Study design

The present study is designed as a multicenter prospective cohort study that will enroll patients from five randomized clinical trials that were originally designed to assess the effects of specific COVID-19 treatments in Brazil (Coalition COVID-19 Brazil, Figure 1). Adult patients requiring hospitalization due to proven or suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection will be followed through structured and centralized telephone interviews performed at 3, 6, 9 and 12 months after enrollment. This study protocol was registered at Clinicaltrials.gov (registration number: NCT04376658).

Figure 1 - Schedule of enrollment, assessments and follow-up.

Figure 1 - RCT - randomized clinical trial; PTSD - posttraumatic stress disorder.

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Figure 1 - Schedule of enrollment, assessments and follow-up.

Figure 1 - RCT - randomized clinical trial; PTSD - posttraumatic stress disorder.

Participant eligibility

Patients aged 18 years or older, requiring hospitalization due to proven or suspected SARS-CoV-2 infection and meeting eligibility criteria for Coalition I (NCT04322123),⁽¹⁴⁾ Coalition II (NCT04321278),⁽¹⁵⁾ Coalition III (Codex; NCT04327401),^(16,17) Coalition IV (Action; NCT04394377) and Coalition VI (Tocibras; NCT04403685)⁽¹⁸⁾ randomized clinical trials (Table 1) will be enrolled. Patients with a positive polymerase chain reaction result for SARS-CoV-2 will be considered as proven cases. Suspected cases will be defined according to the following factors included in the Brazilian Ministry of Health definition: presence of fever and at least one respiratory sign or symptom (dry or productive cough, shortness of breath, nasal or conjunctival congestion, difficulty swallowing, sore throat, runny nose, oxygen saturation < 95%, signs of cyanosis, rhinorrhea, intercostal circulation and dyspnea) and patients from an endemic region, traveling from an endemic region in the last 14 days, or in contact with a suspected or confirmed case in the last 14 days.⁽¹⁹⁾

Table 1 - Coalition COVID-19 Brazil randomized clinical trials

Exclusion criteria include death during hospitalization, absence of telephone contact, absence of proxy for patients with communication difficulties (aphasia, cognitive impairment, severe hearing loss, or non-Portuguese speaker), and refusal or withdrawal of agreement to participate.

Outcomes

Associated factors

Five sets of variables will be assessed as potential associated factors for HRQL and secondary outcomes: 1 - demographic characteristics (age and sex), 2 - premorbid health state (comorbidities, physical functional status one month before hospitalization, previous use of medications, such as corticosteroids, angiotensin II receptor blockers or conversion enzyme inhibitors), 3 - characteristics of acute illness (clinical, radiologic and laboratory manifestations of COVID-19, need for ICU admission, need for ventilatory support, need for neuromuscular blockers, need for vasopressor, need for renal replacement therapy, length of ICU stay, length of hospitalization), 4 - specific COVID-19 treatments received (hydroxychloroquine, azithromycin, dexamethasone, and tocilizumab), and 5 - time-updated postdischarge variables (HRQL, physical functional status and symptoms of anxiety, depression, and PTSD).

Follow-up

The study will begin at the date of enrollment for coalition randomized clinical trials. Patients will be followed using structured telephone interviews performed 3, 6, 9 and 12 months after enrollment with a 30-day window period (15 days before and 15 days after the estimated date). The telephone follow-up calls will be centralized in a single center composed of researchers who have been trained in the use of standardized telephone interviews and who will be blinded to specific COVID-19 treatments. For patients with communication difficulties, the follow-up interviews will be conducted with their proxy. The proxy will be allowed to answer questions related to the following patient outcomes: mortality, rehospitalization, return to work or study, physical functional status, need for long-term ventilatory support, and HRQL. For each telephone follow-up (3, 6, 9, and 12 months), the patient will be classified as follow-up loss after ten attempts of telephone contact without success at different times on several days within the window period.

Procedures to ensure data quality

The following procedures will be performed to ensure the quality of the data:

To ensure standardization of the study procedures, the investigators responsible for data collection at each participating center will receive at least one training session prior to the beginning of recruitment.

The investigators at each participating center will have access to the study coordination centers as a means of dispelling doubts and solving potential problems.

