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Article

Outcomes Evaluated in Controlled Clinical Trials on the Management of COVID-19: A Methodological Systematic Review

1
Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester M23 9LT, UK
2
North West Lung Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester M23 9LT, UK
3
Department of Internal Medicine, Section for Pulmonary Diseases, Herlev Gentofte Hospital, 2900 Hellerup, Denmark
4
Department of Medical Microbiology and Immunology, Faculty of Medicine, Alexandria University, Alexandria 21131, Egypt
5
Department of Respiratory Medicine, Salford Royal Infirmary NHS Foundation Trust, Manchester M6 8HD, UK
6
School of Healthcare Sciences, Manchester Metropolitan University, Manchester M15 6BH, UK
7
School of Healthcare Sciences, Medicines Evaluation Unit, Manchester M23 9QZ, UK
8
MRC/NIHR Trials Methodology Research Partnership, Department of Health Data Science, University of Liverpool, Liverpool L69 3BX, UK
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Life 2020, 10(12), 350; https://doi.org/10.3390/life10120350
Received: 11 November 2020 / Revised: 7 December 2020 / Accepted: 11 December 2020 / Published: 15 December 2020
(This article belongs to the Special Issue Ecology, Evolution and Epidemiology of Coronaviruses)

Abstract

It is crucial that randomized controlled trials (RCTs) on the management of coronavirus disease 2019 (COVID-19) evaluate the outcomes that are critical to patients and clinicians, to facilitate relevance, interpretability, and comparability. This methodological systematic review describes the outcomes evaluated in 415 RCTs on the management of COVID-19, that were registered with ClinicalTrials.gov, by 5 May 2020, and the instruments used to measure these outcomes. Significant heterogeneity was observed in the selection of outcomes and instruments. Mortality, adverse events and treatment success or failure are only evaluated in 64.4%, 48.4% and 43% of the included studies, respectively, while other outcomes are selected less often. Studies focusing on more severe presentations (hospitalized patients or requiring intensive care) most frequently evaluate mortality (72.5%) and adverse events (55.6%), while hospital admission (50.8%) and viral detection/load (55.6%) are most frequently assessed in the community setting. Outcome measurement instruments are poorly reported and heterogeneous. Follow-up does not exceed one month in 64.3% of these earlier trials, and long-term COVID-19 burden is rarely assessed. The methodological issues identified could delay the introduction of potentially life-saving treatments in clinical practice. Our findings demonstrate the need for greater consistency, to enable decision makers to compare and contrast studies.
Keywords: coronavirus disease 2019; COVID-19; outcomes; endpoints; randomized controlled trials; systematic reviews; trial methods coronavirus disease 2019; COVID-19; outcomes; endpoints; randomized controlled trials; systematic reviews; trial methods

1. Introduction

The emergence of the coronavirus disease 2019 (COVID-19) led to an unprecedented research mobilization aiming to understand the virus and develop effective preventive and therapeutic strategies [1,2]. Characteristically, within ten months, over 60 thousand publications focusing on COVID-19 were indexed in PubMed and almost two thousand interventional studies were registered with the ClinicalTrials.gov database. However, the limited knowledge about the disease and the need for an expeditious response to the unfolding pandemic did not allow, in some cases, for adequate methodological planning and co-ordination. Extensive research duplication (or better multiplication) has been observed, with numerous randomized controlled trials (RCTs) evaluating the same interventions for COVID-19 in parallel [3]. Moreover, standardization is lacking in trial design and could limit comparability. An important source of variability in trial design could arise from the outcomes (endpoints) that are selected for evaluation. Heterogeneity in trial outcomes and omission of outcomes that are critically important to patients and clinicians complicate interpreting, comparing and synthesizing trial results, potentially delaying the introduction of novel, life-saving treatments into clinical practice [4,5].
Core outcome sets are developed to address heterogeneity in the selection of outcomes. These are agreed standardized sets of outcomes that should be measured and reported as a minimum in all clinical trials in specific areas of health or health care [6]. The Core Outcome Measures in Effectiveness Trials (COMET) has developed a rigorous methodology for their development, to ensure the most pertinent clinical outcomes are included in core outcome sets [6,7,8]. Core outcomes should be informed by rigorous methodological systematic review [6,7,8].
Upon the emergence of COVID-19 pandemic, there was an urgent need for the development of a core outcome set. Within a few months, four sets were developed, using an accelerated process [9,10,11,12]. These were based on methodological systematic reviews of the first registered RCTs, which were limited in number and design, due to the limited knowledge of the nature of COVID-19, at the time. However, in the meantime, our knowledge of the natural history of COVID-19 is expanding rapidly and numerous clinical trials have been registered. In this methodological survey, we describe the outcomes that are tested in RCTs evaluating therapeutic interventions for COVID-19 and the instruments used to measure these outcomes.

2. Materials and Methods

We followed standard methodology recommended by the Core Outcome Measures in Effectiveness Trials (COMET) initiative for conducting methodological systematic reviews of outcomes evaluated in RCTs [6], that was successfully applied in previous, similar methodological surveys [13,14,15,16]. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) was used for reporting this systematic review (Table S1).

2.1. Study Selection and Data Extraction

Planned, ongoing or completed interventional clinical trials evaluating pharmacological or non-pharmacological interventions for the management of COVID-19 were considered eligible. Phase 1 trials were considered beyond the scope of this manuscript and, thus, excluded. All eligible trials from the U.S. National Library of Medicine clinical trials register (ClinicalTrials.gov, searched on 5 May 2020) were retrieved using standard filters recommended by the library. More specifically, for identifying studies evaluating COVID-19, we used the following terms: COVID-19, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, 2019-nCoV, 2019 novel coronavirus, and Wuhan coronavirus. Only studies identified as interventional by the submitting researcher were retrieved.
Eligible studies were grouped into phase 2 or later stage trials, and according to the recruitment setting (community, hospital, or intensive care unit). The main methodological characteristics of all eligible studies, including the planned study population, age of the participants, recruitment setting, blinding, interventions, outcomes, funding, sponsoring, and geographic distribution of the participating centers were extracted automatically from the ClinicalTrials.gov extract (.csv), using a script developed in the platform R statistics (version 3.4.3; R Foundation for Statistical Computing, Vienna, Austria). One researcher (amongst MF, RH, ASH, AK) confirmed eligibility, cross-checked pre-extracted data for accuracy, searched for additional reports of the study protocol and extracted additional data, that were not automatically captured. A second researcher (AGM) cross-checked all extracted data for accuracy. Disagreement was resolved through discussion. Extracted data included the projected recruitment sizes, study settings, as well as details on the eligibility criteria and evaluated outcome measures.

2.2. Outcome Grouping and Classification

Descriptions of all outcome measures were extracted verbatim from the study protocols or registry entries. After in-depth assessment of the outcomes evaluated in a random sample of 20 studies, we developed a list of generic outcome categories defined by the treatment effect they aim to capture, rather than the specific measurement instrument. Two authors (amongst MF, RH, ASH, AK) categorized each of the extracted outcomes within the generic outcome categories. New generic outcome categories were developed as needed, in cases where the evaluated outcomes did not fit any of the existing categories, based on consensus among the co-authors. The instruments used for the quantification of each outcome were also captured. Disagreement was resolved through discussion with another reviewer (AGM).
Finally, the generic outcomes were further classified according to the COMET taxonomy [17].

