Long COVID, Long Covid19
Conditions
Keywords
PASC
Brief summary
This study is a platform protocol 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 protocol is a prospective, multi-center, multi-arm, double-blind, randomized, controlled platform trial with different interventions organized as appendices to the protocol. Each appendix (or sub-study) evaluates 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, viral reactivation, 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
Participants will be randomized to study interventions or placebo/controls based on the arms that are actively enrolling at the time of randomization. Study interventions may be added or removed according to adaptive design and/or emerging evidence. When there are multiple study interventions available, randomization will occur based on appropriateness of each intervention for the participant as determined by the study protocol.
Interventions
DRUGExperimental: Paxlovid 25 day dosing
Drug: Paxlovid 25 day dosing Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) bid x 25 days See NCT05965726 (Paxlovid Sub-study)
DRUGExperimental: Paxlovid 15 day dosing
Drug: Paxlovid 15 day Dosing Paxlovid (nirmatrelvir 300mg and ritonavir 100mg) bid x 15 days then ritonavir 100mg bid plus nirmatrelvir matching placebo bid x 10 days See NCT05965726 (Paxlovid Sub-study)
Drug: Control ritonavir 100mg taken bid plus nirmatrelvir matching placebo bid bid x 25 days See NCT05965726 (Paxlovid Sub-study)
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
1. ≥ 18 years of age at the time of enrollment 2. Previous suspected, probably or confirmed SARS-CoV-2 infection, as defined by the Pan American Health Organization\* \*Suspected and probable cases will only be allowed if it occurred before May 1, 2021, and will be limited to 10% of the study population. Otherwise, confirmed cases are required. Suspected case of SARS-CoV-2 infection - Three options, A through C: A. A person who meets the clinical OR epidemiological criteria. Clinical criteria: Acute onset of fever AND cough (influenza-like illness) OR Acute onset of ANY THREE OR MORE of the following signs or symptoms: fever, cough, general, weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, nausea, diarrhea, anorexia. Epidemiological criteria: Contact of a probable or confirmed case or linked to a COVID-19 cluster; or B. Acute respiratory infection with history of fever or measured fever of ≥ 38°C; and cough; with onset within the last 10 days; and who requires hospitalization); or C. With no clinical signs or symptoms, NOR meeting epidemiologic criteria with a positive professional use or self-test SARS-CoV-2 antigen-Rapid Diagnostic Test. Probable case of SARS-CoV-2 infection: A. A patient who meets clinical criteria above AND is a contact of a probable or confirmed case or is linked to a COVID-19 cluster. Confirmed case of SARS-CoV-2 infection - Two options, A through B: A. A person with a positive nucleic acid amplification test, regardless of clinical criteria OR epidemiological criteria; or B. Meeting clinical criteria AND/OR epidemiological criteria (See suspect case A). With a positive professional use or self-test SARS-CoV-2 Antigen-Rapid Diagnostic Test. 3. At least two moderate symptoms from the same symptom cluster or one severe cluster-associated symptom identified via the Cluster Targeted COVID-19 Symptom Questions (CTCSQ), with participant identifying new symptoms since COVID-19 illness and having persisted for at least 12 weeks 4. Meeting PRO Symptom Cluster criteria for at least one Symptom Cluster 5. Willing and able to provide informed consent, complete the surveys, clinical assessments, and return for all of the necessary follow-up visits
Exclusion criteria
An individual who meets any of the following criteria will be excluded from participation in this study. Refer to appendices for additional appendix-level criteria: 1. Known active acute SARS-CoV-2 infection ≤ 4 weeks from consent 2. Known severe anemia, defined as \< 8 g/dL 3. Meeting the following symptom cluster exclusion for all eligible clusters\*: a. Cognitive dysfunction: known stroke that resulted in cognitive impairment within 3 months of enrollment b. Autonomic dysfunction: atrial fibrillation or significant cardiac arrhythmia, more than moderate alcohol consumption\*\*, pre-existing sustained severe hypertension (BP\> 180/110 mmHg in the sitting position) c. Exercise intolerance: i. any of the following within 4 weeks of consent - an acute myocardial infarction or unstable angina, uncontrolled arrhythmias causing symptoms or hemodynamic compromise, acute myocarditis or pericarditis, uncontrolled acutely decompensated heart failure (acute pulmonary edema), acute pulmonary embolism, suspected dissecting aneurysm, severe hypoxemia at rest, any acute or chronic disorder that may affect exercise performance ii. if the participant is aggravated by exercise (e.g., infection, thyrotoxicosis, unable to cooperate) \*Participants who are eligible for \> 1 cluster must meet all inclusion and no
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Participants Enrolled in Each Appendix | 90 days | Appendix-specific outcome measure data will be reported under the associated NCT ID. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
This is a platform study record. 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.
