A Phase I/II Clinical Trial to evaluate the efficacy of baricitinib to prevent respiratory insufficiency progression in onco-hematological patients affected with COVID19: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Baricitinib is supposed to have a double effect on SARS-CoV2 infection. Firstly, it reduces the inflammatory response through the inhibition of the Januse-Kinase signalling transducer and activator of transcription (JAK-STAT) pathway. Moreover, it reduces the receptor mediated viral endocytosis by AP2-associated protein kinase 1 (AAK1) inhibition. We propose the use of baricinitib to prevent the progression of the respiratory insufficiency in SARS-CoV2 pneumonia in onco-haematological patients. In this phase Ib/II study, the primary objective in the safety cohort is to describe the incidence of severe adverse events associated with baricitinib administration. The primary objective of the randomized phase (baricitinib cohort versus standard of care cohort) is to evaluate the number of patients who did not require mechanical oxygen support since start of therapy until day +14 or discharge (whichever it comes first). The secondary objectives of the study (only randomized phase of the study) are represented by the comparison between the two arms of the study in terms of mortality and toxicity at day+30. Moreover, a description of the immunological related changes between the two arms of the study will be reported. TRIAL DESIGN: The trial is a phase I/II study with a safety run-in cohort (phase 1) followed by an open label phase II randomized controlled trial with an experimental arm compared to a standard of care arm. PARTICIPANTS: The study will be performed at the Institut Català d'Oncologia, a tertiary level oncological referral center in the Catalonia region (Spain). The eligibility criteria are: patients > 18 years affected by oncological diseases; ECOG performance status < 2 (Karnofsky score > 60%); a laboratory confirmed infection with SARS-CoV-2 by means of real -time PCR; radiological signs of low respiratory tract disease; absence of organ dysfunction (a total bilirubin within normal institutional limits, AST/ALT≤2.5 X institutional upper limit of normal, alkaline phosphatase ≤2.5 X institutional upper limit of normal, coagulation within normal institutional limits, creatinine clearance >30 mL/min/1.73 m2 for patients with creatinine levels above institutional normal); absence of HIV infection; no active or latent HBV or HCV infection. The exclusion criteria are: patients with oncological diseases who are not candidates to receive any active oncological treatment; hemodynamic instability at time of study enrollment; impossibility to receive oral medication; medical history of recent or active pulmonary embolism or deep venous thrombosis or patients at high-risk of suffering them (surgical intervention, immobilization); multi organ failure, rapid worsening of respiratory function with requirement of fraction of inspired oxygen (FiO2) > 50% or high-flow nasal cannula before initiation of study treatment; uncontrolled intercurrent illness (ongoing or severe active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements); allergy to one or more of study treatments; pregnant or breastfeeding women; positive pregnancy test in a pre-dose examination. Patients should have the ability to understand, and the willingness to sign, a written informed consent document; the willingness to accept randomization to any assigned treatment arm; and must agree not to enroll in another study of an investigational agent prior to completion of Day +28 of study. An electronic Case Report Form in the Research Electronic Data Capture (REDCap) platform will be used to collect the data of the trial. Removal from the study will apply in case of unacceptable adverse event(s), development of an intercurrent illness, condition or procedural complication, which could interfere with the patient's continued participation and voluntary patient withdrawal from study treatment (all patients are free to withdraw from participation in this study at any time, for any reasons, specified or unspecified, and without prejudice). INTERVENTION AND COMPARATOR: Treatment will be administered on an inpatient basis. We will compare the experimental treatment with baricitinib plus the institutional standard of care compared with the standard of care alone. During the phase I, we will define the dose-limiting toxicity of baricitinib and the dose to be used in the phase 2 part of the study. The starting baricitinib dose will be an oral tablet 4 mg-once daily which can be reduced to 2 mg depending on the observed toxicity. The minimum duration of therapy will be 5 days and it can be extended to 7 days. The standard of care will include the following therapies. Antibiotics will be individualized based on clinical suspicion, including the management of febrile neutropenia. Prophylaxis of thromboembolic disease will be administered to all participants. Remdesivir administration will be considered only in patients with severe pneumonia (SatO2 <94%) with less than 7 days of onset of symptoms and with supplemental oxygen requirements but not using high-flow nasal cannula, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). In the randomized phase, tocilizumab or interferon will not be allowed in the experimental arm. Tocilizumab can be used in patients in the standard of care arm at the discretion of the investigator. If it is prescribed it will be used according to the following criteria: patients who, according to his baseline clinical condition, would be an ICU tributary, interstitial pneumonia with severe respiratory failure, patients who are not on mechanical ventilation or ECMO and who are still progressing with corticoid treatment or if they are not candidates for corticosteroids. Mild ARDS (PAFI <300 mmHg) with radiological or blood gases deterioration that meets at least one of the following criteria: CRP >100mg/L D-Dimer >1,000µg/L LDH >400U/L Ferritin >700ng/ml Interleukin 6 ≥40ng/L. The use of tocilizumab is not recommended if there are AST/ALT values greater than 10 times the upper limit of normal, neutrophils <500 cells/mm3, sepsis due to other pathogens other than SARS-CoV-2, presence of comorbidity that can lead to a poor prognosis, complicated diverticulitis or intestinal perforation, ongoing skin infection. The dose will be that recommended by the Spanish Medicine Agency in patients ≥75Kg: 600mg dose whereas in patients <75kg: 400mg dose. Exceptionally, a second infusion can be assessed 12 hours after the first in those patients who experience a worsening of laboratory parameters after a first favourable response. The use of corticosteroids will be recommended in patients who have had symptoms for more than 7 days and who meet all the following criteria: need for oxygen support, non-invasive or invasive mechanical ventilation, acute respiratory failure or rapid deterioration of gas exchange, appearance or worsening of bilateral alveolar-interstitial infiltrates at the radiological level. In case of indication, it is recommended: dexamethasone 6mg/d p.o. or iv for 10 days or methylprednisolone 32mg/d orally or 30mg iv for 10 days or prednisone 40mg day p.o. for 10 days. MAIN OUTCOMES: Phase 1 part: to describe the toxicity profile of baricitinib in COVID19 oncological patients during the 5-7 day treatment period and until day +14 or discharge (whichever it comes first). Phase 2 part: to describe the number of patients in the experimental arm that will not require mechanical oxygen support compared to the standard of care arm until day +14 or discharge (whichever it comes first). RANDOMISATION: For the phase 2 of the study, the allocation ratio will be 1:1. Randomization process will be carried out electronically through the REDcap platform ( https://www.project-redcap.org/ ) BLINDING (MASKING): This is an open label study. No blinding will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The first part of the study (safety run-in cohort) will consist in the enrollment of 6 to 12 patients. In this population, we will test the toxicity of the experimental treatment. An incidence of severe adverse events grade 3-4 (graded by Common Terminology Criteria for Adverse Events v.5.0) inferior than 33% will be considered sufficient to follow with the next part of the study. The second part of the study we will perform an interim analysis of efficacy at first 64 assessed patients and a definitive one will analyze 128 assessed patients. Interim and definitive tests will be performed considering in both cases an alpha error of 0.05. We consider for the control arm this rate is expected to be 0.60 and for the experimental arm of 0.80. Considering this data, a superiority test to prove a difference of 0.20 with an overall alpha error of 0.10 and a beta error of 0.2 will be performed. Considering a 5% of dropout rate, it is expected that a total of 136 patients, 68 for each study arm, will be required to complete study accrual. TRIAL STATUS: Version 5.0. 14th October 2020 Recruitment started on the 16th of December 2020. Expected end of recruitment is June 2021. TRIAL REGISTRATION: AEMPs: 20-0356 EudraCT: 2020-001789-12, https://www.clinicaltrialsregister.eu/ctr-search/search (Not publically available as Phase I trial) Clinical trials: BARCOVID19, https://www.clinicaltrials.gov/ (In progress) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in 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."

