Covid-19 living Data

Sofosbuvir/daclatasvir vs Standard care/Placebo (RCT)

Hospitalized patients

FOREST PLOTS -2022-10-07

Studies description

Trial ISRCTN21085622
Publication Abbass S, J Med Virol (2021) (published paper)
Dates: 2020-09-01 to 2021-03-30
Funding: Private (Pharco Pharmaceuticals / European Egyptian Pharmaceutical Industries (EEPI))
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Egypt Follow-up duration (days): 17
Inclusion criteria	aged >18 years laboratory-confirmed symptomatic COVID-19 as determined by PCR assay in any specimen collected <72 h before randomization willing and able to provide written informed consent have the following disease severity grades: moderate (patients with respiratory rate ≥20 breaths/min, oxygen saturation measured through a pulse oximeter [SpO2] >90% on room air and heartrate ≥90 beats/min), severe (not critical) (patients with clinical signs indicative of severe systematic illness with COVID-19 such as respiratory rate ≥30/min, heart rate ≥125/min, SpO2≤ 90% on room air or PaO2/FiO2 <300). Degrees of severity of COVID-19 were defined according to the WHO’s COVID-19 disease severity classification.
Exclusion criteria	Critically severe COVID-19 requiring invasive mechanical ventilation at screening severe concomitant illness hypersensitivity or contraindication to any of the drugs used in the study liver cirrhosis or elevated ALT, and/or AST above three times the upper limit of normal cardiac ischemia or clinically symptomatic cardiac abnormalities history of any malignancy within the last 5 years history of solid organ or bone marrow transplantation received treatment with any other investigational drug/device or involved in another clinical trial within 6 months before screening people living with HIV pregnant or breastfeeding.
Interventions
	Treatment Sofosbuvir-Daclatasvir SOF 400 mg once a day orally + DCV 60 mg once a day orally for 10 days SOF-RDV SOF 400 mg once a day orally + RDV 200 mg once a day orally for 10 days
	Control Standard care
Participants
	Randomized participants : Sofosbuvir-Daclatasvir=40 SOF-RDV=40 Standard care=40
	Characteristics of participants N= 120 Mean age : NR 64 males Severity : Mild: n=0 / Moderate: n=46 / Severe: n=74 Critical: n=0
Primary outcome
	In the register 1. Sum of the counted symptoms (fever, headache, generalized aches (myalgia/arthralgia); respiratory distress combined with no evidence of deterioration (ICU admission and mechanical ventilation) at days3, 7 and 10; 2. Mean Oxygen saturation from day 1 to day 10 (based on daily recording as per CRF)
	In the report 1. Sum of the counted symptoms (fever, headache, generalized aches [myalgia/arthralgia]; respiratory distress combined with no evidence of deterioration [ICU admission and mechanical ventilation]) at Days 7 and 10, controlling for the corresponding count of symptoms at Day 3 for each patient; 2. mean change in oxygen saturation from Day 1 to Day 10 (based on daily recording per CRF)
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 study registry was used in data extraction and risk of bias assessment. Neither protocol nor statistical analysis plan was available. The primary and secondary outcomes reported in the article reflect those in the registry, which was retrospective. The study achieved the target sample size specified in the trial registry.