3. Results

3.1. Description of the Included Studies

Our search retrieved 745 interventional studies. After excluding diagnostic, prognostic, preventive studies, phase 1 trials and those not directly focusing on the management of COVID-19, we selected 415 studies for inclusion in this systematic survey, including 178 phase 2, and 237 later phase RCTs (Figure A1, Table A1).
Most of the included trials are conducted by academic investigators (75.7%) and only one in four is sponsored by the pharmaceutical industry. The planned recruitment ranges between 7 and 12,000 participants (median: 160, interquartile range [IQR]: 67–400). Most trials include two intervention arms (74.8%), but one in four evaluates more than two, and up to 19 interventions. Moreover, 79.8% of the trials are conducted in a hospital setting, including 6.5% conducted in the intensive care unit (ICU), while 15.2% are conducted in the community. Descriptions of disease severity are heterogeneous, with the recruitment setting being the most consistent measure of disease. Details on the characteristics of the included studies are available in Table 1.
Overall, 3948 unique outcomes are evaluated in the included studies, including 1691 from phase 2 trials and 2257 from later phase trials. We identified 25 generic outcome categories (Table 2). Similar number of outcomes are evaluated in phase 2 (median: 8.5, IQR: 5–13) and later phase (median: 7, IQR: 4–11) trials (Figure A2 and Figure A3). Mortality and adverse events, the most frequently assessed outcomes, are only assessed in 64.6% and 48.4% of all trials, respectively. All remaining outcomes are evaluated in less than half of the trials, highlighting an important heterogeneity in outcomes selection (Table 3 and Table 4). Treatment success or failure is only evaluated in 41.6% of phase 2 trials and 44.1% of the later phase trials. Interestingly, the frequency that different outcomes are evaluated as outcomes or as primary outcomes are very similar for phase 2 and later phase trials.
The most frequently reported outcomes among studies conducted in a community setting (thus recruiting less severely ill patients), were viral detection or load (55.6%), need for hospital admission (50.8%), and symptoms (49.2%). In contrast, the most frequently evaluated outcomes in studies recruiting patients with more severe COVID-19, were mortality and adverse events, which were evaluated in 71.6%, and 50.3% of studies recruiting hospitalized patients, and in 88.9% and 66.7% of those recruiting critically ill patients, respectively.

3.2. Outcome Measurement Instruments

3.2.1. Mortality/Survival (Assessed by 284 Outcomes)

All-cause mortality is evaluated in all but six trials measuring mortality. When mortality was not further described, we presumed it referred to all-cause mortality. Time to death is assessed in 16 trials, and cause-specific mortality in six, mainly focusing on SARS-CoV2 mortality, but also including mortality due to pulmonary or cardiovascular complications.

3.2.2. Clinical Outcomes

1. (Time to) Treatment success or treatment failure: Treatment success or the time to treatment success was evaluated by 220 outcomes. Ordinal scales describing different levels of COVID-19 severity are used for assessing treatment success in 113 (51.4%) of these outcomes. Most scales are very similar to the most frequently used WHO scale, which is a 9-point ordinal scale (from 0 to 8), with each point describing a worse clinical status (Table 5) [18]. Treatment success is defined as an improvement in ordinal scales such as the WHO clinical progression scale by 2 points or 1 point in 57.5% and 24.8% of all outcomes using the scale to evaluate treatment success, while in the remaining outcomes, no specific threshold is provided. Complete resolution of the symptoms and signs of COVID-19 (clinical recovery) is used as a measure of treatment success in 51/220 (23.2%) outcomes and clinical improvement in 38/220 (17.3%) outcomes. The definition of complete resolution varies. Often, no further information is provided. In the remaining cases, it is defined as a composite outcome including several of the following components: complete resolution of breathlessness, tachypnoea, hypoxia, desaturation, cough, anosmia, myalgia, fever, or of oxygen requirements; a negative COVID-19 PCR; hospital discharge; or radiological resolution. A definition of clinical improvement as an outcome is also frequently lacking. In the remaining cases, it is defined as an improvement in several of the previously listed components. Improvement is either based on prespecified thresholds, or on a subjective clinicians’ judgement. Finally, 14 outcomes (6.4%), use specific thresholds (0, ≤2 or ≤4) of the National Early Warning Score (NEWS or NEWS-2) to define treatment success.
Treatment failure, or time to treatment failure is evaluated by 76 outcomes. In most cases (40/76, 52.6%), treatment failure is defined as a composite outcome consisting of several components with clear thresholds, such as: death, need for ICU admission, need for invasive ventilation, need for other organ support (e.g., vasopressors or renal replacement therapy), need for non-invasive ventilation (NIV), need for supplemental oxygen, a deterioration in oxygenation, need for hospital admission or re-admission or emergency visit, ventricular tachyarrhythmia. Ordinal clinical severity scales such as the WHO scale are used to define treatment failure in 16/76 (21.1%) outcomes, while the need for rescue therapy is used in 9/76 (11.8%) outcomes. The remaining 11 (14.5%) outcomes do not provide specific criteria and/or state treatment failure will be based on the clinician’s judgement of deterioration in the clinical condition of the patient.
2. Severity scores: Standardized scores are used to evaluate disease severity and progression in 277 outcomes. Ordinal disease severity scales (such as the WHO scale) are the most frequently used scores (144/277 outcomes, 51.2%), followed by the Sequential Organ Failure Assessment (SOFA) Score [19], a validated score for describing the severity of organ dysfunction (54/277 outcomes, 19.5%), and the NEWS score [20]. Acute Physiology and Chronic Health Evaluation II (APACHE II, 5/277), clinical sign score (5/277), Pneumonia Severity Index (PSI, 3/277), BRESCIA-COVID, Murray score, Sepsis Induced Coagulopathy, Small Identification Test, SMART-COP score, and the Vienna Vaccine Safety Initiative (ViVI) disease severity score are used less often.
3. Symptoms: 188 outcomes focus on symptoms, which are either assessed using visual analogue scales, or validated instruments. Composite scores evaluating several symptoms, including breathlessness, cough, sputum production, pyrexia, anosmia, myalgia, headache, or gastrointestinal symptoms are used in 40 outcomes (21.3%). Four composite outcomes specifically assess respiratory symptoms (2.2%). Each of the remaining outcomes focus on a single symptom. These include fever (72/188, 38.3%), breathlessness (18, 9.6%), cough (12, 6.4%), and less often anxiety, depressive symptoms, anosmia, cognitive dysfunction, nausea, insomnia, or fatigue. In this category we also included the assessment of heart rate (8, 4.3%) or blood pressure (5, 2.7%).

