PAXLC: A Decentralized Phase 2 Efficacy and Safety Study of Nirmatrelvir/Ritonavir in Adult Participants With Long COVID
Study Details
Study Description
Brief Summary
This decentralized trial is a Phase 2, 1:1 randomized, double-blind, superiority, placebo-controlled study in an anticipated 100 non-hospitalized highly symptomatic adult participants with long COVID. It seeks to determine the efficacy, safety, and tolerability of 15 days of Paxlovid (nirmatrelvir/ritonavir), an anti-viral agent, compared with placebo plus ritonavir. The hypothesis is that viral persistence contributes to long COVID in some patients and nirmatrelvir/ritonavir compared with placebo/ritonavir can improve general health status in participants with long COVID. The study will also seek immune signatures associated with treatment response (overseen by Professor Akiko Iwasaki).
The decentralized study does not require site visits, and participants in Connecticut and New York who meet entry criteria can enroll. It is designed to make it convenient to participate. The study drugs will be delivered to the participant's designated address.
Long COVID is also known as post-acute sequelae of SARS-CoV-2 (PASC).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Nirmatrelvir / Ritonavir Participants receive nirmatrelvir plus ritonavir (Paxlovid) for 15 days. All three tablets (two of nirmatrelvir and one of ritonavir) must be taken twice daily by mouth for 15 days. |
Drug: Nirmatrelvir
Two 150 mg tablets taken by mouth every 12 hours.
Drug: Ritonavir
One 100 mg capsule taken by mouth every 12 hours.
|
| Placebo Comparator: Placebo / Ritonavir Participants receive placebo to match nirmatrelvir plus ritonavir for 15 days. The control formulation includes two placebo tablets and one ritonavir tablet. |
Drug: Ritonavir
One 100 mg capsule taken by mouth every 12 hours.
Drug: Placebo
Two tablets containing placebo matching nirmatrelvir taken by mouth every 12 hours.
|
Outcome Measures
Primary Outcome Measures
- National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS)-29 version 2.1 Physical Health Summary Score [Day 28]
The difference in National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS)-29 version 2.1 Physical Health Summary Score at Day 28 between nirmatrelvir/ritonavir and placebo/ritonavir treatment estimated with a longitudinal analysis of covariance (ANCOVA) that controls for age, sex, and baseline PROMIS-29 Physical Health Summary Score. PROMIS-29 was selected as a well-validated, non-proprietary general health assessment. PROMIS-29 is a self-report 29 item questionnaire from 7 primary PROMIS domains (depression, physical function, pain interference, fatigue, sleep disturbance, and satisfaction with participation in social roles). PROMIS-29 assessments are transformed into a T-score metric, so that scores have a normal distribution with a population mean T-score of 50 and standard deviation of 10.
Secondary Outcome Measures
- PROMIS-29 Overall and Mental Health Summary Score [Day 28 and at Day 15, and weeks 6, 10, 14, 18 and 24]
Difference in PROMIS-29 Overall and Mental Health Summary Score between nirmatrelvir/ritonavir and placebo/ritonavir groups. The PROMIS-29 v2.0 profile assesses pain intensity using a single 0-10 numeric rating item and seven health domains (physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance) using four items per domain. There is no total score, but each axis forms its own score.
- PROMIS® Cognitive Function v.2.0 - Short Form 6a [Day 28 and at Day 15, and weeks 6, 10, 14, 18 and 24]
Difference in PROMIS® Cognitive Function v.2.0 - Short Form 6a between nirmatrelvir/ritonavir and placebo/ritonavir groups. The PROMIS® Cognitive Function v.2.0 - Short Form 6a is a six-item sub-set scale of the PROMIS® Cognitive Function item bank that assesses patient-perceived cognitive deficits.
- General Symptom Questionnaire-30 (GSQ-30) [Day 28 and at Day 15, and weeks 6, 10, 14, 18 and 24]
Difference in GSQ-30 between nirmatrelvir/ritonavir and placebo/ritonavir groups. The GSQ-30 is a 30-item questionnaire developed to assess symptom burden over a two week time period. The GSQ-30 asks: "how much have you been bothered by any of the following?" with five options: "not at all," "a little bit," "somewhat," "quite a bit," and "very much" (scored 0-4); total score ranges from 0 to 120. The GSQ-30 reflects physical and neuropsychiatric symptoms. An additional question (not included in the scoring) asks whether any of the 30 GSQ symptoms have impaired work, social, or family functioning, and asks the rank order of severity (up to seven items) to identify the symptoms of most concern to the individual.
