Covid-19 living Data

Dexamethasone Low Dose vs Dexamethasone High Dose (RCT)

Hospitalized patients

Studies included but not extracted/included in the analysis: Wu H, PloS one, 2022

FOREST PLOTS -2022-08-04

Studies description

Trial NCT04344730 ; EudraCT 2020-001457-43
Publication COVIDICUS - Bouadma L, JAMA Intern Med (2022) (published paper)
Dates: 2020-04-10 to 2020-11-30
Funding: Mixed (Programme Hospitalier de Recherche Clinique, French Ministry of Health ; Vygon provided continuous positive airway pressure kits for some study centers.)
Conflict of interest: Yes

Methods
	RCT Blinding: quadruple blinding
	Location : Multicenter / France Follow-up duration (days): 60
Inclusion criteria	Adults aged at least 18 years admitted to an ICU within the last 48 hours confirmed or highly suspected COVID-19 AHRF (defined as arterial partial pressure of oxygen, [PaO2] <70 mm Hg, transcutaneous oxygen saturation as measured by pulse oximetry [SpO2] <90% on room air, tachypnea with >30 breaths/min, labored breathing, respiratory distress, or need for O2 flow ≥6 L/min) could receive any available treatment targeting COVID-19. Those with ongoing invasive mechanical ventilation (IMV) at inclusion or with anatomical factors precluding the use of nasal cannula, hypercapnia indicating noninvasive ventilation (PaCO2 ≥50 mm Hg), or intolerance at admission to any of the oxygenation strategies, ie, the IMV population, were only eligible to the dexamethasone randomization.
Exclusion criteria	Decision to limit life-sustaining treatment corticosteroid therapy of 0.5 mg/kg/d or more of prednisone equivalent for 3 weeks or longer active un-treated bacterial, fungal, or parasitic infection hypersensitivity to dexamethasone.
Interventions
	Treatment DEX low dose 6 mg/day intravenously for 100 days (or placebo prior to RECOVERY trial results communication)
	Control DEX high dose 20 mg/day intravenously on days 1-5, then 10 mg/day intravenously on days 6-10
Participants
	Randomized participants : DEX low dose=277 DEX high dose=273
	Characteristics of participants N= 550 Mean age : NR 414 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=448 Critical: n=98
Primary outcome
	In the register The time-to-death from all causes [Time Frame: day-60] ; The time to need for mechanical ventilation (MV) [Time Frame: day-28.]
	In the report Time-to-death from all causes up to day 60 ; time to IMV criteria fulfillment within the first 28 days
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the trial registry, protocol, statistical analysis plan and supplementary appendices were used in data extraction and assessment of risk of bias. This is a factorial trial design with a 2x3 randomization for a 2nd intervention as well based on type of oxygen therapy intervention. The primary and secondary outcomes in the article reflect those in the registry. The trial (n = 550) achieved its target sample size (n = 550). 37/276 participants in the low-dose arm were randomized prior to a protocol amendment and did not receive dexamethasone as a trial intervention because the pre-amendment comparison was high-dose dexamethasone versus placebo.

Trial NCT04395105
Publication Maskin LP, Intensive Care Med (2021) (published paper)
Dates: 2020-06-17 to 2021-03-27
Funding: No specific funding (The author(s) received no financial support for the research, authorship and/or publication of this article.)
Conflict of interest: No

Trial *
Publication Montalvan E, Chest (2021) (published paper)
Dates: 2020-09-01 to 2020-10-31
Funding: Not reported/unclear
Conflict of interest: No

Trial NCT04726098 ; EudraCT 2020-005702-25
Publication Taboada M, Eur Respir J (2021) (published paper)
Dates: 2021-01-15 to 2021-05-26
Funding: Public/non profit (Support was provided solely from institutional and departmental sources.)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / Spain Follow-up duration (days): 60
Inclusion criteria	At least 18 years old SARS-CoV-2 infection confirmed by nasopharyngeal swab polymerase chain reaction receiving supplemental oxygen in order to maintain an oxygen saturation greater than 92% (Level 4 using the World Health Organization 7-point Ordinal Scale for clinical improvement (WHO-CIS)).
Exclusion criteria	Pregnancy or active lactation known history of dexamethasone allergy or known contraindication to the use of corticosteroids indication for corticosteroids use for other clinical conditions (e.g. refractory septic shock) daily use of oral or intravenous corticosteroids in the past 15 days expected death within the next 48 h different level of 4 using the 7-point ordinal scale WHO-CIS need of supplemental oxygen with fraction of inspired oxygen>0.5 in order to maintain an oxygen saturation greater than 92% consent refusal for participating in the trial.
Interventions
	Treatment DEX low dose 6 mg once daily for 10 days
	Control DEX high dose 20 mg once daily for 5 days, followed by 10 mg once daily for 5 days
Participants
	Randomized participants : DEX high dose=98 DEX low dose=102
	Characteristics of participants N= 200 Mean age : NR 123 males Severity : Mild: n=0 / Moderate: n=200 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Percentage of patients with treatment failure at day 11 [ Time Frame: Day 11 after randomization ] defined as death, need of ICU and extracorporeal membrane oxygenation, need of non-invasive ventilation or nasal high-flow oxygen therapy, or worsening of the condition clinic of the patient during treatment (two of these: need to increase Fraction of inspired oxygen inspired>20%, need for fraction inspired oxygenation>50%, increase in respiratory rate>25, increase in inflammatory markers).
	In the report Clinical worsening within 11 days since randomisation, defined as worsening of the patient’s condition during treatment (need to increase fraction of inspired oxygen>0.2, need for fraction of inspired oxygen>0.5, respiratory rate>25) or score higher than 4 on the 7-point ordinal scale WHO-CIS.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the trial registry and supplementary appendices were used in data extraction. Neither protocol nor statistical analysis plan was available. There were minor differences between the primary outcomes in the registry and the article and the extracted 28-day and 60-day outcome were not included in the registry. The study (n = 200) achieved its target sample size (n = 196).

