The PAX LC Trial: A Decentralized, Phase 2, Randomized, Double-Blind Study of Nirmatrelvir/Ritonavir Compared with Placebo/Ritonavir for Long COVID - 23/06/24

Doi : 10.1016/j.amjmed.2024.04.030

Harlan M. Krumholz, MD, SM ^a,^b,^c,^d,^⁎ , Mitsuaki Sawano, MD, PhD ^a,^b, Bornali Bhattacharjee, MS, PhD ^d,^e, César Caraballo, MD ^f, Rohan Khera, MD, MS ^a,^b,^g, Shu-Xia Li, PhD ^b, Jeph Herrin, PhD ^a, Andreas Coppi, PhD ^a,^b, Julie Holub, MBA, CCRP ^h, Yashira Henriquez, MSc ^h, Maria A. Johnson, MBA ^a,^b, Theresa B. Goddard, CCRP, CHRC ^h, Erica Rocco, CCRP ^h, Amy C. Hummel, MS ^h, Mohammad AL Mouslmani, MD, MPH ⁱ, David F. Putrino, PhD ^j, Kevin D. Carr, MD ^k, Santos Carvajal-Gonzalez, PhD ^l, Lawrence Charnas, MD, PhD ^l, Magdia De Jesus, PhD ^l, Frank W. Ziegler, JD ^m, Akiko Iwasaki, PhD ^d,^e,ⁿ
^a Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT
^b Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, CT
^c Department of Health Policy and Management, Yale School of Public Health, New Haven, CT
^d Center for Infection and Immunity, Yale School of Medicine, New Haven, CT
^e Department of Immunobiology, Yale School of Medicine, New Haven, CT
^f Department of Internal Medicine, Yale School of Medicine, New Haven, CT
^g Section of Health Informatics, Department of Biostatistics, Yale School of Public Health, New Haven, CT
^h Yale Center for Clinical Investigation, Yale School of Medicine, New Haven, CT
ⁱ Yale School of Medicine, New Haven, CT
^j Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, NY
^k Trusted Medical, Middletown, CT
^l Pfizer, Inc., Cambridge, Mass and New York, NY
^m Law Offices of Barry J. Gammons, Nashville, TN
ⁿ Howard Hughes Medical Institute, Chevy Chase, MD

^⁎Requests for reprints should be addressed to Harlan M. Krumholz, MD, SM, 195 Church St., Fifth Floor, New Haven, CT 06510.195 Church St., Fifth FloorNew HavenCT06510.

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Abstract

Background

Individuals with long COVID lack evidence-based treatments and have difficulty participating in traditional site-based trials. Our digital, decentralized trial investigates the efficacy and safety of nirmatrelvir/ritonavir, targeting viral persistence as a potential cause of long COVID.

Methods

The PAX LC trial (NCT05668091) is a Phase 2, 1:1 randomized, double-blind, superiority, placebo-controlled trial in 100 community-dwelling, highly symptomatic adult participants with long COVID residing in the 48 contiguous US states to determine the efficacy, safety, and tolerability of 15 days of nirmatrelvir/ritonavir compared with placebo/ritonavir. Participants are recruited via patient groups, cultural ambassadors, and social media platforms. Medical records are reviewed through a platform facilitating participant-mediated data acquisition from electronic health records nationwide. During the drug treatment, participants complete daily digital diaries using a web-based application. Blood draws for eligibility and safety assessments are conducted at or near participants' homes. The study drug is shipped directly to participants' homes. The primary endpoint is the PROMIS-29 Physical Health Summary Score difference between baseline and Day 28, evaluated by a mixed model repeated measure analysis. Secondary endpoints include PROMIS-29 (Mental Health Summary Score and all items), Modified GSQ-30 with supplemental symptoms questionnaire, COVID Core Outcome Measures for Recovery, EQ-5D-5L (Utility Score and all items), PGIS 1 and 2, PGIC 1 and 2, and healthcare utilization. The trial incorporates immunophenotyping to identify long COVID biomarkers and treatment responders.

Conclusion

The PAX LC trial uses a novel decentralized design and a participant-centric approach to test a 15-day regimen of nirmatrelvir/ritonavir for long COVID.

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Keywords : Clinical trial, Decentralized, Long COVID, Nirmatrelvir/ritonavir, PROMIS-29

Plan

Statistical Considerations

Discussion

	Funding: This work was supported by funding from Pfizer, and from Fred Cohen and Carolyn Klebanoff.
	Conflict of Interest: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: in the past 3 years, Harlan Krumholz received options for Element Science and Identifeye and payments from F-Prime for advisory roles. He is a co-founder of and holds equity in Hugo Health, Refactor Health, and Ensight-AI, Inc. He is associated with research contracts through Yale University from Johnson & Johnson, Kenvue, and Pfizer. Bornali Bhattacharjee is supported by, and César Caraballo was supported by, a grant from the Yale-Mayo Clinic Center of Excellence in Regulatory Science and Innovation (CERSI) (U01FD005938). Rohan Khera reports being an Associate Editor of JAMA. He receives support from the National Heart, Lung, and Blood Institute of the National Institutes of Health (under awards R01HL167858 and K23HL153775) and the Doris Duke Charitable Foundation (under award 2022060). He receives research support, through Yale, from Bristol-Myers Squibb, Novo Nordisk, and BridgeBio. He is a coinventor of U.S. Pending Patent Applications 63/562,335, 63/177,117, 63/428,569, 63/346,610, 63/484,426, 63/508,315, and 63/606,203. He is a co-founder of Ensight-AI, Inc. and Evidence2Health, health platforms to improve cardiovascular diagnosis and evidence-based cardiovascular care. Akiko Iwasaki co-founded RIGImmune, Xanadu Bio, and PanV, and is a member of the Board of Directors of Roche Holding Ltd. and Genentech. The other authors report no conflicts of interest.
	Authorship: All authors had access to the data and a role in writing the manuscript. HMK: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Conceptualization. MS: Writing – review & editing, Writing – original draft, Supervision, Project administration, Investigation. BB: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation. CC: Writing – review & editing, Supervision, Project administration, Investigation. RK: Writing – review & editing, Supervision, Resources, Methodology, Conceptualization. SXL: Writing – original draft, Supervision, Software, Methodology, Conceptualization. JH: Writing – review & editing, Writing – original draft, Supervision, Software, Methodology. AC: Writing – review & editing, Resources, Methodology. JH: Writing – original draft, Supervision, Project administration. YH: Writing – original draft, Supervision, Project administration. MAJ: Writing – review & editing, Project administration. TBG: Writing – original draft, Supervision, Project administration. ER: Writing – original draft, Supervision, Project administration. ACH: Writing – original draft, Supervision, Project administration. MALM: Writing – review & editing, Validation, Investigation. DFP: Writing – review & editing, Validation. KDC: Writing – review & editing, Resources. Santos CG: Writing – review & editing, Supervision, Methodology. LC: Writing – review & editing, Supervision, Methodology. MDJ: Writing – review & editing, Supervision, Methodology. FWZ: Writing – review & editing. Akiko Iwasaki: Writing – original draft, Supervision, Project administration, Investigation, Funding acquisition, Conceptualization.