key: cord-0683728-3th4b9z5
authors: Junqueira, Daniela R.; Rowe, Brian H.
title: Efficacy and safety outcomes of proposed randomized controlled trials investigating hydroxychloroquine and chloroquine during the early stages of the COVID‐19 pandemic
date: 2020-10-13
journal: Br J Clin Pharmacol
DOI: 10.1111/bcp.14598
sha: c2052e335a56c0be72ecc2fe1f231c88604c4017
doc_id: 683728
cord_uid: 3th4b9z5

AIMS: To assess whether randomized clinical trials (RCTs) proposed to evaluate the treatment of patients with COVID‐19 with hydroxychloroquine (HQ) or chloroquine early in the pandemic included plans to measure outcomes that would translate into meaningful efficacy/effectiveness and safety outcomes. METHODS: The WHO‐ICTRP database was searched for registers of RCTs evaluating HQ or chloroquine, alone or in combinations, compared with other treatments for patients diagnosed with COVID‐19. The final search was performed on April 8th, 2020. RESULTS: Among 51 registered RCTs (median sample size 262; IQR: 100, 520), 34 (67%) reported a clinical outcome, 12 (24%) a surrogate outcome, and five (10%) a combination of clinical and surrogate outcomes as primary endpoints. Six (15%) trials included the WHO scale for clinical improvement as a primary clinical outcome. Clinical improvement and mortality accounted for 45% of the unique domains among 18 clinical outcome domains of efficacy. Twenty‐four (47%) RCTs did not describe plans to assess safety outcomes; when assessed, safety outcomes were determined in generic terms of total, severe or serious adverse events. CONCLUSIONS: The RCTs investigating HQ or chloroquine during the early stages of the COVID‐19 pandemic included heterogeneous and insufficient approaches to measure efficacy/effectiveness and safety relevant to patients and clinical practice. These findings provide insights to inform clinical and regulatory decisions that can be drawn about the efficacy/effectiveness and safety of these agents in patients with COVID‐19. Trialists need to adapt quickly to the research progress on COVID‐19, ensuring that core outcome measures are assessed in ongoing RCTs.

On December 31, 2019, a cluster of cases of atypical pneumonia of unknown etiology was reported in the city of Wuhan, China, and later identified as being caused by a novel coronavirus. 1 The ability of the novel Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2; hereafter referred to as COVID- 19) 2 to infect human hosts and be transmitted among individuals rapidly evolved into a global pandemic with over 30 million confirmed cases in 235 countries as of October 1st, 2020 (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). Though the majority (~80%) of the COVID-19 cases develop a mild condition, a smaller percentage (~15%) of patients require hospitalization and some develop a severe condition (~5%) that requires mechanical ventilation in the first 24 hours of hospital admission. 3 Clinical complications such as profound acute hypoxemic respiratory failure and sepsis 4, 5 have led to a total of 1,009,270 deaths worldwide (https://www.who.int/emergencies/diseases/novel-coronavirus-2019; last updated on October 1st, 2020).

Worldwide, the capacity of the healthcare systems to offer care for patients diagnosed with COVID-19 depends on the capability of intensive care units (ICU) and emergency departments (ED) to accommodate the additional requirements brought about by the increased patient volumes during the pandemic. This is of critical relevance considering the high ICU occupancy commonly seen in many locations 6 and the long-recognized ED overcrowding and its negative consequences on patient outcomes. [7] [8] [9] Moreover, early in the pandemic, the management of patients with COVID-19 was supportive, and recovery time was estimated at around three to six weeks for critically ill patients. 10 In this challenging scenario, it is not surprising that there has been a frantic search for effective treatments. Early in April 2020, there were 788 entries of registered COVID-19 trials on the World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP). By the end of August 2020, the WHO-ICTRP database registered three times more entries.

