Ethical review of off-label drugs during the COVID-19 pandemic

Table 1 Clinical trials of chloroquine and hydroxychloroquine use for coronavirus disease 2019

NCT Number	Population’s age	Intervention	Control	Outcome measures
NCT04362332	18-110 yr	CQ or HCQ	Standard supportive care	Composite endpoint with disease progression defined as a NEWS2 score within 14 d or resulting in admission to the Intensive/Medium Care unit or resulting in death within 14 d| Side effects
NCT04303507	16 yr and older	CQ or HCQ	Placebo	Number of symptomatic COVID-19 infections | COVID-19 symptom severity | Number of asymptomatic cases of COVID-19 | Number of symptomatic acute respiratory illnesses | Severity of symptomatic acute respiratory illnesses
NCT04360759	18 yr and older	CQ or HCQ	Placebo	Event-free survival at 28 d postrandomization between the experimental group and standard of care group | Incidence of serious adverse events | Incidence of adverse events of special interest related to the investigational product at time of hospitalization | Premature discontinuation of treatment | Time from treatment initiation to death, ARDS (PF/SF ratio < 300), or mechanical ventilation | Proportion with moderate and severe ARDS | Duration of hospitalization and ICU stay for survivors | Incidence of COVID-19 in household contacts
NCT04420247	18 yr and older	CQ or HCQ	Standard care	World Health Organization (WHO) 9-levels scale (from 0-8)|WHO 9-levels scale (from 0-8) | Mortality | Ventilation-free days | Duration of mechanical ventilation | National Early Warning Score (NEWS) | ICU Length of Stay | Hospital Length of Stay | Acute Kidney Disease incidence | Percentage of patients needing dialysis | Mean C Reactive Protein Levels | Mean Leucocytes Levels | Mean Lymphocyte Levels
NCT04351191	20-50 yr	HCQ Sulfate Regular dose, HCQ Sulfate Loading Dose or CQ	Placebo	RT–PCR results | Progression of symptoms | Mortality
NCT04447534	18 yr older	CQ	Zinc	Number of patients with negative PCR
NCT04346667	20-50 yr	HCQ Sulfate Regular dose, HCQ Sulfate Loading Dose or CQ	Placebo	RT–PCR tests | Progression of symptoms | Development of Symptoms | Adverse events
NCT04341727	18 yr older	HCQ Sulfate or Azithromycin	CQ Sulfate	Hours to recovery | Time to fever resolution
NCT04346329	18 yr older	HCQ	Placebo	Adverse effects | Immune score | COVID-19 prevention | Clinical response
NCT04371406	18-75 yr	HCQ and Azithromycin	Dietary Supplement: Azinc	Rate of patients with the occurrence of an unfavorable outcome between randomization and day 14 | Primary outcome of ancillary virological study: The evolution of viral load between day 0 and day 14 | The all-cause mortality rate at day 14 | The all-cause mortality rate at day 28 | Rate of patients with the occurrence of an unfavorable outcome between randomization and day 28 | The rate of use of mechanical ventilation at day 14 | The rate of use of mechanical ventilation at day 28 | The Intensive Care Unit admission rate at day 14 | The Intensive Care Unit admission rate at day 28 | Number of days of hospitalization for any cause between day 0 and day 14 | Number of days of hospitalization for any cause between day 0 and day 28 | The time to resolution of all COVID symptoms at day 14 | The time to resolution of all COVID symptoms at day 28 | The rate of use of oxygen therapy at day 14 | The rate of use of oxygen therapy at day 28 | The rate of use of secondary antibiotic therapy (after day 2) at day 14 | The rate of use of secondary antibiotic therapy (after day 2) at day 28 | Clinical status at day 14 | Clinical status at day 28 | Number of serious adverse events at day 14 | Number of serious adverse events at day 28 | Number of adverse events at day 14 | Number of adverse events at day 28 | The rate of patients with treatment withdrawal | Ancillary virological study: The rate of patients with a negative viral load at day 8 | Ancillary virological study: The rate of patients with a negative viral load at day 14
NCT04340544	18-99 yr	HCQ	Placebo	Difference in the time to resolution of clinical signs and symptoms of mild COVID-19 treated with HCQ or placebo as assessed by daily self-assessment | Difference between HCQ- and placebo-treated patients on an ordinal outcome scale until day 28 (death, admission to intensive care, hospitalization, continuing disease, recovered) | All-cause mortality within 28 d
NCT04342221	18-99 yr	HCQ	Placebo	Effect of HCQ on in vivo viral clearance
NCT04330144	18-99 yr	HCQ	No intervention	The rate of COVID-19
NCT04384380	20-79 yr	HCQ	No intervention	Time to a negative RT–PCR test | Virological assessment | Number of participants with treatment-related adverse events as assessed by the CTCAE v.4.0
NCT04374903	18 yr and older	HCQ and azithromycin	HCQ	Time to Clinical improvement (TTCI) | Clinical failure defined as death or the need for intubation and mechanical ventilation | Adverse effects | QT interval prolongation | Failure to continue assigned therapy | Time to viral clearance
NCT04347512	18 yr and older	HCQ and azithromycin	Placebo	The rate of patients reaching a significant hypoxemia, in each arm.
NCT04391127	16-90 yr	HCQ or Ivermectin	Placebo	Mean days of hospital stay | The rate of respiratory deterioration, the requirement of invasive mechanical ventilation or death | Mean oxygenation index delta | Mean time to viral PCR negativity
NCT04363866	18 yr and older	HCQ	Placebo	Clinical status at Day 5 assessed by a 6-Point Ordinal Scale | Number of participants with detectable SARS-CoV-2 virus from day 0 to day 28 and at day 5 | Toxicity of the study drug assessed by the incidence of adverse events
NCT04443725	18-65 yr	HCQ	Standard treatment	Virological cure
