The study presented the first analysis of components of SoC for COVID-19 in registered and published clinical trials. The results point out that in most (82%) of the clinical trials registered and published in the first 9 months after the onset of COVID-19 that used SoC, the intervention that was labeled as SoC was not described. Among trials that did provide a description of the SoC, 60% used 3 or more components. Antiparasitics, antivirals, and antibiotics were the most commonly used interventions as components of SoC. A fifth of studies reported that SoC was determined by the regulatory government or state authorities.
We were unable to find other studies about the types of SoC used for COVID-19 in the published literature. Thus, we cannot compare our results with other similar reports.
Antiparasitics were the most commonly used single component of the SoC. Early after the emergence of COVID-19, there was much hype regarding antiparasitics, due to evidence that some of them inhibit the replication of viruses in vitro [5]. Even though some of the early studies regarding the efficacy of antiparasitics for COVID-19 appeared to be promising, very soon reports about problems with those studies emerged, and some of them were retracted [6].
Many studies and a Cochrane review provided evidence that there was no benefit in all stages of COVID-19 nor mortality benefits from the use of chloroquine and hydroxychloroquine [7, 8]. Even more, the use of chloroquine and hydroxychloroquine was associated with higher mortality and other adverse events [9]. Another Cochrane review concluded that the reliable evidence does not support the use of ivermectin for treating or preventing COVID-19 outside of well-designed RCTs [10].
Antivirals were the second most used single component of SoC for COVID-19. Early studies have shown that the repurposed medication of combination lopinavir/ritonavir, used to treat HIV infection, might play a role in improving outcomes by severe patients [11]. Subsequent research has shown that there is no benefit in mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death by using lopinavir/ritonavir [12, 13].
Antibiotics were the third most commonly used category of interventions in the SoC. This can appear counterintuitive as COVID-19 is a viral disease, and it could be anticipated that only a few COVID-19 patients would have bacterial co-infection. Adebisi et al. reviewed national treatment guidelines of 10 African countries to explore the use of antibiotics in COVID-19 management; they found that 17 different antibiotics were recommended for use in treating COVID-19, some countries even for the management of mild COVID-19 [14]. Literature analysis also showed the heavy use of antibiotics in the clinical management of COVID-19, warning about the consequences of this repurposing, impending worsening of antibiotic resistance crisis and calling for the strengthening of antibiotic stewardship [15].
It is worth emphasizing that in this study, due to relatively few studies available for the main analysis of the SoC components, we did not conduct a subgroup analysis based on the stage of the disease. COVID-19 can be classified into several stages: mild, moderate, and critical stage [16]. It is presumed that the disease stage would influence the components of SoC. For example, one of the most common components of SoC was oxygen. While it could be anticipated that oxygen would be used for more advanced stages of COVID-19, it has been reported that there are different approaches to oxygen therapy in different settings. Mansab et al. analyzed the association of oxygen and mortality in COVID-19 pneumonia in a comparative analysis of supplemental oxygen policies and health outcomes across 26 countries. They found that national guidelines for starting supplemental oxygen in COVID-19 patients differed significantly between the analyzed countries. Combined, the target SpO2 for the commencement of oxygen and target oxygen saturation for ongoing treatment varied from 90 to 98%. In nations that used a conservative oxygen strategy, they found an association with higher national mortality rates [17].
Some components of SoC were likely motivated by reports about clinical abnormalities observed in the COVID-19 patients. For example, early studies have shown that coagulopathy is a common abnormality in COVID-19 disease [18]. Di Minno et al. have shown that the prevalence of venous thromboembolism (VTE) is 30%, deep vein thrombosis (DVT) was reported for 20%, and pulmonary embolism (PE) was reported for 18% in COVID-19 patients [19]. Despite such a high risk of thromboembolism, with a potentially fatal outcome, anticoagulants were used only in 18 (14%) trials that had described SoC. In 3 trials, anticoagulants were the only intervention category used in SoC, but in other trials, it was used in combination with other interventions.
Srivastava et al. conducted a meta-analysis about the use of acetylsalicylic acid (ASA) in preventing thromboembolism and concluded that the use of ASA is useful in reducing the mortality of COVID-19 patients [20]. Chow et al. showed in an observational study that ASA use among hospitalized COVID- 19 patients is associated with decreased mechanical ventilation, intensive care unit admission, and in-hospital mortality [21]. In our sample, we did not find any study that used ASA as SoC for anticoagulation and prevention of thromboembolism, nor in the analgesic/antipyretic category. The usefulness of ASA for anticoagulation, thromboembolism prevention, analgesic, and antipyretic use in COVID-19 patients remains to be further evaluated by future studies.
Current medical literature regarding vitamin support in the treatment and prevention of COVID-19 is dominated by studies about vitamin D [22,23,24]. Vitamin support was used as a part of SoC in 11 trials in our study; most of them used vitamin C (8 studies), while vitamin D was a part of SoC in only 4 trials. Vitamin D is used with the expectation that it would support immune response during respiratory viral infections [25]. However, a Cochrane review found that there is currently insufficient evidence to determine the benefits and harms of vitamin D supplementation as a treatment of COVID-19. Furthermore, evidence for its effectiveness was very uncertain, and limited safety information was available [26].
Corticosteroids were used in only 12% of the trials that described SoC. It is possible that the decision to use corticosteroids as a part of SoC was determined by the severity of COVID-19. However, corticosteroids have also been tested in non-oxygen requiring COVID-19 patients since the emergence of SARS-SoV-2, with the results now showing that they can be more detrimental than beneficial [27]. A Cochrane review found some benefits of corticosteroids in hospitalized patients [28].
Finally, even though we found 18% of trials that reported components of SoC, it needs to be emphasized that reporting in those trials was frequently very poor, with details about the posology, timing and method of administration often missing. Research that is poorly reported is considered research waste. To be replicable, clinical trials need to be transparently reported, and providing details about interventions is essential. This is also important for many other reasons, such as more accurate risk-benefit assessment, adherence to reporting guidelines, ethics and future research. Authors of future trials need to transparently report their interventions in all reports about the trial, including the study registrations, study protocols and full research reports.
Determining the SoC in an emergent disease is of utmost importance; however, the genuine SoC needs to be evidence-based. Challenges associated with research during such an emergent disease are acknowledged [29]. However, our study indicates that many experimental, i.e. investigational interventions, were called SoC in early COVID-19 trials, even though their risk/benefit profile in targeted patients was unknown. Therefore, we recommend that the term SoC should not be used lightly in reports about interventions for emergent diseases.
It is important to emphasize that this was not a study that aimed to determine the efficacy and safety of any type of SoC for COVID-19. We are aware that many interventions used early in the COVID-19 pandemic to treat patients can be considered experimental (i.e. investigational) as the disease was previously unknown. Instead, our intention was to analyze which interventions the trialists declared as SoC. The trialists did not have to use the term SoC when describing the therapies they decided to give to their patients in the trial. The term SoC implies that something is the standard, i.e. usual therapy, in a certain setting. We consider that in the early stage of the pandemic, there could be no SoC in the real sense, since the disease was new. Thus, it was curious to us that so many trialists opted to use the term SoC. The wide heterogeneity of the SoC found in the included studies showcases all kinds of experimental/investigational approaches that were tested in the trial setting when treating COVID-19 patients.
As a potential limitation of the study, we could have missed some overlap between the analyzed information sources, despite our best efforts to avoid that. Also, we did not attempt to analyze protocols uploaded as a supplementary appendix (in published articles or preprints), or shared publicly in trial registries such as ClinicalTrials.gov.