Trial IRCT20100228003449N31
Publication Toroghi N, Pharmacol Rep (2021) (published paper)
Dates: 2020-10-26 to 2021-01-15
Funding: Public/non profit (Tehran University of Medical Sciences)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / Iran Follow-up duration (days): 60
Inclusion criteria	Hospitalized adult patients above 18 years old with moderate to severe COVID-19 required supplemental oxygen
Exclusion criteria	History of allergy to corticosteroids uncontrolled diabetes mellitus with serum glucose above 250 mg/dL active fungal or parasitic infections closed-angle glaucoma history of myopathy history of corticosteroid-induced neuropsychiatric disorders uncontrolled cardiovascular diseases like acute coronary syndrome, myocardial infarction, acute and massive thrombosis uncontrolled hypertension (systolic blood pressure above 140 mmHg and diastolic blood pressure above 90 mmHg) acute viral hepatitis pregnancy and lactation history of corticosteroid therapy (for more than two weeks) patients with critical COVID-19 (condition that would require the provision of life-sustaining therapies such as mechanical ventilation or vasopressor therapy)
Interventions
	Treatment DEX low dose 8 mg orally once a day for up to 10 days or discharge DEX intermediate 8 mg orally twice a day for up to 10 days or discharge
	Control DEX high dose 8 mg orally three times a day for up to 10 days or discharge
Participants
	Randomized participants : DEX low dose=48 DEX intermediate=48 DEX high dose=48
	Characteristics of participants N= 144 Mean age : NR 80 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
	In the register 1) Improvement of patients' chief complaint 2) Improvement in peripheral blood oxygen saturation 3) Decrease in serum CRP 4) Hyperglycemia 5) Changes in mood 6) Myopathy 7) Secondary infections
	In the report Time to a clinical response that was described as improvement of at least two scores in the eight-category ordinal scale of the National Institute of Health
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the trial registry and supplementary materials were used in data extraction and assessment of risk of bias. Neither protocol nor statistical analysis plan was available. The primary outcome in the published article (an improvement of two or more points on an 8-point ordinal scale) broadly reflects one of the outcomes in the registry (improvement of patient’s chief complaint). Other primary outcomes in the registry were reported as secondary outcomes. The trial (n = 144) achieved its target sample size (n = 144).

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Argentina Follow-up duration (days): 90
Inclusion criteria	18 years old or more ARDS according to the Berlin Definition criteria confirmed SARS-CoV-2 infection by reverse transcription polymerase chain reaction receiving mechanical ventilation for less than 72 hours.
Exclusion criteria	Pregnant or breastfeeding terminal disease therapeutic limitation severe immunosuppression chronic treatment with glucocorticoids participation in another randomized clinical trial prior use of dexamethasone for COVID-19 (> 5 days) consent refusal.
Interventions
	Treatment DEX low dose 6 mg intravenously once a day for 10 days
	Control DEX high dose 16 mg intravenously once a day for 5 days, then 8 mg intravenously once a day for 5 days
Participants
	Randomized participants : DEX low dose=51 DEX high dose=49
	Characteristics of participants N= 100 Mean age : NR 69 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=0 Critical: n=100
Primary outcome
	In the register 1) Ventilator-free days at 28 days [ Time Frame: 28 days after randomization ]; 2) Time to successful discontinuation from mechanical ventilation [ Time Frame: 28 days after randomization ]
	In the report 1) Ventilator-free days during the first 28 days; 2) Time to complete and successful discontinuation of mechanical ventilation or death.
Documents avalaible	Protocol Yes. In English Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published report, the pre-print article, the trial registry, protocol and supplementary appendices were used in data extraction and assessment of risk of bias. No statistical analysis plan was available. The primary outcomes in the article reflect those in the registry. The trial (n = 100) was terminated early due to changes in COVID-19 treatment modalities that led to reduced recruitment, so that it did not achieve its target sample size (n = 282). The study was updated on the March 2nd, 2022 with data extracted from the published report.

Methods
	RCT Blinding: Unblinded
	Location : Single center / Honduras Follow-up duration (days): *
Inclusion criteria	Admitted to hospital with COVID-19
Exclusion criteria	NR
Interventions
	Treatment DEX low dose 8 mg/day
	Control DEX high dose 24 mg/day
Participants
	Randomized participants : DEX high dose=41 DEX low dose=40
	Characteristics of participants N= 81 Mean age : NR 46 males Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register NR
	In the report Reduction in mortality and intubation.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	*
General comment	Only the conference abstract was available for use in data extraction and assessment of risk of bias. No registry, protocol or statistical analysis plan was available. Mortality was reported (6 in the high-dose group and 2 in the low-dose group), but with no time point reported, so no data were extracted.