Safety and tolerability of atogepant for the preventive treatment of migraine: a post hoc analysis of pooled data from four clinical trials.

BACKGROUND: Conventional, non-specific preventive migraine treatments often demonstrate low rates of treatment persistence due to poor efficacy or tolerability. Effective, well-tolerated preventive treatments are needed to reduce migraine symptoms, improve function, and enhance quality of life. Atogepant is a migraine-specific oral calcitonin gene-related peptide receptor antagonist that is indicated for the preventive treatment of migraine in adults. This analysis evaluated the safety and tolerability profile of atogepant for the preventive treatment of migraine, including adverse events (AEs) of interest, such as constipation, nausea, hepatic safety, weight changes, and cardiac disorders. METHODS: This post hoc analysis was performed using data pooled from 2 (12-week) randomized, double-blind, placebo-controlled trials (RCTs) and 2 (40- and 52-week) open-label long-term safety (LTS) trials of oral atogepant for episodic migraine (EM). RESULTS: The safety population included 1550 participants from the pooled RCTs (atogepant, n = 1142; placebo, n = 408) and 1424 participants from the pooled LTS trials (atogepant, n = 1228; standard care [SC], n = 196). In total, 643/1142 (56.3%) atogepant participants and 218/408 (53.4%) placebo participants experienced ≥ 1 treatment-emergent AEs (TEAEs) in the RCTs. In the LTS trials, 792/1228 (64.5%) of atogepant participants and 154/196 (78.6%) of SC participants experienced ≥ 1 TEAEs. The most commonly reported TEAEs (≥ 5%) in participants who received atogepant once daily were upper respiratory tract infection (5.3% in RCTs, 7.7% in LTS trials), constipation (6.1% in RCTs, 5.0% in LTS trials), nausea (6.6% in RCTs, 4.6% in LTS trials), and urinary tract infection (3.4% in RCTs, 5.2% in LTS trials). Additionally, weight loss appeared to be dose- and duration-dependent. Most TEAEs were considered unrelated to study drug and few led to discontinuation. CONCLUSIONS: Overall, atogepant is safe and well tolerated in pooled RCTs and LTS trials for the preventive treatment of EM in adults. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02848326 (MD-01), NCT03777059 (ADVANCE), NCT03700320 (study 302), NCT03939312 (study 309).

Safety and efficacy of atogepant for the preventive treatment of episodic migraine in adults for whom conventional oral preventive treatments have failed (ELEVATE): a randomised, placebo-controlled, phase 3b trial.

BACKGROUND: Atogepant, an oral calcitonin gene-related peptide receptor antagonist, has been approved for the preventive treatment of migraine, but its efficacy and safety in people who have been failed by conventional oral preventive migraine treatments has not yet been evaluated in a dedicated clinical trial. The ELEVATE trial evaluated the safety, tolerability, and efficacy of atogepant for the preventive treatment of episodic migraine in participants for whom two to four classes of conventional oral preventive treatments have failed. METHODS: ELEVATE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3b trial done at 73 sites in Canada, the Czech Republic, Denmark, France, Germany, Hungary, Italy, the Netherlands, Poland, Russia, Spain, the UK, and the USA. Adults (18-80 years) with episodic migraine who had previously been failed by two to four classes of conventional oral treatments for migraine prevention were randomly assigned (1:1) using interactive web response technology to oral atogepant 60 mg once a day or placebo, stratified by baseline monthly migraine days, number of treatment classes participants have been failed by, and region. The primary endpoint was change from baseline in mean monthly migraine days across the 12-week treatment period in the off-treatment hypothetical estimand (OTHE) population, which included participants in the safety population (all participants who received ≥1 dose of study intervention) who had evaluable data available for the baseline period and for one or more of the 4-week post-baseline periods (whether on treatment or off treatment). The primary endpoint was analysed using a mixed model for repeated measures and a fixed-sequence procedure was used to control for multiple comparisons. The trial is registered with ClinicalTrials.gov (NCT04740827) and EudraCT (2019-003448-58), and is completed. FINDINGS: Between March 5, 2021, and Aug 4, 2022, 540 participants were screened, 315 were randomly assigned, and 313 participants (280 [89%] female, 33 [11%] male, and 300 [96%] White) received at least one dose of study intervention. In the OTHE population, which comprised 309 participants (155 assigned to placebo and 154 to atogepant), least squares mean changes from baseline in monthly migraine days across 12 weeks were -1·9 (SE 0·4) with placebo and -4·2 (0·4) with atogepant (least squares mean difference -2·4, 95% CI -3·2 to -1·5; adjusted p<0·0001). The most common treatment-emergent adverse event with atogepant was constipation in 16 (10%) of 156 participants (vs four [3%] of 157 for placebo). Serious adverse events occurred in four [3%] of 156 participants in the atogepant group vs none in the placebo group, and treatment-emergent adverse events resulting in treatment discontinuation occurred in three [2%] in the atogepant group vs two [1%] in the placebo group. INTERPRETATION: Atogepant 60 mg once a day was safe, well tolerated, and showed significant and clinically relevant reductions in mean monthly migraine days compared with placebo across 12 weeks in patients with episodic migraine who had previously been failed by two to four classes of conventional oral preventive treatments. Atogepant might be an effective preventive treatment option for patients in this difficult-to-treat population. FUNDING: Allergan (now AbbVie).

