key: cord-307623-8bd5m5tk
authors: Núñez Gil, Iván J.; Estrada, Vicente; Fernández-Pérez, Cristina; Feltes, Gisela; Vedia, Oscar; Vergara-Uzcategui, Carlos E.; Moreno, Víctor; Cerrato, Enrico; D'Ascenzo, Fabrizio; Raposeiras-Roubin, Sergio; Martín-Sánchez, F. Javier; Alfonso, Emilio; Huang, Jia; Ramakrishna, Harish; Higes, Emma Gil; Fernández-Ortiz, Antonio; Macaya, Carlos
title: Health Outcome Predictive Evaluation for COVID 19 international registry (HOPE COVID-19), rationale and design
date: 2020-09-23
journal: Contemp Clin Trials Commun
DOI: 10.1016/j.conctc.2020.100654
sha: 
doc_id: 307623
cord_uid: 8bd5m5tk

The disease produced by the new coronavirus known as SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), named COVID-19 (Coronavirus Disease-2019) has recently been classified as a pandemic by the World Health Organization (WHO). However, scarce clinical data is available and generally limited to the Chinese population due to the first cases were identified in Wuhan (Hubei, China). This article describes the rationale and design of the HOPE COVID-19 (Health Outcome Predictive Evaluation for COVID 19) registry (ClinicalTrials.gov Identifier: NCT04334291). With an ambispective cohort design, eligible patients are those discharged, deceased or alive, from any hospital center with a confirmed diagnosis or a COVID-19 high suspicion. With a current recruitment of more than 7000 cases, in 46 hospitals in 8 countries, since it is not possible to estimate the sample size based on literature reports, the investigators will try to get the maximum numbers of patients possible. The study primary objective is all cause mortality and aims to characterize the clinical profile of patients infected in order to develop a prognostic clinical score allowing, rapid logistic decision making. As secondary objectives, the analysis of other clinical events, the risk-adjusted influence of treatments and previous comorbidities of patients infected with the disease will be performed. The results of HOPE COVID-19 will contribute to a better understanding of this condition. We aim to describe the management of this condition as well as the outcomes in relation to the therapy chosen, in order to gain insight into improving patient care in the coming months. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov. Unique identifier: NCT04334291.

The disease caused by the new respiratory virus (coronavirus) designated as SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) has recently been deemed as a pandemic by the World Health Organization (WHO) 1,2 .

With an increasing number of confirmed cases in most countries worldwide, it is responsible for a significant morbidity and mortality and has motivated the implementation of measures at national and international levels with a great impact on the way of life of people throughout the whole planet.

In addition, this condition currently threatens many countries with the breakdown of health systems, producing serious logistical problems due to extensive affectation of the population, which can worsen the outcomes of those primarily affected by Coronavirus Disease-2019 (COVID-19) and secondarily the other patients with different pathologies who may suffer difficulties to get healthcare.

Limited clinical information is available and generally limited to the Chinese population, since the first cases were identified in Wuhan (Hubei, China) 3 .

The main objective of the present study is to characterize the clinical profile of patients infected with COVID-19 in order to develop a simple prognostic clinical score allowing a rapid logistic decision making: discharge with follow-up, referral to provisional/field hospitals or admission to regular hospital centers.

J o u r n a l P r e -p r o o f As secondary objectives, the analysis of events and the risk-adjusted influence of treatments and previous comorbidities of patients infected with the disease will be performed.

Ambispective international registry, real-life cohort "all comers" type, with voluntary participation. Without conflicts of interest, it is a investigator initiated study with advanced methodological support from the IMAS foundation (Institute for the Improvement of Health Care, Madrid, Spain).

The study has been approved by the coordinating center Ethic´s Committee (20/241-E) and the institutional board of each participating center. It has received a National drugs agency (AEMPS) classification EPA-0D.

Herein, the protocol proposes to select all the patients attended in any health center, with in hospital beds, who have been discharged or have died at the time of the evaluation.

All will be considered eligible with a positive COVID 19 test, after a RT-PCR, or if their attending physicians consider them highly likely to have presented the infection upon clinical and epidemiological evaluation in a pandemic environment. Consecutive recruitment is strongly warranted.

Given the anonymous characteristics of the registry and the health alarm situation generated by the virus, in principle, written informed consent was waived.