Trial IRCT20200624047908N1
Publication DISCOVER - Mobarak S, J Antimicrob Chemoth (2021) (published paper)
Dates: 2020-07-13 to 2020-10-30
Funding: Public/non profit (International Treatment Preparedness coalition)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Iran Follow-up duration (days): 28
Inclusion criteria	Clinically diagnosed COVID-19 by either PCR positivity or COVID-19 compatible lung chest CT scan findings More than 18 years old Written informed consent Any one of fever (oral temperature ≥ 37.8 °C), dry cough, severe fatigue, dyspnea, and oxygen saturation <95%.
Exclusion criteria	Renal failure Pregnant or breastfeeding Multi-organ failure or required intubation on admission Significant arrhythmias On amiodarone Previous sofosbuvir use for current infection Allergic to sofosbuvir/daclatasvir Enrolled in other interventional trials
Interventions
	Treatment Sofosbuvir-Daclatasvir SOF/DCV: 400/60 mg orally once daily for 10 days
	Control Placebo
Participants
	Randomized participants : Sofosbuvir-Daclatasvir=541 Placebo=542
	Characteristics of participants N= 1083 Mean age : NR 585 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=2
Primary outcome
	In the register Recovery within 10 days of starting the drug. Recovery means: (no fever, no shortness of breath, no cough or improved, no fatigue or improved, tolerated oral nutrition) for 24 hours.
	In the report Hospital discharge within 10 days after randomization where participants were discharged on the managing physician’s decision based on the absence of fever or dyspnoea, no or improved cough and fatigue, and tolerance of oral feeding, with a stable O2 saturation of >=95%.
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 artcile, the pre-print article and the trial registry were used in data extraction and assessment of risk of bias. Neither study protocol nor statistical analysis plan was available. There were no differences between the published/pre-print article and trial registry in population, procedures and interventions. The published article reports on changes to the protocol during the study. These included broadening the inclusion criteria to allow more participants to be recruited, amending the discharge criteria and dropping the ICU outcome due to shortages of hospital beds. Admission to and length of stay in ICU, a secondary outcome in the registry, was not measured because of lack of ICU beds. The report methods state that adverse events were recorded but these were not reported. The trial achieved its pre-stated target sample size. The study was updated on December 16th, 2021 with data from the published article..

Trial IRCT20200128046294N2
Publication Sadeghi A, J Antimicrob Chemoth (2020) (published paper)
Dates: 26/03/2020 to 26/04/2020
Funding: Mixed (Fanavaran Rojan Mohaghegh Daru Co.; Digestive Disease Research Institute of Tehran University of Medical Sciences)
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Iran Follow-up duration (days): 30
Inclusion criteria	All adult patients aged at least 18 years admitted with suspected COVID-19 infection between 26 March and 26 April 2020 were evaluated for eligibility. Participants were enrolled into the study if they had both positive qualitative RT-PCR on nasopharyngeal swab and chest CT scan compatible with moderate or severe COVID-19 infection. In addition, participants were required to have signs of severity of disease defined as fever (oral temperature ?37.8?C at any one time prior to enrolment) and at least one of respiratory rate >24/min, O2 saturation <94% or PaO2/FiO2 ratio <300 mgHg. Only participants whose onset of symptoms was 8 days or less were included. All patients were required to provide written informed consent prior to participation in the study.
Exclusion criteria	A known allergic reaction to the intervention drugs, pregnant or breastfeeding, any prior experimental treatment for COVID-19, heart rate <60 bpm, taking amiodarone, evidence of multiorgan failure, requiring invasive mechanical ventilation at screening and estimated glomerular filtration rate (eGFR) <50mL/1.73 m2/min.
Interventions
	Treatment Sofosbuvir-Daclatasvir SOF/DCV: 400/60 mg orally once daily for 14 days
	Control Standard care
Participants
	Randomized participants : Sofosbuvir-Daclatasvir=35 Standard care=35
	Characteristics of participants N= 70 Mean age : NR 34 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
	In the register Clinical recovery (composite) within 14 days from initiation of study treatment until normalization of fever (/=94% on room air), sustained for at least 24 hours
	In the report Clinical recovery within 14 days of enrolment
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 all available versions of the published article, the study registry was used in data extraction and risk of bias assessment. The target sample size specified in the registry was achieved. There is no change from the trial registration in the intervention and control treatments or in the primary and secondary outcomes.