Clinical trials provide vital evidence to establish the efficacy and safety of new interventions or new indications for existing interventions. To be informative, however, they have to be designed and implemented following standards to ensure valid and meaningful evidence. 11 Meaningful evidence involves defining outcomes comprising the potential benefits (efficacy/effectiveness) and harms (safety) of the treatments under investigation. 12 Moreover, efficacy/effectiveness outcomes should represent clinically meaningful results that directly measure how a patient feels, functions, or survives. 13 Alternatively, trials may report surrogate outcomes, which may provide evidence for benefit that encourages further research. Trials assessing surrogate outcomes may be smaller, completed faster and be less expensive; however, surrogate outcomes may or may not predict clinical results and translate in meaningful evidence of efficacy/effectiveness. 13, 14 Likewise, safety outcomes are essential in defining the value of a treatment intervention for healthcare providers, patients, and health systems. Despite the importance of finding a treatment that effectively mitigates or cures patients diagnosed with COVID-19, it is critical to appropriately define and detect the potential adverse events of the treatment options under investigation. There are guidance and legal requirements for clinical trial protocols to plan the data collection of adverse events, whether applying systematic or non-systematic assessment approaches. 12, 15, 16 The objective of this study was to assess whether the randomized clinical trials (RCTs) of COVID-19 treatments registered on the WHO-ICTRP included definitions and data collection plans to produce evidence on meaningful efficacy, effectiveness and safety outcomes. We focused on RCTs as the highest level of evidence and those evaluating treatments with hydroxychloroquine (HQ) or chloroquine. Traditionally, these immune-suppressants have been used to treat autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease; however, they have also been approved for the treatment of malaria since 1955. 17 In the context of COVID-19, these drugs received widespread support as effective treatments following demonstration of in vitro viral activity against SARS-CoV-2 and a potential viral load reduction in a case series report. 18, 19 During the early stages of the pandemic, HQ and chloroquine received emergency use authorization 20 by the Food and Drug Administration (FDA) in the United States and overwhelming social media and leadership support, resulting in medication shortages. Evolving research has shown that HQ and chloroquine do not reduce the mortality of patients with COVID-19. 21 Nonetheless, there is continued interest in highquality RCTs on the efficacy and safety of these and other drugs in the treatment of patients diagnosed with COVID-19 infection. 21 Furthermore, familiarity with HQ and chloroquine have created a push for expedited clinical trials.

We downloaded the COVID-19 WHO-ICTRP database (https://www.who.int/ictrp/search/en/) on April 8 th , 2020, at 10:30 GMT-6. We filtered studies on the database according to the intervention (HQ or chloroquine) and the study design (randomized versus non-randomized). All the retrieved registers were screened and reviewed for data extraction purposes. Eligible studies were parallel RCTs evaluating either HQ or chloroquine to treat patients diagnosed with COVID-19 infection, used alone or in any combination, and compared with any other treatment option (including placebo). Uncontrolled trials and observational studies were excluded. We included trials recorded in the clinical trial registry of any country and at any recruitment status. Patients and investigators were not aware of this study at the time of their submissions.

One author (DJ) extracted data using a pre-standardized form. Quality control was performed by reextracting data from 15% of the included trial registries. Information on the trial ID, scientific title, date of registration, recruitment status, patient population and funding sources were extracted from the WHO-ICTRP database. Information on the country where the trials were planned to be conducted was extracted primarily from the WHO-ICTRP database and completed using the data from the trial registry when appropriate.

The trial's registry was accessed and provided additional information to characterize the RCTs according to:

 Number of participants planned to be recruited;  Age and sex of the participants planned to be recruited;  Intervention and comparison treatments, including doses and administration schedules;  Treatment duration;  Efficacy/effectiveness outcomes defined as primary endpoints;  Safety outcomes, i.e., adverse events;  Timeframe for the assessment of the efficacy/effectiveness and safety outcomes;  Mode data collection of safety outcomes.

