Article title: Study examines current clinical trials for the treatment of post-acute COVID-19 syndrome worldwide - Location: unknown

Article title: Study examines current clinical trials for the treatment of post-acute COVID-19 syndrome worldwide - Location: unknown

A systematic review of studies currently investigating therapeutic methods for post-acute COVID-19 syndrome registered in the World Health Organization International Clinical Trials Registry

In a recent article published in Clinical Microbiology and Infection, researchers analyzed all registered trials currently investigating potential treatment options for post-acute COVID-19 syndrome (PACS).

Additionally, scientists examined the limitations of current clinical trials to inform future research.

background

Over 663 million people have contracted COVID-19 worldwide, with 10% to 20% suffering from PACS, a complex systemic post-COVID-19 disease with significant morbidity, according to the World Health Organization (WHO) COVID-19 dashboard. Although over 100 persistent symptoms associated with COVID-19 have been identified, fatigue was most commonly documented in most studies, followed by shortness of breath, as the most common PACS symptom.

There is a lack of medical interventions to treat PACS patients. The data shows that the number of PACS patients will increase worldwide in the future, increasing the burden on healthcare facilities. With only four multicenter clinical trials in the pipeline, there is an urgent need for further research to investigate potential therapeutic options for PACS.

About the study

In the present study, researchers searched the WHO Internal Clinical Trials Registry Platform (ICTRP) on September 16, 2022 to identify entries in the registry of PACS trials. The ICTRP collects information from 17 global trial registries.

To select studies, they adhered to the Patient Intervention Comparison Outcomes Study (PICOS) framework, which required each patient sample size to include patients of all ages with COVID-19 and associated persistent symptoms of over four weeks or PACS. Additionally, these studies mentioned treatment of PACS, not prevention, and included every outcome.

A total of 12 reviewers extracted the data from the selected studies in duplicate and checked them according to the PRISMA guidelines. Later, two reviewers merged the overlapping key results and grouped them into appropriate result areas. They then used the experimental arm to identify all interventions studied for PACS for each study. In addition, for each intervention studied, they recorded the study numbers, patients enrolled, nations and their specific clinical use according to the study source. Finally, they organized all interventions into different classes divided into seven human organ systems. They also used the WHO definition to classify the interventions into rehabilitation classes. They used percentages to summarize the characteristics of the studies.

Study results

The study identified 388 studies that examined 144 interventions for PACS. Of these, 108 studies specifically targeted fatigue and 133 targeted the respiratory system. Most interventions that focused on a single organ system were not specific to any organ system, and 70 studies took an all-encompassing approach to attenuate the symptoms of PACS. This raises questions about the reproducibility of these studies and efforts to later determine their clinical utility.

Additionally, the researchers noted that most studies examined therapeutic strategies for PACS that were repurposed from similar diseases. For example, rehabilitation interventions are currently investigating treatment strategies for cancer-related fatigue syndrome.

Furthermore, most interventions targeted multiple PACS symptoms simultaneously or proposed the same intervention for different symptoms. Furthermore, these studies examined few new therapeutic agents specifically for PACS (e.g., RSLV-132, AXA1125).

The clinical category of the patient, inpatient or outpatient, undergoing treatment in the intensive care unit (ICU) is crucial. However, over 60% of these studies barely reported the hospitalization status of the study population in their inclusion and exclusion criteria.

Most importantly, all included studies used a different definition of PACS. Therefore, researchers noted significant heterogeneity among the included studies in this aspect, and the main results reported were also often not standardized. Furthermore, they did not refer to time zero, with approximately 66 clinical trials mentioning PACS patients who had a positive and then a negative COVID-19 test. This made it difficult to determine whether patients in the study population had recovered from COVID-19 and had PACS symptoms.

The cohort size of almost three quarters of the studies was less than 100. In addition, over a third of the participants were open. As a result, several interventions reported in these studies likely provided only preliminary evidence for the safety and effectiveness of the PACS treatment options. Additionally, these studies used subjective and patient-reported scales, which increased the risk of assessing outcomes.

Conclusions

In conclusion, the study highlights the need for appropriate diagnostic tests for PACS, which hinders the systematic identification of patients with PACS and the formation of a control group. Notably, two international multicenter studies neither explicitly mentioned PACS nor defined a time reference. A clinical study mentioned PACS patients but did not define a time reference.

In addition, many registered studies need to define their inclusion criteria more precisely. They did not report the acute phase of the disease, which made it impossible to determine whether all included patients experienced symptoms due to some other chronic/infectious diseases (e.g., post-intensive care syndrome) or PACS.

The need for medical care for PACS patients will continue to increase. Therefore, there is an urgent need for robust PACS treatment research with standardized outcome reporting in accordance with WHO recommendations. Data from the present study could inform future PACS research to develop robust treatment options. Although repurposing existing treatments could work, the focus for now should be on developing new therapies that specifically address the pathophysiology of PACS. In this context, international collaborations such as the National Institutes of Health's RECOVER initiative for PACS should be promoted.

Furthermore, it is important to include studies on alternative medicine, which currently has low registration quality. The authors have also advocated improving the quality of research report protocols and making them available for public access. All of these efforts could greatly benefit all clinical trial evidence stakeholders, including PACS patients.