[Coverage of cervical cancer screening in Catalonia, Spain (2008-2011)]. / Cobertura del cribado de cáncer de cuello uterino en Cataluña (2008-2011).

OBJECTIVE: To estimate cervical cytology coverage for the period 2008-2011 by age groups and health regions from data recorded in the medical records of women attending centers within the Catalan national health system. METHODS: The data used to estimate coverage were obtained from the primary care information system. This information was anonymous and included age, center, date, and the results of cytological smears for a total of 2,292,564 women aged 15 years or more. RESULTS: A total of 758,690 smears were performed in 595,868 women. Among women aged 25-65 years, the estimated coverage was 32.4% of the assigned population and was 40.8% in the population attended. Geographical variation was observed, with higher coverage among health regions closer to Barcelona. Abnormal Pap smears increased slightly from 2008 to 2011 (from 3% to 3.5%, respectively, p <0.001). In women with a negative first smear, the mean interval until the second smear was 2.4 years, but only 50% of women with a negative first smear in 2008 attended a second round during the study period. CONCLUSIONS: Cervical screening coverage in the National Health Service of Catalonia includes one in three women. Second round participation was poor. Existing computer systems in primary care centers can ensure monitoring of population-based screening programs for cervical cancer. These systems could be used to plan an organized screening program to ensure wider coverage and better follow-up.