The efficacy/effectiveness outcomes were classified as clinical (e.g., improvement or recovery of respiratory symptoms) or surrogate outcomes (e.g., viral load, biomarkers, etc.). The mode of data collection of the adverse events was classified as ''systematic assessment'' when specific ascertaining methods to detect the occurrence of adverse events were described by the use of checklists, questionnaires, or laboratory tests at regular intervals, and as ''non-systematic assessment'' when the detection methods relied on the spontaneous report of adverse events by clinicians or participants. 15

The characteristics of the RCTs were summarized according to clinical or surrogate outcomes and ascertainment methods to detect adverse events. Simple proportions were reported for dichotomous outcomes. For continuous data, means and standard deviations (SD) or medians and interquartile ranges (IQR) were reported, as appropriate. Comparisons between continuous variables were made using t-test and reporting the mean difference (MD) with 95% confidence intervals (CI). Finally, outcomes planned to be measured in the RCTs were compared to the primary outcome defined in the master protocol for COVID-19 studies published by WHO on February 18, 2020, 22 which comprised a composite measure of clinical improvement and/or survival measured on an ordinal scale ranging from 0, uninfected, to 8, dead.

This article is protected by copyright. All rights reserved.

Among 927 clinical trials registered on the WHO-ICTRP database as of April 8 th , 2020, 72 registrations were identified as RCTs investigating the use of HQ or chloroquine for COVID-19 infection and considered potentially eligible for this study ( Figure 1 ). Among these 72 registered trials, two were duplicate entries of the same trial in more than one clinical trial registry, seven trials had been cancelled, and 12 entries related to trials testing prophylaxis interventions. Therefore, 51 registered clinical trials were included for analysis. An updated search (conducted on August 24 th , 2020) revealed approximately 300 registered trials involving treatments with HQ or chloroquine that would be potentially eligible. Table 1 summarizes the characteristics of the clinical trials planned to investigate the use of HQ or chloroquine to treat patients diagnosed with COVID-19. The RCTs proposed to test the hypothesis of whether these drugs could be beneficial for people infected with SARS-CoV2 started in February 2020 when 12 trials were registered. In the following month of March, the number of trials registered tripled. All trials planned to include adults of both sexes, and three trials (6%) also planned to include adolescents. A total of 27 registered RCTs (53%) were not yet actively recruiting patients. The trials were mainly planned to evaluate the treatments in patients hospitalized with COVID-19 (28; 55%) among a variety of severity scenarios.

The proposed dosing schedule and treatment duration varied among the trials ( Table 2 ). Seventeen trials reported at least one arm with a fixed dosing administration schedule of HQ or chloroquine ranging from a daily amount of 200 to 1,200 mg. One trial planned to administer one single dose of HQ (200 mg) combined with other drugs. Considering the dosing schedule of all treatment arms of either HQ or chloroquine, maximum treatment duration ranged from seven days to 14 days. Twenty trials reported at least one arm with a variable dosing administration schedule of HQ or chloroquine. Considering all treatment arms with a variable dosing schedule, treatment duration varied from 5 to 16 days. Fourteen registered trials did not report information on the treatment duration. One trial (2%) reported plans to monitor adherence and two trials (4%) reported funding support from sources with potential commercial interest (data not shown).

