A Decentralized, Randomized Phase 2 Efficacy and Safety Study of Nirmatrelvir/Ritonavir in Adults With Long COVID.
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|ClinicalTrials.gov Identifier: NCT05668091|
Recruitment Status : Recruiting
First Posted : December 29, 2022
Last Update Posted : November 14, 2023
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 all 48 states including the District of Columbia, 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|
|Long COVID||Drug: Nirmatrelvir Drug: Ritonavir Drug: Placebo||Phase 2|
This decentralized Phase 2, 1:1 randomized, double-blind, superiority, placebo-controlled trial in non-hospitalized symptomatic adult participants with long COVID will investigate the efficacy, safety, and tolerability of 15 days of treatment with nirmatrelvir/ritonavir compared with placebo/ritonavir. The hypothesis is that 15 days of treatment with nirmatrelvir/ritonavir compared with placebo/ritonavir for the treatment of highly symptomatic, adult participants with long COVID will improve their general health as assessed by the National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS)-29 version 2.1 Physical Health Summary Score at Day 28 (2 weeks after the end of the trial drug treatment). This randomized trial is intended to inform future research and will involve an investigation into markers of response.
The primary outcome is the PROMIS-29 Physical Health Summary Score. Secondary outcomes will include the PROMIS subscales and items; the Modified General Symptom Questionnaire (Modified GSQ-30) with PROMIS Cognitive Function v.2.0 - Short Form 6a and supplemental symptoms questionnaire and items; the COVID Core Outcome Measure for Recovery; the EuroQol EQ-5D-5L (USA Version); the Functional Assessment of Chronic Illness Therapy (FACIT)-Item GP5; the Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), and symptom assessments and healthcare utilization and death. The trial will also employ immunophenotyping to explore the effects of treatment on immune signatures and immune markers of response. In addition, there will be an evaluation of safety endpoints.
The trial will randomize 100 participants 18 years and older and able to provide legal consent, with long COVID (history of SARS-CoV-2 infection, symptoms consistent with long COVID beginning after the index infection and continuing more than 12 weeks); with a current fair or worse health status and a good or better health status before the index infection and no known other obvious reason for a depressed health status. Exclusion criteria include HIV infection; pregnancy; breastfeeding; renal impairment (eGFR <60 mL/min/1.73 m2); hepatic impairment (Child-Pugh Class B or C); history of clinically significant hypersensitivity reactions [e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome] to the product; known or suspected debilitating chronic conditions or those associated with an impaired immune system that pre-date the long COVID syndrome.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||100 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||An Interventional Decentralized Phase 2, Randomized, Double-Blind, 2-Arm Study to Investigate the Efficacy and Safety of Orally Administered Nirmatrelvir/Ritonavir Compared With Placebo/Ritonavir in Participants With Long COVID|
|Actual Study Start Date :||April 14, 2023|
|Estimated Primary Completion Date :||April 30, 2024|
|Estimated Study Completion Date :||October 31, 2024|
Experimental: Nirmatrelvir / Ritonavir
Participants receive nirmatrelvir plus ritonavir (Paxlovid) for 15 days. All 3 tablets (2 of nirmatrelvir and 1 of ritonavir) must be taken twice daily by mouth for 15 days.
Two 150 mg tablets taken by mouth every 12 hours.
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 2 placebo tablets and 1 ritonavir tablet.
One 100 mg capsule taken by mouth every 12 hours.
Two tablets containing placebo matching nirmatrelvir taken by mouth every 12 hours.
Other Name: sugar pill
- National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS)-29 version 2.1 Physical Health Summary Score [ Time Frame: Day 28 ]The difference in NIH 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. Higher scores mean better outcomes.
- Modified General Symptom Questionnaire-30 (Modified GSQ-30) [ Time Frame: 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 2-week time period. The GSQ-30 asks: "how much have you been bothered by any of the following?" with 5 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 7 items) to identify the symptoms of most concern to the individual. Total score ranges from 0 to 120; a higher score means worse outcome. To align with the other trial questionnaires, we will modified the recall period to 1-week.
