Methods

Criteria for considering studies for this review

Types of studies

We include Randomized Controlled trials (RCTs). As of March 1, 2022, the COVID-NMA revised its protocol to include only studies evaluating immunomodulators and antiviral therapies.

No restriction on language

Types of participants

Ambulatory COVID-19 outpatients

Hospitalized COVID-19 patients

Children or adults with no restriction in age

Types of interventions

Up to 28 February 2022, any pharmacological intervention for treating COVID-19 (anti-infectious agents, specific and non-specific immunomodulators,mononoclonal antibidies supportive treatments for patients admitted to the ICU, general treatments for viral infection).

On Februay 28, 2022, the COVID-NMA revised its protocol. We continue to update comparisons of immunomodulators and antivirals only up as of this date As of December 14, 2022, the COVID-NMA revised its protocol and stopped including pharmacological interventions trials.

List of outcomes

On the 1st of February 2021, the protocol of the review on pharmacological and nonpharmacological treatments was amended to consider only the following outcomes:

Critical outcomes:

Clinical improvement Day (D) 28 / D60 or more) defined as a hospital discharge or improvement on the scale used by trialists to evaluate clinical progression and recovery.

WHO Clinical Progression Score level 7 or above (i.e., Mechanical ventilation +/- additional organ support (ECMO, vasopressors or dialysis) OR death (D28 / D60 or more)

All-cause mortality (D28 / D60 or more)

Viral negative conversion (D7)

Incidence of any adverse events

Incidence of serious adverse events (SAEs)

Hospitalisation or death (only for studies with outpatient setting)

Important outcomes:

Time to clinical improvement

Time to WHO Clinical Progression Score level 7 or above

Time to death

Time to viral negative conversion

DISEASE SEVERITY

Disease severity was classified as described below according to the clinical status or clinical management of patients. This classification relies on existing classification and clinical expertise (WHO 2020a, WHO 2020b). We considered the description of eligibility criteria as well as the baseline characteristics of participants and classified the severity as follow:

Ambulatory covid-19 outpatients whose clinical symptoms are mild with no sign of pneumonia on imaging.

Hospitalized Patients

Mild disease — clinical symptoms requiring hospitalization but no need for supplemental oxygen
Moderate disease — fever and respiratory symptoms with radiological findings of pneumonia and requiring standard oxygen therapy O2 (3–5 L/min).
Severe disease — meeting any of the following criteria:
- respiratory distress (≧ 30 breaths/min)
- oxygen saturation ≤ 93% at rest in ambient air or oxygen saturation ≤97% with O2 > 5 L/min
- PaO2/FiO2 ≦ 300 mmHg (l mmHg=0.133 kPa). PaO2/FiO2 in high-altitude areas (> 1000 m above sea level) is corrected by the following formula: PaO2/FiO2 x [atmospheric pressure (mmHg)/760]
- patients hospitalized on Non-invasive ventilation (NIV)/High flow Nasal oxygen (HFNO).
Critical disease — cases meeting any of the following criteria
- respiratory failure requiring invasive mechanical ventilation
- shock
- other organ failure requiring Intensive Care Unit care

Worth mentioning that since the classification of severity class was heterogenous among studies, we reclassified the participant disease severity based on the above severity criteria. Consequently, the severity reported by investigators might differ from the severity reported in this review.

Assessment of risk of bias in the included studies

Each study is assessed with the Cochrane 'Risk of Bias 2' (RoB 2) tool for randomized controlled trials.We record judgments and justification per domain for all collected outcomes. The Cochrane RoB 2 tool is structured into five domains: 1) risk of bias arising from the randomization process, 2) risk of bias due to deviations from intended interventions, 3) risk of bias due to missing outcome data, 4) risk of bias in the measurement of the outcome, 5) risk of bias in the selection of the reported result.

Note:The risk of bias by domain corresponds to the highest risk of bias among outcomes by domain. The overall risk of bias corresponds to the overall highest risk of bias assessed among outcomes.

Summary of findings and assessment of the certainty of the evidence

We use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the certainty of a body of evidence related to studies that contributed data to pairwise meta-analyses for prespecified outcomes.

We present 'Summary of findings' tables to present estimated relative and absolute risks for critical outcomes only.

For more information on our methods see our protocol here.