- COVID Core Outcome Measure for Recovery [Day 28 and at Day 15, and weeks 14 and 24]
Difference in COVID Core Outcome Measure for Recovery Score between nirmatrelvir/ritonavir and placebo/ritonavir groups. The COVID Core Outcome Measure for Recovery is a single item intended to measure a return to the pre-illness state. Its purpose in this trial is to have a question that directly assesses the participant's perception of their recovery from their SARS-CoV-2 infection. It is scored on a 5- point Likert scale from 0 (completely recovered) to 4 (not recovered at all). Complete recovery means participant no longer has symptoms related to illness and can do usual daily activities and has returned to previous state of health and mind (before illness).
- EuroQol EQ-5D-5L Utility Score-VAS [Day 28 and at Day 15, and weeks 14 and 24]
Difference in EuroQol EQ-5D-5L Utility Score and VAS Score between nirmatrelvir/ritonavir and placebo/ritonavir groups. The EQ-5D-5L is a descriptive system in which respondents are asked to report their current state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each of which has 5 levels of response (no problems, slight problems, moderate problems, severe problems, and extreme problems).6,31-33 There is also a visual analogue scale (VAS). In total there are 6 items. The higher the EQ-VAS score, the better the quality of life.
- Functional Assessment of Chronic Illness Therapy (FACIT)-Item GP5 [Day 28 and Day 15]
Difference in Functional Assessment of Chronic Illness Therapy (FACIT)-Item GP5 Score between nirmatrelvir/ritonavir and placebo/ritonavir groups. The single-item FACIT-Item GP5, "I am bothered by side effects of treatment," was included to have a question on the experience with the trial drug and will be prefaced to focus on the trial drug. It is a summary measure of the overall tolerability of treatment, with 5 levels of response: not at all, a little bit, somewhat, quite a bit, and very much. It has a 7-day recall period.
- Difference in number of Hospitalizations and Deaths [Day 28]
Difference in occurrence of hospitalizations and deaths between nirmatrelvir/ritonavir and placebo/ritonavir groups.
- Proportion of participants who experience individual SAEs [up to 6 weeks post starting study drug]
Proportion of participants who experience individual SAEs
- Incidence of SAEs leading to discontinuation [Day 15]
The number of SAEs leading to discontinuation in the study
- Free Text [Day 28 and at Day 15, and weeks 6, 10, 14, 18 and 24]
At every assessment there will be an opportunity for participants to share information about their experience, including their perceptions about how their lives, including symptoms, have changed since starting the study drug.
Eligibility Criteria
Criteria
Inclusion Criteria:
- Demographics:
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≥18 years of age at the time of the screening visit.
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English fluency adequate for communication and able to self-complete the patient-reported outcomes instruments.
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Be in Connecticut or New York (for the purpose of distributing study drug and being able to obtain biospecimens and transport them in a timeframe necessary for processing).
- Disease Characteristics:
- Prior SARS-CoV-2 infection is required. Given the extensive use of home testing, we will ask for medical record verification of testing, but also accept self-report. We will collect information on the following (with medical documentation, as possible): a) positive Nucleic Acid Amplification Test (NAAT);
- positive SARS-CoV-2 Antigen-RDT and symptoms consistent with infection; c) positive SARS-CoV-2 Antigen-RDT who was a contact of a probable or confirmed case; d) positive SARS-CoV-2 nucleocapsid protein antibody test or self-report of a positive SARS-CoV-2 test and type.
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Symptoms consistent with long COVID that began within 4 weeks of the index infection and persisted for >12 weeks. These symptoms, according to the World Health Organization definition, 'include fatigue, shortness of breath, cognitive dysfunction but also others, and generally have an impact on everyday functioning. Symptom(s) may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness.'10
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Baseline "fair" or worse general health status and "good" or better before the index infection and no obvious other reason for the depressed general health status. This is determined from a single-item general health question on the pre-randomization surveys and comorbidity questions.
