Covid-19 living Data

Nitazoxanide vs Standard care/Placebo (RCT)

Mild outpatients

FOREST PLOTS -2022-08-18

Studies description

Trial NCT04498936
Publication Medhat M, Arab J Gastroenterol (2022) (published paper)
Dates: 2020-07-15 to 2021-10-30
Funding: Public/non profit (Egyptian Science, Technology and Innovation Funding Authority (STDF))
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Egypt Follow-up duration (days): 14
Inclusion criteria	COVID-19 diagnosis based on positive reverse-transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 on nasopharyngeal swabs Patients either attended, 1–2 days after diagnosis, to the outpatient clinic or were admitted to the quarantine hospitals of Helwan University Hospital, Al-Rajhy Liver University Hospital, and Tanta University Hospital, Egypt older than 18 years old creatinine clearance of >30 mL/ml without any malignancy non-severe COVID-19 infection, according to WHO cases definition, were included. Non-severe COVID-19 cases are defined by the absence of criteria for acute respiratory distress syndrome (ARDS), sepsis, septic shock, or other conditions requiring life sustaining therapies such as mechanical ventilation (invasive or non-invasive) or vasopressor therapy. All included patients had oxygen saturation >90% on room air and did not have signs of pneumonia nor signs of severe respiratory distress.
Exclusion criteria	Severe or critical COVID-19 infection with signs of ARDS, sepsis, septic shock patients required invasive or non-invasive mechanical ventilation ARDS is diagnosed when the PaO2/FiO2 ratio is < 200 pregnancy renal impairment with a creatinine clearance of <30 mL/min evidence of malignancies and use of FVP or LPV/RTV therapy
Interventions
	Treatment SOF/LDP 400 mg + 90 mg orally once a day for 14 days Nitazoxanide 500 mg orally four times a day for 14 days
	Control Standard care
Participants
	Randomized participants : SOF/LDP=70 Nitazoxanide =77 Standard care=73
	Characteristics of participants N= 220 Mean age : NR 100 males Severity : Mild: n= */ Asymptomatic: n=0
Primary outcome
	In the register 1) Change of PCR from positive to negative [ Time Frame: 2 weeks ] The PCR will be done at time of recruitment, day 5, 8, 11, and 14. The time taken to have negative will be measured in each group 2) Clinical improvement [ Time Frame: 2 weeks ] Clinical improvement will be measured by detection of downgrading of cases severity according to the World Health Organization case severity classification.
	In the report Viral clearance
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 trial registry was used in data extraction and assessment of risk of bias. Neither protocol nor statistical analysis plan was available. Only one of the two primary outcomes in the registry is reported in the article. The registry reports an additional primary outcome, clinical improvement. The trial (n = 220) did not achieve the target sample size in the registry (n = 240).

Trial NCT04552483
Publication Rocco PRM, Eur Respir J (2020) (published paper)
Dates: 2020-06-08 to 2020-08-20
Funding: Mixed (Brazilian Council for Scientific and Technological Development (CNPq), Brazilian Ministry of Science, Technology, and Innovation for Virus Network; Brasilia, Brazil, and Funding Authority for Studies and Projects, Brasil)
Conflict of interest: Yes

