Paxlovid for Treatment of Long Covid

Study Overview
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Brief Summary
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The purpose of this study is to compare whether being treated with Paxlovid (nirmatrelvir plus ritonavir) for 15 days works better than being treated with placebo (plus ritonavir) to reduce severe symptoms of Long Covid (the placebo does not have any active drug). Participants will have 5 planned visits to the study clinic over 15 weeks and will take the drug (or placebo) for the first 15 days. This study uses the term post-acute sequelae of SARS-CoV-2 (PASC), which is another name for Long Covid.

Detailed Description
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An exploratory sub-study will investigate the correlation of physical activity and biometric parameters from digital wearable devices with the subjective symptom severity and other patient-reported outcomes in the main study. All participants with iPhone 6S Plus or newer will be offered an opportunity to opt-in to this sub-study. An Apple Watch and Bluetooth-enabled blood pressure monitor will be provided to participants and data will be collected for the duration of the main study to track participants' physiological and behavioral trends in the Paxlovid versus placebo groups.

Official Title
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Selective Trial Of Paxlovid for PASC (STOP-PASC): Randomized Double-Blind Placebo-Controlled Pilot Trial of Paxlovid for the Treatment of PASC

Conditions
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Long COVID, Post-acute Sequelae of SARS-CoV-2 Infection

Intervention / Treatment
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* Drug: Nirmatrelvir
* Drug: Placebo
* Drug: Ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Normal or near-normal kidney function History of confirmed COVID-19 infection that preceded the post-COVID symptoms Post-COVID-19 symptoms persisting greater than three months At least 2 post-COVID symptoms of moderate or severe intensity (fatigue, brain fog, shortness of breath, body aches, gastrointestinal symptoms, or cardiovascular symptoms) Willing to report all vaccinations Women of childbearing potential or men whose partners may become pregnant must use acceptable method of contraception during the treatment period and for 28 days after the last dose of the study drug Willing and able to adhere to study procedures and available for the duration of the study Exclusion Criteria: Suspected or confirmed pregnancy or breastfeeding Severe liver disease Prior use of study drug or other COVID treatment within 30 days Hypersensitivity or other contraindication to any components of the study drug Current or expected use of any medication dependent on or inducer of CYP3A4 Current or expected use of supplements or herbs (unless medically necessary) that cannot be temporarily held (period as determined necessary by investigators) HIV infection with viral load >50 copies/ml Suspected or confirmed active COVID infection within 30 days History of COVID vaccine within 28 days prior to enrollment, or other vaccine (influenza, shingles, etc.) within 14 days of enrollment, or planned use of any vaccine until the primary endpoint has been met (10 weeks) Other medical condition(s) or concomitant therapy that would compromise participant's safety or compliance with the study protocol or significantly confound interpretation of study results, as determined by study investigators Current enrollment in, or discontinuation within the last 30 days from, a clinical trial involving any investigational drug or device Inability to provide informed consent Currently hospitalized

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nirmatrelvir plus ritonavir<br>Participants receive nirmatrelvir plus ritonavir (Paxlovid) for 15 days, and attend follow-up visits through week 15. | Drug: Nirmatrelvir<br>* Two 150 mg tablets taken by mouth every 12 hours<br>Drug: Ritonavir<br>* One 100 mg capsule taken by mouth every 12 hours<br>|
| Placebo Comparator: Placebo plus ritonavir<br>Participants receive placebo to match nirmatrelvir plus ritonavir for 15 days, and attend follow-up visits through week 15. | Drug: Placebo<br>* Two tablets containing placebo matching nirmatrelvir taken by mouth every 12 hours<br>Drug: Ritonavir<br>* One 100 mg capsule taken by mouth every 12 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Symptoms Severity Scale Score | This measure will evaluate whether there is a difference between treatment with Paxlovid versus placebo on any of the 6 core symptoms of PASC at week 10 (adjusting for patients' baseline levels). Each symptom (fatigue, brain fog, dyspnea, body aches, gastrointestinal symptoms, cardiovascular symptoms) is assessed on a 4-point Likert scale (range: 0 to 3; 0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms). | Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Symptoms Severity Scale Score | This measure will evaluate whether there is a difference between treatment with Paxlovid versus placebo on any of the 6 core symptoms of PASC at day 15 (adjusting for patients' baseline levels). Each symptom (fatigue, brain fog, dyspnea, body aches, gastrointestinal symptoms, cardiovascular symptoms) is assessed on a 4-point Likert scale (range: 0 to 3; 0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms). | Day 15 | 
| Number of participants reporting relief of at least one core symptom for 2 weeks | Relief defined as reduction of severity from moderate to none, or severe to mild/none (≥ 2-point Likert score change). Likert score range: 0 to 3; 0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms. | Baseline through week 10, assessed at week 10 | 
| Number of participants with overall alleviation for 2 weeks | Overall alleviation defined as both: Any core symptom(s) that are none/mild (Likert 0 or 1) at baseline are none at 10 weeks, and Any core symptom(s) that are moderate/severe (Likert 2 or 3) at baseline are none/mild at 10 weeks. Likert score range: 0 to 3; 0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms. | Baseline through week 10, assessed at week 10 | 
| Severity of the most bothersome symptom | Severity assessed on a 4-point Likert scale (range: 0 to 3; 0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms). | Assessed at weeks 5, 10, and 15 | 
| Time to relief of the 6 core symptoms | Relief defined as reduction of severity from moderate to none, or severe to mild/none (≥ 2-point Likert score change). Likert score range: 0 to 3; 0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms. | Up to 15 weeks | 
| Change in PROMIS Physical Function Score | The PROMIS-Physical Function Short Form assesses difficulty level performing activities of daily living such as doing chores, climbing stairs, walking, and running errands. | Baseline and week 10 | 
| Change in PROMIS Fatigue Score | The PROMIS Fatigue Score assesses level of fatigue and its interference on daily activities. | Baseline and week 10 | 
| Change in PROMIS Dyspnea-Severity Score | The PROMIS-Fatigue Dyspnea-Severity Short Form assesses shortness of breath and its interference on daily activities. | Baseline and week 10 | 
| Change in PROMIS Cognitive Function Abilities Score | The PROMIS-Cognitive Function Abilities Short Form assesses brain fog and its interference on daily activities. | Baseline and week 10 | 
| Change in orthostatic vitals test | This outcome measures the difference in seated versus standing blood pressure. | Baseline and week 10 | 
| Change in 1-minute sit-to-stand test | Number of times participant is able to go from sitting (in an armless chair) to standing in 1 minute. | Baseline and week 10 | 
| Patient Global Impression of Severity (PGIS) scale score | Change in health status rated from 1 to 6. 1 = not present; 2 = very mild; 3 = mild; 4 = moderate; 5 = severe; 6 = extremely severe. | Weeks 5, 10, and 15 | 
| Patient Global Impression of Change (PGIC) scale score | Change in health status rated from 1 to 7. 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse. | Baseline and weeks 5, 10, and 15 |