- Surveys and Health Records:
• Have connected health records and completed baseline surveys so assessments can be made before randomization of eligibility for the trial. Laboratory results in the last 6 months will be reviewed for evidence of renal or liver dysfunction. Absence of testing, in the context of having a usual source of care, will be considered absence of the renal or liver abnormalities. There will not be any protocol-required laboratory evaluation.
- Usual Source of Care:
• Have a usual source of medical care and have had a general health encounter within the last 6 months. (The purpose is to have a health care provider who can be notified of their involvement in the trial and can be a source of care for any adverse effects; and general health encounters over the last 6 months will have produced records for review of patient eligibility for the trial.)
- Informed Consent:
- Willing and able to provide informed consent, complete the surveys, clinical assessments and biospecimen collections. The study does not have sites and participants will not need to travel for any study visits.
Exclusion Criteria:
- Medical Conditions:
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Known active SARS-CoV-2 infection
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HIV infection
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Known medical history of active liver disease (other than nonalcoholic hepatic steatosis), including chronic or active hepatitis B or C infection, primary biliary cirrhosis, Child-Pugh Class B or C, or acute liver failure.
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Receiving dialysis or have known renal impairment (eGFR estimate <60 mL/min/1.73 m2 within 6 months of the trial) or known liver dysfunction (see below).
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Any comorbidity requiring hospitalization and/or surgery within 7 days before trial entry, or that is considered life threatening within 30 days before trial entry, as determined by the Yale team.
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History of hypersensitivity or other contraindication to any of the components of the trial intervention, as determined by the Yale team.
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Other medical or psychiatric condition, in the Yale team's judgment, that makes the participant inappropriate for the trial.
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Any concomitant prior chronic condition that has caused debilitating symptoms, even if episodic, such as myalgic encephalomyelitis/chronic fatigue syndrome, chronic Lyme disease, multiple sclerosis, fibromyalgia, mast cell activation disorder, and small fiber neuropathy, postural orthostatic tachycardia syndrome, lupus erythematosus, and others or any prior condition associated with immune dysfunction.
- Prior/Concomitant Therapy:
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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 the trial drugs. A list of these medications is in Appendix 3.
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Concomitant use of any medications or substances that are strong inducers of CYP3A4 are prohibited within 28 days prior to first dose of nirmatrelvir/ritonavir and during trial treatment. A list of these medications will be provided.
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Prior treatment with nirmatrelvir/ritonavir within 2 months prior to randomization
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Prior treatment with nirmatrelvir/ritonavir at any time if for more than 5 days
- Prior/Concurrent Clinical Trial Experience:
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Unwillingness to abstain from participating in another interventional clinical study with an investigational compound or device, including those for long COVID therapeutics, through 90 days. (People may be concurrently enrolled in observational studies in general; including the Yale LISTEN study.)
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Previous administration with any investigational drug in a clinical study within 30 days or 5 half-lives preceding the first dose of trial intervention used in this trial (whichever is longer)
- Diagnostic Assessments:
Known history of any of the following abnormalities within the past 6 months or currently present:
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AST or ALT level ≥2.5 X ULN
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Total bilirubin ≥2 X ULN (≥3 X ULN for Gilbert's syndrome)
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eGFR <60 mL/min/1.73 m2 within 6 months of the screening visit, using the updated CKD-EPI formula without the race term
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Absolute neutrophil count <1000/mm3
- Other Exclusions:
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Potential participants who are or plan to become pregnant or breastfeeding. Potential participants will need to take a pregnancy test; a home urine pregnancy testing kit with a sensitivity of at least 25 mIU/mL may be used by the participant to perform the test at home. The pregnancy test outcome will be documented by an uploaded photo and recorded in the participant's trial records.
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Anyone directly involved in the conduct of the trial and their immediate family members.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Harlan M Krumholz
- Pfizer
Investigators
- Principal Investigator: Harlan Krumholz, MD, Yale University
- Principal Investigator: Akiko Iwasaki, PhD, Yale University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 2000034086