Analysis of Initial Nonresponders to Galcanezumab in Patients With Episodic or Chronic Migraine: Results From the EVOLVE-1, EVOLVE-2, and REGAIN Randomized, Double-Blind, Placebo-Controlled Studies.

OBJECTIVE: To examine the likelihood of response with continued galcanezumab treatment in patients with episodic or chronic migraine without initial clinical improvement. BACKGROUND: A percentage of patients with migraine may require additional time on pharmacotherapy but discontinue treatment prematurely. Additionally, recognizing when continued treatment is unlikely to provide improvement limits unnecessary exposure. METHODS: Post hoc analysis of response after continued galcanezumab treatment was conducted in a subset of patients with episodic (N = 879) and chronic (N = 555) migraine who did not achieve "good" early improvement (episodic, ≥50% reduction in baseline migraine headache days [MHD] and chronic, ≥30% reduction) after 1 month of dosing (NR-1; episodic, n = 450 and chronic, n = 306). This subset was categorized by level of reduction in MHD during 1 month of treatment: "modest" (>30% to <50% fewer MHD for episodic and >10% to <30% fewer MHD for chronic), "limited" (episodic only; >10% to ≤30% fewer MHD), or "minimal/no" early improvement (≤10% fewer MHD to ≤10% more MHD), or "worsening" (>10% more MHD). The percentages of patients having "better" (≥75% fewer MHD for episodic and ≥50% for chronic), "good," or "little-to-no" (≤10% fewer MHD) response during the remaining treatment period were calculated for each category. Similarly, the subset of NR-1 patients who did not achieve "good" early improvement after 2 months of treatment (NR-2; episodic, n = 290 and chronic, n = 240) were categorized by level of their average monthly reduction across 1 and 2 months using similar categories. RESULTS: Of NR-1 patients with episodic migraine having "modest" early improvement, 62% (96/155) achieved "good" and 20% (31/155) achieved "better" responses with continued treatment. A percentage of patients with "limited" (43%; 46/108) or "minimal/no" (34%; 29/85) early improvement, or "worsening" (20%; 20/102) achieved a "good" response after continued treatment. A percentage of NR-1 patients with chronic migraine having "modest" early improvement achieved "good" (38%; 44/116) and "better" (13%; 15/116) responses with continued treatment. A "good" response was achieved for a percentage of patients with "minimal/no" early improvement (17%; 23/133). Similar patterns were observed for the NR-2 subset, though percentages were lower. CONCLUSIONS: Galcanezumab-treated patients with episodic or chronic migraine without response following 1 or 2 months of treatment appear to have a reasonable likelihood of continued improvement in months following initial treatment and this opportunity is more likely in patients showing greater early improvements. While a small percentage of patients with episodic or chronic migraine who experienced worsening in the number of MHD following initial treatment responded with continued treatment, most do not show substantial reduction in MHD. Overall benefit of therapy should be determined collaboratively between the patient and physician.

