Phase 2 trial of Paxlovid for Long COVID cognitive, autonomic, and exercise symptoms completedCan Paxlovid help people with Long COVID? A major trial is underway

ClinicalTrials.gov Published April 3, 2026 Study authors: Kanecia Obie Zimmerman NCT05965726 ↗ Editorial oversight: Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

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Key Takeaway

Note: No efficacy or safety results from the Paxlovid Long COVID trial are yet available.

A prospective, multi-center, double-blind, randomized, controlled Phase 2 trial evaluated nirmatrelvir/ritonavir (Paxlovid) in 964 individuals with Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). The study was conducted across a wide range of healthcare and community settings integrated into COVID-19 programs. The comparator was ritonavir control plus nirmatrelvir-matching placebo.

The primary outcomes were patient-reported improvements in three symptom clusters: cognitive dysfunction measured by PROMIS Cognitive 8a, autonomic dysfunction measured by the Orthostatic Hypotension Questionnaire (OHQ), and exercise intolerance measured by the Modified Depaul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM). No secondary outcomes were specified. The follow-up duration was not reported.

No main efficacy results, adverse events, serious adverse events, discontinuation rates, or tolerability data have been reported. Key study limitations, funding sources, and conflicts of interest are also not reported. The practice relevance of the findings cannot be assessed until complete trial results are available.

If you're one of the many people living with the exhaustion, brain fog, and other relentless symptoms of Long COVID, you know the desperate search for something that helps. Now, researchers are testing whether the antiviral Paxlovid, used to treat early COVID-19, might also work for the long-haul version of the illness. They've enrolled nearly 1,000 people with Long COVID in a major, carefully designed trial to see if different lengths of Paxlovid treatment can improve specific symptom clusters, including problems with thinking, dizziness, and severe fatigue after exertion. This is a serious scientific effort to find a treatment, but it's important to know this is a Phase 2 trial—its main job is to see if Paxlovid shows enough promise to justify a larger, final-stage study. We don't have the results yet, and we don't know if the drug will work for these long-term symptoms or if it will be safe for this new use. The trial is happening, and that in itself is significant progress for a condition with few options.

What this means for you:

A major trial is testing Paxlovid for Long COVID. Results are not yet available.

Study Details

Study typePhase2

Sample sizen = 964

EvidenceLevel 3

Follow-up16.4 mo

PublishedMar 2026

TrialNCT05965726

View Original Abstract ↓

Status: COMPLETED | Phase: PHASE2 Condition(s): Long COVID-19, Long COVID Intervention(s): Paxlovid (DRUG), Ritonavir (DRUG), Nirmatrelvir-matching placebo (DRUG) This is an appendix of master protocol (NCT05595369) designed to be flexible so that it is suitable for a wide range of settings within health care systems and in community settings where it can be integrated into COVID-19 programs and subsequent treatment plans. This sub-study is a prospective, multi-center, double-blind, randomized, controlled trial evaluating nirmatrelvir/ritonavir (Paxlovid) in two dosing durations for the treatment of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). The study is evaluating potential mechanisms of action, efficacy, and safety of antivirals and other therapeutics in individuals with PASC, according to the platform protocol objectives. The hypothesis is that persistent viral infection and/or overactive/chronic immune response and inflammation are underlying contributors to PASC and that antiviral and other applicable therapies may result in viral clearance or decreased inflammation and improvement in PASC symptoms. Detailed: For this appendix of the master protocol (NCT05595369), participants will be randomized to Paxlovid (nirmatrelvir/ritonavir) vs. ritonavir control plus nirmatrelvir-matching placebo. When there are multiple study interventions (sub-studies) available under the master protocol (NCT05595369), randomization will occur based on the specific inclusion/exclusion criteria of each appendix. Primary Outcome(s): Percentage of Participants Who Improved in Cognitive Dysfunction Symptom Cluster, as Measured by Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive 8a Function T-score; Percentage of Participants Who Improved in Autonomic Dysfunction Symptom Cluster, as Measured by the Orthostatic Hypotension Questionnaire (OHQ); Percentage of Participants Who Improved in Exercise Intolerance Symptom Cluster, as Measured by the Modified Depaul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM) Enrollment: 964 (ACTUAL) Lead Sponsor: Kanecia Obie Zimmerman Start: 2023-07-26 | Primary Completion: 2024-12-05 Results posted: 2026-03-27

Phase 2 trial of Paxlovid for Long COVID cognitive, autonomic, and exercise symptoms completedCan Paxlovid help people with Long COVID? A major trial is underway

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Phase 2 trial of Paxlovid for Long COVID cognitive, autonomic, and exercise symptoms completedCan Paxlovid help people with Long COVID? A major trial is underway

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