Covid-19 living Data

Lopinavir + Ritonavir vs Standard care (RCT)

Mild outpatients

FOREST PLOTS -2022-04-15

Studies description

Trial NCT04499677
Publication FLARE - Lowe DM, PLoS Med (2022) (published paper)
Dates: 2020-10-06 to 2021-11-04
Funding: Mixed (LifeArc, UK; Fujifilm Toyama Chemical Co. provided favipiravir and favipiravir placebo free of charge.)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / UK Follow-up duration (days): 28
Inclusion criteria	Aged between 18 and 70 years Recently (within the last 5 days) developed symptoms of COVID-19 Tested positive for SARS-CoV-2 by PCR Were within 7 days of symptom onset, or who were asymptomatic but had tested positive by PCR within the previous 48 hours
Exclusion criteria	Known hypersensitivity to either drug or their ingredients/excipients Chronic liver or kidney disease Taking concomitant medicines known to interact with the trial treatments Being treated as a hospital inpatient for any condition Pregnant or breastfeeding Participating in another interventional clinical trial (treatment or vaccination) Female participants of childbearing potential were required to provide a negative pregnancy test before commencement of trial medication and on Day 14, and to use highly effective contraceptive measures during the trial Male participants with a female partner of childbearing potential were also required to use highly effective contraception
Interventions
	Treatment LPV/r+FAV Initial dose: 1800 mg FAV + 400/100 mg LPV/r orally twice a day on Day 1 -Maintenance dose: 400 mg FAV + 200/50 mg LPV/r orally 4 times a day on Days 2-7. Lopinavir-Ritonavir Initial dose: 400/100 mg LPV/r orally twice a day on Day 1 -Maintenance dose: 200/50 mg LPV/r orally 4 times a day on Days 2-7. Favipiravir Initial dose: 1800 mg FAV orally twice a day on Day 1 -Maintenance dose: 400 mg orally 4 times a day on Days 2-7.
	Control Placebo
Participants
	Randomized participants : Placebo=60 LPV/r+FAV=61 Lopinavir-Ritonavir =60 Favipiravir=59
	Characteristics of participants N= 240 Mean age : NR 123 males Severity : Mild: n= 239/ Asymptomatic: n=1
Primary outcome
	In the register Upper respiratory tract viral load at Day 5 [ Time Frame: Day 5 from randomisation ] Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy
	In the report Viral load measured by quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5
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	Some concerns
General comment	In addition to the published article, the pre-print article, protocol, statistical analysis plan and prospective study registry were used in data extraction and risk of bias assessment. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome. The study (n=240) achieved the target sample size (n=240) specified in the trial registry. This study was updated on August 8th, 2022 with data obtained from contact with authors. This study was updated on January 19th, 2023 with data extracted from the published report.

Trial NCT04403100
Publication TOGETHER - Reis G, JAMA (2021) (published paper)
Dates: 2020-06-02 to 2020-10-09
Funding: Public/non profit (Bill and Melinda Gates Foundation)
Conflict of interest: No

Methods
	RCT Blinding:
	Location : Multicenter / Brazil Follow-up duration (days): 90
Inclusion criteria	18 years or older reported less than 8 days since onset of flu-like symptoms or chest computerized tomography scan consistent with COVID-19 at least one additional criterion for high risk: aged 50 years or older presence of pulmonary disease, specifically moderate or severe persistent asthma, chronic obstructive pulmonary disease, pulmonary hypertension, or emphysema diabetes requiring oral medication or insulin hypertension requiring treatment known cardiovascular diseases (congestive heart failure of any etiology, documented coronary artery disease, clinically manifest miscellaneous heart disease) symptomatic lung disease on chronic treatment history of transplantation obesity (body mass index ≥30 [calculated as weight in kilograms divided by height in meters squared]) immunocompromised status due to disease (eg, those living with HIV with a CD4 T-cell count of <200 cells/mm3, confirmed malignant neoplasm) immunocompromised status due to medication (eg, people taking 10 mg or more of prednisone equivalents a day) and patients with cancer
Exclusion criteria	Use of any of study drugs in 30 days prior to screening clinical evidence of progression of COVID-19 (ie, use of oxygen supplementation arterial oxygen saturation less than 94% use of noninvasive positive-pressure ventilation support) history of known life-threatening cardiac arrhythmias long QT syndrome known allergy to study drugs
Interventions
	Treatment Hydroxychloroquine Initial dose: 800 mg orally once-off - Maintenance dose: 400 mg orally once per day for 9 days Lopinavir-Ritonavir LPV/r: Initial dose 800/200 mg orally twice on day 1 - Maintenance dose: 400/100 mg orally every 12 hours for 9 days
	Control Placebo
Participants
	Randomized participants : Placebo=227 Hydroxychloroquine=214 Lopinavir-Ritonavir =244
	Characteristics of participants N= 685 Mean age : NR 308 males Severity : Mild: n= 685/ Asymptomatic: n=0
Primary outcome
	In the register Proportion of participants who were hospitalized for progression of COVID-19 disease [ Time Frame: Measuring during 28-day period since randomization (Intention to treat analysis) ]; Proportion of participants who died due to COVID-19 progression and/ or complications [ Time Frame: Measuring during 28-day period since randomization (Intention to treat analysis) ]
	In the report COVID-associated hospitalization 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 the published article, the study registry and protocol were used in data extraction and risk of bias assessment. Enrollment into the hydroxychloroquine and lopinavir-ritonavir groups was discontinued in this platform study based on a decision from the independent Safety Monitoring Board following interim analysis results showing that it would be clinically irrelevant to recommend either treatment. The longest follow up in the report was 90 days, and in the registry 28 days. A number of outcomes in the registry were not reported (need for mechanical ventilation, shock and need for vasoactive amines, death due to pulmonary or cardiovascular complications). The definition used in the time to symptom resolution outcome in the paper (resolution of combined symptoms using the WURSS scale) was not pre-specified in the registry [Time to clinical improvement - Proportion of participants with clinical improvement, defined as normalization of temperature, Respiratory rate, SaO2, and cough relief (> 50% compared to baseline measured on a visual analog scale) in the last 72 hours] or in the protocol [Time until clinical improvement (up to 28 days), defined normalization of temperature, respiratory rate, SaO2, and cough relief (> 50 in relation to baseline measured on a visual analog scale) in the last 72 hours; Reduction in the perception of dyspnea (upper respiratory tract respiratory symptoms scale - WURSS-11) on days 0, 3, 7, 14 and 28 days)].