Pre-assignment details
Consented participants were required to endorse two moderate or one severe symptom in one of 3 symptom clusters (exercise intolerance, autonomic dysfunction, or cognitive dysfunction), then meet or exceed a minimal score on a symptom specific questionnaire prior to being assigned. In addition to platform protocol inclusion and exclusion, participants had to meet no symptom cluster exclusion criteria and meet all drug appendix inclusion criteria and no drug appendix exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Paxlovid 25 Day Dosing Drug: Paxlovid 25 day dosing Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) bid x 25 days See NCT05965726 (Paxlovid Sub-study)
Experimental: Paxlovid 25 day dosing: Drug: Paxlovid 25 day dosing Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) bid x 25 days See NCT05965726 (Paxlovid Sub-study) | 321 |
| Experimental: Paxlovid 15 Day Dosing Drug: Paxlovid 15 day Dosing Paxlovid (nirmatrelvir 300mg and ritonavir 100mg) bid x 15 days then ritonavir 100mg bid plus nirmatrelvir matching placebo bid x 10 days See NCT05965726 (Paxlovid Sub-study)
Experimental: Paxlovid 15 day dosing: Drug: Paxlovid 15 day Dosing Paxlovid (nirmatrelvir 300mg and ritonavir 100mg) bid x 15 days then ritonavir 100mg bid plus nirmatrelvir matching placebo bid x 10 days See NCT05965726 (Paxlovid Sub-study) | 312 |
| Placebo Comparator: Control Drug: Control ritonavir 100mg taken bid plus nirmatrelvir matching placebo bid bid x 25 days See NCT05965726 (Paxlovid Sub-study)
Placebo Comparator: Control: Drug: Control ritonavir 100mg taken bid plus nirmatrelvir matching placebo bid bid x 25 days See NCT05965726 (Paxlovid Sub-study) | 318 |
| Total | 951 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 0 |
| Overall Study | Did Not Meet Eligibility Criteria | 0 | 4 | 0 |
| Overall Study | Lost to Follow-up | 11 | 10 | 10 |
| Overall Study | Moved Out of State Unexpectedly | 0 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 |
| Overall Study | Study Drug Non-compliance | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 7 | 6 |
Baseline characteristics
| Characteristic | Experimental: Paxlovid 25 Day Dosing | Experimental: Paxlovid 15 Day Dosing | Placebo Comparator: Control | Total |
|---|---|---|---|---|
| Age, Continuous | 49.5 years STANDARD_DEVIATION 13.77 | 48.8 years STANDARD_DEVIATION 13.89 | 47.1 years STANDARD_DEVIATION 14.31 | 48.4 years STANDARD_DEVIATION 14.01 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants | 33 Participants | 44 Participants | 108 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 288 Participants | 277 Participants | 272 Participants | 837 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 9 Participants | 13 Participants | 41 Participants |
| Race (NIH/OMB) Black or African American | 41 Participants | 31 Participants | 37 Participants | 109 Participants |
| Race (NIH/OMB) More than one race | 9 Participants | 9 Participants | 8 Participants | 26 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 9 Participants | 10 Participants | 25 Participants |
| Race (NIH/OMB) White | 244 Participants | 254 Participants | 249 Participants | 747 Participants |
| Region of Enrollment United States | 321 Participants | 312 Participants | 318 Participants | 951 Participants |
| Sex/Gender, Customized Sex/Gender Female | 217 Participants | 209 Participants | 212 Participants | 638 Participants |
| Sex/Gender, Customized Sex/Gender Male | 103 Participants | 102 Participants | 106 Participants | 311 Participants |
| Sex/Gender, Customized Sex/Gender Undifferentiated | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Sex/Gender, Customized Sex/Gender Unknown | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 321 | 0 / 312 | 0 / 318 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 321 | 0 / 312 | 0 / 318 |
Outcome results
Primary
Total Number of Participants Enrolled in Each Appendix
Appendix-specific outcome measure data will be reported under the associated NCT ID.
Time frame: 90 days
Population: Enrolled participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Paxlovid 25 Day Dosing | Total Number of Participants Enrolled in Each Appendix | 323 Participants |
| Experimental: Paxlovid 15 Day Dosing | Total Number of Participants Enrolled in Each Appendix | 320 Participants |
| Placebo Comparator: Control | Total Number of Participants Enrolled in Each Appendix | 320 Participants |