imPROving Quality of LIFe In the Long COVID Patient

Study Overview
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Brief Summary
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The purpose of this study is to investigate the efficacy of orally administered nirmatrelvir/ritonavir compared with placebo/ritonavir to improve quality of life in non-hospitalized adult participants suffering from post-acute COVID-19 syndrome.

Detailed Description
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At present there is no curative treatment for post-acute COVID-19 syndrome (PACS). Treatment is focused on symptom management and individualized rehabilitation. There is data indicating SARS-CoV-2 viral persistence and chronic immune system activation in PACS. We are proposing an interventional, randomized and placebo-controlled clinical intervention trial of nirmatrelvir/ritonavir (300/100 mg) or placebo/ritonavir (100mg), twice daily for 15 days, in patients suffering from severe PACS. Patients meeting the WHO definition of severe PACS will be identified from a database of 988 patients cared for by the Karolinska University Hospital Post-COVID clinics since May 2020, and in whom extensive clinical and laboratory examinations have been performed. A total of 400 patients will be enrolled in this study and these will be randomized in a 2:1 ratio to receive either nirmatrelvir/ritonavir or placebo/ritonavir. The study will include deep exploratory systems-level analyses of the immune system in PACS patients, including changes induced by nirmatrelvir/ritonavir (Paxlovid®) treatment. The purpose of this study is to evaluate the efficacy of nirmatrelvir/ritonavir for its potential ability to provide sustained improvement in quality of life, in non-hospitalized patients with post-COVID, a patient group with high unmet medical needs. Hypothesis: Nirmatrelvir/ritonavir (Paxlovid®) improves health-related quality of life measured using the EQ-5D-5L VAS scale, as compared to placebo/ritonavir, in objective and pre-defined clinical phenotypes: postural orthostatic tachycardia syndrome (POTS), microvascular dysfunction, inappropriate sinus tachycardia, persistent fever, post exertional malaise (PEM), fatigue, brain fog, dyspnea, dysfunctional breathing patterns or inflammatory phenotypes (increased plasma D-dimer, CRP, ESR and ferritin).

Official Title
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An Interventional, Double-Blinded, 2-Arm Study to Investigate the Efficacy of Orally Administered Nirmatrelvir/Ritonavir Compared With Placebo/Ritonavir in Non-hospitalized Adult Participants Suffering From Post-COVID

Conditions
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Long COVID, Long Covid19, Post-COVID-19 Syndrome, COVID-19, POTS - Postural Orthostatic Tachycardia Syndrome, Post COVID-19 Condition, Post-COVID Syndrome, Post COVID-19 Condition, Unspecified, Postinfectious Inflammation, Postinfectious Disorder

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject has given written consent to participate in the study. ≥18 years of age at the time of the Screening Visit. Post-acute COVID-19 syndrome (PACS) according to the WHO definition. EQ-5D-5L VAS< 50 All fertile participants must agree to use a highly effective method of contraception for the duration of the study and 28 days after last intake of the IMP. Exclusion Criteria: General exclusion criteria Other non-related conditions with PACS like symptoms. Renal function eGFR eGFRCysC < 60 mL/min/1.73 m2. Not able to comply with the study protocol. Previous Paxlovid treatment. Pregnancy or breastfeeding. Drug-drug interaction with ongoing treatment, including concomitant use of any medications or substances that are strong inducers of CYP3A4 within 28 days prior to first dose of nirmatrelvir/ritonavir and during study treatment. Participants who are planning or considering vaccination (including boosters) through Study Day 45. Active COVID-19 infection as verified by SARS CoV-2 positive antigen test. Self-reported medical conditions, including: Type 1 or Type 2 diabetes mellitus. Chronic kidney disease. Neurodevelopmental disorders (e.g., cerebral palsy, Down's syndrome) or other conditions that confer medical complexity (e.g., genetic or metabolic syndromes and severe congenital anomalies). Active cancer other than localized skin cancer, including those requiring treatment including palliative treatment), as long as the treatment is not among the prohibited medications that must be administered/continued during the trial period. Immunosuppressive disease (e.g., bone marrow or organ transplantation or primary immune deficiencies) OR prolonged use of immune-weakening medications: i. Has received corticosteroids equivalent to prednisone ≥20 mg daily for at least 14 consecutive days within 30 days prior to study entry. ii. Has received treatment with biologics (e.g., infliximab, ustekinumab, etc.), immunomodulators (e.g., methotrexate, 6MP, azathioprine, etc.), or cancer chemotherapy within 90 days prior to study entry. iii. HIV infection with CD4+ cell count <200/mm3. History of hospitalization for the medical treatment of acute COVID-19 Current need for hospitalization or anticipated need for hospitalization within 48 hours after randomization in the clinical opinion of the site investigator. Prior/Concomitant Therapy: Current or expected use of any medications or substances that are highly dependent on CYP3A4 for clearance, and for which elevated plasma concentrations may be associated with serious and/or life-threatening events during treatment and for 4 days after the last dose of nirmatrelvir/ritonavir. List of potential interactions provided by Pfizer provided in Appendix A. Has received or is expected to receive monoclonal antibody treatment, antiviral treatment (e.g., molnupiravir), or convalescent COVID-19 plasma. Prior/Concurrent Clinical Study Experience: Is unwilling to abstain from participating in another interventional clinical study with an investigational compound or device, including those for post-COVID-19 therapeutics, through the long-term follow-up visit. Previous administration with any investigational drug or vaccine within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). Known prior participation in this trial or other trial involving nirmatrelvir. Diagnostic Assessments: Known history of any of the following abnormalities in clinical laboratory tests (within past 6 months of the screening visit): AST or ALT level ≥2.5 X ULN Total bilirubin ≥2 X ULN (≥3 X ULN for Gilbert's syndrome)