Forty-five of the RCTs (90%) were planned to be conducted in a single country (Supplement , Table  S1 ) with a median sample size of 262 (IQR: 100, 520). Among the trials planned to be implemented in a single country, China was the main location (16; 32%) followed by the United States (5; 10%). Five (10%) of the registered RCTs were designed to be conducted in multiple countries; one trial did not provide information on the location where the RCT was planned to be implemented. Overall, the proposed clinical trials anticipate recruiting a total of 37,303 participants, among outpatients and inpatients, to be randomized to receive a variety of experimental and comparison treatments with HQ, chloroquine or other agents in diverse combinations and dose schedules (Supplement , Table S2 ). Only fourteen (27%) of the registered trials reported the number of patients being recruited to the treatment and comparison arms; among these trials, a total of 1,138 patients would receive HQ or chloroquine alone or in combination with other drugs (data not shown). Table 3 summarizes the type of outcomes described in the registry of the RCTs and the related assessment timeframe. One-third of the clinical trials included in their registry information a surrogate outcome to be measured as a primary endpoint; the remaining trials (34; 67%) described plans to assess one clinical outcome as a primary endpoint. The timeframe of outcome assessment varied substantially among the designs of the RCTs. Trials planning to measure only clinical efficacy/effectiveness outcomes described timeframes of assessment ranging from 5 to 120 days (median 15; IQR: 15, 28). Trials planning to measure only surrogate outcomes defined timeframes of assessment ranging from 3 to 56 days (median 15; IQR: 15, 28). The RCTs planning to evaluate a clinical outcome were compared with trials planning to assess a surrogate outcome; however, no statistical difference in timeframes for outcome assessment was identified (MD 6.3; 95% CI: -10.51 to 23.12; P = 0.45). Among all 51 registered RCTs describing at least one clinical or surrogate efficacy/effectiveness outcome, 13 (26%) did not report a timeframe for outcome assessment.

The WHO scale for clinical improvement was described in the outcome assessment plans of six (15%) RCTs, and 16 (41%) trials mentioned clinical improvement among the primary outcomes without using the WHO scale or without detailing how it was planned to be measured. Overall, eighteen different clinical outcomes were described among trials with at least one clinical efficacy/effectiveness outcome defined in the trial registration (Supplement , Table S3 ). Clinical improvement and mortality accounted for 45% of the unique clinical outcome domains proposed to assess the efficacy/effectiveness of HQ or chloroquine treatment in patients diagnosed with COVID-19. Twenty-one different surrogate outcomes were identified in the registered RCTs planning to measure at least one surrogate outcome, with viral load and virologic clearance accounting for 36% of the surrogate outcomes.

Twenty-four (47%) of the registered RCTs did not describe plans to assess a single safety outcome. Among the trials including a description of at least one safety outcome (n=28), most (25; 89%) did not report the method to be implemented for the detection of adverse events. The timeframe for the assessment of safety outcomes was not defined in 13 (46%) of the trials reporting plans to measure at least one safety outcome. The timeframe for the assessment of the safety outcomes ranged from 7 to 120 days (median 28; IQR: 14, 30). The timeframe of safety outcome assessment was planned to be longer in comparison with the assessment of clinical outcomes (MD -9.8; 95% CI: -26.08 to 6.56; P = 0.23). The generic terminologies total, severe and serious adverse events accounted for 41% of the unique domains reported in at least two registered trial (Supplement , Table S4 ). Twenty-five different domains were reported by only one clinical trial in which the assessment of at least one safety outcome was described.

Clinical trials are study designs central to the regulatory and commercialization process of therapeutic interventions such as pharmaceutical agents and devices. Regulatory decisions informed by clinical trials data often represents a certificate of clinical and safety value to new medicines or new indications of existing medicines. 23 Given the potential severity of the COVID-19 infection, the need to find a mitigating or curative treatment is beyond urgent. Several candidate compounds addressing different disease processes (e.g., antibiotics, anti-viral, immune-suppressants, anticoagulants, oxygen delivery, etc.) have been proposed and are now undergoing clinical trials. Both HQ and chloroquine have been popular potential therapies described in the scientific literature and social media, and evidence for their efficacy/effectiveness and safety are desperately needed. Nevertheless, one recent evaluation of the three published HQ trials found important methodological weaknesses and suboptimal reporting of key information. 24 In this study, we found that RCTs proposed to evaluate the clinical efficacy/effectiveness and safety of HQ or chloroquine in the treatment of patients diagnosed with COVID-19 are designed to collect data that vary substantially in terms of the outcome domain used to determine the evidence base upon which these drugs will be judged. Moreover, data on safety outcomes are overlooked or only superficially included among the outcomes planned to be measured in these trials. Finally, essential information related to dosing schedules, treatment duration and timeframe of outcome assessment were frequently missing in the description of the RCTs. Overall, this analysis yielded three major areas of concern.

