Post-COVID-19 Syndrome, Long COVID, Long Covid19, COVID-19, POTS - Postural Orthostatic Tachycardia Syndrome, Post COVID-19 Condition, Post-COVID Syndrome, Post COVID-19 Condition, Unspecified, Postinfectious Inflammation, Postinfectious Disorder
Conditions
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 and meeting the WHO definition of severe PACS. A total of 180 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).
Interventions
300/100 mg tablet twice daily (q12h) administered orally for 15 days
DRUGPlacebo/ritonavir
100mg tablet twice daily (q12h) administered orally for 15 days
Sponsors
Karolinska University Hospital
Pfizer
Karolinska Institutet
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in persistence of SARS-CoV-2 virus over time | At baseline and day 16 | The effect of oral administration of nirmatrelvir/ritonavir on persistence of SARS-CoV-2 virus as measured by: Protein profiling using Olink Explore Inflammation panel. Nucleosome-profiling (using Volition) and circulating spike (using SIMOA™, Quanterix). PBMC profiling for scTCR-sequencing (using BD Rhapsody) with assessment of Super-Ag-mediated T-cell activation. Immune system signatures associated with disease states using RNA-sequencing of stabilized whole blood (PaxGene). |
| Change from baseline in immune cell function over time | At baseline and day 16 | The effect of oral administration of nirmatrelvir/ritonavir on changes in immune cell function as assessed by high-dimensional cytometry. |
| Change from baseline in relationships between genotypes and immune function over time | At baseline and day 16 | The effect of oral administration of nirmatrelvir/ritonavir on the relationship between genotypes and immune function at the molecular level. Circulating protein levels adjusted for DNA-variants. |
Countries
Sweden
Outcome results
None listed