Long COVID-19, Long COVID
Conditions
Keywords
PASC, Paxlovid
Brief summary
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.
Detailed description
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.
Interventions
DRUGPaxlovid
Nirmatrelvir 300mg and ritonavir 100mg taken BID (twice a day)
DRUGRitonavir
Ritonavir 100mg taken BID (twice a day)
DRUGNirmatrelvir-matching placebo
A nirmatrelvir-matching placebo taken BID (twice a day)
Sponsors
Kanecia Obie Zimmerman
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-blind
Intervention model description
As part of screening, potential participants will answer symptom questions. Eligible participants will then complete relevant Symptom Cluster assessments at the Screening visit. Participants will subsequently be assigned to one of the three Symptom Clusters based on the assessments. Participants must meet certain criteria within a specific symptom cluster in order to be included in the cluster. After study enrollment and initial cluster assignment, further assessments will be performed. Participants will undergo assessments for the symptom clusters for which the participants qualify.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
See NCT NCT05595369 for RECOVER-VITAL: Platform Protocol level
Exclusion criteria
which applies to this appendix Additional Appendix Level
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Improved in Cognitive Dysfunction Symptom Cluster, as Measured by Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive 8a Function T-score | Baseline, Day 90 | PROMIS Cognitive 8a is a questionnaire assessing self-reported cognitive impairments over the past 7 days using 8 items. It assesses the frequency that respondents experienced cognitive impairments on a scale ranging from 5 (never) to 1 (very often; several times a day). The total raw score is transformed into a T-score, with higher scores representing better cognitive function. The T-scores are interpreted in relation to a US reference population and are scaled to have mean = 50 and SD = 10 in the reference population. The primary endpoint for the cognitive dysfunction symptom cluster is improvement of at least 5 T-score points on the PROMIS-cognitive 8a as measured at Day 90 compared to baseline. |
| Percentage of Participants Who Improved in Autonomic Dysfunction Symptom Cluster, as Measured by the Orthostatic Hypotension Questionnaire (OHQ) | Baseline, Day 90 | The Orthostatic Hypotension Questionnaire (OHQ) is a patient reported outcome designed to assess the severity and impact of orthostatic hypotension (OH), a condition characterized by a sudden drop in blood pressure when standing. The OHQ consists of two main components: the Orthostatic Hypotension Symptom Assessment (OHSA) and the Orthostatic Hypotension Daily Activity Scale (OHDAS). The OHSA consists of 6 items measuring severity on a scale ranging from 0 (none) to 10 (worst possible). The OHDAS assesses the extent to which OH interferes with daily life on a scale ranging from 0 (no interference) to 10 (total interference). The primary endpoint for the autonomic dysfunction symptom cluster is improvement as defined by at least a 1-point decrease in the response to OHQ question 1 at Day 90 compared to baseline. |
| Percentage of Participants Who Improved in Exercise Intolerance Symptom Cluster, as Measured by the Modified Depaul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM) | Baseline, Day 90 | The Modified Depaul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM) is a patient-reported outcome designed to assess the frequency and severity of symptoms worsening after physical or mental exertion. The first 10 items of DSQ-PEM assess frequency and severity of the following 5 exercise-related impairments. These items were modified for the current study to use a 7-day instead of 6-month 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. The primary endpoint for the exercise symptom cluster 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Improved in Cognitive Dysfunction Symptom Cluster, as Measured by a Neurocognitive Battery | Baseline, Day 90 | The Neurocognitive battery is a performance measure used to assess various elements related to cognition. The neurocognitive battery consists of a cognitive assessment sequence of the following: WHO/UCLA Auditory Verbal Learning Test (WHO/UCLA AVLT) and Symbol Digit Modalities Test (SDMT). The major secondary endpoint for the cognitive dysfunction symptom cluster is a binary endpoint defined as an increase by at least 1 point in either or both of the AVLT delayed recall Z-score and/or SDMT number of correct substitutions Z-score, and no decrease exceeding 0.15 in either of these measures, at Day 90 compared to baseline. |
| Percentage of Participants Who Improved in Autonomic Dysfunction Symptom Cluster, as Measured by the Active Stand Test | Baseline, Day 90 | The active stand test is performed to assess presence of orthostatic intolerance, orthostatic hypotension, and postural orthostatic tachycardia syndrome. The participant's blood pressure and heart rate are recorded after 5 minutes of lying and then at minutes 1, 3, 5, and 10 after standing. Changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate beats per minute (HR BPM) are assessed from lying to standing for 10 minutes. The major secondary endpoint for the autonomic dysfunction cluster is a binary endpoint defined as improvement in change from lying to standing in at least one of HR, DBP, or DBP from baseline to Day 90 (defined as an increase of at least 10mmHg in SBP, an increase of at least 5mmHg on DBP, or a decrease of at least 10 BPM on HR) and no worsening in any of HR, DBP, or DBP from baseline to Day 90 (defined as any decrease in SBP or DBP, or any increase in HR. |
| Percentage of Participants Who Improved in Exercise Intolerance Symptom Cluster, as Measured by the Endurance Shuttle Walk Test (ESWT) | Baseline, Day 90 | The endurance shuttle walk test (ESWT) is a performance measure that consists of timed walking on a 10 meter course. The major secondary endpoint for the exercise intolerance symptom cluster is defined as an increase of at least 3 minutes in walk time at Day 90 compared to baseline. |
| Total Number of SAEs (Serious Adverse Events) | Up to 190 days | — |
| Number of Participants Experiencing One or More SAEs (Serious Adverse Events) | Up to 190 days | — |
| Number of Participants Experiencing AEs (Adverse Events) or SAEs (Serious Adverse Events) Leading to Treatment Discontinuation | Up to 25 days | — |
| Number of Participants With an Event of Special Interest (ESI) | Up to 190 days | — |
Countries
United States
Participant flow
Recruitment details
Study recruitment period was from late July 2023 to mid-August 2024 at 69 US sites. Recruiting centers were a mix of large academic and small independent research sites in rural and urban, outpatient settings.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 48.4 years STANDARD_DEVIATION 14.07 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 33 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 281 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 42 Participants |
| Race (NIH/OMB) Black or African American | 111 Participants |
| Race (NIH/OMB) More than one race | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants |
| Race (NIH/OMB) White | 255 Participants |
| Region of Enrollment United States | 959 Participants |
| Sex/Gender, Customized Sex/Gender Female | 643 Participants |
| Sex/Gender, Customized Sex/Gender Intersex | 1 Participants |
| Sex/Gender, Customized Sex/Gender Male | 103 Participants |
| Sex/Gender, Customized Sex/Gender Prefer Not to Answer | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 323 | 0 / 320 | 0 / 320 |
| other Total, other adverse events | 212 / 323 | 203 / 320 | 180 / 320 |
| serious Total, serious adverse events | 13 / 323 | 13 / 320 | 16 / 320 |
Outcome results
None listed