ImPROving Quality of LIFe in the Long COVID Patient

Phase 2

Completed

• Conditions: COVID-19; Post COVID-19 Condition, Unspecified; Long Covid19; POTS - Postural Orthostatic Tachycardia Syndrome; Postinfectious Inflammation; Post-COVID-19 Syndrome; Long COVID; Post COVID-19 Condition; Post-COVID Syndrome; Postinfectious Disorder
• Interventions: Drug: Nirmatrelvir/ritonavir; Drug: Placebo/ritonavir

• Registration Number: NCT05823896
• Lead Sponsor: Karolinska Institutet

Brief Summary

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

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).

Study Timeline

• Study First Submitted: 2023-04-20
• Study First Submitted QC: 2023-04-20
• Study First Posted: 2023-04-21
• Study Start: 2023-05-01
• Status Verified: 2024-09
• Primary Completion: 2024-11-28
• Study Completion: 2024-11-28
• Last Update Submitted: 2024-12-03
• Last Update Posted: 2024-12-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 219

Inclusion Criteria

1. The subject has given written consent to participate in the study.
2. ≥18 years of age at the time of the Screening Visit.
3. Post-acute COVID-19 syndrome (PACS) according to the WHO definition.
4. EQ-5D-5L VAS< 50
5. 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

1. Other non-related conditions with PACS like symptoms.

2. Renal function eGFR eGFRCysC < 60 mL/min/1.73 m2.

3. Not able to comply with the study protocol.

4. Previous Paxlovid treatment.

5. Pregnancy or breastfeeding.

6. 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.

7. Participants who are planning or considering vaccination (including boosters) through Study Day 45.

8. Active COVID-19 infection as verified by SARS CoV-2 positive antigen test.

9. Self-reported medical conditions, including:

   1. Type 1 or Type 2 diabetes mellitus.
   2. Chronic kidney disease.
   3. 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).
   4. 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.
   5. 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.

10. History of hospitalization for the medical treatment of acute COVID-19

11. Current need for hospitalization or anticipated need for hospitalization within 48 hours after randomization in the clinical opinion of the site investigator.

12. Prior/Concomitant Therapy:

    1. 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.
    2. 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:

13. 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.

14. 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).

15. Known prior participation in this trial or other trial involving nirmatrelvir.

    Diagnostic Assessments:

16. 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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Nirmatrelvir/ritonavir	Nirmatrelvir/ritonavir	Oral nirmatrelvir/ritonavir (Paxlovid) 300/100 mg twice daily for 15 days
Placebo/ritonavir	Placebo/ritonavir	Oral placebo/ritonavir 100 mg twice daily for 15 days

Primary Outcome Measures

Name	Time	Method
Change from baseline in quality of life over time	Baseline and 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.

Secondary Outcome Measures

Name	Time	Method
Change from baseline in quality of life over time	Baseline and 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.
Change from baseline in hemodynamic response over time	Baseline and 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.
Change from baseline in dysautonomia over time	Baseline and 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.
Change from baseline in fever in patients with POTS over time	Baseline and 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.
Change from baseline in endothelial function over time	Baseline and 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.
Change from baseline in heart rate over time	Baseline and 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.
Change from baseline in fever over time	Baseline and days 16, 45 and 90	The effect of oral administration of nirmatrelvir/ritonavir on fever. Change from baseline in body temperature.
Change from baseline in physical capacity over time	Baseline and 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.
Change from baseline in handgrip strength over time	Baseline and 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.
Change from baseline in physical activity over time	Baseline and days 16, 45 and 90	The effect of oral administration of nirmatrelvir/ritonavir on physical activity. Change from baseline as measured by accelerometer.
Change from baseline in post-exertional malaise over time	Baseline and 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.
Change from baseline in fatigue over time	Baseline and 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).
Change from baseline in cognitive dysfunction over time	Baseline and 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.
Change from baseline in dyspnea over time	Baseline and 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.
Change from baseline in plasma biomarkers over time	Baseline and 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.
Change from baseline in dysfunctional breathing patterns over time	Baseline and days 16, 45 and 90	The effect of oral administration of nirmatrelvir/ritonavir on dysfunctional breathing patterns. Change from baseline in Njimegen questionnaire.

Trial Locations

Locations (1)

Karolinska Institutet; 🇸🇪 Stockholm, Sweden