NCT04344951	18-90 yr	CQ	Standard treatment	50% reduction in the symptom score for patients with lower respiratory tract infections | Lack of progression for patients with upper respiratory tract infections | Comparison of the primary endpoint with respective patients not receiving the treatment | Serious respiratory failure until Day 14. This was compared with respective patients not receiving the treatment | Frequency of AEs and SAEs
NCT04359095	18 yr and older	HCQ or Lopinavir/Ritonavir Pill or Azithromycin	Standard treatment	Mortality | Number of participants with treatment-related severe adverse events as assessed by the NCORP Guidance for Collection of Adverse Events Related to COVID-19 Infection | Time to death | Number of participants transferred to the intensive care unit (ICU) | Number of participants that need mechanical ventilation support with endotracheal intubation | Number of participants cured as assessed by nasopharyngeal swabs, oropharyngeal swabs, and blood aspiration for COVID-19 (RT–PCR) without clinical symptoms and normal chest X ray | Number of participants with any adverse event related to treatment as assessed by the NCORP Guidance for Collection of Adverse Events Related to COVID-19 Infection
NCT04321278	18 yr and older	HCQ + azithromycin	HCQ	Evaluation of clinical status | All-cause mortality | Number of days free from mechanical ventilation | Duration of mechanical ventilation | Duration of hospitalization | Other secondary infections | Time from the start of treatment to death | Medium- and long-term outcomes of SARS-CoV-2 infection on morbimortality, daily life activities, mental health, and quality of life | Assessment of whether the tested therapies may be affected by leucocyte phenotype
NCT04316377	18 yr and older	HCQ	No intervention	Rate of decline in SARS-CoV-2 viral load | Change in National Early Warning Score scores | Admission to the intensive care unit | In-hospital mortality | Duration of hospital admission | Mortality at 30 and 90 d | Clinical status | Change in C-reactive protein concentrations | Change in alanine aminotransferase concentrations | Change in aspartate aminotransferase concentrations | Change in bilirubin concentrations | Change in the estimated glomerular filtration rate | Change in cardiac troponin concentrations | Change in natriuretic peptide concentrations
NCT04331470	15-100 yr	Levamisole Pill + Budesonide+Formoterol inhaler	Lopinavir/Ritonavir + HCQ	Clear chest CT-scan | PCR test | Physical status of the patient
NCT04325893	18 yr and older	HCQ	Placebo	Number of deaths from any cause, or the need for intubation and mechanical ventilation during the 14 d following inclusion and the start of treatment | Number of deaths from any cause, or the need for intubation and mechanical ventilation during the 28 d following inclusion and the start of treatment | Clinical evolution on the WHO Ordinal Scale for Clinical Improvement for COVID-19 between day 0 and day 14 | Clinical evolution on the WHO Ordinal Scale for Clinical Improvement for COVID-19 between day 0 and day 28 | Number of all-cause mortalities at day 14 | Number of all-cause mortalities at day 28 | Rate of positive SARS-CoV-2 RT–PCR nasopharyngeal samples at day 5 | Rate of positive SARS-CoV-2 RT–PCR nasopharyngeal samples at day 10 | The rate of venous thromboembolic events at day 28, documented and confirmed by an adjudication committee | Number of all-cause mortalities at day 28 in patients aged 75 yr and older | Clinical evolution on the WHO OSCI scale for COVID-19 between day 0 and day 28 for patients aged 75 yr or older | Rate of severe adverse events at day 28 | Number of all-cause mortalities at day 14 in patients aged 75 yr and older
NCT04353037	50-75 yr	HCQ	Placebo	Sub Study 1: Patients | Sub Study 2: Health Care Workers | Sub Study 1: Patients: Rate of secondary infection of coinhabitants | Sub Study 1: Patients: Adverse Events | Sub Study 1: Patients: Negative for COVID-19 | Sub Study 2: Health Care Workers: Number of shifts missed | Sub Study 2: Health Care Workers: Rate of adverse events | Sub Study 2: Health Care Workers: Rate of hospitalization
NCT04351724	18-99 yr	CQ or HCQ	Placebo	Sustained improvement (> 48 h) of one point on the WHO scale | Time to improvement on the WHO scale | Mean change in the ranking on an ordinal scale from baseline | Time to discharge or a National Early Warning Score (NEWS) (maintained for 24 h), whichever occurs first | Change from baseline in the National Early Warning Score (NEWS) | Oxygenation-free days | Incidence of new oxygen use during the trial | Duration of oxygen use during the trial | Ventilator-free days until day 29 | Incidence of new mechanical ventilation use during the trial | Duration of mechanical ventilation use during the trial | Viral load/viral clearance | Duration of hospitalization | Mortality | Obesity – mortality | Obesity - duration of hospitalization | Obesity - ICU admission | Obesity - new oxygen use | Drug–drug interactions with lopinavir/ritonavir | Renin Angiotensin System (RAS) fingerprint
NCT04359316	18 yr and older	HCQ	Azithromycin	Time to clinical improvement | Mortality | SpO2 improvement | Incidence of new mechanical ventilation use | Duration of hospitalization | Cumulative incidence of serious adverse events
NCT04334148	18 yr and older	HCQ	Placebo oral tablet	Number of participants with clinical COVID-19 infection | Number of participants with COVID-19 viral shedding | Safety as measured by the number of adverse events

CQ: Chloroquine; HCQ: Hydroxychloroquine; COVID-19: Coronavirus disease 2019; SARS-CoV2: Severe acute respiratory syndrome coronavirus 2.