Covid-19 living Data

Intravenous Immunoglobulin vs Standard care/Placebo (RCT)

Hospitalized patients

Studies included but not extracted/included in the analysis: NCT04480424 results posted on clinicaltrials.gov

FOREST PLOTS -2022-04-29

Studies description

Trial IRCT20200501047259N1
Publication Gharebaghi N, BMC Infect Dis (2020) (published paper)
Dates: 2020-05-09 to 2020-06-09
Funding: Public/non profit (Urmia University of Medical Sciences)
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Single center / Iran Follow-up duration (days): *
Inclusion criteria	Over 18 years of age, possessing a PCR-confirmed COVID-19 diagnosis, involvement of > than 30% of both lungs (ground-glass opacity) in high resolution computed tomography (HRCT) (confirmed by two radiologists), O2 saturation (satO2) of < 90%, and a lack of adequate response to initial treatment including at least both one antiviral and one chloroquine-class drug.
Exclusion criteria	In addition to an age of less than 18 years, included pregnancy, coagulation disorders (such as hemophilia, Von Willebrand disease, other clotting factor deciencies), history of hypersensitivity to IVIg, advanced heart failure (dened as a left ventricular ejection fraction less than 35%), pulmonary brosis/history of lung surgery, and the presence of either sarcoidosis or tuberculosis (that may interfere with an accurate estimation of the severity of pulmonary interference by COVID-19). Those patients who died before 72 hours after the distribution of IVIg and placebos were excluded from our study due to an incomplete course of treatment.
Interventions
	Treatment IV Ig 5 g IV four times a day for 3 consecutive days
	Control Placebo
Participants
	Randomized participants : IV Ig=30 Placebo=29
	Characteristics of participants N= 59 Mean age : NR 41 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=* Critical: n=*
Primary outcome
	In the register Increasing of patient's O2 saturation above 90%, improvement of lung involvement in lung CT scan
	In the report In-hospital mortality
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication:
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	This study is pending author reply. The timepoints for outcomes were not reported. In addition to the pre-print article, the study registry was used in data extraction and risk of bias assessment. The study achieved the target sample size reported in the registry. There is no change from the trial registration in the intervention and control treatments. Safety analysis was not performed.

Trial NCT04350580; EudraCT2020-001570-30
Publication ICAR - Mazeraud A, Lancet Respir Med (2021) (published paper)
Dates: 2020-04-03 to 2020-10-20
Funding: Public/non profit (Programme Hospitalier de Recherche Clinique; French ministry of Health; Laboratoire Français du fractionnement et des Biotechnologies)
Conflict of interest: No

Trial CTRI/2020/06/026222
Publication Raman RS, J Infect Dis (2021) (published paper)
Dates: 2020-06-29 to 2020-09-30
Funding: Private (Virchow Biotech)
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / India Follow-up duration (days): 28
Inclusion criteria	Male or female aged ≥18 years RT-PCR confirmed COVID-19 illness Moderate pneumonia were defined as: body temperature ≥38.0℃ or PaO2/ FiO2 100-300 mmHg or respiratory rate >24/min and oxygen saturation 90-93% on room air or lung involvement confirmed with chest X-ray
Exclusion criteria	Viral pneumonia with other viruses besides COVID-19 Patients with IgA deficiency or history of anaphylaxis to immunoglobulin therapy Patients with severe pneumonia were defined as: respiratory rate ≥ 30 times/min or oxygen saturation ≤90% in resting state or PaO2/FiO2 ≤100 mmHg or respiratory failure requiring mechanical ventilation or Intensive Care Unit (ICU) monitoring with signs of other organ failure Patients on either immunoglobulin or hydroxychloroquine treatment Female patients who are pregnant or lactating
Interventions
	Treatment IV Ig 0.4 g/kg body weight IV once daily for 5 days
	Control Standard care
Participants
	Randomized participants : Standard care=50 IV Ig=50
	Characteristics of participants N= 100 Mean age : NR 33 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
	In the register Number of days to clinical improvement. It is defined as no. of days from initiation of treatment day to discharge day
	In the report Number of days from initiation of treatment to hospital discharge
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	Some concerns
General comment	In addition to the published accepted manuscript, the prospective study registry was used in data extraction and risk of bias assessment. Neither study protocol nor statistical analysis plan was available. The target sample size specified in the registry was achieved. There was no important change from the trial registration in the inclusion criteria or intervention and control treatments. Adverse events and serious adverse events were reported but were not pre-specified as outcomes in the registry.