Bacterial pneumonia in HIV-infected patients: use of the pneumonia severity index and impact of current management on incidence, aetiology and outcome.

OBJECTIVES: Despite a recent decrease, bacterial pneumonia (BP) is still the most common admission diagnosis in HIV patients. We analyse BP incidence, characteristics and prevention measures. METHODS: Observational study of all patients hospitalized for BP in a tertiary hospital in Barcelona, Spain, from January 2000 to December 2005. Demographic and HIV-related data, BP risk factors, characteristics of BP and outcomes are analysed. RESULTS: One hundred and eighty-six BP episodes in 161 patients were included; patients were mainly male (73.7%) and intravenous drug users (73.7%). A decrease in BP incidence was seen during the study period, especially in vaccinated patients. The most commonly isolated microorganism was Streptococcus pneumoniae (31.7%), followed by Legionella pneumophila (5.9%). Legionella pneumophila was more likely in patients with undetectable viral load, higher CD4 cell counts or prior vaccination. Highly active antiretroviral therapy, cotrimoxazole prophylaxis and pneumococcal vaccination did not have a significant influence on bacteraemia rate, in-hospital complications or BP mortality. High Pneumonia Severity Index (PSI) predicted mortality accurately [relative risk 15.2, 95% confidence interval 3.2-71.7; P=0.001]. Mortality was 9.1%, but was significantly higher in patients with CD4 counts under 200 cells/microL (P=0.022). CONCLUSIONS: A decline in BP incidence was seen during the study period. Combining CD4 cell count and PSI score could become a good strategy in deciding which patients have to be hospitalized.

Investigation of the ability of the Pneumonia Severity Index to accurately predict clinically relevant outcomes: a European study.

In order to confirm the validity of the Pneumonia Severity Index (PSI) for patients in Europe, data from adults with pneumonia who were enrolled in two prospective multicentre studies, conducted in France (Pneumocom-1, n = 925) and Spain (Pneumocom-2, n = 853), were compared with data from the original North American study (Pneumonia PORT, n = 2287). The primary outcome was 28-day mortality; secondary outcomes were subsequent hospitalisation for outpatients, and intensive care unit admission and length of stay for inpatients. All outcomes within individual risk classes, and mortality rates in low-risk (PSI I-III) and higher-risk patients, were compared across the three cohorts. Overall mortality rates were 4.7% in Pneumonia PORT, 6.3% in Pneumocom-2 and 10.6% in Pneumocom-1 (p <0.01), ranging from 0.4% to 1.6% (p 0.06) for low-risk patients and from 13.0% to 19.1% (p 0.24) for high-risk patients. Despite significant differences in baseline patient characteristics, none of the study outcomes differed within the low-risk classes. The sensitivity and negative predictive value of low-risk classification for mortality exceeded 93% and 98%, respectively. Thus, in two independent European cohorts, the PSI predicted patient outcomes accurately and reliably, particularly for low-risk patients. These findings confirm the validity of the PSI when applied to patients from Europe.

¿Es posible ahorrar en el tratamiento de la neumonía comunitaria atendida en los servicios de urgencias hospitalarios? / Is it possible to achieve savings in the management of community-acquired pneumoniaat the Hospital Emergency Services?

No disponible

[Drug inhalation therapy. Therapy for patients with respiratory disorders]. / Inhalador de fármacos. Terapéutica del paciente con enfermedad respiratoria.

We detected a high number of patients suffering from respiratory ailments which require successive hospital stays due to acute setbacks in their chronic respiratory ailments. The majority of these patients receive outpatient clinic treatment based on use of an inhaler. Given the direct relationship between the correct use of an inhaler and its effectiveness, we designed our project with the goal to discover the adroitness these patients have with an inhaler. The results of our study showed that 67% of the patients tested did not correctly use their inhaler, there by annulling or diminished the effectiveness of its use.