Efficacy and Safety of Trazodone and Gabapentin Fixed-Dose Combination in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose-Finding Study.

INTRODUCTION: Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on quality of life. Gabapentin is widely used for PDN, albeit with frequent dose-limiting effects. Trazodone, an antidepressant with multi-modal action, has shown promising results when given at low doses as an add-on to gabapentin. Upon previous clinical trials and experimental evidence, a fixed-dose combination (FDC) of both compounds, at low doses, was developed for neuropathic pain. METHODS: This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25 mg t.i.d. for 8 weeks, Trazo/Gaba 5/50 mg t.i.d. for 8 weeks, Trazo/Gaba 10/100 mg t.i.d. for 8 weeks, gabapentin (Gaba), or placebo (PLB). The aim of the study was to collect preliminary information on the effect of the 3 different FDCs of Trazo/Gaba on pain intensity based on the 11-point numeric rating score (NRS) after 8 weeks of treatment. The secondary objectives were the evaluation of the percentage of responders, neuropathic pain symptoms, anxiety, sleep, quality of life, safety, and tolerability. The primary efficacy endpoint was evaluated with last observation carried out forward (LOCF), using an analysis of covariance (ANCOVA), including treatment and centers as factors and baseline as covariate and applying linear contrast test, excluding the active treatment. Only if the linear contrast test was significant (p < 0.05), the step-down Dunnett test would be used to determine the minimum effective dose significantly different from PLB. If linearity was not verified, an adjusted ANCOVA model and comparisons with Dunnett test were performed. Before the application of the ANCOVA model, the non-significance of interaction treatment per baseline was verified. RESULTS: A total of 240 patients were included in the modified intention-to-treat (m-ITT) population: 39 in Trazo/Gaba 2.5/25 mg, 38 in Trazo/Gaba 5/50 mg, 37 in Trazo/Gaba 10/100 mg, 83 in PLB, and 43 in Gaba. After 8 weeks of treatment, changes of the average daily pain score based on the 11-point NRS from baseline were - 2.52 ± 2.31 in Trazo/Gaba 2.5/25 mg group, - 2.24 ± 1.96 in Trazo/Gaba 5/50 mg group, - 2.46 ± 2.12 in Trazo/Gaba 10/100 mg group, - 1.92 ± 2.21 in Gaba group, and - 2.02 ± 1.95 in the PLB group. The linear contrast test did not result in significant differences (p > 0.05) among treatment groups. Consequently, the minimum effective dose against PLB was not determined. The multiple comparison with Dunnett adjustment did not show any statistically significant differences vs. PLB after 8 weeks of treatment: Trazo/Gaba 2.5/25 mg (95% confidence interval (CI) - 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50 mg (95% CI - 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100 mg (95% CI - 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25 mg showed a statistically significant difference to PLB after 6 weeks of treatment (95% CI - 1.6648, - 0.2126; p = 0.0116). Positive results were also found for responder patients, other items related to the pain, anxiety, depression, sleep, and quality of life, consistently in favor to the lowest Trazo/Gaba FDC. Two serious adverse events (SAEs) occurred but were judged unrelated to the study treatment. Treatment-emergent adverse events (TEAEs) were mainly mild-to-moderate in intensity and involved primarily nervous system, gastrointestinal disorders, and investigations. CONCLUSIONS: The primary end point of the study was the change from baseline of the average daily pain score based on the 11-point NRS after 8 weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25 mg t.i.d. showed statistically significant improvement of pain and other scores after 6 weeks and reported consistent better results in comparison to PLB on primary and secondary endpoints for the overall study duration. According to these results, the lowest dose of Trazo/Gaba FDC may be the best candidate for further clinical development to confirm the potential benefits of the FDC drug for this condition. CLINICAL TRIAL REGISTRATION: NCT03749642.

Clinical evaluation of switching from immediate-release to prolonged-release lithium in bipolar patients, poorly tolerant to lithium immediate-release treatment: A randomized clinical trial.

AIM: The effect of switching from lithium immediate release (Li-IR) to lithium prolonged release (Li-PR) on lithium-induced tremor after 1 and 12 weeks of treatment was evaluated in a randomized, multicenter, open trial, in bipolar patients from the participating sites with a tremor severity ≥2 (Udvalg for Kliniske Undersøgelser [UKU] rating scale) despite optimal lithium titration. METHODS: The primary endpoint was the evaluation of tremor by means of the UKU scale after 1 week of treatment. Secondary endpoints included manic Young Mania Rating Scale (YMRS) and depressive symptoms (Montgomery-Asberg Depression Rating Scale), a global assessment of the patient's status (Clinical Global Impression), polyuria/polydipsia (UKU item 3.8) and patient-reported outcomes. RESULTS: Owing to difficulties in including suitable patients the enrollment phase was closed when 73 patients were randomized. Notwithstanding the lower number of patients, in the modified intention-to-treat population (n = 70) the primary endpoint was statistically significant: tremor improved after 1 week in 62.9% in Li-PR group against 20.0% of patients in Li-IR group (p = .0006; two-tailed Fisher's exact test). The difference remained statistically significant after 4 (p = .0031) and 12 weeks (p = .0128). The same analysis performed in the PP population confirmed these results. Among the secondary endpoints, only the factor convenience of the treatment satisfaction questionnaire showed a statistically significant difference between groups. There were no apparent differences in the safety profile of the two formulations. CONCLUSIONS: This study is the first comparative documentation of a potential benefit of the prolonged-release formulation in reducing the symptom tremor, a well-known adverse effect of lithium therapy. Indeed, the study results should be interpreted taking into account the sample size lower than planned.

