David S. Knopman, Deborah Koltai, Daniel T. Laskowitz, Jacqueline Becker, Leigh Charvet, Juan P. Wisnivesky, Alex D. Federman, Adam M. Silverstein, Yuliya Lokhnygina, Giuseppina Pilloni, Michelle M. Haddad, Henry W. Mahncke, Tom Van Vleet, Rong Huang, Wendy C. Cox, Diana Terry, Jeannie Karwowski, Netia McCray, Jenny Lin, Grace A. McComsey, Upinder Singh, Linda N. Geng, Helen Y. Chu, Rebecca Reece, James N. Moy, Zoe Arvanitakis, Sairam Parthasarathy, Thomas F. Patterson, Aditi Gupta, Luis Ostrosky‐Zeichner, Jeffrey Parsonnet, Elaine T Kiriakopoulos, Tamara G. Fong, Janet Mullington, Sarah E. Jolley, Nirav S. Shah, Sarah Shizuko Morimoto, Joyce Lee‐Iannotti, William D. S. Killgore, Brigid Dwyer, William W. Stringer, Carmen Isache, Jennifer Frontera, Jerry A. Krishnan, Ashley O’Steen, Melissa James, Barrie Harper, Kanecia O. Zimmerman, Andrew Lawler, Brandon M. Johnson, Chloe E. Pitsch, Elen Feuerriegel, Jeffrey McKeehan, Joie Molden, Kayleigh M. Reid, Kristine M. Erlandson, Sarah Dowling, Thomas Wodushek, Diara Canton, Dilara Turut, Ethan Sheppard, Jennifer Scott‐Sutherland, Kristine Hauser, Lynn Shaughnessy, Michael L. Doyle, Michelle L. Beck, Sabrina Heisey, Vaishanvi Katragadda, Amidat Yusuff, Amy Perlack, Anh Phuong Tran, Brigid Dwyer, Caroline Altaras, Christie Merisme, David Krause, Duncan Schulte, Fabiola Dupre, Gina A. Montealegre Sanchez, Maxine Krengel, Monica T. Ly, Olanike Asupoto, Quinneil Simmons, Ryan W. Schroeder, Shannon Timlin, Ycar Devis, Della Carter, Leomaris Caba Caceres, Miguel Grande Rodríguez, Zariya Alvarez, Amin Yakubov, Celia Engelson, Michael Reyes, Alvin Youkhana, Cheryl Jennings, David Andrés González, Dina Naquiallah, Dylan Behun, Ellen Stephen, Emily Timm, Farrah Bilimoria
Importance: Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective: To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants: This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions: Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures: Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results: A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, -0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, -0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance: This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration: ClinicalTrials.gov Identifier: NCT05965739.