Clinical trial NCT05823896: ImPROving Quality of LIFe in the Long COVID Patient
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
Collaborators: name: Karolinska University Hospital
name: Pfizer
First posted: 2023-04-21
Enrollment: 219
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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).

Eligibility criteria: 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 \&lt; 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 \&lt;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)

Primary outcomes:
measure: Change from baseline in quality of life over time
timeFrame: Baseline and day 16
Secondary outcomes:
measure: Change from baseline in quality of life over time
timeFrame: Baseline and days 45 and 90
measure: Change from baseline in hemodynamic response over time
timeFrame: Baseline and days 45 and 90
measure: Change from baseline in dysautonomia over time
timeFrame: Baseline and days 45 and 90
measure: Change from baseline in fever in patients with POTS over time
timeFrame: Baseline and days 45 and 90
measure: Change from baseline in endothelial function over time
timeFrame: Baseline and day 45
measure: Change from baseline in heart rate over time
timeFrame: Baseline and days 45 and 90
measure: Change from baseline in fever over time
timeFrame: Baseline and days 16, 45 and 90
measure: Change from baseline in physical capacity over time
timeFrame: Baseline and days 16, 45 and 90
measure: Change from baseline in handgrip strength over time
timeFrame: Baseline and days 16, 45 and 90
measure: Change from baseline in physical activity over time
timeFrame: Baseline and days 16, 45 and 90
measure: Change from baseline in post-exertional malaise over time
timeFrame: Baseline and day 90
measure: Change from baseline in fatigue over time
timeFrame: Baseline and days 16, 45 and 90
measure: Change from baseline in cognitive dysfunction over time
timeFrame: Baseline and days 16, 45 and 90
measure: Change from baseline in dyspnea over time
timeFrame: Baseline and days 16, 45 and 90
measure: Change from baseline in plasma biomarkers over time
timeFrame: Baseline and days 16, 45 and 90
measure: Change from baseline in dysfunctional breathing patterns over time
timeFrame: Baseline and days 16, 45 and 90
Other outcomes:
measure: Change from baseline in relationships between genotypes and immune function over time
timeFrame: At baseline and day 16
measure: Change from baseline in immune cell function over time
timeFrame: At baseline and day 16
measure: Change from baseline in persistence of SARS-CoV-2 virus over time
timeFrame: At baseline and day 16
Locations:
city: Stockholm
country: Sweden
facility: Karolinska Institutet
Study officials:
affiliation: Karolinska University Hospital
name: Michael Runold, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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