Trial DRKS00022203
Publication Yakoot M, medRxiv (2022) (preprint)
Dates: 2020-06-20 to 2020-09-30
Funding: Private (PHARCO CORPORATE)
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Single center / Egypt Follow-up duration (days): 21
Inclusion criteria	Between 18 and 75 years of age presented with laboratory-confirmed COVID-19 infection as determined by polymerase chain reaction (PCR) assay in any specimen collected within 72 hours prior to randomization symptomatic at screening presenting with clinical manifestations under one of three severity categories - Mild, Moderate or Severe disease. Mild was defined as having mild symptoms with no picture of pneumonia in Computerized Tomography scan (CT-scan). Moderate was defined as having moderate fever and respiratory symptoms plus evidence of pneumonic lesions in CT-scan. The severe disease (but Not Critical) included patients with laboratory confirmed COVID-19, presenting at baseline by any of the following criteria: respiratory distress and respiratory rate (RR)≥30 times/min Finger oxygen saturation ≤93% in rest state Arterial partial pressure of oxygen / concentration of fractional inspired oxygen (PaO2/FiO2) ≤300mmHg and > 200mmHg under oxygen inhalation not necessitating ICU admission or mechanical ventilation
Exclusion criteria	Refusal or inability to sign the informed consent form pneumonia due to other etiology patients with acute respiratory distress syndrome requiring invasive mechanical ventilation at screening late presentation of patient after 10 days from the appearance of symptoms severe concomitant illness that affects survival or course of the disease including uncontrolled malignancy, HIV, active bleeding, shock/or multiple organ failure at screening pregnancy or lactating females hypersensitivity or contraindication to any of the experimental drugs used in the study (Prolonged QT syndrome, G6PD deficiency, psoriasis, retinal damage or others) decompensated liver cirrhosis or abnormal liver enzyme tests above three times the upper limit values (alanine aminotransferase – (ALT) and aspartate aminotransferase (AST) renal dysfunction (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73m2)
Interventions
	Treatment Sofosbuvir-Daclatasvir 400 mg sofosbuvir + 60 mg daclatasvir orally once a day for 10 days
	Control Standard care
Participants
	Randomized participants : Sofosbuvir-Daclatasvir=44 Standard care=45
	Characteristics of participants N= 89 Mean age : NR 38 males Severity : Mild: n=12 / Moderate: n=61 / Severe: n=16 Critical: n=0
Primary outcome
	In the register 1. Proportion of clinical recovery (composite) within 14 & 21 days (Normalization of fever (≤37.2 °C oral), Respiratory rate (≤24/minute on room air), Oxygen saturation (≥94% on room air)), sustained for at least 24 hours (using Exact test with Boot-Strapping) ; 2. Time to clinical recovery (composite) [Time frame: 21 days after randomization (using Kaplan Meier curve and Cox-regression) ; 3. Time to viral negativity assessed twice 48 hours apart (log10 viral load assessed by reverse transcription-PCR) during hospital stay (Kaplan Meier curve and Cox-regression) ; 4. Mean change in Clinical status using 8 point ordinal scale [Day 3 through Day 14, 21 (using Repeated measure Factorial ANOVA test]: 1) Death; 2) Hospitalized, on invasive ventilation or ECMO; 3) Hospitalized, on NIV or HFO2; 4) Hospitalized with oxygen supplement; 5) Hospitalized, not requiring oxygen but need medical care; 6) Hospitalized, not requiring supplemental oxygen or ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized with normal activity.
	In the report 1) Proportions-of and 2) time-to-clinical recovery within the 21day time-frame following enrolment
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 pre-print article, the trial registry, protocol, statistical analysis plan and supplementary appendices were used in data extraction and assessment of risk of bias. In the registry the study had three arms (sofosbuvir/daclatasvir + SOC, hydroxychloroquine + SOC, and SOC alone), but the article reports on two arms (sofosbuvir/daclatasvir + SOC, and SOC alone, with both arms receiving hydroxychloroquine as part of SOC). The primary outcome indicated in registry reflects the primary outcome reported in the paper.