PROTECT Trial: A cluster-randomized study with hydroxychloroquine versus observational support for prevention or early-phase treatment of Coronavirus disease (COVID-19): A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: Hydroxychloroquine has shown to have antiviral activity in vitro against coronaviruses, specifically SARS-CoV-2. It is believed to block virus infection by increasing endosomal pH required for virus cell fusion and glycosylation of viral surface proteins. In addition to its antiviral activity, hydroxychloroquine has an immune-modulating activity that may synergistically enhance its antiviral effect in vivo, making it a potentially promising drug for the prevention and the cure of SARS-CoV-19. However, randomized controlled trials are needed to assess whether it can be used safely to treat COVID-19 patients or to prevent infection. The main objective of the present study is to evaluate the efficacy of hydroxychloroquine for (I) the prevention of COVID-19 or related symptoms in SARS-CoV-2-exposed subjects, such as as household members/contacts of COVID-19 patients and (II) the treatment of early-phase asymptomatic or paucisymptomatic COVID-19 patients. TRIAL DESIGN: This is a controlled, open label, cluster-randomized, superiority trial with parallel group design. Subjects will be randomized either to receive hydroxychloroquine or to observation (2:1). PARTICIPANTS: SARS-CoV-2-exposed subjects, including household members and/or contacts of COVID-19 patients and healthcare professionals (Group 1) or patients with COVID-19 (positive PCR test on a rhinopharyngeal or oropharyngeal swab for SARS-CoV-2), asymptomatic or paucisymptomatic in home situations who are not undergoing treatment with any anti COVID-19 medication (Group 2), will be enrolled. Paucisymptomatic patients are defined as patients with a low number of mild symptoms. All subjects must be aged ≥18 years, male or female, must be willing and able to give informed consent and must not have any contraindications to take hydroxychloroquine (intolerance or previous toxicity for hydroxychloroquine/chloroquine, bradycardia or reduction in heart rhythm with arrhythmia, ischemic heart disease, retinopathy, congestive heart failure with use of diuretics, favism or glucose-6-phosphate dehydrogenase (G6PD) deficiency, diabetes type 1, major comorbidities such as advanced chronic kidney disease or dialysis therapy, known history of ventricular arrhythmia, any oncologic/hematologic malignancy, severe neurological and mental illness, current use of medications with known significant drug-drug interactions, and known prolonged QT syndrome or current use of drugs with known QT prolongation). The study is monocentric and will be conducted at Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS. Subjects will be enrolled from a large epidemic region (North-Central Italy). The Public Health Departments of several Italian regions will collaborate by identifying potentially eligible subjects. INTERVENTION AND COMPARATOR: The participants will be randomized (2:1 randomization) to receive either hydroxychloroquine (Arm A) or to Observation (Arm B). Hydroxychloroquine will be administered with the following schedule: Group1: A loading dose hydroxychloroquine 400 mg twice daily on day 1, followed by a weekly dose of hydroxychloroquine 200 mg twice daily on days 8, 15 and 22, for a total of one month of treatment. Group 2: A loading dose hydroxychloroquine 400 mg twice daily on day 1 followed by 200 mg twice daily for a total of 5-7 days. The comparator in this trial is observation given that currently neither treatment is administered to asymptomatic or paucisymptomatic subjects, nor prophylaxis is available for contacts. Hydroxychloroquine will be shipped to subjects within 24 hours of randomization. Given the extraordinary nature of the COVID-19 pandemic, only telephonic interviews will be carried out and electronic Patient Reported Outcomes (ePRO) completed. During treatment, each subject will be contacted every other day for the first week and weekly thereafter (Group 2) or weekly (Group 1) by a study physician to assess early onset of any COVID-19 symptom or any adverse reaction to hydroxychloroquine and to check subject compliance. Furthermore, all subjects will receive periodic ePROs which may be completed through smartphone or tablets to record drug self-administration and onset of any symptom or adverse event. All subjects will be followed up for a total of 6 months by periodic telephonic interviews and ePROs. MAIN OUTCOMES: The primary endpoint/outcome measure for this trial is: for Group 1, the proportion of subjects who become symptomatic and/or swab-positive in each arm within one month of randomization; for Group 2, the proportion of subjects who become swab-negative in each arm within 14 days of randomization. RANDOMIZATION: All household members and/or contacts of each COVID-19 index case, and the COVID-19 patient himself/herself, fulfilling all inclusion criteria will be grouped into a single cluster and this cluster will be randomized (2:1) to either arm A or arm B. Information on each subject will be recorded in specific data records. Randomization lists will be stratified according to the following factors regarding COVID-19 index cases: 1. COVID-19 risk level on the basis of province of residence (high vs. low/intermediate); 2. Index case is a healthcare professional (yes vs.no) 3. Index case with COVID-19 treatment (yes vs. no) An independent statistician not otherwise involved in the trial will generate the allocation sequence, and COVID-19 response teams will be unaware of the allocation of clusters. Randomization will be performed through an interactive web-based electronic data-capturing database. An Independent Data Monitoring Committee has been established. BLINDING (MASKING): This study is open label. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): For Group 1, a sample size of about 2000 SARS-CoV-2-exposed subjects such as household members and/or contacts of COVID-19 patients will take part in the study. Assuming around 1.5-2.0 asymptomatic household members and/or contacts for each COVID-19 patient, we expect to identify approximately 1000-1300 COVID-19 index cases to be randomized. An interim analysis on efficacy is planned using standard alpha-spending function. For Group 2, sufficient power for primary objective (negative swab within 14 days of randomization) will be reached given a sample size of 300 asymptomatic or paucisymptomatic COVID-19 subjects in home situations not treated for COVID-19 (25%-30% of about 1000-1300 expected index cases). Since up to date reduced evidence about COVID-19 infection epidemiology, the continuous update of diagnostic and therapeutic approaches, the sample size estimation could be updated after a one third of population will be recruited and eventually modified according to a substantial protocol amendment. An interim analysis at 100 enrolled COVID-19 patients is planned. We have planned a Generalized Estimating Equation analysis, which is more efficient than a cluster level analysis, to take advantage of subject-specific covariates. The above reported sample size analysis is therefore to be considered conservative. TRIAL STATUS: The current version of the PROTECT trial protocol is 'Final version, 15 April 2020'. The study started on 9th May 2020. The first patient was enrolled on 14th May 2020. Recruitment is expected to last through September 2020. TRIAL REGISTRATION: The PROTECT trial is registered in the EudraCT database (no. 2020-001501-24) and in ClinicalTrials.gov ( NCT04363827 ), date of registration 24 April 2020. FULL PROTOCOL: The full PROTECT protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interests of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol (Protocol final version, 15th April 2020). The study protocol has been reported in accordance with Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

