In a recent article published in Clinical Microbiology and Infection, researchers reviewed all registered trials currently investigating potential treatment options for post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS).
Additionally, the scientists examined the limitations of the current clinical trials to inform future research.
Over 663 million people contracted COVID-19 globally, of which 10% to 20% suffered from PACS, a complex systemic post-COVID-19 disease with substantial morbidity, per the World Health Organization (WHO) COVID-19 dashboard. Though studies have identified over 100 persistent symptoms associated with COVID-19, most studies have documented fatigue, followed by dyspnea, as the most reported PACS symptom.
There is a shortage of medical interventions to treat PACS patients. The data indicate that PACS patients will continue to spike globally in the coming future, increasing the burden on healthcare facilities. With just four multi-center clinical trials in the pipeline, there is an urgent need for more research investigating potential therapeutic options for PACS.
About the study
In the present study, researchers screened the WHO Internal Clinical Trials Registry Platform (ICTRP) on September 16th, 2022, to identify PACS trial registry entries. The ICTRP gathers records from 17 trial registries collecting information globally.
For trial selection, they adhered to the Patient Intervention Comparison Outcomes Study type (PICOS) framework, which mandated any patient sample size with patients of any age diagnosed with COVID-19 and related persistent symptoms for over four weeks or PACS. Additionally, these trials mentioned treatment of PACS, not prevention, and covered any outcome.
In total, 12 reviewers extracted data from the selected trials in duplicate and reviewed them as per the PRISMA guidelines. Later, two reviewers merged the overlapping primary outcomes and grouped them into appropriate outcome domains. Further, they used experimental arm(s) to identify all interventions under investigation for PACS for each trial. Furthermore, the team recorded trial numbers, patients enrolled, nations, and their specific clinical use per the trial source for each intervention under investigation. Finally, they organized all interventions into different classes, sorted into seven human organ systems. Also, they used the WHO definition to organize interventions under the rehabilitation classes. They used percentages to summarize trial characteristics.
The study identified 388 trials exploring 144 interventions for PACS. From all, 108 and 133 clinical trials specifically targeted fatigue and the pulmonary system, respectively. Among the interventions targeting a single human organ system, most were not specific to an organ system, and 70 trials adopted an all-inclusive approach to weaken PACS symptoms. It raises the issue of the reproducibility of these trials and the efforts to determine their clinical benefits later.
Further, the researchers noted that most trials investigated PACS treatment strategies repurposed from similar conditions; for instance, the rehabilitation interventions are currently exploring treatment strategies for cancer-related fatigue syndrome.
In addition, most interventions targeted multiple PACS symptoms concurrently or proposed the same intervention for different symptoms. Furthermore, these trials investigated barely a few novel therapeutic agents specifically for PACS (e.g., RSLV-132, AXA1125).
The clinical category of the patient, in or outpatient, admitted to the intensive care unit (ICU) under treatment is crucial. However, over 60% of these trials barely indicated the hospitalization status of the trial population in their inclusion/exclusion criteria.
Most importantly, all the included trials used a different PACS definition. So, the researchers noted a considerable heterogeneity among the included trials in this aspect, and the reported primary outcomes were also often not standardized. Additionally, they did not refer to time zero, with around 66 clinical trials mentioning PACS patients as having a positive and then a negative COVID-19 test. It made it difficult to ascertain whether the patient trial population recovered from COVID-19 exhibited PACS symptoms.
The cohort size of almost three-fourths of the trials was under 100. Moreover, over one-third of the participants were open-label. Accordingly, several interventions reported in these trials likely yielded only preliminary evidence of the safety and effectiveness of the PACS treatment options. Additionally, these trials used subjective and patient-reported scales that increased the risk of outcome assessment bias.
To conclude, the study highlighted the issue of the need for proper diagnostic tests for PACS, which hindered the systematic identification of patients with PACS and the assembling of a control group. Remarkably, of the four international multi-center trials, two trials neither explicitly mentioned PACS nor defined a time reference. A clinical trial mentioned PACS patients but did not define a time reference.
Moreover, many registered trials needed to have more effectively defined their inclusion criteria. They did not indicate the acute phase of illness, which made it impossible to ascertain whether all the included patients were experiencing symptoms due to some other chronic/infectious diseases (e.g., post-intensive care syndrome) or PACS.
The healthcare demands of PACS patients will continue to rise. Thus, there is an urgent need for robust PACS treatment research with standardized outcome reporting adhering to WHO’s recommendations. Data from the current study could inform future PACS research for developing robust treatment options. Though repurposing existing treatments could work, for now, the focus should be on developing novel therapies, specifically targeting PACS pathophysiology. In this regard, International collaborations, such as the National Institutes of Health's RECOVER initiative for PACS, should be encouraged.
Furthermore, it is crucial to include trials investigating alternative medicine, which currently has low registration quality. The authors also advocated improving the quality of research protocols reporting and sharing them for public access. All these endeavors could greatly benefit all the handlers of clinical trial evidence, including PACS patients.
- Nader A. Fawzy, Bader Abou Shaar, RandM. Taha, Tarek Z. Arabi b, Belal N. Sabbah, Mohamad S. Alkodaymi, Osama A. Omrani, Tariq Makhzoum, Najwa E. Almahfoudh, Qasem A. Al-Hammad, Wed Hejazi, Yasin Obeidat, Naden Osman, Khaled M. Al-Kattan, Elie F. Berbari, Imad M. Tleyjeh. (2023). A Systematic Review of Trials Currently Investigating Therapeutic Modalities for Post-Acute COVID-19 Syndrome and Registered on World Health Organization International Clinical Trials Platform. Clinical Microbiology and Infection. doi: https://doi.org/10.1016/j.cmi.2023.01.007 https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(23)00009-5/fulltext