian settings such as camp and camp-like settings fordisplaced persons; anytime within the 14 days before symptom onset; or

2. Residing or travel to an area with community transmission anytime within the 14 daysbefore symptom onset; or

3. Working in any health care setting, including within health facilities or thecommunity, anytime within the 14 days before symptom onset. b. A patient with severe acute respiratory illness: (acute respiratory infectionwith history of fever or measured fever of ≥38C°; and cough; with onset within thelast ten days; and requires hospitalization). c. An asymptomatic patient not meeting any of the epidemiologic criteria above butwith a previously positive SARS-CoV-2 Antigen- RDT. d. Adults with probable SARS-CoV-2 infection. An adult qualifies as having probableSARS-CoV-2 infection if meeting any one of 1-3 below: i. A patient who meetsclinical criteria for suspected SARS- CoV-2 AND is a contact of a probable orconfirmed case or linked to a COVID-19 cluster; ii. A suspect case with chestimaging showing findings suggestive of COVID-19 disease; iii. A person with recentonset of anosmia (loss of smell) or ageusia (loss of taste) in the absence of anyother identified cause; e. Adults with confirmed SARS-CoV-2 infection. An adultqualifies as having confirmed SARS-CoV-2 infection if meeting any one of 1-4 below:i. Any person with a positive Nucleic Acid Amplification Test (NAAT); ii. Any personwith of a positive SARS-CoV-2 Antigen-RDT AND meeting either the probable casedefinition or suspect criteria A OR B; iii. An asymptomatic person with a positiveSARS-CoV-2 Antigen-RDT who is a contact of a probable or confirmed case; iv. Anyperson with a positive SARS-CoV-2 nucleocapsid protein antibody test OR a positiveSARS-CoV-2 spike protein antibody test IF not vaccinated

4. Women of child-bearing potential must have a negative serum pregnancy test atscreening and agree to on-site urine pregnancy testing at all subsequent studyvisits. Women confirmed to be of non-childbearing potential do not require pregnancytesting. Pregnancy tests will not be required for remote visits. To be considered ofnon-child-bearing potential, the patient must be:

a. Post-menopausal (defined as no menses for at least one year); or b. Surgically sterile (s/p hysterectomy, bilateral oophorectomy, or bilateral tubal ligation at least six months prior to beginning treatment with study drug); or c. At least three months s/p a non-surgical permanent sterilization procedure 6. A urine drug screen performed at the Screening Visit must be negative for drugs of abuse such as methamphetamine, cocaine, phencyclidine (PCP), and non-disclosed amphetamines and opioids/opiates. The following stipulations also apply:

1. Patients with a positive screening UDS due to prescribed amphetamines for allowedconditions do not require further UDS testing. They may proceed with studytreatment, assuming no evidence of abuse or dependency.

2. Patients positive for prescribed opioids at the Screening Visit yet deemedappropriate for washout and study participants must have a negative repeat UDS atthe Baseline Visit.

3. Patients must be willing and able to withdraw and refrain from chronic use ofantivirals (as defined in Exclusion Criterion, below). In the judgement of theinvestigator, it must be medically advisable for these therapies to bewithdrawn.

4. Qualified patients with mild to moderate depression who in the judgment of theinvestigator are not at risk of suicidal ideation or behavior. The dose ofallowed antidepressants should have been stable for at least 30 days prior toBaseline Visit..

5. In the opinion of the Investigator, the patient is willing and able to complywith all protocol-specified requirements.

6. Women of child-bearing potential must be willing to utilize an effective birthcontrol method for the duration of the study. Allowable contraceptive methodsinclude:

a. Oral, implantable, injectable, or transdermal hormonal contraceptives (should have been used for a minimum of one full cycle prior to administration of study drug) b. Intrauterine devices (IUD) c. Double barrier method (male or female condom, sponge, diaphragm, or vaginal ring with simultaneous use of spermicidal jelly or cream) 11. Patients should not require routine treatment with warfarin, heparin, lithium, digoxin, amiodarone, isoniazid, phenytoin, fluconazole, methotrexate, probenecid, or raloxifene. Patients on these medications should not be screened. PRN usage of fluconazole for short time periods is permitted.

12. Patients must have successfully completed at least two PROMIS Fatigue and two PROMISSleep Disturbance surveys a minimum of 7 days apart during the interval leading upto the baseline visit.