Methods
	RCT Blinding:
	Location : Multicenter / Brazil Follow-up duration (days): 14
Inclusion criteria	1. Patients with one or more of three selected symptoms of Covid-19 (fever and/or dry cough and/or fatigue) of 1 to 3 days’ duration. 2. Age 18 years of age or older. 3. Willingness to take the study therapy. 4. Provision of written informed consent (by patient or a health care surrogate).
Exclusion criteria	1. Negative result on RT-PCR for SARS-CoV-2 in a nasopharyngeal swab specimen collected at admission. 2. Inability to swallow. 3. History of severe liver disease. 4. Chronic kidney disease requiring renal replacement therapy. 5. Severe heart failure (NYHA class 3 and class 4). 6. Severe chronic obstructive pulmonary disease (COPD) (GOLD 3 and 4). 7. Any cancer in the last 5 years. 8. Any known autoimmune disease. 9. Known allergy to nitazoxanide. 10. Nitazoxanide treatment in the last 30 days. 11. Clinical suspicion of tuberculosis or bacterial pneumonia.
Interventions
	Treatment Nitazoxanide 500 mg orally three times a day for 5 days
	Control Placebo
Participants
	Randomized participants : Nitazoxanide =238 Placebo=237
	Characteristics of participants N= 475 Mean age : NR 184 males Severity : Mild: n= 475/ Asymptomatic: n=0
Primary outcome
	In the register Days with fever; Days with cough; Days with asthenia [ Time Frame: Day8 ]
	In the report Complete resolution of symptoms
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 pre-print, the study registry and supplementary materials were used in data extraction and risk of bias assessment. Study protocol and statistical analysis plan were not available at the time of data extraction. Trial registration was retrospective. Sample size justification was calculated retrospectively to describe power of the included sample size following considerable loss to follow up. The registry primary outcomes and timepoint does not reflect the combined reported primary outcome. Data for the outcome Viral negative conversion Day 7 correspond to day 5 in the trial. This study was updated on December 3rd, 2020 after contact with authors. This study was updated on January 18th, 2021 after publication of the study report.

Trial NCT04486313
Publication Rossignol JF, EClinicalMedicine (2022) (published paper)
Dates: 2020-08-18 to 2021-01-08
Funding: Private (Romark Institute of Medical Research)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Puerto Rico, USA Follow-up duration (days): 28
Inclusion criteria	At least 12 years of age presenting within 72 hours of onset of symptoms of mild or moderate COVID-19 Minimum symptom requirements were: At least two respiratory symptom domains (head, throat, nose, chest, cough) with a score of ≥2 as determined by scoring the InFLUenza Patient-Reported Outcomes (FLU-PRO©) questionnaire administered at screening (only one domain score required to be ≥2 if pulse rate ≥90 beats per minute or respiratory rate ≥16 breaths per minute) no improvement in overall symptom severity from the prior day.
Exclusion criteria	Signs or symptoms suggestive of severe COVID-19 including shortness of breath at rest, resting pulse rate ≥125 beats per minute, resting respiratory rate ≥30 breaths per minute, or SpO2 ≤ 93% on room air at sea level previous COVID-19 infection or any symptom suggestive of COVID-19 recent episodes (two weeks) of acute upper respiratory tract infection, otitis, bronchitis or sinusitis immunodeficiency, such as in subjects undergoing chemotherapy, transplant recipients receiving immunosuppressive therapy, and HIV patients with a CD4 count below 350 cells/mm3 in the last six months females of childbearing potential who were either pregnant or sexually active and not using birth control.
Interventions
	Treatment Nitazoxanide 600 mg orally twice a day for 5 days
	Control Placebo
Participants
	Randomized NR Analyzed 379 participants Nitazoxanide =184 Placebo=195
	Characteristics of participants N= 379 Mean age : NR 165 males Severity : Mild: n= 379/ Asymptomatic: n=0
Primary outcome
	In the register Reducing the Time to Sustained Response [ Time Frame: Up to 21 days ]
	In the report Time from the first dose to sustained response (TSR), a measure of meaningful within-subject change in symptoms
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: N
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 all versions of the published and pre-print articles (SSRN and medRxiv), the prospective trial registry was used in data extraction and assessment of risk of bias. Neither study protocol nor statistical analysis plan was available. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome. Several outcomes reported in the article were not included in the trial registry. When all participants randomized or included for safety are considered, the study achieved its original target sample size. Of note, participants were recruited, randomized and tested at first clinic visit with suspected COVID-19. Many were subsequently excluded from efficacy analysis for a number of reasons: a) Of 1,092 randomized, 156 subjects positive for rhinovirus/enterovirus and negative for SARS-CoV-2 at baseline were not included in ANY analysis as they are to be analyzed later as part of a separate study targeting enterovirus/ rhinovirus infection. b) 1 participant withdrew consent prior to receiving treatment, but not reported which arm. All remaining participants (n=935) who received treatment were included in the safety analysis after receiving intervention or placebo. (All outcomes extracted were in this population: mortality, AE, SAE). This study study was updated on March 9th, 2022 with data from the new versions of the preprints. This study was updated on April 27th, 2022 with data extracted from the peer-reviewed article.