A Decentralized, Randomized Phase 2 Efficacy and Safety Study of Nirmatrelvir/Ritonavir in Adults with Long COVID.

NCT05668091 | Completed Phase 2 DMC FDA Drug

• 2 other identifiers: 2000034086CIICORE-01
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

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 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).

Conditions

Long COVID

Keywords

Long COVID

Outcome Measures

Primary Outcomes (1)

• National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS)-29 version 2.1 Physical Health Summary Score

  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.

  Day 28

Secondary Outcomes (11)

• Modified General Symptom Questionnaire-30 (Modified GSQ-30)

  Day 28 and at Day 15, and Weeks 6, 10, 14, 18, and 24

• PROMIS® Cognitive Function v.2.0 - Short Form 6a

  Day 28 and at Day 15, and Weeks 6, 10, 14, 18 and 24

• COVID Core Outcome Measure for Recovery

  Day 28 and at Day 15, and Weeks 14 and 24

• EuroQol EQ-5D-5L Utility Score-VAS (USA Version)

  Day 28 and at Day 15, and Weeks 14 and 24

• Functional Assessment of Chronic Illness Therapy (FACIT)-Item GP5

  Day 28 and Day 15

Other Outcomes (1)

• Exploratory Outcome Measure

  Baseline, Day 14 and at Day 28

Study Arms (2)

Nirmatrelvir / Ritonavir

EXPERIMENTAL

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.

Drug: Nirmatrelvir; Drug: Ritonavir

Placebo / Ritonavir

PLACEBO COMPARATOR

Participants receive placebo to match nirmatrelvir plus ritonavir for 15 days. The control formulation includes 2 placebo tablets and 1 ritonavir tablet.

Drug: Ritonavir; Drug: Placebo

Interventions

Nirmatrelvir DRUG

Two 150 mg tablets taken by mouth every 12 hours.

Nirmatrelvir / Ritonavir

Ritonavir DRUG

One 100 mg capsule taken by mouth every 12 hours.

Nirmatrelvir / Ritonavir; Placebo / Ritonavir

Placebo DRUG

Two tablets containing placebo matching nirmatrelvir taken by mouth every 12 hours.

Also known as: sugar pill

Placebo / Ritonavir

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Demographics
• ≥18 years of age and above the age of majority as defined for their state at the time of the screening visit.
• English fluency adequate for communication and able to self-complete the patient-reported outcomes instruments.
• Reside in the 48 contiguous United States
• Disease Characteristics
• Prior SARS-CoV-2 infection is required. Documented confirmation of previous COVID-19 infection from either a documented positive PCR test and/or medical records from a healthcare provider (HCP) that coincides with the diagnosis of long-COVID from a healthcare provider.
• 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'.
• 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. Documentation in the subject's medical record of a physical examination, including vital signs measurement, by a HCP performed after the onset of post-COVID symptoms or within 3 months prior to randomization, whichever is more recent, is required.
• Usual Source of Care • Have a usual source of medical care with medical record documentation as required above. (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.)
• 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.

You may not qualify if:

• HIV infection as determined by laboratory testing at screening.
• Acute medical illness currently or within the past 2 weeks, including COVID-19 infection.
• 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. (ALT or ALT level ≥2.5 X ULN or total bilirubin ≥2 X ULN (≥3 X ULN for Gilbert's syndrome) as determined by laboratory testing at screening.
• Receiving dialysis or renal impairment (eGFR estimate \<60 mL/min/1.73 m2 ) as determined by laboratory testing at screening.
• 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.
• History of hypersensitivity or other contraindication to any of the components of the trial intervention, as determined by the Yale team.
• Other medical or psychiatric condition, in the Yale team's judgment, that makes the participant inappropriate for the trial.
• Immunocompromised, as defined by the CDC; "Examples of medical conditions or treatments that may result in moderate to severe immunocompromise include but are not limited to:
• Active treatment for solid tumor and hematologic malignancies.
• Hematologic malignancies associated with poor responses to COVID-19 vaccines regardless of current treatment status (e.g., chronic lymphocytic leukemia, non-Hodgkin lymphoma, multiple myeloma, acute leukemia).
• Receipt of solid-organ transplant or an islet transplant and taking immunosuppressive therapy.
• Receipt of chimeric antigen receptor (CAR)-T-cell therapy or hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppressive therapy).
• Moderate or severe primary immunodeficiency (e.g., common variable immunodeficiency disease, severe combined immunodeficiency, DiGeorge syndrome, Wiskott-Aldrich syndrome).
• Advanced or untreated HIV infection (people with HIV and CD4 cell counts less than 200/mm3, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV).
• Active treatment with high-dose corticosteroids (i.e., 20 ≥ mg of prednisone or equivalent per day when administered for 2 or more weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor necrosis factor blockers, and other biologic agents that are immunosuppressive or immunomodulatory".

Sponsors & Collaborators

• Harlan M Krumholz: lead
• Pfizer: collaborator

Study Sites (1)

Yale University

New Haven, Connecticut, 06510, United States

Location

Related Publications (1)

• Sawano M, Bhattacharjee B, Caraballo C, Khera R, Li SX, Herrin J, Christian D, Coppi A, Warner F, Holub J, Henriquez Y, Johnson MA, Goddard TB, Rocco E, Hummel AC, Mouslmani MA, Hooper WB, Putrino DF, Carr KD, Charnas L, De Jesus M, Nepert D, Abreu P, Ziegler FW 3rd, Spertus JA, Iwasaki A, Krumholz HM. Nirmatrelvir-ritonavir versus placebo-ritonavir in individuals with long COVID in the USA (PAX LC): a double-blind, randomised, placebo-controlled, phase 2, decentralised trial. Lancet Infect Dis. 2025 Aug;25(8):936-946. doi: 10.1016/S1473-3099(25)00073-8. Epub 2025 Apr 3.

  PMID: 40188838 DERIVED

MeSH Terms

Conditions

Post-Acute COVID-19 Syndrome

Interventions

nirmatrelvir; Ritonavir; Sugars

Condition Hierarchy (Ancestors)

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Post-Infectious Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Carbohydrates

Study Officials

• Harlan M Krumholz, MD, SM

  Yale University

  PRINCIPAL INVESTIGATOR

• Akiko Iwasaki, PhD

  Yale University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: December 24, 2022
• First Posted: December 29, 2022
• Study Start: April 14, 2023
• Primary Completion: April 9, 2024
• Study Completion: August 21, 2024
• Last Updated: December 2, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)