Selection of efficacy/effectiveness outcomes The outcomes measured in clinical trials are critical in providing meaningful data and in allowing comparison among the results of other RCTs and different interventions. 25 Though most of the evaluated RCTs specified at least one clinical outcome as a primary endpoint, the outcome domains varied widely. For example, while half of the registered trials described plans to assess all-cause mortality/mortality and clinical status/recovery to evaluate the efficacy/effectiveness of the drugs, the remaining trials defined over 15 different outcome domains. Ideally, the results of RCTs are subsequently combined in systematic reviews and meta-analysis, which are vital to inform all healthcare providers and health decision-makers. This may be particularly true during the COVID-19 pandemic, as many of the existing trials are small, and a definitive, mega-trial trial may not emerge from the list identified. In the presence of highly heterogeneous outcomes, the development of systematic reviews and meta-analysis is likely less informative if not precluded.

During the early stages of the COVID-19 pandemic, core outcomes of relevance to be measured in studies including adult hospitalized patients diagnosed with COVID-19 were proposed by different groups (http://www.comet-initiative.org/Studies/Details/1538). The core outcomes comprised mortality and respiratory support, outcome domains included in some, but not all the RCTs planned to evaluate the effect of HQ or chloroquine in patients diagnosed with COVID-19. Particularly, on February 18 th , 2020, the WHO published a protocol for COVID-19 therapeutic trials recognizing that consistency among outcome measures and time points is vital for interpretation and combination of results across trials. 22 This document informed a consensus exercise that culminated in the development of a minimal common outcome measure set for COVID-19 clinical research, published on 12 th June, 2020. 26 Several RCTs registered up to April 2020 did not plan to assess the domains proposed in the WHO protocol from February. Similarly, a post-hoc comparison of the outcomes included in the RCT registries against the minimal common outcome measure set for COVID-19 clinical research proposed by the WHO 26 shows that none of the trials described measuring all the three proposed core outcome measure set: viral burden, survival, and clinical progression. More concerning, several of the clinical trials registered in the WHO-ICTRP database included only surrogate outcomes to estimate the efficacy/effectiveness of the drugs. There exist several examples where positive results in trials measuring surrogate outcomes were not replicated in efficacy/effectiveness trials where clinical outcomes were measured. 14, 27 To increase research usefulness and relevance to patients and the health system, any investigation on drugs that might potentially treat patients diagnosed with COVID-19 needs to include a minimal standardized set of clinical outcomes of efficacy/effectiveness. This set of outcomes will be continually informed by the evolving research on the clinical characteristics of this new disease. Trialists should move quickly to adapt any planned and ongoing RCT to the clinical research progress on COVID-19, particularly ensuring that the minimal outcome measure set viral burden, survival, and clinical progression is determined. Ultimately, the strain on the health system's capacity will only abate when we identify treatments that improve clinical outcomes for patients, such as reducing intubation rates and subsequent deterioration. The development of a safe, effective, and widely available vaccine will be the long-term solution to the COVID-19 pandemic.

Chloroquine, and its derivate HQ, have been approved by the FDA since 1955. 17 These are antimalarial drugs, besides also important in the treatment of immune-mediated diseases such as lupus erythematosus and rheumatoid arthritis. 28 Both drugs can induce irreversible retinal damage, cardiomyopathy and QTc prolongation, severe hypoglycemia and dermatologic adverse events. 17 The severity of these adverse effects range from mild to severe; occasionally, these agents have been found to cause death.

Since we can anticipate a set of adverse events that are highly relevant to patients and clinical practice, the proposal of RCTs should contain plans to systematically assess fully defined adverse events according to appropriate timeframes. 12, 16, 29 For instance, QTc prolongation and drug-induced arrhythmias like torsades de pointes, are of concern in critically ill patients with COVID-19 30 and should be carefully ascertained. Monitoring QTc through electrocardiographic tracings regularly would represent a systematic approach to the problem, even if monitoring is required to be performed remotely for safety reasons. The systematic assessment of adverse events can improve the accuracy of estimates within trials 31 while also minimizing bias. 32 Finally, the assessment of defined anticipated adverse events, together with their seriousness, severity and duration, would be more informative than the mere documentation of generic events.