A model of an inflammatory bowel disease population-based registry: The Forlì experience (1993-2013).

BACKGROUND AND AIMS: The article presents a population-based registry designed to estimate incidence and prevalence of inflammatory bowel disease (IBD) in the area of Forlì (north-eastern Italy). METHODS: The registry included all patients with IBD ulcerative colitis (UC) and Crohn's disease (CD) in the Forlì area from 1993 to 2013. A data manager matched records from various sources. RESULTS: Seven hundred ninety-one patients were registered during the study period, 564 (71.3%) with UC and 227 (28.7%) with CD. The standardized annual incidence rate for UC was 12.8 per 100,000 females (95% CI 11.1-14.4) and 15.7 per 100,000 males (95% CI 13.9-17.5). That of CD was 7.0 per 100,000 for females (95% CI 5.7-8.3) and 5.4 per 100,000 males (95% CI 4.3-6.4). The prevalence of CD and UC on 1 January 2014 was 109.2 per 100,000 inhabitants (95% CI 94.3-124.2) and 266.4 per 100,000 inhabitants (95% CI 243.4-289.7), respectively. CONCLUSIONS: Although further studies are needed, the data suggest that incidence and prevalence of IBD in Italy are underestimated.

Implementing an evidence-based computerized decision support system linked to electronic health records to improve care for cancer patients: the ONCO-CODES study protocol for a randomized controlled trial.

BACKGROUND: Computerized decision support systems (CDSSs) are computer programs that provide doctors with person-specific, actionable recommendations, or management options that are intelligently filtered or presented at appropriate times to enhance health care. CDSSs might be integrated with patient electronic health records (EHRs) and evidence-based knowledge. METHODS/DESIGN: The Computerized DEcision Support in ONCOlogy (ONCO-CODES) trial is a pragmatic, parallel group, randomized controlled study with 1:1 allocation ratio. The trial is designed to evaluate the effectiveness on clinical practice and quality of care of a multi-specialty collection of patient-specific reminders generated by a CDSS in the IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) hospital. We hypothesize that the intervention can increase clinician adherence to guidelines and, eventually, improve the quality of care offered to cancer patients. The primary outcome is the rate at which the issues reported by the reminders are resolved, aggregating specialty and primary care reminders. We will include all the patients admitted to hospital services. All analyses will follow the intention-to-treat principle. DISCUSSION: The results of our study will contribute to the current understanding of the effectiveness of CDSSs in cancer hospitals, thereby informing healthcare policy about the potential role of CDSS use. Furthermore, the study will inform whether CDSS may facilitate the integration of primary care in cancer settings, known to be usually limited. The increasing use of and familiarity with advanced technology among new generations of physicians may support integrated approaches to be tested in pragmatic studies determining the optimal interface between primary and oncology care. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02645357.

