A systematic review of trials currently investigating therapeutic modalities for post-acute COVID-19 syndrome and registered on WHO International Clinical Trials Platform

Abstract

Background: Post-acute COVID-19 syndrome (PACS) is a well-recognized, complex, systemic disease which is associated with substantial morbidity. There is a paucity of established interventions for the treatment of patients with this syndrome.

Objectives: To systematically review registered trials currently investigating therapeutic modalities for PACS.

Data sources: A search was conducted up to the 16 September, 2022, using the COVID-19 section of the WHO Internal Clinical Trials Registry Platform.

Study eligibility criteria, participants, and interventions: Interventional clinical trials of any sample size examining any therapeutic modality targeting persistent symptoms among individuals after diagnosis with COVID-19.

Methods: Data on trial characteristics and intervention characteristics were collected and summarized.

Results: After screening 17 125 trials, 388 trials, from 42 countries, were eligible. In total, we had 406 interventions, of which 368 were mono-therapeutic strategies, whereas 38 were intervention combinations. Among 824 primary outcomes identified, there were >300 different outcomes. Rehabilitation was the most employed class of intervention in 169 trials. We encountered 76 trials examining the pharmacological agents of various classes, with the most common agent being colchicine. Complementary and alternative medicine encompassed 64 trials exploring traditional Chinese medicine, Ayurveda, homeopathic medications, naturopathic medications, vitamins, dietary supplements, and botanicals. Psychotherapeutic and educational interventions were also employed in 12 and 4 trials, respectively. Other interventions, including transcranial direct current stimulation, transcutaneous auricular vagus nerve stimulation, general electrical stimulation, cranial electrotherapy stimulation, various stem cell interventions, and oxygen therapy interventions, were also employed.

Conclusion: We identified 388 registered trials, with a high degree of heterogeneity, exploring 144 unique mono-therapeutic interventions for PACS. Most studies target general alleviation of symptoms. There is a need for further high-quality and methodologically robust PACS treatment trials to be conducted with standardization of outcomes while following WHO's recommendation for uniform evaluation and treatment.

Keywords: COVID-19; Coronavirus; Long COVID; Post-acute COVID-19 syndrome; SARS-CoV-2.

Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Figures

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram.

Fig. 2

Mono-therapeutic interventions were organized by treatment category with their target organ system (n = 368). BREATHE, Breathing, Rest/recovery, Education, Activity management, Thinking/cognition, Healthy voice strategies, and Eating/nutrition; DiRECT, Diabetes Remission Clinical Trial; ENO, English National Opera; Hb-adMSC, Hope Biosciences adipose-derived mesenchymal stem cell; HUS, Helsinki University Hospital; LISTEN, Long COVID PersonalIsed Self-managemenT support EvaluatioN; PACS, post-acute COVID-19 syndrome; PEEP, positive end-expiratory pressure; REMM-HIIT, REmotely Monitored, Mhealth supported High Intensity Interval Training; TCM, traditional Chinese medicine; tSVF, tissue stromal vascular fraction.