3.2.3. Physiological Outcomes

1. Oxygenation (evaluated by 215 outcomes): Oxygenation is evaluated using the partial pressure of oxygen (PaO2), fraction of inspired oxygen (FiO2), oxygen saturation (SatO2), or respiratory rate. Oxygenation is often measured as the PaO2 or SatO2 corrected for FiO2 (95/215, 44.2%). In this category we also included measurements of the partial pressure of carbon dioxide (PaCO2) and pH, which are only rarely evaluated as outcomes.
2. Pulmonary function and physiology (28 outcomes): There is significant heterogeneity in this domain, with different outcomes evaluating peak flow rate, forced vital capacity (FVC), the ratio of forced expiratory volume in 1 second (FEV1) to FVC, vital capacity, diffusing capacity, lung compliance, and respiratory muscle function.
3. Viral detection and load (235 outcomes): The vast majority assess virologic clearance by a specific timepoint, or the time until virologic clearance. A small number of outcomes track changes in viral load over time, or differences in the viral detection and load when using different samples (nasal, nasopharyngeal, oropharyngeal swabs or sputum).
4. Viral antibodies: The development of antibodies against SARS-CoV2 is assessed in 31 outcomes. Evaluation of specific antibody types (IgA, IgG, or IgM) is only described in five trials.
5. Radiological outcomes (61 outcomes): Definitions of this outcome are inadequate. In most cases, it is broadly stated that the progression, regression, or resolution of the radiological findings are monitored. Details are only provided in six outcomes, which monitor the extent of the lesion as a proportion of the full lung volume, or perform lung densitometry. Development of fibrosis is evaluated in seven outcomes. Computed tomography (CT) is used in 21 (34.4%) outcomes, a chest X-ray (CXR) in 8 (13.1%), either a CT or a CXR in three, either CT or CXR or lung ultrasound in one and nuclear imaging in one outcome. The imaging modality used is not declared in the remaining 28 (45.9%) outcomes.
6. Inflammatory biomarkers (321 outcomes, each describing either a single or multiple biomarkers): The most frequently evaluated biomarkers are the total white cell count, neutrophils, lymphocytes, eosinophils, monocytes, c-reactive protein, interleukins 1, 6, and 8, followed by other interleukins, procalcitonin, tumour necrosis factors, complement components, lymphocytes subtypes, immunoglobulins, and other inflammatory biomarkers.
7. Other biomarkers: 309 outcomes evaluate either a single or multiple non-inflammatory biomarkers. Mostly, these are surrogates for safety or adverse events. The most frequently captured biomarkers are d-dimers, cardiac enzymes, kidney function, liver function, clotting, red blood cells and haemoglobin, followed by a variety of other molecules.
8. Pharmacokinetics/Pharmacodynamics: Here, we categorized 33 outcomes, mostly evaluating plasma drug concentrations (12/33, 36.4%), but also half-life, maximum/minimum observed concentration, time to reach the maximum/minimum observed concentration, area under the plasma concentration-time curve.

3.2.4. Adverse Events

Adverse events (448 outcomes): 108 (24.1%) outcomes evaluate any adverse event; either their frequency, or participants experiencing at least one adverse event. 80 (17.9%) outcomes specifically assess serious adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE). Nineteen (4.2%) outcomes focused on drug reactions, 14 (3.1%) on grade 3 or 4 adverse events, as defined by the CTCAE, and 22 (4.9%) assessed the rate of study drugs discontinuation due to adverse events or due to any reason. The remaining outcomes focused on specific adverse events, mostly cardiac (38, 10.3%), secondary infections (37, 10.0%), thrombotic or bleeding events (29, 8.1%), or local administration reactions (13, 3.6%)

3.2.5. Life Impact (13 Outcomes)

The EuroQol 5 Dimensions (EQ-5D) is used in four outcomes, followed by the Research and Development Corporation’s (RAND) 36-Item Health Survey (SF-36), which is used in three outcomes. Other instruments include the WHO Disability Assessment Schedule (WHODAS 2.0), the Control, Autonomy and Pleasure (CASP-19), and the Nottingham Health Profile.

3.2.6. Resources Use

1. Need for a (higher) level of care (352 outcomes): Need for hospital admission is evaluated by 68 outcomes (19.3%), need for hospital re-admission by 9 (2.6%), need for intensive care admission by 82 (23.4%), need for invasive ventilation by 167 (47.4%), and need for extracorporeal membrane oxygenation (ECMO) by 26 (7.4%; merged with the outcome need for ventilation in the tables). In studies conducted in the hospital setting, need for hospital admission at a specific follow-up timepoint, refers to the proportion of patients who remain inpatients at that timepoint. Similarly, for studies conducted in the ICU, and the need for ICU admission.
In this category, we also included composite outcomes consisting of one of the above outcomes and mortality (e.g., need for ICU admission or death), as these composite outcomes focus on the need for a higher level of care, while death is added to account for patients who decease before accessing the higher level of care, or those who are not eligible for higher level of care due to their baseline clinical status. Such approaches could be crucial to account for bias, especially in situations such as the COVID-19 pandemic, when hospitals and ICUs are over-burdened and not infrequently unable to accommodate a significant proportion of the patients, leading to the introduction of stricter criteria for triaging patients. Moreover, some outcomes in this category also evaluate time-to-higher level of care (e.g., time-to-hospital admission).
2. Duration of stay in a specific level of care (469 outcomes): Of those, 206 (43.9%) focus on the length of hospital stay, 96 (20.5%) on the length of ICU stay, and 167 (35.6%) on the duration of invasive ventilation. Delays in discharging patients who are medically optimized due to social or other reasons could introduce bias in the outcome length of hospital stay. To account for this issue, 11 outcomes are defined as the time to discharge or to a NEWS ≤2, maintained for 24 h and another outcome as the time until participants are deemed medically optimized for discharge by a clinician.
3. Need for supplemental oxygen or NIV: This category includes 105 outcomes evaluating the need for supplemental oxygen or NIV in any setting. Most evaluate the need for supplemental oxygen administration at specific follow-up timepoints; 34 (32.4%) outcomes assess the need for NIV (including continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BiPAP]), and 21 (20.0%) the need for high-flow oxygen. One outcome evaluates the need for domiciliary oxygen after hospital discharge.
4. Duration of supplemental oxygen or NIV (95 outcomes): Twelve (12.6%) evaluate the duration of NIV, and seven (7.4%) evaluate the duration of high-flow oxygen.
5. Need for other organ support (other than invasive ventilation, 44 outcomes): 26 (59.1%) outcomes focus on the need for vasopressors, and 18 (40.9%) for renal replacement therapy.
6. Other outcomes: Here, we grouped 145 outcomes that could not be categorized in the previous categories and were evaluated in <10 RCTs each. Need for concurrent treatments is assessed in 22 outcomes, including 7 that specifically focus on the administration of antibiotics. Exercise capacity is assessed by 13 outcomes (mostly using the 6-minutes walking test), COVID-19 transmission by 9, resource requirements, and costs by 8 outcomes. Other outcomes include the use of prone positioning, ability to perform activities of daily living, incidence, and progression of cytokine storm syndrome, resilience, lost workdays, and discharge destinations.

