Exploratory data on the clinical efficacy of monoclonal antibodies against SARS-CoV-2 Omicron variant of concern.

Background: Recent in-vitro data have shown that the activity of monoclonal antibodies (mAbs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) varies according to the variant of concern (VOC). No studies have compared the clinical efficacy of different mAbs against Omicron VOC. Methods: The MANTICO trial is a non-inferiority randomised controlled trial comparing the clinical efficacy of early treatments with bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab in outpatients aged 50 or older with mild-to-moderate SARS-CoV-2 infection. As the patient enrolment was interrupted for possible futility after the onset of the Omicron wave, the analysis was performed according to the SARS-CoV-2 VOC. The primary outcome was coronavirus disease 2019 (COVID-19) progression (hospitalisation, need of supplemental oxygen therapy, or death through day 14). Secondary outcomes included the time to symptom resolution, assessed using the product-limit method. Kaplan-Meier estimator and Cox proportional hazard model were used to assess the association with predictors. Log rank test was used to compare survival functions. Results: Overall, 319 patients were included. Among 141 patients infected with Delta, no COVID-19 progression was recorded, and the time to symptom resolution did not differ significantly between treatment groups (Log-rank Chi-square 0.22, p 0.90). Among 170 patients infected with Omicron (80.6% BA.1 and 19.4% BA.1.1), two COVID-19 progressions were recorded, both in the bamlanivimab/etesevimab group, and the median time to symptom resolution was 5 days shorter in the sotrovimab group compared with the bamlanivimab/etesevimab and casirivimab/imdevimab groups (HR 0.53 and HR 0.45, 95% CI 0.36-0.77 and 95% CI 0.30-0.67, p<0.01). Conclusions: Our data suggest that, among adult outpatients with mild-to-moderate SARS-CoV-2 infection due to Omicron BA.1 and BA.1.1, early treatment with sotrovimab reduces the time to recovery compared with casirivimab/imdevimab and bamlanivimab/etesevimab. In the same population, early treatment with casirivimab/imdevimab may maintain a role in preventing COVID-19 progression. The generalisability of trial results is substantially limited by the early discontinuation of the trial and firm conclusions cannot be drawn. Funding: This trial was funded by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA). The VOC identification was funded by the ORCHESTRA (Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic) project, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement number 101016167. Clinical trial number: NCT05205759.

[The impact of the use of treatments not included in the reimbursement classes in the care of rare patients: a real world study.] / L'impatto dell'uso dei trattamenti non compresi nelle classi di rimborsabilità nella presa in carico dei malati rari: uno studio in campo reale.

INTRODUCTION: Rare disease (RD) patients present complex therapeutic needs. When there are therapeutic options available, orphan drugs (OD) represent only a limited proportion of prescribed treatments. This study aims at investigating the real-world use of treatments considered not replaceable and essential for the care of RD patients, besides their reimbursement status, using data from a RD population-based registry. METHODS: The study is based on data derived from the Veneto region RD registry. For the period 2019-2020, we have analyzed the prescriptions of treatments defined as essential and not replaceable, besides their reimbursement status, included in therapeutic plans issued by RD expert Centres for patients resident in the Veneto region (north-east of Italy, 4.9 million inh.). The correspondent pharmaceutical costs have been estimated as well. RESULTS: In the study period there have been 22.186 prescriptions, included in 9,197 therapeutic plans issued for RD patients resident in the monitored area. The plans present a high level of complexity in terms of number and type of prescribed treatments, with 11% of the plans containing 5 or more prescriptions. 3,041 medicinal products have been prescribed in the study period, of whom 41% are drugs. Although these prescriptions are distributed among all the groups of RD patients, only a limited proportion of products (n=10) is responsible of the 50% of all the costs attributable to these treatments. Overall, the annual cost attributable to essential treatments not directly reimbursed by the national health system is quantifiable in 1 million euros per million inhabitants. CONCLUSIONS: This real-world study offers a snapshot of the complexity of treatments defined as essential, besides their reimbursement status, in therapeutic plans issued by RD expert Centres for a consistent group of RD patients monitored by a population-based registry. It highlights the complexity of the therapeutic approaches put in place for the care of RD patients, including drugs and a variety of other treatments. Population-based registries collecting data on prescribed treatments can contribute to understand the therapeutic needs of RD patients, treatments' accessibility and the impact of prescriptions on the global pharmaceutical costs.