Evaluation outcomes of a sex education strategy in high schools of Pavia (Italy).

AIM: We aimed to provide process and effectiveness evaluations of a sex education intervention realized with interactive techniques in high schools of Pavia (Italy). METHODS: Six public high schools, divided into 'treated' and 'control' units, voluntarily joined this mixed-methods study. Only second-year classes were enrolled: treated adolescents followed a sex education course, performed by trained 'near-peer educators' (undergraduate medical students) with interactive techniques. All adolescents compiled an anonymous effectiveness evaluation questionnaire at baseline (pre-test) and 3 months later (post-test). Sexual knowledge and reported behavioural changes were compared between the two groups through linear mixed-effects models. The process was assessed through a satisfaction questionnaire for treated students, monitoring cards for working group members and cards/diaries for educators. RESULTS: The final sample consisted of 547 treated and 355 control adolescents (mean age = 15.28 ± 0.61 years). Highly significant changes (p < 0.001) from pre-test to post-test, with strong improvements of treated adolescents, were evident for all knowledge items. No significant changes for behavioural items were reported. Process evaluation showed positive results in adolescents' satisfaction, highlighting the need for more youth gathering places. Working group members and educators generally provided positive evaluations, although difficult communication was perceived. CONCLUSIONS: The intervention was effective in improving adolescents' sexual knowledge. The present work highlighted that in Italy sex education in adolescence is still neglected: this could encourage misinformation and health-risk behaviour. Young people perceive the need for a serious health-promoting action in which they could play an active role, spreading educational messages with organized interactive methods.

An Italian population-based case-control study on the association between farming and cancer: Are pesticides a plausible risk factor?

This population-based case-control study investigated the association between farming (a proxy for pesticide exposure) and cancer in the Vercelli suburban area (northwest Italy). The residents, aged 25 to 79 years, in the above-mentioned area during the period 2002-2009 were considered. Cases were all the first hospital admissions for cancer. Controls were all the subjects not included in the cases and not excluded from the study. Cases and controls were classified according to whether they occupationally resulted farmers or nonfarmers during the period 1965-2009. Cancer odds ratios (ORs) between farmers and nonfarmers were calculated with generalized linear mixed models adjusted by gender and age. Farmers showed higher odds for all cancers (OR=1.459; p < .001), nonmelanoma skin cancer, colorectal cancer, and breast cancer. The results suggest a plausible association between pesticide exposure and cancer occurrence.

[The "Smoke-free hospital" project: prevalence of smokers in a large hospital in Pavia (Italy) from 2006 to 2010]. / Il progetto "Ospedale senza fumo": indagine sulla prevalenza dei fumatori nell'ambito dell'Azienda Ospedaliera di Pavia dal 2006 al 2010.

This study was conducted in the context of the "Smoke-free Hospital" project and its aims were to describe the prevalence of smokers among employees and patients of the Hospital of Pavia from 2006 to 2010, and to evaluate its determinants. The target population was represented by all employees (healthcare and other staff) and patients (inpatients and outpatients) of the Hospital of Pavia. Data collection took place by means of two self-administered and anonymous questionnaires (one for employees and one for patients). Overall, 3,996 employees and 2,301 patients completed the questionnaires. The prevalence of smokers among participating individuals remained largely unchanged in the observed period. The percentage of smokers among employees ranged from 21.88% in 2007 to 23% in 2006, while among patients it ranged from 16.67% in 2006 to 24.05% in 2008. Knowledge about tobacco-related issues was found to be poor and did not change over time. The low response rate did not allow us to generalize results to the entire target population. However, results indicate the need for health promotion campaigns both among hospital employees and among the general population, to raise awareness regarding the risks of tobacco smoking and to reduce the prevalence of smokers.

["Let's play with the Earth": a project of environmental education for primary school children]. / "Giochiamo con la Terra": un progetto di educazione ambientale per la scuola primaria.

