The purpose of this research study is to test if the combination of three drugs, valacyclovir, celecoxib, and Paxlovid will decrease the symptoms of Long COVID in adults compared to a placebo (this does not contain the medications).

This is an off-label, randomized, double-blind, active placebo-controlled, two-arm clinical trial of a combination of celecoxib, valacyclovir, and Paxlovid in adults with Long COVID. This study aims to evaluate the safety and efficacy of the combination of celecoxib, valacyclovir, and Paxlovid in adults with Long COVID (LC). Safety will be primarily measured through blood and urine measures. Efficacy will be evaluated by measuring patient-reported outcomes.

Inclusion Criteria:

• 18-65 years of age at the time of study entry
• Diagnosed with Long COVID
• Individuals of child-bearing potential must have a negative serum pregnancy test at screening and agree to on-site urine pregnancy testing at all subsequent study visits
• 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.
• Those with mild to moderate depression should be clinically stable for three months, without risk of suicidal ideation or behavior.

Exclusion Criteria:

• Breastfeeding, pregnant, or planning to become pregnant during the next six months.
• In the opinion of the Investigator, any clinically significant, uncontrolled, or unstable medical or surgical condition that could affect the individual's ability to participate in the study or potentially compromise their well-being while enrolled in the study.
• In the opinion of the Investigator or based on results of the HADS, evidence of a clinically significant psychiatric disorder, e.g., severe, unstable or poorly controlled depression, anxiety or obsessive-compulsive disorder; moderate or severe alcohol use disorder; substance use disorder other than mild cannabis use disorder; or any history of bipolar disorder, schizophrenia, schizoaffective disorder or other psychotic disorder.
• Currently meeting criteria for ME/CFS at the pre-screening or screening visit, or a prior confirmed diagnosis of ME/CFS within the last 5 years. This may be determined as part of the initial screening call or visit.
• Any anticipated need for surgery that in the opinion of the Principal Investigator or Sub-I might confound results or interfere with the participant's ability to comply with the protocol.
• Symptomatic and/or otherwise clinically significant cardiac disease
• Acute non-COVID systemic infection (e.g., HIV, hepatitis) or other active viral or bacterial infection during the screening/washout period or at the Baseline visit.
• Currently receiving chronic systemic corticosteroids (>5 mg prednisone daily, or equivalent)
• Routine treatment with warfarin, heparin, lithium, digoxin, amiodarone, isoniazid, phenytoin, fluconazole, methotrexate, probenecid, or raloxifene. Participants on these medications should not be screened.
• Uncontrolled sleep apnea.
• Use of chronic nucleoside analog antiviral suppression therapy within one month of the Screening Visit or requiring on average more than one acute treatment course every two months.
• Current use of celecoxib either alone or in combination with valacyclovir or famciclovir
• In the opinion of the Investigator, evidence of current drug or alcohol abuse or dependency, or history of abuse or dependence during the preceding 12 months.
• The participant has undergone a malabsorptive weight loss procedure (e.g., Roux-en-Y or other bypass procedure).
• Severe IBS-C or colonic inertia as evidenced by seven or more days between bowel movements.