Clinical efficacy of different monoclonal antibody regimens among non-hospitalised patients with mild to moderate COVID-19 at high risk for disease progression: a prospective cohort study.

This study aimed to compare the clinical progression of COVID-19 in high-risk outpatients treated with the monoclonal antibodies (mAb) bamlanivimab, bamlanivimab-etesevimab and casirivimab-imdevimab. This is an observational, multi-centre, prospective study conducted from 18 March to 15 July 2021 in eight Italian tertiary-care hospitals including mild-to-moderate COVID-19 outpatients receiving bamlanivimab (700 mg), bamlanivimab-etesevimab (700-1400 mg) or casirivimab-imdevimab (1200-1200 mg). All patients were at high risk of COVID-19 progression according to Italian Medicines Agency definitions. In a patient subgroup, SARS-CoV-2 variant and anti-SARS-CoV-2 serology were analysed at baseline. Factors associated with 28-day all-cause hospitalisation were identified using multivariable multilevel logistic regression (MMLR) and summarised with adjusted odds ratio (aOR) and 95% confidence interval (CI). A total of 635 outpatients received mAb: 161 (25.4%) bamlanivimab, 396 (62.4%) bamlanivimab-etesevimab and 78 (12.2%) casirivimab-imdevimab. Ninety-five (15%) patients received full or partial SARS-CoV-2 vaccination. The B.1.1.7 (Alpha) variant was detected in 99% of patients. Baseline serology showed no significant differences among the three mAb regimen groups. Twenty-eight-day all-cause hospitalisation was 11.3%, with a significantly higher proportion (p 0.001) in the bamlanivimab group (18.6%), compared to the bamlanivimab-etesevimab (10.1%) and casirivimab-imdevimab (2.6%) groups. On MMLR, aORs for 28-day all-cause hospitalisation were significantly lower in patients receiving bamlanivimab-etesevimab (aOR 0.51, 95% CI 0.30-0.88 p 0.015) and casirivimab-imdevimab (aOR 0.14, 95% CI 0.03-0.61, p 0.009) compared to those receiving bamlanivimab. No patients with a history of vaccination were hospitalised. The study suggests differences in clinical outcomes among the first available mAb regimens for treating high-risk COVID-19 outpatients. Randomised trials are needed to compare efficacy of mAb combination regimens in high-risk populations and according to circulating variants.

SARS-CoV-2 and COVID-19 in diabetes mellitus. Population-based study on ascertained infections, hospital admissions and mortality in an Italian region with ∼5 million inhabitants and ∼250,000 diabetic people.

BACKGROUND AND AIMS: Diabetes conveys an increased risk of infectious diseases and related mortality. We investigated risk of ascertained SARS-CoV-2 infection in diabetes subjects from the Veneto Region, Northeastern Italy, as well as the risk of being admitted to hospital or intensive care unit (ICU), or mortality for COVID-19. METHODS AND RESULTS: Diabetic subjects were identified by linkage of multiple health archives. The rest of the population served as reference. Information on ascertained infection by SARS-CoV-2, admission to hospital, admission to ICU and mortality in the period from February 21 to July 31, 2020 were retrieved from the regional registry of COVID-19. Subjects with ascertained diabetes were 269,830 (55.2% men; median age 72 years). Reference subjects were 4,681,239 (men 48.6%, median age 46 years). Ratios of age- and gender-standardized rates (RR) [95% CI] for ascertained infection, admission to hospital, admission to ICU and disease-related death in diabetic subjects were 1.31 [1.19-1.45], 2.11 [1.83-2.44], 2.45 [1.96-3.07], 1.87 [1.68-2.09], all p < 0.001. The highest RR of ascertained infection was observed in diabetic men aged 20-39 years: 1.90 [1.04-3.21]. The highest RR of ICU admission and death were observed in diabetic men aged 40-59 years: 3.47 [2.00-5.70] and 5.54 [2.23-12.1], respectively. CONCLUSIONS: These data, observed in a large population of ∼5 million people of whom ∼250,000 with diabetes, show that diabetes not only conveys a poorer outcome in COVID-19 but also confers an increased risk of ascertained infection from SARS-CoV-2. Men of young or mature age have the highest relative risks.