Patterns and determinants of receipt of follow-up mammography and/or clinical examination in a cohort of Italian breast cancer survivors.

Information regarding the use of mammography by breast cancer survivors is limited. This study aimed at evaluating the compliance to surveillance mammography and/or clinical breast examination and the associated factors among patients living in northern Italy. A cancer registry-based cohort of 1304 patients living in the Health Care District of Forlì was followed up for 10 years. Eighty percent of patients had a mammogram and/or clinical breast examination during the first year after treatment. The proportion decreased to 67 % at 10 years of follow-up. Three demographic characteristics were independently associated with lower odds of having an annual mammogram and/or clinical breast examination: age at diagnosis [odds ratio (OR) 0.51, 95 % confidence interval (CI) 0.41-0.63 for patients aged 65-74 years; and OR 0.14, 95 % CI 0.11-0.18, for patients ≥75 years versus patients aged <64 year]; socio-economic status (OR 0.81, 95 % CI 0.65-1.00, for deprived patients versus patients of the reference class); and hospital travel time greater than 30 min (OR 0.44, 95 % CI 0.29-0.68 versus ≤15 min). With respect to clinical and disease characteristics, lower odds were observed for patients treated with mastectomy (OR 0.79, 95 % CI 0.65-0.97), for patients diagnosed with in situ breast cancer (OR 0.68, 95 % CI 0.46-0.99) as well as with stage II + breast cancer (OR 0.77, 95 % CI 0.63-0.94), and for patients with ≥3 Elixhauser comorbidities (OR 0.43, 95 % CI 0.26-0.71). Adherence to follow-up declined over time. Knowledge of associated factors may assist in improving access to care for breast cancer survivors.

Gastric cancer incidence in the Romagna Region of Italy: A spatial and temporal analysis.

BACKGROUND: The worldwide decrease in gastric cancer incidence is due to a birth-cohort-dependent decrease in exposure to major risk factors. METHODS: In an area of northern Italy with a historically strong internal geographical gradient in gastric cancer incidence, variations in rates by municipality and age group between 1987 and 2008 were evaluated. The study period was divided into three nonadjacent periods. End points included: age- and sex-standardised incidence rates; incidence rate ratio between age- and sex-standardised incidence rates; smoothed relative risks of gastric cancer incidence, and posterior probabilities of the relative risk being >1. RESULTS: In 1987-1990, the estimate of posterior probabilities of relative risk being >1 showed a higher incidence in hilly/mountainous areas. Between 1987-1990 and 2005-2008, a uniform decrease of more than 50% was observed (incidence rate ratio: plain, 0.45 (95% confidence interval 0.40-0.51); hill, 0.44 (0.34-0.58); mountain, 0.48 (0.22-1.02)). The decrease in the mountainous area was weak in the middle time period, with an incidence rate ratio of 0.92 (0.46-1.84), and intensified afterwards. The decrease occurred earlier and was more pronounced among younger people. In 2005-2008, gastric cancer risk was uniform across ages and municipalities. CONCLUSIONS: The observed changes in gastric cancer incidence is the epilogue of a birth-cohort-dependent decrease in exposure to major risk factors.

Colonoscopic surveillance of first-degree relatives of colorectal cancer patients in a faecal occult blood screening programme.