3.3. Study Follow-Up

Planned follow-up for all included studies varies from less than a week, to over a year (Figure 1, Figure A4). However, in most cases, it does not exceed one month (263/415 63.4%). Follow-up exceeds four months only in 50 (12.0%) studies and one year only in one. Follow-up plans do not differ between phase 2 and later phase trials, where they are limited to one month or less in 105/178 (59.0%) and in 158/237 (66.7%) trials, respectively. Longer-term follow-up, exceeding 4 months, is planned for 163 outcomes (Figure 2, Figure A5), evaluating mortality (16 outcomes), adverse events (15), life impact (12), severity scores (12), length of hospital stay (11), viral detection and load (11), inflammatory biomarkers (7), pulmonary function/physiology (6), need for ventilation (5), and duration of ventilation (5).

4. Discussion

In this methodological survey, we analysed the outcomes and outcome measurement instruments used in 415 RCTs evaluating therapeutic interventions for COVID-19. We identified a remarkable heterogeneity in the selection of outcomes, that is not unexpected given that these trials were designed within a few months from the emergence of the new coronavirus strain. More specifically, only 64.6% and 48.4% of the studies evaluate mortality and adverse events, respectively, while each of the remaining outcomes is assessed by markedly less than half of the studies.
Variability was also observed in the choice of instruments used to measure different outcomes. Ordinal clinical severity scales were consistently used across the included studies to assess treatment success or failure and disease severity. Given the acute nature of COVID-19, and significant changes in the clinical status of patients in the course of the disease, such scales can effectively capture disease progression, especially in more severe presentations. Most of these scales follow the structure of the WHO scale, removing scale points for simplicity. Despite sharing a similar structure, these scales group patients differently, limiting interpretability and comparability. The WHO recently introduced a revised 11-point Scale, with increased granularity, and it would be advisable for all studies to align relevant outcomes with this revised scale, to improve interpretability and comparability [12]. To evaluate treatment success or failure, most studies used a 2-point change in the ordinal scale as a threshold, that corresponds to a significant change in the clinical status of the patient and this seems appropriate.
Our study revealed a lack of focus on the long-term sequelae of SARS-CoV2 infection. The planned study follow-up exceeds four months only in 12% of all studies. Moreover, only 13 trials assess life impact beyond the acute phase, while exercise capacity is assessed by 13 trials, and the ability to perform simple daily activities during convalescence in only four trials. Only seven trials stated an intent to explore the development of pulmonary fibrosis. However, persistent symptoms, such as fatigue or breathlessness, and quality of life deficits are detected in many hospitalized patients, two to three months after discharge [21,22,23]. Moreover, fibrotic changes are detected in about one in three survivors of a hospitalization for COVID-19 infection [24,25]. However, it should be noted that we evaluated RCTs registered by May 2020 and longer-term follow-up may have been planned for newer studies, in view of the emerging data.
While this study did not focus on the analytical approaches used for evaluating outcomes, we observed that several studies described specific approaches to account for the bias introduced by mortality as a competing factor for other outcomes, including the duration of hospital stay, ICU stay and the duration of respiratory support. Several methods were described to account for this bias. Some studies stated the duration of hospital or ICU stay will be censored for deceased participants, while others assessed the days that participants are alive and out of hospital or ICU, instead. Homogenization and detailed description of the analytical approaches in the study protocols, along with the outcomes and outcome measurement instruments are crucial for increasing transparency and comparability. Future methodological studies should address analytical approaches.
Four core outcome sets have already been published, with overlapping but not identical selection of components. The WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection recommends the minimal use of three outcomes: mortality, viral burden and non-mortal clinical outcomes evaluated using the WHO clinical progression scale [12]. WHO also highlighted the need for a longer follow-up, of at least 60 days, to capture disease mortality, which is not adopted by most identified trials. Two other groups prioritized specific outcomes and measurement instruments, all of which were captured in our analysis, but were not necessarily the most frequently used [10,11]. The last core outcome set prioritized broader domains to be addressed, rather than specific outcomes [9]. These domains encompass most outcomes identified in this methodological review. The same group also highlighted the need to evaluate the impact of COVID-19 on patient status and life impact in the longer term. Looking across these core outcome sets, a meta-core outcome set (meta-COS) was identified, only including the two domains that were prioritized by all initiatives (mortality and respiratory support), as the most critical, to be evaluated in all future RCTs in hospitalized patients [26]. Both domains recommended by the meta-COS were evaluated in 205 (49.4%) of the included studies.
In view of the multiple available core outcome sets, the authors of this review believe that outcomes selection for future trials should (i) adhere to the recommendations by the WHO and the meta-COS, and (ii) attempt to address all of the domains proposed by Tong et al., a core outcome set that was informed by consensus of >9000 participants [9]. Undeniably, the objectives of individual trials vary and, accordingly, additional outcomes could be selected to address specific trial objectives. However, evaluating the most pertinent outcomes summarized in the previously mentioned core outcomes could improve the interpretability and comparability of their results.
Methodological systematic reviews were conducted as part of the development of three core outcome sets. However, these reviews were almost exclusively based on studies conducted in China. Moreover, two of these reviews included approximately 100 RCT protocols [10,11], while the WHO document was informed by 1135 protocols, including both observational and interventional studies [12]. However, the outcomes of RCTs often differ from those selected in observational studies. Our methodological review was based on a globally representative sample of 415 RCTs, it employed more rigorous methodology to assess all outcomes, and it is the first review to evaluate the instruments used to evaluate the different outcomes beyond mortality.
Our study only included clinical trials that were registered until May 2020 and this may be a limitation as trial designs and endpoints may have evolved since then, in view of the emerging knowledge on the nature and outcomes of COVID-19 infection, and the published core outcome sets. Importantly, the study protocols of some of the included RCTs have been amended since then and our methodological systematic review is a snapshot of the RCT designs and plans as of May-August 2020. Moreover, we only evaluated studies registered with the U.S. National Library of Medicine clinical trials register (ClinicalTrials.gov). However, our extensive, globally representative sample of 415 ongoing RCTs was a major strength of our methodological survey and we strongly believe it was sufficient to capture all relevant outcomes and measurement instruments. Characteristically, after extracting data from approximately 25% and 70% of the included trials, we reached saturation with regards to the outcome categories and the outcome measurement instruments, respectively. Therefore, we are confident that we have not missed important outcomes by focusing exclusively on clinicaltrials.gov. Future studies will need to assess the impact of the emerging evidence on the natural history and outcomes of COVID-19 and of the four published core outcome sets and the meta-COS on the selection of outcomes in more recently registered trials. Another limitation of our study is the lack of a prospectively registered protocol. However, we have used rigorous methodology recommended by the COMET Initiative, that we have previously employed in similar methodological systematic reviews [13].
Overall, this methodological survey reveals significant heterogeneity in the outcome categories and measurement instruments selected by trialists in the management of COVID-19 and highlights the need for greater consistency, to enable decision-makers to compare and contrast studies.

Supplementary Materials

The following are available online at https://www.mdpi.com/2075-1729/10/12/350/s1, Table S1. Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist.

Author Contributions

Study conception: A.G.M., M.F., T.F. and J.V. Study design: A.G.M., M.F., T.F. and J.V. Data collection: A.G.M., M.F., R.H., A.K., A.S.H. Data analysis: A.G.M. Methodological expertise: A.G.M., M.F., P.R.W., J.V. Interpretation of the findings: A.G.M., M.F., T.F., J.V., R.H., A.K., A.S.H., P.R.W., S.B.K., N.D.B. and D.S. Manuscript preparation: A.G.M. Critical revision of the manuscript: A.G.M., M.F., T.F., J.V., R.H., A.K., A.S.H., P.R.W., S.B.K., N.D.B. and D.S. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the NIHR Manchester Biomedical Research Centre (BRC).