OBJECTIVE: Raising awareness and knowledge in Pavia Public Primary School students, and indirectly in their parents, about environmental problems like waste recycling and energy saving, developing with games the concept of separate collection of rubbish; creating an environmentally conscious awareness and sense of responsibility towards sustainable behavior. DESIGN: The educational program lasted six months. Data collection was performed using anonymous questionnaires, administered to "treated" students at the beginning and at the end of the program. The "control" population only answered a single questionnaire at the end of the project. It was also carried out an assessment of the fallout of the project on parents, through a questionnaire at the beginning and at the end of the program. At the end of the educational intervention, a satisfaction questionnaire was administered to teachers. SETTING AND PARTICIPANTS: The enrolled population was composed of 1,358 students from 3rd, 4th and 5th classes of Public Primary Schools of the four Pavia School Districts: 938 "treated" students followed the program and 420 "controls" only answered the final questionnaire. MAIN OUTCOME MEASURES: The data concerning the pupils' knowledge are expressed in terms of frequencies: at first, we evaluated the comparison between "treated" students knowledge at the beginning and at the end of the program in each class, then we made the comparison between "treated" and "control" students at the end of the program. RESULTS: The comparison of the final questionnaires ("treated" students vs "controls") revealed in "treated" students higher knowledge of terms "waste" (94.5% vs 89.0%) and "separate collection" (97.3% vs 90.7%): the differences are statistically significant. Also the practice of separate collection of rubbish is more frequent in "treated" students' families than in "control" ones (83.5% vs 71.4%, p =0.0001).The analysis of teachers' satisfaction questionnaires showed positive ratings with high average scores for each item investigated. The analysis of parents' questionnaires revealed that 99.8% of them knows the meaning and 89% practice separate collection of rubbish. CONCLUSION: The program has proved effective in increasing students' short-term knowledge and making also families more interested in problems like waste recycling and separate collection of rubbish. The need of an awareness and environmental education campaign for the general population is apparent and the role of children, promoting knowledge and environmental behaviour changes in parents and community, has not to be underestimated.

[Evaluation of the efficacy of a school-based program to prevent tobacco smoking among adolescents in Lombardy (Italy)]. / Valutazione dell'efficacia del programma "Liberi di decidere", per la prevenzione del tabagismo nella Scuola Secondaria di secondo grado.

The program "Free to choose" was a school-based program aimed at encouraging secondary school students to lead healthy lifestyles and free from tobacco smoke. The project was part of a wider project named "Free from tobacco smoke", implemented in kindergarten, elementary and secondary schools in Lombardy (Italy). The "Free to choose" program was a controlled, non randomized study involving 2,145 subjects aged 16 years, of whom 1,063 participated in the activities laid out by the program (treatment group) and 1,082 only completed the questionnaires (control group). The program did not achieve the aim of reducing the number of subjects who start smoking. However, an increased awareness of the risks of smoking was observed among "treated" subjects as well as an increased number of non smokers who intend to refuse a cigarette if they were offered one.

[Surveillance of the health status of the population of the city of Parona (Italy), Phase 2]. / La sorveglianza dello stato di salute della popolazione del Comune di Parona (PV) (II Fase).

This study is part of a prospective study, which started in the year 2000, to monitor the health status of the population of the city of Parona, a previously agricultural area which has been transformed in a prevalently industrial area. This is the second phase of a project regarding the epidemiological surveillance of this population. The aim of the project was to detect changes in the health status of the population, particularly with regard to respiratory diseases associated with air pollution. Data was collected through the use of a questionnaire and a spirometry test. A control group was used in both parts of the study; control subjects lived in the city of Rovescala. In total 1484 subjects were invited by letter to participate and 399 (27%) accepted. The mean age of participants was 48 years (range 15-74 years). Only 149/399 (37%) subjects had participated in part 1 of the study. No significant changes were found in respiratory symptoms during the period considered. Three hundred eighty six subjects underwent spirometry testing, 36 of which (9%) were found to have an abnormal result. A moderately increased prevalence of obstructive airway signs on spirometry was registered in female participants, with respect to the year 2000 (5.9% vs 2.6%). On the other hand, the prevalence of restrictive signs remained similar in both males (1,7% vs 2,4%) and females (2% vs 1,5%). The spirometry changes detected in the149 subjects (65 male and 84 female) who participated in both parts of the study (parts 1 and 2) were most likely age-related. No significant differences were found with respect to the control group, although the prevalence of obstructive signs among males was greater in the city of Parona (9.2% vs 6.9%.

