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
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Karolinska Institutet
- Enrollment
- 219
- Locations
- 1
- Primary Endpoint
- Change from baseline in quality of life over time
Study Overview
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 Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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 m
- •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
- •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/mm
- •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)
Arms & Interventions
Nirmatrelvir/ritonavir
Oral nirmatrelvir/ritonavir (Paxlovid) 300/100 mg twice daily for 15 days
Intervention: Nirmatrelvir/ritonavir (Drug)
Placebo/ritonavir
Oral placebo/ritonavir 100 mg twice daily for 15 days
Intervention: Placebo/ritonavir (Drug)
Outcomes
Primary Outcomes
Change from baseline in quality of life over time
Time Frame: 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 Outcomes
- Change from baseline in quality of life over time(Baseline and days 45 and 90)
- Change from baseline in hemodynamic response over time(Baseline and days 45 and 90)
- Change from baseline in dysautonomia over time(Baseline and days 45 and 90)
- Change from baseline in fever in patients with POTS over time(Baseline and days 45 and 90)
- Change from baseline in endothelial function over time(Baseline and day 45)
- Change from baseline in heart rate over time(Baseline and days 45 and 90)
- Change from baseline in fever over time(Baseline and days 16, 45 and 90)
- Change from baseline in physical capacity over time(Baseline and days 16, 45 and 90)
- Change from baseline in handgrip strength over time(Baseline and days 16, 45 and 90)
- Change from baseline in physical activity over time(Baseline and days 16, 45 and 90)
- Change from baseline in post-exertional malaise over time(Baseline and day 90)
- Change from baseline in fatigue over time(Baseline and days 16, 45 and 90)
- Change from baseline in cognitive dysfunction over time(Baseline and days 16, 45 and 90)
- Change from baseline in dyspnea over time(Baseline and days 16, 45 and 90)
- Change from baseline in plasma biomarkers over time(Baseline and days 16, 45 and 90)
- Change from baseline in dysfunctional breathing patterns over time(Baseline and days 16, 45 and 90)
Investigators
Petter Brodin
Principal Investigator
Karolinska Institutet