Safety and tolerability of a novel oral nutritional supplement in healthy volunteers.

BACKGROUND AND OBJECTIVE: Foods for Special Medical Purposes (FSMPs) are formulated to support the nutritional needs of subjects with impaired capacity to ingest, digest or absorb ordinary food or nutrients. Polglumyt® is a proprietary highly purified, high quality glycogen obtained from mussels. Here we report the results of a single-center, single dose, open label, single arm study carried out to investigate acceptance (i.e. gastrointestinal tolerance and palatability), metabolic profile and safety of a low osmolarity, high-density energy Polglumyt®-based drink (the investigational product, IP) as a novel FSMP. METHODS: Twelve healthy subjects received a single oral administration of the IP under fasting conditions. The study endpoints were: changes in gastrointestinal system tolerability at 3 h, 6 h and 24 h after IP intake; IP palatability evaluation; metabolic evaluation through the kinetic profile of circulating glucose, insulin and C-peptide from 0 h to 6 h after IP intake and changes from baseline in circulating triglycerides at 3 h and 6 h after IP intake. RESULTS: The IP showed a good gastrointestinal tolerability and an acceptable palatability. The IP did not affect the physiological glycemic profile and the triglycerides levels 6 h after the intake. The IP was well tolerated by study subjects, with no or minor adverse events. CONCLUSIONS: The study results encourage additional clinical investigations on the IP as a novel FSMP in patients with impaired digestion or gastrointestinal absorption, unable to assume an ordinary diet, e.g. patients undergoing invasive gastrointestinal surgery, elderly or oncological patients, even with certain metabolic disorders.

Electronic cigarette use as an aid to quit smoking in the representative Italian population PASSI survey.

This study explored electronic cigarette (e-cigarette) use as an aid to quit smoking and compared abstinence rates for different quitting methods in a representative sample of the Italian population. In the 2014-2015 PASSI survey, the ongoing Italian behavioural risk factor surveillance system, 6112 adults who smoked and made at least one quit attempt in the previous 12months, were categorized into three groups according to the method used in their most recent quit attempt: e-cigarette only, no aid, other quitting methods (medications; programmes delivered in smoking cessation services; other unspecified methods). The primary outcome was self-reported abstinence for a period ≥6months, adjusted for potential confounders. Eleven percent used e-cigarettes only, 86% no aid, 3% other quitting methods. Smoking abstinence was reported among 9% of those using no aid; 8% of e-cigarette users; 15% of those using other methods. No significant differences in abstinence were observed for e-cigarette users compared with those reporting no aid (adjusted Prevalence Ratio [aPR]=0.81; 95%Confidence Interval (CI)=0.58-1.14). Changing the reference group to e-cigarette users, those using other quitting methods were significantly more likely to report abstinence than e-cigarette users (aPR=1.76; 95%CI=1.07-2.88). One out of ten smokers who attempted to quit in 2014-2015 in Italy used e-cigarettes. E-cigarettes users were as likely to report abstinence as those using no aid, but were less likely to report abstinence than users of established quitting methods. Further studies are needed to understand the relationship between e-cigarette types used to quit and abstinence rates.

Quit attempts and smoking cessation in Italian adults (25-64 years): factors associated with attempts and successes.

Background: Over the past 50 years there was a substantial decrease in the prevalence of smoking in Italy. The objective of this work is to describe attempts to quit and cessation success in Italian smokers. Methods: A surveillance on health-related behaviors (PASSI) was conducted in 2007-13 on a sample of 203 610 Italian adults 25-64 years of age. An analysis of smokers' characteristics and behaviors was performed, focusing on attempts to quit and quit success. Data from national surveys (ISTAT) from 1983 to 2013 (Italian adults, 25-64 years of age, 1983: 46 634; 1987: 40 915; 1990: 36 622; 2000: 77 531; 2005: 71 032; 2013: 64 205) were used to explore if a cessation trend in Italy exists. Results: Smokers who quit in the previous year and were still abstinent when interviewed increased from 1990 to 2013. In the years 2011-13, 38% of people who had smoked in the last 12 months reported at least a quit attempt during the same period and 7% were still abstinent when interviewed. An association of successful recent quit attempts with higher educational level, absence of economic difficulties and younger age was found. In the years 2007-13, the great majority tried to stop unaided. Having received assistance from a cessation program did not increase the probability of enduring abstinence. Conclusions: In Italy interventions to drive more smokers to quit should be focused in particular on disadvantaged groups. Initiatives have to be studied not only to incentive more smokers to try to quit, but also to maintain abstinence over time.

