Covid-19 living Data

Ivermectin+Doxycycline vs Standard care/Placebo (RCT)

Hospitalized patients

FOREST PLOTS -2021-07-22

Studies description

Trial NCT04407130
Publication Ahmed S, Int J Infect Dis (2020) (published paper)

Funding: Private (Beximco Pharmaceutical Limited, Bangladesh)
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : * / Bangladesh Follow-up duration (days): 28
Inclusion criteria	age 18-65 years admitted to hospital within the last 7 days with either fever (≥37.5C) cough or sore throat and diagnosed positive for SARS-CoV-2 by rRT-PCR
Exclusion criteria	allergic to or potential drug-drug interaction for ivermectin or doxycycline chronic illnesses (e.g., ischemic heath disease, heart failure, documented cardiomyopathy, chronic kidney disease, chronic liver disease) received ivermectin and/or doxycycline in the last 7 days were pregnant or lactating or participated in any other clinical trial within the last month
Interventions
	Treatment IVM+DX Ivermectin : 12mg once-off orally. Doxycycline : 200mg orally at day-1 followed by 100mg twice a day for next 4 days Ivermectin 12mg once a day orally for 5 days
	Control Placebo
Participants
	Randomized participants : IVM+DX=24 Ivermectin=24 Placebo=24
	Characteristics of participants N= 72 Mean age : NR 33 males Severity : Mild: n=72 / Moderate: n=0 / Severe: n=0 Critical: n=0
Primary outcome
	In the register 1.Virological clearance [ Time Frame: within 7 days after enrollment ] 2.Remission of fever [ Time Frame: within 7 days after enrollment ] 3.Remission of cough [ Time Frame: within 7 days after enrollment ]
	In the report Time required for virological clearance (a negative rRT-PCR result on nasopharyngeal swab); remission of fever (≥37.5C) and cough within 7 days
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	The published article and the regsitry were used in data extraction and assessment of risk of bias. No study protocol or statistical analysis plan were available. 4/72 participants withdrew consent because of family obligations and unwillingness to be tested further. Baseline characteristics were not reported by study group. Some efficacy outcomes were not reported in the results section of the paper although they were listed in the methods section. Mortality, reported as a study outcome in the methods, was not clearly reported. This study was updated on February 2nd, 2021 after contact with authors.

Trial NCT04591600
Publication Hashim A, medRxiv (2020) (preprint)
Dates: 2020-07-01 to 2020-09-30
Funding: Public/non profit (Baghdad-Alkarkh General Directorate of Health in Bghadad, Iraq)
Conflict of interest: No

Trial NCT04523831
Publication Mahmud R, J Int Med Res (2021) (published paper)
Dates: 2020-06-01 to 2020-08-30
Funding: drug donation only (No specific grant; "Popular Pharmaceuticals Bangladesh Limited for supplying the study intervention and personal protective equipment")
Conflict of interest: No

Methods
	RCT Blinding:
	Location : Single center / Bangladesh Follow-up duration (days): 30
Inclusion criteria	18 years and older COVID-19 infection, confirmed by polymerase chain reaction (PCR) test within 3 days prior enrollment Only mild and moderate COVID-19 infected cases Able to provide informed consent
Exclusion criteria	Unable to take oral medication Pregnant or breast feeding lady Patients with severe COVID symptoms(defined as tachypnea [>30 breaths/minute] and hypoxia [oxygen saturation(SpO2) <90%] requiring supplemental oxygen), or admission in ICU/HDU Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) more than 5 upper limit of normal (ULN) Known hypersensitivity to Doxycycline or ivermectin or its components Registry: non-invasive positive pressure ventilation or mechanical ventilation at time of study entry
Interventions
	Treatment IVM+DX Ivermectin : 12 mg orally once off. Doxycycline : 100 mg orally twice a day for 5 days.
	Control Placebo
Participants
	Randomized participants : IVM+DX =200 Placebo=200
	Characteristics of participants N= 400 Mean age : NR 235 males Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register Number of Patients With Early Clinical Improvement [ Time Frame: 7 days ]; Number of Participants With Late Clinical Recovery [ Time Frame: 12 days ]
	In the report Number of days required for clinical recovery from day 1
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 study registry (retrospective), protocol and statistical analysis plan (retrospective) was used in data extraction and risk of bias assessment. Outcomes for adverse and serious adverse events were extracted from the result section of the study registry.Target sample size specified in the registry and protocol was achieved. There is no change from the trial registration or protocol in the intervention and control treatments or in the outcomes. However, the study registry and protocol were retrospective and therefore interpreted with caution. Denominators for SAEs/withdrawal due to AEs and Mortality do not seem to include the participants with these outcomes. On 19th of May, 2021, this study was updated based on the published report.

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Iraq Follow-up duration (days): 56
Inclusion criteria	COVID-19 patients at any stage of this disease Symptomatic for no more than three days for mild-moderate cases, no more than two days after being severe cases, and no more than one day after being critical cases
Exclusion criteria	Patients of allergic history to Ivermectin or to doxycyline
Interventions
	Treatment IVM+DX IVM: 200 mcg/kg/day PO for 2 days, third dose 7 days after the first, as needed; DX: 100 mg PO every 12 hrs for 5-10 days
	Control Standard care
Participants
	Randomized NR Analyzed 140 participants IVM+DX=70 Standard care=70
	Characteristics of participants N= 140 Mean age : NR 73 males Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register 1. Mortality rate [ Time Frame: Up to 8 weeks ] The effect of the experimental drugs to reduce the mortality rate (death rate) of treated patients. 2. Rate of progression disease [ Time Frame: up to 8 weeks ] Rate of patients under treatment who undergo progression of disease to a more advanced stage
	In the report NR
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	High
General comment	In addition to all available versions of the pre-print, the study register was used in data extraction and risk of bias assessment. No sample size calculation was reported. The study used quasi-randomized allocation, with participants allocated to treatments according to their day of recruitment; this method was compromised in that all critical patients were allocated to the experimental treatment arm, reported as being for ethical reasons. The type of blinding extracted for the study was based on the registry as no information was stated in the report regarding this. There was also no primary or secondary outcomes reported in the paper, nor a flow chart or explicit mention of the absolute number of patients randomized per arm.