In this study, we showed that retinopathy, cardiac and dermatologic adverse events, and hypoglycemia were planned to be assessed in a single clinical trial among the 51 trials that had been registered to evaluate the treatment with HQ or chloroquine for patients diagnosed with COVID-19.

Outcomes of safety were not included among the outcomes defined in several of the proposed trials (24, 47%), while the remaining RCTs reported a non-specific approach for observing safety outcomes. Based on these results, and the fact the many adverse effects are rare in small clinical trials, we are concerned that the evidence on the harms of these investigational drugs to patients diagnosed with COVID-19 may likely be incomplete and biased.

The comprehensive and prospective registration of clinical trials has been internationally supported since 2004 as a way to reduce the selective publication of studies and the selective reporting of outcomes. 33 Since the early years of clinical trial registration, ensuring that the registered data are complete and accurate has been a challenging objective of multiple enforcement mechanisms, including legal requirements. 29, 33 Remarkably, approximately one-third of the registered RCTs included in this study had at least one piece of missing information, either related to treatment dose, duration, timeframes of outcome assessment or the lack of definition of a safety outcome. This is of particular concern amid the current pandemic scenario where the rush to test any potential helpful drug may pose a risk that low-quality evidence may be used to support clinical decisions with unpredictable impacts on patients and the health system.

We reviewed the information provided by all clinical trials focused on HQ and chloroquine for patients diagnosed with COVID-19 available in the WHO-ICTRP database until April 8 th , 2020, at 10:30 GMT-6. We chose the WHO-ICTRP because it compiles data from ClinicalTrials.gov and 10 primary registries (https://www.who.int/ictrp/en/). In the scenario of the COVID-19 pandemic, we judged that this approach would provide an improved overview of clinical trials being planned in different countries. Nevertheless, as we did not search the primary registries directly, it is possible that some potentially eligible registered RCTs could have been missed. Also, the data analyzed in this study is limited to the information provided in the record of the clinical trials' registry. A minority of the clinical trials provided access to the full study protocol; therefore, the data collected and analyzed in this study may be incomplete if authors have deliberately left information missing on the publicly available record of the planned trials. Nevertheless, if the trial registries are incomplete for lowquality designs or deliberate actions, this represents a risk to the strength of the evidence that will ultimately be available to inform decisions.

Similar to any analysis of secondary data, the findings reported may be impacted by the heterogeneity of the primary information extracted from the trial registry. For instance, the patient population and case severity varied among the RCTs from mild cases treated in the community (outpatients) to severe cases requiring hospitalization. Nevertheless, since this analysis was focused on whether the planned outcomes represented clinical or surrogate results, variability in the patient population and the severity of the disease likely have not impact our findings and conclusions.

Finally, as the development of research on COVID-19 is evolving rapidly, additional RCTs exist which were planned but registered after the study timeline; these trials were not included in the present analysis. Our analysis focused on the clinical research proposed during the early phase of the COVID-19 pandemic. Since this work was completed, approximately 300 additional trials have been registered. It will be important to analyze the progress of the research on potential treatments for COVID-19, and such work needs to be developed in line with the rapidly evolving scenario that characterizes this pandemic. For instance, the largest RCTs evaluating the value of HQ and chloroquine to treat patients with COVID-19 have now halted these treatment arms (e.g., the WHO Solidarity, RECOVERY, and ORCHID trials), which will certainly impact the trials that continue to study these drugs in a variety of treatment combinations.