Spontaneous Reversion of Mild Cognitive Impairment to Normal Cognition: A Systematic Review of Literature and Meta-Analysis.

OBJECTIVES: The issue of subjects with mild cognitive impairment (MCI) reverting to normal cognition (NC) has to date been taken in limited consideration, and no conclusive data are available on the rate of reversion. We aimed at systematically reviewing available longitudinal studies on MCI and meta-analyzing data with the purpose of estimating the proportion of subjects reverting to NC. DESIGN: We performed a systematic bibliographic search on PubMed, the Cochrane Library, and the ISI Web of Science databases. We included in the review all longitudinal studies on MCI published from 1999 up to November 2015. Only studies with a longitudinal design, a follow-up ≥2 years, enrolling subjects with MCI, and reporting the number or the percentage of subjects reverting to NC were included. Data extraction was performed independently by 2 authors. The methodological quality of studies was also assessed by 2 independent authors using the QUIPS tool. RESULTS: Twenty-five studies were included. The quality of evidence was found to be moderate. We observed an overall 18% (95% CI 14-22) reversion rate from MCI to NC. Results from the metaregression showed a significant association between effect size and study setting. In particular, estimates significantly varied according to study setting, with an 8% (95% CI 4-11) reversion rate in clinical-based studies and a 25% (95% CI 19-30) rate in population-based studies. The frequency of reversion from MCI to NC further increased to 26% when considering only studies of better quality. Only a few studies were designed to specifically investigate the reversion from MCI to NC, thus relevant information on this topic was frequently missing. CONCLUSION: Our data confirm that reversion to normality is a common outcome in subjects with MCI, thus leading to recommend a more balanced view when approaching the construct of MCI both in a clinical and in a research setting.

[Behavioural risk factors in L'Aquila (Central Italy) 3-5 years after the 2009 earthquake]. / Fattori di rischio comportamentali all'Aquila 3-5 anni dopo il terremoto del 2009.

OBJECTIVES: to evaluate the long-term impact on the health of the general population of L'Aquila earthquake that occurred on April 6th, 2009. DESIGN, SETTING AND PARTICIPANTS: three consecutive surveys were performed on samples of the population of 18-69 years resident in L'Aquila and in the other towns affected by the earthquake. Data on health-related quality of life, depressive disorders, behaviour risk factor, and adoption of preventive measures were collected through telephone interviews in 2007-2008, in 2010, and in 2011-2014. RESULTS: the prevalence of individuals who declared to have economic difficulties increased after 3-5 years from the earthquake (8% in 2010 vs. 14% in 2011-2014). Nevertheless, health-related quality of life improved (decrease of unhealthy days: 7 in 2010 vs. 5 in 2011-2014), while the prevalence of depressive symptoms decreased so that it reached the national average rates (16% in 2010 vs. 7% in 2011-2014). Lack of physical activity, a serious consequence of the first period after the earthquake, became less habitual (39% in 2010 vs. 27% in 2011-2014), probably due to an improvement in the urban redevelopment. The prevalence of smoking and harmful use of alcohol is high (34% and 21%), mostly among young adults. CONCLUSIONS: 3-5 years after the earthquake of L'Aquila, compared to 2010 the quality of life related to health is improved (except in people with at least one chronic disease), and the frequency of depressive symptoms decreased, a sign of an extended recovery from conditions caused by the earthquake, despite of an increasing economic difficulties. On the other hand, we must emphasize critical elements, such as the high prevalence of smoking and consumption of alcoholic beverages other than as part of the meals, especially among young people, and very frequent physical inactivity, particularly among the elderly, although lower than in 2010. Finally, adherence to preventive measures and screening for cancer, and adoption of road safety devices could be improved.

Cancer screening uptake: association with individual characteristics, geographic distribution, and time trends in Italy.