There are no exclusion criteria, except for the patient's or relatives´ (in intubated patients) explicit refusal to participate. An anonymized database is presented in electronic format, to be filled in at each participating center (www.HopeProjectMD.com). In theory, all information could be obtained from electronic records (medical history). If deemed necessary, the investigator may call patients in order to establish their vital status (strongly warranted), as well as the results of the RT-PCR test (or others diagnostic tests available: antibodies), if they were pending during their stay.

We consider it is not possible to estimate a precise sample size based on literature reports. Thus, HOPE will aim to get the maximum numbers of patients possible.

OUTCOMES.

-Primary: All-cause mortality. The major contributors of increased mortality will be assessed. o Causes of death.

Qualitative variables will be reported as their frequencies and quantitative data as the mean and standard deviation or median and interquartile range, as appropriate.

Univariate analysis will be performed for qualitative variables by a mixed-model of country and reported as odds ratios (OR) with 95% confidence interval (CI). Mixedlogistic regression models will be adjusted by backward-stepwise regression based on the maximum likelihood estimators. The likelihood-ratio and its significance will be calculated for each variable according to criteria for entry (P<0.05) and removal (P>0.10). Thus, we will select risk factors showing a P<0.10 in the univariate analysis or that were clinically relevant. Possible collinearity and interactions will be evaluated with the introduction of multiplicative terms.

Discriminative capacity for the models will be assessed by the area under the ROC curve (AUC) and its 95%CI. The model calibration assessing will be performed by comparing predicted versus observed probabilities after their calculation from the adjusted model coefficients. We will use the Hosmer-Lemeshow test to estimate model´s goodness-of-fit. The model with the greatest discriminative power, good calibration, viable capacity, and meeting the principle of parsimony, explaining the maximum variability outcome variable with the smallest number of parameters J o u r n a l P r e -p r o o f included, is to be selected. Finally, internal validity estimation with bootstrap of 1000 samples and optimistic value will be produced.

We aim to provide a mortality risk-score from the point estimate for each variable using the OR of the final model. AUCs of the scores will be assessed with the nonparametric ROC Mann-Whitney U-test. Propensity-score matching (PSM) will serve to determine how near subjects were to each other by using estimated treatment probabilities.

Variables included in the PSM generally will be those identified by the multivariate analysis. In all cases, the distribution of the variable would be checked against theoretical models and the assumption of homogeneity of variance tested. In all hypothesis, tests the null hypothesis will be rejected with a type I error or α error <0.05.

The present registry is conducted by a multinational independent research group and led by a steering committee comprised of internal medicine specialists, cardiologists and statisticians. Appendix table 1 depicts a list of centers with their principal investigators and Appendix table 2 list the multidisciplinary scientific committee. The first patient was admitted in February 2020. As of May 21 ST Probably, the home confinement, the professionals attempt to attend patients by telephone to prevent them from visiting flooded hospitals or offices and more importantly, the fear of patients and relatives to go to the dreaded and "contagious" emergency rooms explain an intense decrease in admission of no COVID-19 conditions, with even the delay in presentation of other urgent diseases, like acute myocardial infarction 7 , with dramatic results.

We recognize some limitations in the registry, inherent to this type of observational design. The focus will be put in the most severe patients, those needing admission, so the extrapolation to the general population would be complex but otherwise allowing the identification of most complications. With the current participating centers distribution, we feel the analysis would be closer to reality for Western Europe Caucasians and perhaps for Latins/Hispanic people, but not so close/certain for Asians or Blacks. Nevertheless, its data probably reflect the real-life practice in certain countries at a concrete point of the pandemic curve.

J o u r n a l P r e -p r o o f

The results of HOPE COVID-19 will contribute to a better understanding of this condition, primarily focusing in mortality. It will define a precise epidemiological profile of COVID-19 patients with higher severity and thus, admitted to a hospital. We aim to describe the management of this condition as well as the outcomes in relation to the therapy chosen, in order to gain insight into improving patient care in the coming months. 

WHO. WHO statement regarding cluster of pneumonia cases in Wuhan

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention

Clinical Characteristics of Coronavirus Disease 2019 in China

Clinical characteristics and outcomes of older patients with coronavirus disease 2019 (COVID-19) in Wuhan, China (2019): a single-centered, retrospective study

Impacto de la pandemia de COVID-19 sobre la actividad asistencial en cardiología intervencionista en España

J o u r n a l P r e -p r o o f

1) We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.2) None coauthor has any disclosure.Signed by all authors as follows:Ivan J Nuñez Gil, on behalf of all the authors J o u r n a l P r e -p r o o f