BACKGROUND: In some Italian areas, colonoscopic surveillance of first-degree relatives (FDRs) of colorectal cancer (CRC) patients is provided as a part of local population-based faecal occult blood test (FOBT) screening programmes. The objective of the present study was to assess the feasibility and early results of this surveillance model. METHODS: Data from district screening centres were used to evaluate the process of identification and selection of eligible FDRs (residence in the Emilia-Romagna Region, age 40-75 years, no recent colonoscopy) of screen-detected CRC patients and the detected prevalence of disease. The probability for an FDR to undergo colonoscopy and to be diagnosed with CRC and advanced adenoma was estimated using the Kaplan-Meier method. The sex- and age-standardised ratio of detected prevalence to that expected based on results from a colonoscopy screening study of the Italian general population was estimated. RESULTS: Between 2005 and 2011, 9319 FDRs of 2437 screen-detected CRC patients (3.8 per patient) were identified and contacted. Their likelihood of being eligible for, and accepting, colonoscopy was 0.11 (95% confidence interval: 0.11-0.12). Among the 926 subjects undergoing colonoscopy, the prevalence of previous negative screening FOBT was 63%. Eleven CRCs (1.2%) and 100 advanced adenomas (10.8%) were detected. The standardised ratio of detected prevalence to that expected was 0.91 (95% confidence interval: 0.19-2.66) for CRC and 1.48 (1.04-2.05) for advanced adenoma. CONCLUSIONS: The procedure of selection of FDRs was extremely ineffective. Due to previous negative screening tests, the prevalence of disease was less than expected. A population-based FOBT screening programme is a highly unsuitable setting for the provision of surveillance to FDRs of CRC patients.

Incidence, detection, and tumour stage of breast cancer in a cohort of Italian women with negative screening mammography report recommending early (short-interval) rescreen.

BACKGROUND: Although poorly described in the literature, the practice of early (short-interval) rescreen after a negative screening mammogram is controversial due to its financial and psychological burden and because it is of no proven benefit. METHODS: The present study targeted an Italian 2-yearly screening programme (Emilia-Romagna Region, 1997-2002). An electronic dataset of 647,876 eligible negative mammography records from 376,257 women aged 50-69 years was record-linked with the regional breast cancer registry. The statistical analysis addressed the following research questions: (1) the prevalence of recommendation for early (<24 months) rescreen (RES) among negative mammography reports; (2) factors associated with the likelihood of a women receiving RES; and (3) whether women receiving RES and women receiving standard negative reports differed in terms of proportional incidence of interval breast cancer, recall rate at the next rescreen, detection rate of breast cancer at the next rescreen and the odds of having late-stage breast cancer during the interscreening interval and at the next rescreen. RESULTS: RES was used in eight out of 13 screening centres, where it was found in 4171 out of 313,320 negative reports (average rate 1.33%; range 0.05%-4.33%). Reports with RES were more likely for women aged 50-59 years versus older women (odds ratio (OR) 1.33; 95% CI 1.25-1.42), for the first versus subsequent screening rounds (OR 1.91; 95% CI 1.79-2.04) and with a centre-specific recall rate below the average of 6.2% (OR 1.41; 95% CI 1.32-1.50). RES predicted a 3.51-fold (95% CI 0.94-9.29) greater proportional incidence of first-year interval cancers, a 1.90-fold (95% CI 1.62-2.22) greater recall rate at the next screen, a 1.72-fold (95% CI 1.01-2.74) greater detection rate of cancer at the next screen and a non-significantly decreased risk of late disease stage (OR 0.59; 95% CI 0.23-1.53). CONCLUSION: The prevalence of RES was in line with the maximum standard level established by the Italian national guidelines. RES identified a subset of women with greater incidence of interval cancers and greater prevalence of cancers detected at the next screen.

Incidence of interval breast cancers after 650,000 negative mammographies in 13 Italian health districts.

OBJECTIVES: To estimate the total proportional incidence of interval breast cancers in a two-yearly mammography screening programme, and to perform subgroup analyses by woman's age, screening centre-specific recall rate and screening round. METHODS: Using unconverted electronic data-sets from the 13 screening centres in the Emilia-Romagna Region of northern Italy (540,450 women aged 50-69 years), a database of 919,538 mammography records was created. Of these, 655,175 eligible single-mammography records (1997-2002) from 379,318 women were record-linked with the regional Breast Cancer Registry. In the two-year inter-screening interval, a total of 1,022,694.3 woman-years at risk were accumulated, with 695 interval cancers observed and 2428.3 expected. The observed number of interval cancers was divided by the expected number to obtain the proportional incidence. RESULTS: The total proportional incidence of first- and second-year interval cancers was 0.18 (95% CI 0.15-0.20) and 0.43 (0.39-0.47), respectively. Woman's age was inversely associated with proportional incidence in both interval years, with a cut-off point at age 60. A screening centre-specific recall rate greater than the regional average of 5% was associated with a proportional incidence of 0.14 (0.11-0.17) versus 0.20 (0.17-0.24) in the first interval year, and of 0.36 (0.31-0.41) versus 0.50 (0.44-0.56) in the second. The proportional incidence remained unchanged between the first and subsequent screening rounds. CONCLUSIONS: The results were in line with the previous Italian data and with the recommended European standards. The inverse effect of woman's age and of recall rate was expected.