The data will be entered on printed standardized data collection forms and stored in an electronic data capture system (REDCap, Vanderbilt University, Nashville, TN, USA).⁽²⁶⁾ To ensure the adequacy of data transcription, routine doublechecking will be performed as data are entered into the electronic data capture system.

A data cleaning routine will be applied frequently. The investigators at the participating centers will be contacted in cases of inconsistencies or missing data. This information will also provide feedback regarding the need for retraining.

Telephone interviews will be taped and audited to verify consistency in data collection. The audio files will be anonymously stored in a server that meets the same security norms as those used for data in electronic medical records. Access to the files, which is restricted to the study team, will require user identification and a password.

Sample size

The sample size of the present study will be determined by the number of patients enrolled in the Coalition COVID-19 Brazil randomized clinical trials who were discharged from the hospital. Considering the in-hospital mortality ratio of published coalition studies (3% to 60%)^(14-16) and an estimated one-year survival after hospitalization due to community-acquired pneumonia of 66%,⁽²⁷⁾ the present study will include approximately 1,000 participants. This sample size will allow a power of 80% to detect a difference of 0.05 utilities (within the range of minimally clinically important difference; 0.03 to 0.52)⁽²¹⁾ among two groups of equal sizes at 12 months, with a standard deviation of 0.28 for utility values (estimated based on a previous publication)⁽¹⁰⁾ and an alpha level of 0.05.

Handling of missing data

The missing values for the variables that compose HADS and IES-R will be imputed, replacing the missing items with the mean of the answered items in the same subscale, if at least half of that subscale has been answered.

Statistical analysis

We will examine the normality of the data by visual inspection of histograms and by using the Shapiro-Wilk test for normality. At baseline, continuous variables will be expressed as the mean and standard deviation or as the median and interquartile range. Categorical variables will be expressed as counts and percentages.

The adjusted result of the primary outcome (EQ-5D3L utility index) will be summarized for each comparison group using central tendency and dispersion measures, together with the mean or median difference as an effect size measure. All-cause mortality, major cardiovascular events, rehospitalization and return to work or study will be reported as incidence ratios. Physical functional status, degree of dyspnea, need for long-term ventilatory support, symptoms of anxiety, depression or PTSD, and self-rated health will be reported as prevalence ratios using clinically relevant cutoff points. The association between independent variables and outcomes will be assessed using generalized estimated equations accounting for the cluster effect (study of origin) and repeated measures. The variance inflation factor will be used to assess multicollinearity. A statistical significance level of 0.05 will be considered for all comparisons. Since this study is exploratory, we will not adjust analyses of secondary outcomes for multiple comparisons. Sensitivity analyses will be performed considering each coalition study as an independent cohort to check the consistency of the findings. Analyses will be performed with R software (R Development Core Team).⁽²⁸⁾

Ethics approval and consent to participate

This study will be conducted according to resolution no. 466/12 of the Brazilian National Health Council⁽²⁹⁾ and the Guidelines for Good Clinical Practice E6(R1).⁽³⁰⁾ All five randomized clinical trials that compose the present observational study, including their amendments for one-year telephone follow-up to assess quality of life and patient-centered outcomes at 3, 6, 9, and 12 months, were approved by Brazil´s National Ethics Committee (Conselho Nacional de Ética em Pesquisa - Conep). Informed Consent will be collected from participants or their proxies at the time of enrollment for one of the five randomized clinical trials that compose this observational study. Participants will be reconsented during the first telephone contact. Enrolled patients or their proxies will have the option to withdraw from participation at any time. Records of participation in this study will be kept confidential and will be accessed in a restricted way only by researchers trained in good clinical practices, who will transfer the clinical information to specific forms (which do not have information that can identify the participants).

Dissemination

A detailed statistical analysis plan will be made available online. The study results will be submitted for publication regardless of the results after completion. We hope to make the study findings widely available and plan to disseminate our results through conferences and peer-reviewed journals. Due to the pandemic crisis and importance of study findings, we plan to submit preliminary data for publication.

Data sharing

The authors encourage interested parties to contact the corresponding author with data sharing requests, including for access to additional unpublished data.