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
Interventional Model Description: This is a phase II, interventional, randomized, parallel group, double-blind, placebo-controlled, single-center study of nirmatrelvir/ritonavir (300/100 mg) or placebo/ritonavir (100mg), administered orally twice daily for 15 days in non-hospitalized patients with post- COVID conditions.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nirmatrelvir/ritonavir<br>Oral nirmatrelvir/ritonavir (Paxlovid) 300/100 mg twice daily for 15 days | Drug: Nirmatrelvir/ritonavir<br>* 300/100 mg tablet twice daily (q12h) administered orally for 15 days<br>* Other names: Paxlovid;|
| Placebo Comparator: Placebo/ritonavir<br>Oral placebo/ritonavir 100 mg twice daily for 15 days | Drug: Placebo/ritonavir<br>* 100mg tablet twice daily (q12h) administered orally for 15 days<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in quality of life at day 16 | The effect of oral administration of nirmatrelvir/ritonavir on quality of life measured as change from baseline using the EQ-5D-5L VAS scale. | Baseline and day 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in quality of life at days 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on quality of life measured as change from baseline using the EQ-5D-5L VAS scale. | Baseline and days 45 and 90 | 
| Change from baseline in hemodynamic response at days 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on hemodynamic response (only patients diagnosed with postural orthostatic tachycardia syndrome, POTS). Change from baseline in delta maximum heart rate during active standing test. | Baseline and days 45 and 90 | 
| Change from baseline in fever in patients with POTS at days 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on fever (only patients diagnosed with POTS). Change from baseline in POTS-specific symptoms as measured by using the Malmo POTS score, MAPS. | Baseline and days 45 and 90 | 
| Change from baseline in endothelial function at day 45 | The effect of oral administration of nirmatrelvir/ritonavir on reactive hyperemia index. Change from baseline in endothelial function measured using the EndoPat® device. | Baseline and day 45 | 
| Change from baseline in heart rate at days 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on 24-h average heart rate. Change from baseline in heart rate using ECG monitoring device. | Baseline and days 45 and 90 | 
| Change from baseline in fever at days 16, 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on fever. Change from baseline in body temperature. | Baseline and days 16, 45 and 90 | 
| Change from baseline in physical capacity at days 16, 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on physical capacity. Change from baseline as measured by 6-minute walk test. | Baseline and days 16, 45 and 90 | 
| Change from baseline in handgrip strength at days 16, 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on handgrip strength. Change from baseline as measured by JAMAR hand dynamometer. | Baseline and days 16, 45 and 90 | 
| Change from baseline in physical activity at days 16, 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on physical activity. Change from baseline as measured by accelerometer. | Baseline and days 16, 45 and 90 | 
| Change from baseline in post-exertional malaise at day 90 | The effect of oral administration of nirmatrelvir/ritonavir on post-exertional malaise. Change from baseline in total score as measured by the Post-Exertional Malaise (PEM) short form. | Baseline and day 90 | 
| Change from baseline in fatigue at days 16, 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on fatigue. Change from baseline as measured by the fatigue severity scale (FSS) and mental fatigue scale (MFS). | Baseline and days 16, 45 and 90 | 
| Change from baseline in cognitive dysfunction at days 16, 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on cognitive dysfunction. Change from baseline over time as measured by the Montreal Cognitive Assessment (MoCA) test. | Baseline and days 16, 45 and 90 | 
| Change from baseline in dyspnea at days 16, 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on dyspnea measured as change from baseline in respiratory symptoms using the Chronic obstructive disease assessment (CAT) and Modified Medical Research Council (mMRC) tests. | Baseline and days 16, 45 and 90 | 
| Change from baseline in dysfunctional breathing patterns, maximum inspiratory pressure and lung function at days 16, 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on dysfunctional breathing patterns, maximum inspiratory pressure, and lung function. Change from baseline in Njimegen questionnaire, maximal inspiratory pressure (MIP), forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). | Baseline and days 16, 45 and 90 | 
| Change from baseline in plasma biomarkers at days 16, 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on plasma biomarkers. Change from baseline in the following plasma biomarkers: D-dimer, CRP, ESR, ferritin, NTproBNP and LD. | Baseline and days 16, 45 and 90 | 
| Change from baseline in dysautonomia at days 45 and 90 | The effect of oral administration of nirmatrelvir/ritonavir on dysautonomia symptoms. Change from baseline as measured using the Composite Autonomic Symptom Score (Compass31) questionnaire. | Baseline and days 45 and 90 |