Conflicts of Interest

None of the authors report and CoIs related to this work. A.G.M. reports grants from Boehringer Ingelheim outside the submitted work. N.D.B. reports personal fees and non-financial support from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, TEVA, Chiesi, and Novartis, outside the submitted work. D.S. reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Genentech, GlaxoSmithKline, Glenmark, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Therevance and Verona, outside the submitted work. T.F. reports personal fees from Theravance Biopharma, Gilead and Menarini, outside the submitted work. J.V. reports grants and personal fees from Boehringer Inghelheim and personal fees from AstraZeneca, Chiesi, GlaxoSmithKline and Novartis, outside the submitted work. The remaining authors do not have any CoIs. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Appendix A

Figure A1. PRISMA flowchart.
Figure A1. PRISMA flowchart.
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Figure A2. The association between the number of outcomes reported in each RCT and the study population. Having observed that some trials listed numerous inflammatory or other biomarkers as distinct outcomes, for each RCT we have summarized inflammatory biomarkers as a single outcome and other biomarkers as another single outcome. Figure A3 is a non-corrected version of this figure. (A) Phase 2 trials, (B) Later phase trials.
Figure A2. The association between the number of outcomes reported in each RCT and the study population. Having observed that some trials listed numerous inflammatory or other biomarkers as distinct outcomes, for each RCT we have summarized inflammatory biomarkers as a single outcome and other biomarkers as another single outcome. Figure A3 is a non-corrected version of this figure. (A) Phase 2 trials, (B) Later phase trials.
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Figure A3. The association between the number of outcomes reported in each RCT and the study population. Non-corrected data. (A) Phase 2 trials, (B) Later phase trials.
Figure A3. The association between the number of outcomes reported in each RCT and the study population. Non-corrected data. (A) Phase 2 trials, (B) Later phase trials.
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Figure A4. Duration of follow-up in the included studies. (A) Phase 2 trials, (B) Later phase trials.
Figure A4. Duration of follow-up in the included studies. (A) Phase 2 trials, (B) Later phase trials.
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Figure A5. Selected follow-up timepoints for the most frequently evaluated outcomes. All evaluation timepoints described in each of the included trials were included in this figure. Presented as a percentage of the outcomes of the same category. (AC) Phase 2 trials, (DF) Later phase trials.
Figure A5. Selected follow-up timepoints for the most frequently evaluated outcomes. All evaluation timepoints described in each of the included trials were included in this figure. Presented as a percentage of the outcomes of the same category. (AC) Phase 2 trials, (DF) Later phase trials.
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Table A1. Registration numbers of the included studies. N: Planned study population.
Table A1. Registration numbers of the included studies. N: Planned study population.
NCT NumberNNCT NumberNNCT NumberNNCT NumberN
NCT04336904100NCT04346147165NCT0432452830NCT043930381034
NCT04345445310NCT0436087690NCT0434365175NCT04392141200
NCT043590951600NCT04336332160NCT043669081008NCT0440510248
NCT0434791560NCT0435744430NCT04349618200NCT04385043400
NCT043334073170NCT04317040230NCT0435596264NCT044015791032
NCT04336462100NCT04342897200NCT04347239390NCT04390594258
NCT043426891500NCT0436523150NCT04323800487NCT0438594064
NCT0437678815NCT0434636820NCT04321096580NCT0440531080
NCT04333420130NCT043714062770NCT04268537120NCT04380519372
NCT04360356100NCT0428810290NCT0433266660NCT0438275581
NCT04370262942NCT04286503520NCT04349098230NCT04400890200
NCT04350593900NCT04351581215NCT0433283580NCT0439171220
NCT0437297980NCT04351243270NCT04361461500NCT04394416204
NCT04325633584NCT04347512405NCT04366271106NCT04393311150
NCT0433966030NCT04339816240NCT04366089152NCT0439241460
NCT04362813450NCT04347980122NCT04373733450NCT0439830370
NCT0435438982NCT0435780830NCT04312009200NCT04391127200
NCT04362137402NCT0435892630NCT04361474120NCT04396106180
NCT0435961540NCT042936920NCT043159483100NCT04405843400
NCT0435931640NCT04362176500NCT04311177580NCT0438105230
NCT0434376860NCT04338828260NCT0426142680NCT04397562204
NCT04280705800NCT0435318045NCT04255017400NCT04385264800
NCT04329832300NCT04371952330NCT04254874100NCT04385264800
NCT04365257220NCT0433530524NCT0434193520NCT0438258652
NCT0435067140NCT0434753890NCT0426127060NCT04381858500
NCT0435068440NCT04372628900NCT04342169400NCT04379479562
NCT04330586141NCT04350320102NCT04329195554NCT04386616300
NCT04361318100NCT04364763252NCT04321616700NCT04382651120
NCT0436194224NCT04344730550NCT04311697144NCT043932461407
NCT04315298400NCT0434103884NCT0435773060NCT04390503200
NCT043599531600NCT0432827275NCT04367077400NCT0439420850
NCT04377620500NCT04374487100NCT04360096288NCT04402866159
NCT04330638342NCT043284802500NCT04359810105NCT0439517075
NCT0436673940NCT04350580138NCT0304214375NCT04404426100
NCT04369742626NCT043233451000NCT0433336840NCT0438669430
NCT0436337290NCT0436623250NCT027357077100NCT04395768200
NCT0432692080NCT04342663152NCT0434869594NCT0440220350
NCT04353284114NCT0434300110000NCT0434738230NCT04391309300
NCT043592771000NCT0435653440NCT04358081444NCT04389840524
NCT04351763804NCT04344288304NCT04342650210NCT04397718198
NCT043405442700NCT04348383120NCT04279197136NCT0437907648
NCT04366115126NCT0434187027NCT043458617NCT04401475510
NCT04366050560NCT04352400256NCT04376684800NCT04401475510
NCT0434167530NCT04360824170NCT04349592456NCT04379271230
NCT04329923400NCT04369469270NCT043244634000NCT04390061116
NCT04329923400NCT04367831100NCT043244634000NCT04383535333
NCT04329923400NCT042517670NCT04371393300NCT04405921200
NCT04361643120NCT0436892360NCT0435129540NCT04382053120
NCT04355143150NCT0434851360NCT043638401080NCT0439829030
NCT04333628210NCT04257656237NCT04351347300NCT04392128114
NCT04333628210NCT0433812660NCT03808922250NCT04406532100
NCT043343821550NCT04334850194NCT0434149386NCT04403646140
NCT0435799081NCT04335071100NCT0436205924NCT04392531120
NCT04335136200NCT043483051000NCT0434644629NCT04385095400
NCT04362189110NCT0436211120NCT04365582640NCT043904641167
NCT04330690440NCT04355364100NCT0436343770NCT04381871110
NCT04359511210NCT0437750340NCT04325906346NCT0439013930
NCT04351724500NCT043734601344NCT04346628120NCT04386447145
NCT04344444600NCT04343963436NCT04327388409NCT04395456144
NCT0434423648NCT04349410500NCT04344535500NCT04401527200
NCT04307693150NCT04354428630NCT04338906334NCT04387760150
NCT04331899120NCT043514903140NCT043258931300NCT0439394848
NCT04362332950NCT0434141560NCT04371367108NCT0438724022
NCT0433625420NCT04374552140NCT04374539116NCT04390217120
NCT04332094276NCT0436515345NCT04251871150NCT0439751050
NCT042928996000NCT04356937300NCT04361253220NCT0439002224
NCT04370782750NCT04361032260NCT04322123630NCT0440557044
NCT04312997100NCT04364009240NCT0436350230NCT04399356100
NCT04377711400NCT0435327158NCT04322396226NCT0439998060
NCT0434840950NCT04364737300NCT04346693320NCT0438204050
NCT0434795445NCT0435572824NCT04344041260NCT04401293308
NCT0436055140NCT0436624572NCT04321278440NCT04379492120
NCT0434398990NCT04357457212NCT043452891500NCT04389580160
NCT042927301600NCT04333914273NCT0435878330NCT0438444520
NCT0435854950NCT04351191400NCT04353037850NCT0440092930
NCT04345523278NCT0435840660NCT04260594380NCT0439117980
NCT04346615120NCT04326790180NCT04326426300NCT0440573980
NCT0424459180NCT04372082480NCT0434540660NCT04401150800
NCT04329650200NCT04331054436NCT04366856500NCT0439749750
NCT0433147030NCT04344184200NCT0433880296NCT0440295760
NCT04320615330NCT04338698500NCT0434588760NCT04381377394
NCT04372186379NCT04335786651NCT0437447475NCT044031001968
NCT04358809480NCT04335552500NCT04322773200NCT0438577180
NCT04273529100NCT04357860120NCT04345419120NCT0438193612000
NCT0437427960NCT04351516350NCT04347031320NCT0440206066
NCT0427358140NCT0436606360NCT0435028160NCT0439277830
NCT04374032120NCT04374019240NCT04343729416NCT04394377600
NCT0436386640NCT043564951057NCT04261907160NCT0440324370
NCT04342221220NCT04346667400NCT04264533140NCT0440294460
NCT04315896500NCT04354441600NCT04275388426NCT0438284680
NCT04355767206NCT04347941200NCT043226826000NCT0440355540
NCT04338074100NCT043280124000NCT04355052250NCT04395807120
NCT0436800060NCT04338009152NCT04341727500NCT04404218480
NCT04331600400NCT04310228150NCT0434692730NCT0438093560
NCT0434717440NCT0429555180NCT043284671500NCT04404361358
NCT04363060104NCT04365985500NCT0385253790NCT04389450140
NCT043321072271NCT0427376318NCT04367168174NCT04395144346
NCT0427364648NCT043697941000NCT04276688127NCT04396067360
NCT04349241100NCT0437110764NCT0434694030NCT0438371760
NCT04363203300NCT0435986250NCT03680274800NCT0438518660
NCT04252664308NCT0432402154NCT043086681309NCT0438239120
NCT04341116144NCT043349671250NCT0434697950NCT0439015240
NCT0437539746NCT04298060280NCT04401423100NCT04380961270
NCT043580682000NCT04332991510NCT04406389186