Diagnostic issues in tension-type headache.

The diagnosis of tension-type headache (TTH) is divided into two categories: episodic TTH and chronic TTH. It is important to differentiate TTH from other headaches, including primary and secondary headaches. Significant overlap in the diagnostic criteria makes it difficult to differentiate TTH from other headache disorders and, in particular, migraine. A controversy exists about whether TTH and migraine represent a continuum of the same pathophysiological process.

[Smoking habits among 13-18 year old students in Lombardy]. / L'abitudine al fumo tra gli studenti dai 13 ai 18 anni di età in Lombardia.

OBJECTIVE: to describe the prevalence of smokers among 13- 18-years-old students in Lombardy and to evaluate some related motives. DESIGN: a survey has been carried out with anonymous questionnaires, distributed at the beginning of the school year 2005-2006. SETTING: the study involved 3,593 classes of the third year of middle school and 2,893 classes of the second and the fifth year of high school, sampled among all the schools of Lombardy. PARTICIPANTS: the study interested 11,494 students aged either 13, 15 or 18. MAIN OUTCOME MEASURES: the prevalence of habitual smokers was 6%, 26.5% and 33.2%. RESULTS: a higher percentage of smokers report to have low school performances and to receive more than 15 euros as weekly tip. The number of smokers among family components and friends always appears higher for smoker students. Unemployed fathers and working mothers were higher among smokers. Both parents of smoker students have a lower educational level. CONCLUSION: an organized and systematic regional surveillance could highlight some characteristics of smoking habit among young students useful to set health education programs and to evaluate the efficacy of interventions already being carried out. Besides, it could enhance the awareness of the problem.

Placental site trophoblastic tumor: an overview.

OBJECTIVE: To analyze 15 consecutive cases of placental site trophoblastic tumor seen in a single reference institution for gestational trophoblastic disease, San Gerardo Hospital, Monza, Italy. STUDY DESIGN: Consecutive patients affected by placental site trophoblastic tumors were selected from our computerized database. RESULTS: There were 15 patients with placental site trophoblastic tumor, with a median age of 35 years. The antecedent pregnancy was a term one in 6 cases (40%), a miscarriage in 4 cases (27%), a termination in 2 cases (13%) and a molar abortion in 2 cases (13%). In 1 case the previous pregnancy was unrecognized. The median interval from the last pregnancy was 12 months, and the presenting symptom in 11 cases was vaginal bleeding, in 2 cases amenorrhea, in 1case a nephrotic syndrome and in 1 case, presenting with metastatic disease, hemoptysis. Six patients were treated using neoadjuvant chemotherapy with etoposide/methotrexate/actinomycin-etoposide/ vincristine (EMA-CO) followed in 5 of 6 (83%) cases by hysterectomy. One patient had only medical treatment with EMA-CO because of a strong desire for or childbearing and had a complete response; after 15 months she was free from disease. The last 9 patients underwent surgery as the first therapy. Among these patients 1 had presented with metastatic pulmonary disease and underwent chemotherapy, with complete disappearance of the pulmonary lesions. Two of these 9 patients had a relapse; the mirst patient had a pelvic and bladder relapse, and 14 months after multiple chemotherapy and surgery, she died. The second had a suburethral relapse 2 months after initial surgery; after chemotherapy and surgery she was well and free of disease. CONCLUSION: Our experience suggests that the role of chemotherapy may be reconsidered not only for metastatic disease but als of or uterine disease when choosing conservative management in young, fertile patients who desire childbearing. Chemotherapy may play an important role in avoiding relapse or early metastases even in patients who underwent hysterectomy as primary treatment.