- PROMIS® Cognitive Function v.2.0 - Short Form 6a [ Time Frame: 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 6-item sub-set scale of the PROMIS® Cognitive Function item bank that assesses patient-perceived cognitive deficits.
- COVID Core Outcome Measure for Recovery [ Time Frame: 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 the participant no longer has symptoms related to illness and can do usual daily activities and has returned to their previous state of health and mind (before illness).
- EuroQol EQ-5D-5L Utility Score-VAS (USA Version) [ Time Frame: 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). 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 [ Time Frame: Day 28 and Day 15 ]Difference in 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.
- PROMIS-29 Overall and Mental Health Summary Score [ Time Frame: 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 7 health domains (physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance) using 4 items per domain. There is no total score, but each axis forms its own score. Higher scores mean better outcomes.
- Difference in number of hospitalizations and deaths [ Time Frame: Day 1 through Week 24 (End of Study) ]Difference in occurrence of hospitalizations and deaths between nirmatrelvir/ritonavir and placebo/ritonavir groups.
- Proportion of participants who experience individual Serious Adverse Events (SAE) [ Time Frame: up to 6 weeks post starting study drug ]Proportion of participants who experience individual SAEs
- Incidence of SAEs leading to discontinuation [ Time Frame: Day 15 ]The number of SAEs leading to discontinuation in the study
- Patient Global Impression of Severity [ Time Frame: Baseline, Day 15, Day 28, Week 6, Week 10, Week 14, Week 24 ]Based on FDA's recommendations, we will include the Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC) scales. These anchor scales can help interpret a clinically meaningful within-patient score change for the key primary and secondary endpoints. We will include two PGIS and two PGIC scales. The PGIS 1 is a single-item questionnaire that asks respondents: "Overall, how would you rate the severity of your long COVID symptoms over the past week?". Responses are: "none," "mild," "moderate," "severe," and "very severe." The PGIS 2 asks "Overall, how would you rate the impact of your symptoms on your overall health over the past week?". Responses are: "none," "mild," "moderate," "severe," and "very severe." The PGISs will be administered at the same intervals as the primary endpoint (PROMIS-29).
- Patient Global Impression of Change [ Time Frame: Day 15, Day 28, Week 6, Week 10, Week 14, Week 24 ]The PGIC 1 asks: "Overall, how would you rate the change in your long COVID symptoms since you started the study?". There 7-point scale options: 1) "very much better", 2) "much better", 3) "minimally better", 4) "no change", 5) "minimally worse", 6) "much worse", or 7) "very much worse". Higher scores indicate a change for the worse. The PGIC 2 asks "Overall, how would you rate your overall health since you started the study?". There 7-point scale options: 1) "very much better", 2) "much better", 3) "minimally better", 4) "no change", 5) "minimally worse", 6) "much worse", or 7) "very much worse". Higher scores indicate a change for the worse. The PGICs will be administered at the same intervals as the primary endpoint (PROMIS-29) with the exception of baseline. These instruments have been used extensively in patient-centered research.
- Exploratory Outcome Measure [ Time Frame: Baseline, Day 14 and at Day 28 ]Differences in immune signatures between baseline and nirmatrelvir/ritonavir treatment relative to placebo/ritonavir. Immunophenotyping assays will include flow cytometry, multiplex proteomic analysis, linear peptide profiling, and rapid extracellular antigen profiling, among others.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05668091
|Contact: Study Team||203-497-1246||YalePaxStudy@yale.edu|
|United States, Connecticut|
|New Haven, Connecticut, United States, 06510|
|Contact: Study Team 203-497-1246 YalePaxStudy@yale.edu|
|Sub-Investigator: Mitsuaki Sawano, PhD|
|Sub-Investigator: Rohan Khera, MD|
|Sub-Investigator: Cesar Caraballo, MD|
|Sub-Investigator: Erica Spatz, MD|
|Sub-Investigator: Bornali Bhattacharjee, PhD|
|Principal Investigator:||Harlan M Krumholz, MD, SM||Yale University|
|Principal Investigator:||Akiko Iwasaki, PhD||Yale University|