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Figure 1. Duration of follow-up in the included studies.
Figure 1. Duration of follow-up in the included studies.
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Figure 2. Planned follow-up timepoints for the most frequently evaluated outcomes. All timepoints described in each of the included trials were included in this figure. Presented as a percentage of the outcomes of the same category. (A) Mortality/Survival, Treatment success/failure, Severity scores, Symptoms, Oxygenation, Pulmonary function/Physiology, (B) Virus detection and load, Virus antibodies, Life impact, Adverse events, Hospital admission, Hospital: Length of stay, (C) ICU admission, ICU: Length of stay, Need for supplemental oxygen, Duration of supplemental oxygen, Need for ventilation, Duration of ventilation.
Figure 2. Planned follow-up timepoints for the most frequently evaluated outcomes. All timepoints described in each of the included trials were included in this figure. Presented as a percentage of the outcomes of the same category. (A) Mortality/Survival, Treatment success/failure, Severity scores, Symptoms, Oxygenation, Pulmonary function/Physiology, (B) Virus detection and load, Virus antibodies, Life impact, Adverse events, Hospital admission, Hospital: Length of stay, (C) ICU admission, ICU: Length of stay, Need for supplemental oxygen, Duration of supplemental oxygen, Need for ventilation, Duration of ventilation.
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Table 1. Characteristics of the included studies. * Studies conducted in multiple continents are counted in each participating continent.
Table 1. Characteristics of the included studies. * Studies conducted in multiple continents are counted in each participating continent.
Study CharacteristicsPhase 2 Trials (n = 178)Later Phase Trials (n = 237)
Number of participants
Median (range)120 (15–2000)253 (7–12,000)
Setting
Community25 (14.0%)38 (16.0%)
Hospital137 (77.0%)167 (70.5%)
Community and Hospital3 (1.7%)1 (0.4%)
ICU9 (5.1%)18 (7.6%)
Other0 (0.0%)1 (0.4%)
Unclear4 (2.2%)13 (5.5%)
Continent
Africa5 (2.8%)21 (8.9%)
Asia29 (16.3%)51 (21.5%)
Europe46 (25.8%)94 (39.7%)
North America90 (50.6%)67 (28.3%)
Oceania1 (0.6%)1 (0.4%)
South America12 (6.7%)22 (9.3%)
Multiple continents *6 (3.4%)15 (6.3%)
Unclear6 (3.4%)0 (0.0%)
Age range
Minimum age
Median (range)18 (3–50)18 (1–70)
Not reported2 (1.1%)0 (0.0%)
Maximum age
Median (range)80 (50–110)80 (40–110)
Not reported115 (64.6%)157 (66.0%)
Number of interventions
2139 (78.1%)172 (72.6%)
325 (14.0%)40 (16.9%)
410 (5.6%)11 (4.6%)
51 (0.6%)5 (2.1%)
63 (1.7%)4 (1.7%)
80 (0.0%)3 (1.3%)
110 (0.0%)1 (0.4%)
190 (0.0%)1 (0.4%)
Sponsor
Academic124 (69.7%)190 (80.2%)
Pharmaceutical industry54 (30.3%)47 (19.8%)
Table 2. Definitions of the generic outcome categories.
Table 2. Definitions of the generic outcome categories.
Outcome CategoriesDefinitions
Mortality/SurvivalEvaluation the survival status.
Clinical/Physiological
Treatment success or treatment failureA clinical evaluation of whether COVID-19 was successfully treated. Usually a composite endpoint based on one or more of the following: survival, symptoms progression or regression, pyrexia regression, oxygen requirements and/or the requirement for ventilation. We only considered in this category binary outcomes describing criteria either for treatment success or treatment failure.
Time-to-treatment success or failure is a measurement instrument that could provide more granular information.
Severity scoresA quantitative evaluation of disease severity. In this category we included outcomes presenting mean/median scores or change from baseline in a validated score. Outcomes describing predefined score thresholds for treatment success or failure were classified in the previous category.
SymptomsQuantitative or qualitative evaluation of the intensity of one or more symptoms, including but not limited to breathlessness, cough, pyrexia or anosmia.
OxygenationPhysiological measures of oxygenation, including oxygen saturation (SatO2), the partial pressure of oxygen (PaO2) or carbon dioxide (PaCO2). The need for supplementary oxygen or ventilation were summarized in separate outcome categories.
Pulmonary function and physiologyMeasures of pulmonary functions and lung physiology including the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), respiratory muscle strength or the lung compliance.
Viral detection and loadPolymerase chain reaction (PCR) to evaluate the presence, persistence and/or load of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV2).
Viral antibodiesDetection of the presence and titres of antibodies against SARS-CoV2.
Radiological outcomesRadiological progression in chest x-ray (CXR) or computed tomography (CT) of the chest.
Inflammatory biomarkersThe levels and trajectories of any inflammatory biomarkers, including white blood cells count, lymphocytes, neutrophils, eosinophils, monocytes, CD4+ or CD8+ T cell counts, c-reactive protein, interleukins, tumour necrosis factors, or any other inflammatory biomarkers.