Non-Small-Cell Lung Cancer: Real-World Cost Consequence Analysis.

PURPOSE: The present work aimed at conducting a real-world data analysis on the management costs and survival analysis comparing data from non-small-cell lung cancer (NSCLC) cases diagnosed in the Veneto region before (2015) and after (2017) the implementation of a regional diagnostic and therapeutic pathway including all new diagnostic and therapeutic strategies. METHOD: This study considered 254 incidental cases of NSCLC in 2015 and 228 in 2017 within the territory of the Padua province (Italy), as recorded by the Veneto Cancer Registry. Tobit regression analysis was performed to verify if total and each item costs (2 years after NSCLC diagnosis) are associated with index year, adjusting by year of diagnosis, sex, age, and stage at diagnosis. Logistic regression models were run to study overall mortality at 2 years, adjusting by the same covariates. RESULTS: The 2017 cohort had a lower mortality odd (odds ratio, 0.93; P = .02) and a significant increase in the average overall costs (P = .009) than the 2015 cohort. The Tobit regression analysis by cost item showed a very significant increase in the average cost of drugs (coefficient = 5,953, P = .008) for the 2017 cohort, as well as a decrease in the average cost of hospice care (coefficient = -1,822.6, P = .022). CONCLUSION: Our study showed a survival improvement for patients with NSCLC as well as an economic burden growth. Physicians should therefore be encouraged to follow new clinical care pathways, while the steadily rising related costs underscore the need for policymakers and health professionals to pursue.

Heart failure in the Veneto region of Italy: analysis of therapeutic pathways and the utilization of healthcare resources.

Objectives: Aim of the study was to describe the use and pharmacoutilization profiles of recommended drugs for HF patients, hospital re-admission rates, mortality rates and determine healthcare resource consumption and related costs for HF patients in an Italian region. Methods: We retrospectively analyzed data from the administrative database and included adult patients who were discharged alive with a primary or secondary HF diagnosis between 1 January 2010 and 31 December 2015. We assessed data on HF-related drug prescriptions at discharge and during a 12-month follow-up period, as well as treatment adherence and treatment modification. All-cause mortality, hospital HF re-admission, and mean direct cost per patient were also analyzed during the follow-up period. Results: A total of 69,164 patients were included. One in ten patients had discontinued all treatment initially prescribed by the end of follow-up. In total, 25.9% of patients were re-hospitalized with an HF diagnosis during the follow-up period; the mortality rate at 12 months was 24.3%. The mean annual cost per patient was €6,303.7, with nearly three-fourths attributable to hospitalizations. Conclusions: In our study, we observed an under-prescription of recommended drugs for the treatment of HF. Moreover, one out of four HF patients were re-hospitalized for HF-related causes and the healthcare costs related to hospitalization accounted for the great majority of the total healthcare resource costs.

Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: A prospective population study.