Exclusion Criteria:

1. Breastfeeding, pregnant, or planning to become pregnant during the next six months.

2. In the opinion of the Investigator, any clinically significant, uncontrolled, orunstable medical or surgical condition that could affect the patient's ability toparticipate in the study or potentially compromise her well-being while enrolled inthe study.

3. In the opinion of the Investigator or based on results of the HADS, evidence of aclinically significant psychiatric disorder; e.g., severe, unstable or poorlycontrolled depression, anxiety or obsessive-compulsive disorder; moderate or severealcohol use disorder; substance use disorder other than mild cannabis use disorder;or any history of bipolar disorder, schizophrenia, schizoaffective disorder or otherpsychotic disorder.

4. A score of >15 on the Patient Health Questionnaire-9 (PHQ-9) determined by survey atscreening.

5. A positive response to thoughts of suicide or self-harm on the PHQ-9 determined bysurvey at screening.

6. A diagnosis of ME/CFS prior to January 2020.

7. Any anticipated need for surgery that in the opinion of the Principal Investigatoror Sub-I might confound results or interfere with the patient's ability to complywith the protocol.

8. Symptomatic and/or otherwise clinically significant cardiac disease, including butnot limited to myocardial infarction during the preceding two years; uncontrolledhypertension; symptomatic heart failure (e.g., New York Heart Association Class IIor higher); angina or other evidence of significant coronary artery disease;clinically significant cardiac rhythm or conduction abnormality or anticipation ofbypass or other cardiac surgery within the next 12 months.

9. Acute non-COVID systemic infection (e.g., HIV, hepatitis) or other active viral orbacterial infection during the screening/washout period or at the Baseline visit. (Patient may remain in screening until the active infection has resolved, orre-screen after recuperation.)

10. Currently receiving chronic systemic corticosteroids (>5 mg prednisone daily, orequivalent).

11. Uncontrolled sleep apnea. Patients successfully treated with CPAP or other devicesare eligible.

12. Use of chronic nucleoside analog antiviral suppression therapy within one month ofthe Screening Visit or requiring on average more than one acute treatment courseevery two months.

13. Current use of celecoxib either alone or in combination with valacyclovir orfamciclovir

14. In the opinion of the Investigator, evidence of current drug or alcohol abuse ordependency, or history of abuse or dependence during the preceding 12 months.

15. The patient has undergone a malabsorptive weight loss procedure (e.g., Roux-en-Y orother bypass procedure).

16. Severe IBS-C or colonic inertia as evidenced by seven or more days between bowelmovements.

17. History of significant adverse reaction or allergy to sulfonamides, celecoxib,famciclovir, acyclovir, valacyclovir or penciclovir cream (Denavir®).

18. History of aspirin-sensitive asthma, or any other history of other allergic- typereactions after taking aspirin or other NSAID such as asthma or urticaria.

19. History of Sulfa Allergy.

20. History of peptic ulcer disease or upper gastrointestinal bleeding that is thoughtto pose a significant risk of GI bleeding with the daily use of celecoxib.

21. Clinically significant elevations of AST, ALT, or bilirubin at the screeningassessment (or at the last assessment prior to baseline, if repeated) in the opinionof the Investigator.

22. Presence of active kidney disease, as evidenced by an estimated glomerularfiltration rate (eGFR) of less than 60 mL/min/1.73m2.

23. History of acute kidney injury within the past year, any history of chronic kidneydisease stage 3 or higher.

24. In the opinion of the Investigator, evidence of other clinically significantlaboratory abnormality(ies) based on the screening laboratory assessments and/ormedical history.

25. Untreated, symptomatic gall bladder disease (i.e., symptoms within preceding sixmonths).

26. Plans to undergo vaccination against Herpes varicella/ zoster (i.e., shingles orchickenpox) during the study. Instead, vaccination should be completed at least 14days prior to the Baseline Visit or delayed until at least two weeks after the lastdose of study medication.

27. Patients known or suspected to be slow CYP2C9 metabolizers based on genotype orprevious history/experience with other CYP2C9 substrates (such as warfarin,phenytoin, glimepiride, tolbutamide, celecoxib, meloxicam, piroxicam, or ibuprofen).

28. Investigational drug usage within 30 days of Screening.