Other biomarkersThe levels and trajectories of any other biomarkers, including but not limited to kidney function, liver function, haematocrit, coagulation profile, d-dimers, troponin or the brain natriuretic peptide (BNP).
Pharmacokinetics/pharmacodynamicsEvaluation of the pharmacokinetics and/or pharmacodynamics of the drug interventions (mainly serum levels over time).
Adverse eventsAdverse events or grade 3 or more severe adverse events, or serious adverse events, according to the Common Toxicity Criteria for Adverse Events (CTCAE). In this category, we also included outcomes evaluating specific adverse events, such as renal failure, liver failure, pulmonary embolism, myocardial infarction or tachyarrhythmias. Treatment discontinuation was also included in this category.
Life impactQuantitative assessment of the general well-being of participants.
Resource use
Need for (higher) level of careThis group of outcomes include the need for (i) hospital admission, (ii) hospital re-admission, (iii) intensive care admission, (iv) invasive ventilation, or need for ECMO. In each category, we also included the composite outcomes consisting of the need for the specific level of care or death. For example: “intensive care admission or death”, as these composite outcomes were developed to account for patients who might have benefitted by the higher level of care but died or patients who were not eligible for the higher level of care due to their baseline clinical status. In studies conducted in the hospital setting, need for hospital admission at a specific follow-up timepoint, refers to the proportion of patients who remain inpatients at that timepoint. Similarly, for studies conducted in the ICU stay and the need for ICU admission.
Duration of stay in a specific level of careThis group of outcomes include length of (i) hospital stay, (ii) intensive care admission, or (iii) mechanical ventilation. The end date was often defined as the last day of stay in a specific level of care, or the last day that the stay was indicated (to account for cases when patients are medically optimized for hospital discharge but remain at hospital for social or other reasons.
Need for supplemental oxygen or NIVAn assessment of the need for supplemental oxygen, the required oxygen flow or modality of delivery (e.g., oxygen, continuous positive airways pressure [CPAP], bilevel positive airway pressure [BiPAP], or high flow nasal oxygen).
Duration of supplemental oxygen or NIVAn evaluation of the duration of supplemental oxygen needs.
Need for other organ supportThis category included the need for (a) vasopressors and (b) need for renal replacement therapy.
Other outcomesIn this category we summarized outcomes that were reported in less than 10 of all eligible trials. These included changes in activities of daily living, quality of life, pharmacodynamics and pharmacokinetics, drug compliance, feasibility outcomes, use of antibiotics or other drugs, emergency room visits or use of other healthcare resources, the need for prone positioning, need for transfusion and discharge destinations.
Table 3. Frequency that outcome measures are reported in randomized controlled trials (RCTs) on the management of coronavirus disease 2019 (COVID-19). RCTs grouped in phase 2 and later phase trials. Outcomes evaluated in <10 RCTs were grouped as “Other outcomes”. Time to treatment success or failure is a measurement instrument of the outcome treatment success or failure. However, it is reported separately here, as it provides more granular information. NIV: Non-invasive ventilation.
Table 3. Frequency that outcome measures are reported in randomized controlled trials (RCTs) on the management of coronavirus disease 2019 (COVID-19). RCTs grouped in phase 2 and later phase trials. Outcomes evaluated in <10 RCTs were grouped as “Other outcomes”. Time to treatment success or failure is a measurement instrument of the outcome treatment success or failure. However, it is reported separately here, as it provides more granular information. NIV: Non-invasive ventilation.
Outcome CategoryPhase 2 Trials (n = 178)Later Phase Trials (n = 237)
Any OutcomePrimary OutcomeAny OutcomePrimary Outcome
Mortality/survival115 (64.6%)24 (13.5%)153 (64.6%)32 (13.5%)
Clinical/physiological outcomes
Treatment success or treatment failure70 (39.3%)31 (17.4%)103 (43.5%)69 (29.1%)
Success55 (30.9%)19 (10.7%)88 (37.1%)54 (22.8%)
Failure23 (12.9%)12 (6.7%)31 (13.1%)14 (5.9%)
Subgroup: Time to treatment success or treatment failure37 (20.2%)12 (6.7%)62 (26.2%)36 (15.2%)
Success30 (16.9%)9 (5.1%)59 (24.9%)33 (13.9%)
Failure8 (4.5%)3 (1.7%)11 (4.6%)3 (1.3%)
Severity scores76 (42.7%)21 (11.8%)93 (39.2%)25 (10.5%)
Symptoms43 (24.2%)5 (2.8%)60 (25.3%)7 (3.0%)
Oxygenation63 (35.4%)22 (12.4%)72 (30.4%)23 (9.7%)
Pulmonary function/physiology12 (6.7%)3 (1.7%)9 (3.8%)1 (0.4%)
Viral detection and load59 (33.1%)20 (11.2%)97 (40.9%)36 (15.2%)
Viral antibodies17 (9.6%)0 (0.0%)8 (3.4%)2 (0.8%)
Radiological outcomes25 (14.0%)3 (1.7%)25 (10.5%)9 (3.8%)
Inflammatory biomarkers69 (38.8%)7 (3.9%)66 (27.8%)9 (3.8%)
Other biomarkers47 (26.4%)4 (2.2%)51 (21.5%)2 (0.8%)
Pharmacokinetics/pharmacodynamics10 (5.6%)0 (0.0%)5 (2.1%)0 (0.0%)