BACKGROUND & AIMS: Direct-acting antiviral agents (DAAs) are safe and effective in patients with hepatitis C. Conflicting data were reported on the risk of hepatocellular carcinoma (HCC) during/after therapy with DAAs. The aim of this study was to evaluate the incidence of newly diagnosed HCC and associated risk factors in patients with advanced hepatitis C treated with DAAs. METHODS: The study is based on the NAVIGATORE platform, a prospectively recording database of all patients with hepatitis C receiving DAAs in the Veneto region of Italy. The inclusion criteria were: fibrosis stage ≥F3. The exclusion criteria were: Child-Turcotte-Pugh (CTP)-C, liver transplantation before DAAs, history or presence of HCC, follow-up <4 weeks after starting DAAs. A total of 3,917 out of 4,234 consecutive patients were included, with a mean follow-up of 536.2 ±â€¯197.6 days. RESULTS: Overall, HCC was diagnosed in 55 patients. During the first year, HCC incidence was 0.46% (95% CI 0.12-1.17) in F3, 1.49% (1.03-2.08) in CTP-A and 3.61% (1.86-6.31) in CTP-B cirrhotics; in the second year, HCC incidences were 0%, 0.2%, and 0.69%, respectively. By multivariate analysis, HCC was significantly associated with an aspartate aminotransferase to platelet ratio ≥2.5 (hazard ratio [HR] 2.03; 95% CI 1.14-3.61; p = 0.016) and hepatitis B virus infection (HR 3.99; 1.24-12.91; p = 0.021). Failure to achieve a sustained virological response was strongly associated with development of HCC (HR 9.09; 5.2-16.1; p = 0.0001). A total of 29% of patients with HCC had an aggressive tumor, often seen in the early phase of treatment. CONCLUSIONS: These data, obtained in a large, prospective, population-based study, indicate that in patients with advanced hepatitis C receiving DAAs, the risk of "de novo" hepatocarcinoma during the first year is not higher, and might be lower, than that of untreated patients. The risk further declines thereafter. Early hepatocarcinoma appearance may reflect pre-existing, microscopic, undetectable tumors. LAY SUMMARY: Hepatocellular carcinoma is one of the complications of hepatitis C related cirrhosis. Treating patients with advanced hepatitis C with the new interferon-free direct-acting antiviral agents has been associated with improvement in liver function and survival, while more conflicting data have been reported regarding the risk of hepatocellular carcinoma. We report the results of a prospective population study on the incidence of newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with direct-acting antiviral agents, clearly indicating that the residual hepatocellular carcinoma risk is reduced and declines progressively with time after a sustained virological response. Development of a liver tumor during/after therapy was associated with known risk factors and with virological failure.

Patient and General Practitioner characteristics influencing the management of non-insulin-treated diabetes mellitus: A cross-sectional study in Italy.

AIMS: We assessed the influence of patient and General Practitioner (GP) characteristics on the adherence to process of care indicators for non-insulin-treated type 2 diabetes management in the Veneto Region (northeastern Italy). METHODS: Among non-insulin-treated diabetic patients aged 18-84years identified by multiple information sources, we assessed the measurement of glycated hemoglobin, microalbumin, and lipids through the year 2013. Patients' variables included gender, age, citizenship, and the attendance to Diabetes Clinics, while GP characteristics were gender, age and an attitude score derived from a questionnaire. The influence of patient and GP variables were investigated through multilevel regression with the execution of two HbA1c tests in 2013 as the outcome. RESULTS: Out of 139,935 study subjects, more than 70% had at least one HbA1c test in 2013; this percentage decreased to about 40% for two HbA1c examinations. 67% of patients had an assessment of lipid profile, while 45% underwent a microalbumin test. These percentages were lower for immigrant patients and increased with age until the 65-74years age class. Patients attending Diabetes Clinics were usually better monitored than those who did not. In this latter group, female gender (risk ratio 1.08, 1.02-1.14), younger age (risk ratio 1.15, 1.06-1.25) and high attitude score of GPs (risk ratio 1.20, 1.13-1.27) were associated with a better management. CONCLUSIONS: Both patient and GP variables influence the adherence to process of care indicators. The implementation of effective strategies of disease management at the primary care level may improve the control of glycemic and cardiovascular risk factors.

Multi-tier drugs assessment in a decentralised health care system. The Italian case-study.

