This is an appendix of master protocol (NCT05595369) designed to be flexible so that it is suitable for a wide range of settings within health care systems and in community settings where it can be integrated into COVID-19 programs and subsequent treatment plans. This sub-study is a prospective, multi-center, double-blind, randomized, controlled trial evaluating nirmatrelvir/ritonavir (Paxlovid) in two dosing durations for the treatment of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). The study is evaluating potential mechanisms of action, efficacy, and safety of antivirals and other therapeutics in individuals with PASC, according to the platform protocol objectives. The hypothesis is that persistent viral infection and/or overactive/chronic immune response and inflammation are underlying contributors to PASC and that antiviral and other applicable therapies may result in viral clearance or decreased inflammation and improvement in PASC symptoms.
For this appendix of the master protocol (NCT05595369), participants will be randomized to Paxlovid (nirmatrelvir/ritonavir) vs. ritonavir control plus nirmatrelvir-matching placebo. When there are multiple study interventions (sub-studies) available under the master protocol (NCT05595369), randomization will occur based on the specific inclusion/exclusion criteria of each appendix.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
964
Nirmatrelvir 300mg and ritonavir 100mg taken BID (twice a day) for 30 days
Nirmatrelvir 300mg and ritonavir 100mg taken BID (twice a day) for 15 days then ritonavir 100mg taken BID plus nirmatrelvir matching placebo BID for 15 days
Ritonavir 100mg taken BID (twice a day) plus nirmatrelvir matching placebo BID for 30 days
All sites listed under NCT05595369
Durham, North Carolina, United States
Change in cognitive dysfunction symptom cluster, as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) cognitive function T-score
The PROMIS cognitive function-8a (PRO assessment) T-score is a quantitative measure of current cognitive function. The primary endpoint for cognitive dysfunction is improvement of at least 5 T-score points on the PROMIS-cognitive function as measured at 90 days compared to baseline.
Time frame: Baseline to Day 90
Change in autonomic dysfunction symptom cluster, as measured by the orthostatic hypotension questionnaire (OHQ)
The OHQ \[Orthostatic Hypotension Questionnaire \[PRO assessment)\] is a measure of orthostatic intolerance, which has been the primary presentation of patients with PASC-related autonomic dysfunction. This measure includes the Orthostatic Intolerance Daily Activity Scale (OIDAS) and the Orthostatic Intolerance Symptom Assessment (OISA). The primary endpoint for autonomic dysfunction is improvement in autonomic function as defined by a ≥ 1-point decrease in the OHQ question 1 at 90 days compared to baseline.
Time frame: Baseline to Day 90
Change in exercise intolerance symptom cluster, as measured by the Modified Depaul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM)
DSQ-PEM assesses symptom frequency and severity over a 6-month look back period, however, for the purposes of this study, it will be modified to assess over a 1-week look back period. Frequency is rated on a 5-point Likert scale: 0 = none of the time, 1 = a little of the time, 2 = about half the time, 3 = most of the time, and 4 = all of the time. Severity is also rated on a 5-point Likert scale: 0 = symptom not present, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe. For exercise intolerance, the primary endpoint is improvement in PEM, defined as having no symptoms of moderate or greater severity with 50% or more frequency as determined by the DSQ-PEM short form at day 90.
Time frame: Baseline to Day 90
Change in cognitive dysfunction symptom cluster, as measured by a neurocognitive battery
The neurocognitive battery outcome is a binary indicator of whether the participant has evidence of deficits (at least one standard deviation below the mean on at least one test within the battery).
Time frame: Baseline to Day 90
Change in autonomic dysfunction symptom cluster, as measured by the active stand test
The active stand test outcome is a binary indicator of whether the follow-up active stand test result was abnormal or normal.
Time frame: Baseline to Day 90
Change in exercise intolerance symptom cluster, as measured by the endurance shuttle walk test (ESWT)
The ESWT \[endurance shuttle walk test (performance measure)\] consists of timed walking on a 10m course.The ESWT will primarily be analyzed as a binary endpoint defined as an increase of at least 3 minutes of walking time at follow-up compared to baseline.
Time frame: Baseline to Day 90
Occurrence of individual SAEs
Time frame: Baseline to Day 190
Occurrence of one or more SAEs
Time frame: Baseline to Day 190
Occurrence of AEs and SAEs leading to discontinuation
Time frame: Baseline to Day 25
Occurrence of Events of Special Interest (ESIs)
Time frame: Baseline to Day 190
Adherence in intervention versus control groups as measured by number of missed doses
Time frame: Baseline to Day 25
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