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Early in the COVID-19 pandemic, an impressive number of RCTs were planned to evaluate the clinical efficacy/effectiveness and safety of HQ or chloroquine in the treatment of patients diagnosed with COVID-19. Outcome domains described in these clinical trials were highly heterogeneous and included both clinical and/or surrogate measures. Moreover, despite HQ and chloroquine being known to induce cardiovascular and other adverse events that can be irreversible and potentially lifethreatening, the registered RCTs did not describe systematic assessment methods to accurately detect adverse events. The pandemic scenario is demanding researchers to register, plan and deploy RCTs at an incredibly rapid pace. The present analysis supports the need for improvements in the design of ongoing and future RCTs. Ultimately, finding safe and effective treatments is required to decrease the burden on patients, providers and health care systems worldwide created by patients diagnosed with COVID-19. Table 1 Characteristics of the randomized controlled trials for the treatment of COVID-19 with hydroxychloroquine or chloroquine (n=51). IQR interquartile range; SD: standard deviation. a Minimum: 30, maximum: 5,000; b Studies could enroll more than one patient population; c Among all trial registers describing at least one arm with a fixed dosing administration schedule of hydroxychloroquine or chloroquine (17 trials with one or multiple arms; 15 valid data);], minimum: 7, maximum: 14; d Among all trial registers describing at least one arm with a variable dosing administration schedule of hydroxychloroquine or chloroquine (20 trials with one or multiple arms; 22 valid data), minimum: 5, maximum: 16. 

World Health Organization (WHO)

Severe acute respiratory syndrome-related coronavirus: The species and its viruses -a statement of the Coronavirus Study Group

Covid-19: most patients require mechanical ventilation in first 24 hours of critical care

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet

Covid-19 in Critically Ill Patients in the Seattle Region -Case Series

Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response

A systematic review examining the impact of redirecting low-acuity patients seeking emergency department care: is the juice worth the squeeze?

The role of triage liaison physicians on mitigating overcrowding in emergency departments: a systematic review

World Health Organization Director. General's opening remarks at the media briefing on COVID-19 -24

Harms From Uninformative Clinical Trials

Food and Drug Administration. Surrogate Endpoint Resources for Drug and Biologic Development

Surrogate end points in clinical trials: are we being misled?

The ClinicalTrials.gov results database--update and key issues

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Chloroquine Phosphate or Hydroxychloroquine Sulfate Supplied From the Strategic National Stockpile for Treatment of 2019 Coronavirus Disease

Update I. A systematic review on the efficacy and safety of chloroquine/hydroxychloroquine for COVID-19

Therapeutic Trial Synopsis

Providing Value to New Health Technology: The Early Contribution of Entrepreneurs, Investors, and Regulatory Agencies

COVID-19 research has overall low methodological quality thus far: case in point for chloroquine/hydroxychloroquine

The COMET Handbook: version 1.0. Trials

A minimal common outcome measure set for COVID-19 clinical research. The Lancet Infectious Diseases

Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990-2011. J Am Heart Assoc

Use of Hydroxychloroquine and Chloroquine During the COVID-19

Pandemic: What Every Clinician Should Know

Trial Reporting in ClinicalTrials.gov -The Final Rule

Canadian Pharmacists Association; c2016

Harms are assessed inconsistently and reported inadequately part 1: systematic adverse events

Opportunities for selective reporting of harms in randomized clinical trials: Selection criteria for non-systematic adverse events

From Mexico to Mali: four years in the history of clinical trial registration

Chloroquine HQ: 1,200 mg on day 1 (600 mg loading dose + 600 mg after 6 hours)

Chloroquine: 1,000 mg for 3 days (500 mg 2x/day for 3 days) HQ: 200 mg 2x/day for 5 days

Chloroquine: 250 mg 2x/day for 2 days HQ: 6 days

Chloroquine: 5 days ChiCTR2000029898 1. HQ

Chloroquine HQ: 1,200 mg on day 1 (600 mg loading dose + 600 mg after 6 hours)

Chloroquine: 1,000 mg HQ: 200 mg 2x/day for 5 days

Chloroquine: 250 mg 2x/day for 2 days HQ: 6 days

HQ: Hydroxychloroquine; NR: not reported