Adverse events95 (53.4%)18 (10.1%)121 (51.1%)8 (3.4%)
Life impact3 (1.7%)1 (0.6%)10 (4.2%)0 (0.0%)
Resource use
Hospital admission21 (11.8%)9 (5.1%)30 (12.7%)18 (7.6%)
Hospital re-admission6 (3.4%)1 (0.6 %)3 (1.3%)0 (0.0%)
Length of hospital stay70 (39.3%)5 (2.8%)103 (43.5%)7 (3.0%)
ICU admission35 (19.7%)6 (3.4%)38 (16.0%)2 (0.8%)
Length of ICU stay42 (23.6%)0 (0.0%)49 (20.7%)3 (1.3%)
Need for supplemental oxygen or NIV31 (17.4%)12 (6.7%)44 (18.6%)3 (1.3%)
Duration of supplemental oxygen or NIV40 (22.5%)2 (1.1%)39 (16.5%)1 (0.4%)
Need for invasive ventilation62 (34.8%)16 (9.0%)87 (36.7%)27 (11.4%)
Duration of invasive ventilation65 (36.5%)9 (5.1%)68 (28.7%)9 (3.8%)
Need for vasopressors11 (6.2%)0 (0.0%)10 (4.2%)0 (0.0%)
Need for renal replacement therapy6 (3.4%)0 (0.0%)7 (3.0%)0 (0.0%)
Other outcomes31 (17.4%)2 (1.1%)42 (17.7%)5 (2.1%)
Table 4. Frequency that outcome measures are reported in RCTs on the management of COVID-19. RCTs grouped by recruitment setting (community, hospital, intensive care unit (ICU)). Outcomes evaluated in <10 RCTs were grouped as “Other outcomes”. Time to treatment success or failure is a measurement instrument of the outcome treatment success or failure. However, it is reported separately here, as it provides more granular information. NIV: Non-invasive ventilation. * Continued need of hospital/critical care admission, at a specific timepoint.
Table 4. Frequency that outcome measures are reported in RCTs on the management of COVID-19. RCTs grouped by recruitment setting (community, hospital, intensive care unit (ICU)). Outcomes evaluated in <10 RCTs were grouped as “Other outcomes”. Time to treatment success or failure is a measurement instrument of the outcome treatment success or failure. However, it is reported separately here, as it provides more granular information. NIV: Non-invasive ventilation. * Continued need of hospital/critical care admission, at a specific timepoint.
Outcome CategoryCommunity (n = 63)Hospital (n = 304)ICU (n = 27)
Any OutcomePrimary OutcomeAny OutcomePrimary OutcomeAny OutcomePrimary Outcome
Mortality/survival19 (30.2%)3 (4.8%)216 (71.6%)44 (14.5%)24 (88.9%)8 (29.6%)
Clinical/Physiological Outcomes
Treatment success or treatment failure25 (39.7%)15 (23.8%)140 (46.2%)81 (26.6%)2 (7.4%)0 (0.0%)
Success16 (25.4%)7 (11.1%)121 (39.8%)63 (20.7%)1 (3.7%)0 (0.0%)
Failure12 (19.0%)8 (12.7%)41 (13.5%)17 (5.6%)1 (3.7%)0 (0.0%)
Subgroup: Time to treatment success or treatment failure12 (19.0%)5 (7.9%)83 (27.3%)40 (13.2%)0 (0.0%)0 (0.0%)
Success7 (11.1%)3 (4.8%)79 (26.0%)37 (12.2%)0 (0.0%)0 (0.0%)
Failure4 (6.3%)2 (3.2%)13 (4.3)3 (0.9%)0 (0.0%)0 (0.0%)
Severity scores16 (25.4%)5 (7.9%)136 (44.7%)40 (13.2%)12 (44.4%)1 (3.7%)
Symptoms31 (49.2%)4 (6.3%)61 (20.1%)7 (2.3%)2 (7.4%)0 (0.0%)
Oxygenation6 (9.5%)2 (3.2%)110 (36.2%)35 (11.5%)15 (55.6%)7 (25.9%)
Pulmonary function/physiology1 (1.6%)1 (1.6%)12 (3.9%)1 (0.3%)5 (18.6%)0 (0.0%)
Viral detection and load35 (55.6%)18 (28.6%)107 (35.2%)34 (11.1%)7 (25.9%)0 (0.0%)
Viral Antibodies4 (6.3%)0 (0.0%)19 (6.3%)2 (0.7%)1 (3.7%)0 (0.0%)
Radiological outcomes4 (6.3%)3 (4.8%)40 (13.2%)8 (2.6%)3 (11.1%)0 (0.0%)
Inflammatory biomarkers6 (9.5%)1 (1.6%)114 (37.5%)14 (4.6%)11 (40.7%)1 (3.7%)
Other biomarkers4 (6.3%)0 (0.0%)79 (26.0%)5 (1.6%)10 (37.0%)0 (0.0%)
Pharmacokinetics / Pharmacodynamics2 (3.2%)0 (0.0%)13 (4.3%)0 (0.0%)0 (0.0%)0 (0.0%)
Adverse events25 (39.7%)3 (4.8%)166 (54.6%)21 (6.9%)18 (66.7%)2 (7.4%)
Life Impact0 (0.0%)0 (0.0%)7 (2.3%)0 (0.0%)3 (11.1%)0 (0.0%)
Resource Use
Hospital admission32 (50.8%)21 (33.3%)15 (4.9%) *4 (1.3%) *1 (3.7%) *0 (0.0%) *
Hospital re-admission0 (0.0%)0 (0.0%)9 (3%)1 (0.3%)0 (0.0%)0 (0.0%)
Length of hospital stay9 (14.3%)1 (1.6%)152 (50%)11 (36.2%)10 (37.0%)1 (3.7%)
ICU admission8 (12.7%)0 (0.0%)61 (20.1%) *8 (2.6%) *2 (7.4%) *0 (0.0%) *
Length of ICU stay5 (7.9%)1 (1.6%)70 (23.0%)1 (0.3%)14 (51.9%)1 (3.7%)
Need for supplemental oxygen or NIV4 (6.3%)0 (0.0%)68 (22.4%)13 (4.3%)1 (3.7%)0 (0.0%)
Duration of supplemental oxygen or NIV3 (4.8%)0 (0.0%)70 (23.0%)3 (0.9%)3 (11.1%)0 (0.0%)
Need for invasive ventilation7 (11.1%)2 (3.2%)130 (42.8%)34 (11.2%)6 (22.2%)4 (14.8%)
Duration of invasive ventilation5 (7.9%)1 (1.6%)106 (34.9%)10 (3.3%)19 (70.4%)7 (25.9%)
Need for vasopressors0 (0.0%)0 (0.0%)18 (5.9%)0 (0.0%)2 (7.4%)0 (0.0%)
Need for renal replacement therapy0 (0.0%)0 (0.0%)10 (3.3%)0 (0.0%)3 (11.1%)0 (0.0%)
Other outcomes13 (20.6%)3 (4.8%)44 (14.5%)5 (1.6%)8 (29.6%)0 (0.0%)
Table 5. The WHO 9-point ordinal clinical progression scale [18].
Table 5. The WHO 9-point ordinal clinical progression scale [18].
Patient StateDescriptorScore
UninfectedNo clinical or virological evidence of infection0
AmbulatoryNo limitation of activities1
Limitation of activities2
Hospitalized,
Mild disease
Hospitalized, no oxygen therapy3
Hospitalized, oxygen therapy by mask or nasal prongs4
Hospitalized,
Severe disease
Non-invasive ventilation or high-flow oxygen5
Intubation and mechanical ventilation6
Ventilation and additional organ support (vasopressors, renal replacement therapy, or ECMO)7
DeadDeath8
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