Trial NCT04411667
Publication Sakoulas G, Crit Care Expl (2020) (published paper)
Dates: 2020-05-01 to 2020-06-16
Funding: drug donation only (no specific funding, IVIG (Octagam 10%) was provided by Octapharma USA, Hoboken, NJ (donation))
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / USA Follow-up duration (days): 30
Inclusion criteria	Adult patients > 18 years of age presenting with COVID-??19 infection confirmed by positive polymerase chain reaction testing for SARS-??CoV2 genome in nasopharyngeal or oropharyngeal swab sample were considered for inclusion if they demonstrated moderate to severe hypoxia (sPO2 <96% on > 4 liters O2 by nasal cannula) but not on mechanical ventilation. This corresponds to FiO2 of 37% to maintain a PaO2 of 90 mm Hg (alveolar-??arterial [A-??a] gradient of 120 mm Hg or PaO2/FiO2 243).
Exclusion criteria	Quote from the registry Severe allergy to any IVIG product formulation History of DVT, PE, thromboembolic stroke or other thrombotic events Hypersensitivity to corn. Octagam?? contains maltose which is a sugar derived from corn. Uncontrolled hypertension (SBP>180 mm Hg or DBP>120mmHg) Active participant in another research treatment study Mechanically ventilated patient Code status is Do Not Resuscitate or Do Not Intubate
Interventions
	Treatment IV Ig 0.5 g/kg IV once a day for 3 days
	Control Standard care
Participants
	Randomized participants : Standard care=17 IV Ig=17
	Characteristics of participants N= 34 Mean age : NR 20 males Severity : Mild: n=0 / Moderate: n=7 / Severe: n=26 Critical: n=0
Primary outcome
	In the register Mechanical Ventilation [ Time Frame: from date of patient admission to date of patient discharge or date of death, whichever came first, assessed up to 45 days ]
	In the report Respiratory failure requiring receipt of mechanical ventilation (a composite of either receiving ventilation or the subject status changed to a do not resuscitate/do not intubate resulting in progressive respiratory failure and death)
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
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 all available versions of the published article, the study registry was used in data extraction. The protocol or and statistical analysis plan were available. There is no change from the trial registration in the intervention and control treatments. Quote: "For subjects not already receiving glucocorticoid therapy, enrolled treatment arm subjects received methylprednisolone 40 mg IV once 30 minutes before IVIG to mitigate headache commonly experienced after IVIG therapy." Quote: "Immediately after randomization and notification of the principal investigator, one subject was immediately deemed unevaluable by the principal investigator and excluded due to a high risk of bacterial superinfection (elevated absolute neutrophil count of 9900/mm3 and concomitant procalcitonin of 1.45 ng/mL). On August 25th, 2020 we received additional information from authors on this study.

Trial IRCT20151227025726N20
Publication Tabarsi P, Int Immunopharmacol (2020) (published paper)

Funding: Public/non profit (Shahid Beheshti University of Medical Sciences)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / Iran Follow-up duration (days): 28
Inclusion criteria	Severely ill patients between 18 and 65 years old with COVID-19, confirmed based on the reports of Reverse Transcription-Polymerase Chain Reaction (RT-PCR) or bilateral pulmonary infiltration in computed tomography (CT) scan of the chest were included in the study. Severe pneumonia cases were determined based on World Health Organization (WHO) case definitions for COVID-19 consisting of the following: respiratory rates: ≥ 30 breaths/min, SpO2 ≤ 93%, and PaO2/ FiO2 ≤ 300 mmHg.
Exclusion criteria	Patients who denied signing the consent form those with allergy reaction while injecting IVIg with severe extravasation and anaphylactic shock mildly ill patients patients recovering and improving upon Hydroxychloroquine, Lopinavir/Ritonavir, and supportive therapy and pregnancy or breastfeeding.
Interventions
	Treatment IV Ig 400 mg/kg IV once a day for 3 days
	Control Standard care
Participants
	Randomized participants : Standard care=32 IV Ig=52
	Characteristics of participants N= 84 Mean age : NR 65 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=84 Critical: n=0
Primary outcome
	In the register Need for mechanical ventilation, need of admission to critical care unit, and death.
	In the report Need for invasive mechanical ventilation and oxygenation, the need for admission to the Intensive Care Unit (ICU), and the mortality rate.
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	Some concerns
General comment	In addition to the published article, the study registry was used in data extraction and risk of bias assessment. The study protocol and statistical analysis plan were not available at time of extraction. The target sample size specified in the registry was achieved. Some outcomes that were reported (e.g., length of hospital stay, length of ICU stay, lab values) were not pre-specified in the registry. There is no change from the trial registration in the intervention and control treatments. All participants in the intervention group only were pre-medicated with hydrocortisone, paracetamol, and antihistamine 30 minutes before the IV Ig injection.

Methods
	RCT Blinding: double blinding
	Location : Multicenter / France Follow-up duration (days): 90
Inclusion criteria	Critically ill patients ≥18 years With COVID-19 confirmed by a positive PCR test Admitted to the intensive care unit Required invasive mechanical ventilation for moderate-to-severe ARDS, according to the Berlin Definition criteria Enrolled in the study within 72 h after starting invasive mechanical ventilation Written informed consent, in accordance with local legislation, was obtained from all patients or their surrogates. If written informed consent could not be obtained, patients were included because the study was considered an emergency research by the institutional review board, consent was obtained as soon as the patients were able to provide it.
Exclusion criteria	Acute renal failure at admission, defined as plasma creatinine above 354 μmol/L, an increase in plasma creatinine baseline concentration by three-times or more, a diuresis of less than 0·3 mL/kg over the last 24 h, or anuria over the last 12 h Pregnancy Immunoglobulin A deficit Allergy to IVIG Participation in another intervention trial
Interventions
	Treatment IV Ig Four intravenous perfusions of 0.5g/kg each given over at least 8 h over 4 days
	Control Placebo
Participants
	Randomized participants : Placebo=77 IV Ig=69
	Characteristics of participants N= 146 Mean age : NR 103 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=0 Critical: n=146
Primary outcome
	In the register Ventilator-free days [ Time Frame: 28 days ]
	In the report Number of ventilator-free days at day 28, defined as the number of days between the last extubation day and day 28.
Documents avalaible	Protocol Yes. In English Statistical plan Yes 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	Low
General comment	In addition to the published article, the protocol, statistical analysis plan, supplementary material and study registry were used in data extraction and risk of bias assessment. The study (n=146) achieved the target sample size specified in the trial registry (n=138). There is no change from the trial registration in the intervention and control treatments. The primary outcome indicated in registry reflects the primary outcome reported in the paper. This study was updated on March 16th, 2022 with data extracted after contact with authors.