OBJECTIVE: To investigate the organisation and decision-making processes of regional and local therapeutic committees in Italy, as a case-study of decentralised health care systems. METHODS: A structured questionnaire was designed, validated, and self-administered to respondents. Committee members, prioritisation, assessment process and criteria, and transparency of committees were investigated. RESULTS: The respondents represent 100% of the 17 regional committees out of 21 regions (in 4 regions there is not any regional formulary), 88% of the 16 hospital networks and 42% of the 183 public hospitals. The assessment process appears fragmented and may take a long time: drugs inclusion into hospital formularies requires two steps in most regions (regional and local assessment). Most of the therapeutic committees are closed to industry and patients associations involvement. Prioritisation in the assessment is mostly driven by disease severity, clinical evidence, and the absence of therapeutic alternatives. Only 13 out of the 17 regional committees have a public application form for drugs inclusion into regional formulary. Regional and local committees (i) often re-assess the clinical evidence already evaluated at central level and (ii) mostly rely on comparative drug unit prices per DDD and drug budget impact. The level of transparency is quite low. CONCLUSIONS: The Italian case-study provides useful insights into an appropriate management of multi-tier drugs assessment, which is particularly complex in decentralised health care systems, but exists also in centralised systems where drugs are assessed by local therapeutic committees. A clear definition of regulatory competences at different levels, a higher collaboration between central, regional and local actors, and increased transparency are necessary to pursue consistency between central policies on price and reimbursement and budget accountability at the regional and local levels.

Risk factors of peptic ulcer in 4943 inpatients.

BACKGROUND: Over the past few years, major changes have taken place in the treatment of gastroduodenal peptic ulcer. AIM: To evaluate risk factors associated with the incidence of peptic ulcer in inpatients. METHODS: From 2001 to 2004, the number of prescriptions of H2-antagonists and proton pump inhibitors (PPIs) in each department of Verona University Hospital was monitored. Over the same period we prospectively recorded the number of upper endoscopies per department for inpatients with a diagnosis of peptic ulcer. RESULTS: We analyzed 4943 inpatients. A significantly decreasing trend in H(2)-antagonist prescriptions (r=-0,88; P<0.001) and an increasing trend in PPI prescriptions (r=0.97; P<0.001) were observed. The endoscopic incidence of duodenal ulcers decreased linearly from 2001 to 2004 as follows: 6.5% (94/1439) in 2001, 5.6% (82/1473) in 2002, 4.5% (63/1411) in 2003, and 3.1% (22/702) (P<0.001) in 2004. Gastric ulcer incidence, sex, age, indication for endoscopy, use of nonsteroidal anti-inflammatory drugs (NSAIDs), presence of Helicobacter pylori (32%), and smoking and drinking habits showed no significant changes over the study period. Considering time-dependent variables, multivariate regression analysis identified only PPI use and NSAID use as factors predictive of duodenal ulcer but not of gastric ulcer. CONCLUSIONS: In inpatients, PPIs are associated with a reduced risk of duodenal ulcer, whereas NSAIDs are associated with an increased risk. Gastric ulcer was not associated with any increased or degreased risk with the 2 above-mentioned variables.

Biosimilars, generic versions of the first generation of therapeutic proteins: do they exist?

This contribution describes the present regulatory status in the EU of biosimilars, the generic versions of the first generation of therapeutic proteins. It points out why and where recombinant protein molecules and low-molecular-weight drugs differ in their behaviour and why biosimilars should be handled differently than generic low-molecular-weight drugs. This information is important for practitioners (pharmacists and physicians) while selecting the best supplier of a therapeutic protein.

Computer-based drug management in a bone marrow transplant unit: a suitable tool for multiple prescriptions even in critical conditions.

Drug prescription or administration errors are the most common causes of adverse events for hospital patients. Computer-based systems can be effective in reducing these errors. The aim of this study was to assess whether computer-based systems are easily exploitable even in critical conditions. The oral and handwritten system for drug management was completely replaced by a computer-based system in our bone marrow transplant unit, chosen because: (i) the intensive treatments could test the efficiency of the system; (ii) the very frequent occurrence of complications and emergencies could test the flexibility of the system; and (iii) the pre-existing system could be used as comparison. From May to November 2002, 41 patients were repeatedly admitted to undergo high-dose chemotherapy, autologous/allogeneic stem cell transplantation or because of severe complications. In 27 consecutive admissions, 2264 drug prescriptions (average, 29 drugs/patient admission) and 36 786 drug administrations (39.8/patient/d) were carried out. Despite the large number of procedures, the computerized system effectively replaced the oral and handwritten transmission of information among medical staff, pharmacists and nurses, and lowered the error risks. In addition, it contributed to medical updating through warnings on potential problems in case of multiple drug prescriptions, and gave the pharmacy a valuable tool to monitor drug use.