BACKGROUND: In Italy, organized screening programmes invite the vast majority of the population for cervical and breast cancer, and about one half of the population for colorectal cancer. Programme activity and quality are closely monitored. Nevertheless, there is a vast spontaneous activity, both public and private, for which information on service and coverage is missing. To estimate actual population coverage for the three types of screening the extent of spontaneous screening needs to be known. METHODS: PASSI is a national telephone-interview surveillance system that continuously collects information about behavioural health risk factors and the diffusion of preventive health interventions. From 2010 to 2013, more than 151,000 18- to 69-year-olds were interviewed. During 2013, 136 out of 147 Italian local health authorities participated in the survey. Information about screening includes: test uptake (Pap smear, HPV, mammography, faecal occult blood test, colonoscopy), date of the last test, provider of the last test (whether paid or for free, proxy of the organized screening programme), reason for not participating in screening, and screening promotion/recommendation received. Individual information on socio-economic characteristics is available. RESULTS: Seventy-seven percent of the 25-64 year-old women interviewed said they had undergone a Pap smear or HPV test in the three years before the interview, 40%within the screening programme, 37% spontaneously and paying. Seventy percent of the 50-69 year-old women interviewed reported having had a mammography in the two years before the interview, 51% within the screening programme, 19% spontaneously and paying. Thirty-eight percent of the 50-69 year olds interviewed reported having undergone colorectal screening in the two years before the interview, 31% within the screening programme, 7% spontaneously and paying. All three screening programmes showed a decreasing North-South trend in coverage. From 2010 to 2013, coverage increased for all types of screening; the trend was stronger in the South; the increase was mostly due to the tests performed within the organized programmes. People with low education, economic problems, and immigrants from high migration pressure countries had lower coverage levels. In regions with well-implemented organized screening programmes, test coverage was higher and differences for socio-economic factors were smaller than in regions with incomplete programme activation.

Preliminary investigation on tick fauna in the neighborhood of Tarquinia, Lazio, Italy.

INTRODUCTION: This study represents a preliminary inquiry on tick fauna composition carried out in Maremma, Central Italy, where very few data are available. MATERIALS AND METHODS: The study area was selected in the limestone hills surrounding Tarquinia town, on the base of suitable elements directly affecting the tick occurrence and the possible circulation of tick-borne pathogens, such as wild cattle rearing, kind of vegetation and human activities. Since a proper understanding of tick ecology is critical in predicting the risk of tick-borne pathogen transmission in a given area, a series of surveys was planned in such area in 2011. RESULTS: One hundred fifty-four ticks belonging to 4 genera and 6 species, namely Ixodes ricinus (n. = 109; 70%), Rhipicephalus bursa (n. = 18; 12%), Rhipicephalus turanicus (n. = 14; 9%), Rhipicephalus sanguineus (n. = 6; 4%), Hyalomma marginatum (n. = 4; 3%) and Dermacentor marginatus (n. = 3; 2%) were identified and reported for the area. DISCUSSION: The results of this acarological research represent a significant contribution to the knowledge of the tick fauna of rural areas in Northern Lazio Region, as first step toward a future molecular investigation on pathogen circulation.

Compliance with the smoking ban in Italy 8 years after its application.

OBJECTIVES: The aim of this paper is to report compliance with the smoking ban and the spread of smoke-free homes after 3-8 years since the Italian smoking ban implementation, according to the ongoing Italian surveillance system for behavioural risk factors (PASSI). METHODS: PASSI is based on representative annual samples of the Italian population aged 18-69 years. We considered questions on smoking habits, self-reported compliance with the ban, and on smoke-free homes of 176,236 interviews conducted in 2008-2012. RESULTS: Ninety percent of respondents in 2012 reported that the smoking ban was enforced in hospitality premises (HPs), with a significant 3% increase from 2008. Similarly, 91.3% in 2012 reported a high compliance in workplaces other than HPs, with a significant 5% increase. Perception of compliance did not change among smokers and non-smokers. Seventy-eight percent of respondents in 2012 reported smoke-free homes, with a significant increase from 2008 to 2012. CONCLUSIONS: The high compliance with the ban that is still increasing even after 8 years since its implementation may partially have caused the concurrent increase in smoke-free homes.

Detection of microbial agents in ticks collected from migratory birds in central Italy.

Tick species characterization and molecular studies were performed within ornithological surveys conducted during 2010 and 2011 in the Lazio Region of central Italy. A total of 137 ticks were collected from 41 migratory birds belonging to 17 species (four partial migrants and 13 long-distance migrants). Most ticks were nymphs, with a predominance of Hyalomma marginatum marginatum and H. m. rufipes, and a small portion of Ixodes and Amblyomma species. All tick species analyzed were infected, and the molecular pathogen recognition revealed the presence of Rickettsia aeschlimannii, Rickettsia africae, Erlichia spp., Coxiella burnetii, Borrelia burgdorferi sensu lato group, and Babesia microti, whereas no genomic DNA of Bartonella spp. or Francisella tularensis was detected. The results of the survey show that H. marginatum ticks appear to be a vector of microbial agents that may affect human and animal health and that migratory birds may be an important carrier of these ticks. Additional studies are needed to better investigate the role of migratory birds in the epidemiology of these pathogens.