Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study.

BACKGROUND: Neurokinin 3 receptor antagonists are potential non-hormonal therapies for the treatment of vasomotor symptoms in menopausal women as options are scarce for those who cannot or do not want to take hormone therapy. Fezolinetant is one of the first non-hormonal neurokinin 3 receptor antagonists in development for the treatment of vasomotor symptoms due to menopause. This study investigated the safety and efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms associated with menopause. METHODS: SKYLIGHT 1 is a randomised, double-blind, placebo-controlled, 12-week, phase 3 trial with a 40-week active treatment extension. This trial was done at 97 facilities across the USA, Canada, Czech Republic, Hungary, Poland, Spain, and the UK. Women aged 40-65 years with an average of seven or more moderate-to-severe hot flashes per day were randomly assigned (1:1:1) to once-daily exact-matched placebo, fezolinetant 30 mg, or fezolinetant 45 mg. Randomisation was done using a web-based interactive response system and investigators, project team members, clinical staff, and participants were masked to treatment assignment. Coprimary endpoints were mean change in frequency and severity of vasomotor symptoms from baseline to weeks 4 and 12. The efficacy and safety analyses comprised all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04003155) and is completed. FINDINGS: Between July 11, 2019, and Aug 11, 2021, 2205 women were recruited of whom 175 were assigned to placebo, 176 to fezolinetant 30 mg, and 176 to fezolinetant 45 mg (175 in the placebo group, 174 in the fezolinetant 30 mg group, and 173 in the fezolinetant 45 mg received at least one dose [safety analysis set]). One participant randomly assigned to fezolinetant 45 mg received fezolinetant 30 mg in error, so the efficacy analysis set (full analysis set) consisted of 173 in the fezolinetant 30 mg group and 174 in the fezolinetant 45 mg group. 23 participants in the placebo group, 31 in the fezolinetant 30 mg group, and 13 in the fezolinetant 45 mg group discontinued treatment before week 12, mostly due to adverse events or participant withdrawal. Compared with placebo, fezolinetant 30 mg and fezolinetant 45 mg significantly reduced the frequency of vasomotor symptoms at week 4 (difference in change in least squares mean -1·87 [SE 0·42; p<0·001], -2·07 [SE 0·42; p<0·001]) and week 12 (-2·39 [SE 0·44; p<0·001], -2·55 [SE 0·43; p<0·001]). Compared with placebo, fezolinetant 30 mg and 45 mg significantly reduced the severity of vasomotor symptoms at week 4 (-0·15 [0·06; p=0·012], -0·19 [0·06; p=0·002]) and week 12 (-0·24 [0·08; p=0·002], -0·20 [0·08; p=0·007]). Improvements in frequency and severity of vasomotor symptoms were observed after 1 week and maintained over 52 weeks. During the first 12 weeks, treatment-emergent adverse events occurred in 65 (37%) of 174 women in the fezolinetant 30 mg group, 75 (43%) of 173 in the fezolinetant 45 mg group, and 78 (45%) of 175 in the placebo group. The incidence of liver enzyme elevations was low (placebo n=1; fezolinetant 30 mg n=2; fezolinetant 45 mg n=0) and these events were generally asymptomatic, transient, and resolved while on treatment or after treatment discontinuation. INTERPRETATION: Data support the clinical use of fezolinetant as a non-hormonal treatment for vasomotor symptoms associated with menopause. The study was placebo-controlled for 12 weeks followed by a 40-week blinded extension to assess the maintenance of effect. Furthermore, the population studied was diverse and representative of the potential target population for fezolinetant therapy. Further characterisation of the benefit of fezolinetant on quality of life, including on symptoms of mood and sexual wellbeing, merits investigation. FUNDING: Astellas Pharma.

Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT.

CONTEXT: Vasomotor symptoms (VMS) are common, bothersome, and can persist for years before and after menopause. OBJECTIVE: We aimed to assess efficacy/safety of fezolinetant for treatment of moderate to severe VMS associated with menopause. METHODS: In this double-blind, placebo-controlled, 12-week phase 3 trial with a 40-week active treatment extension (NCT04003142; SKYLIGHT 2), women aged 40 to 65 years with minimum average 7 moderate to severe VMS/day were randomized to 12 weeks of once-daily placebo, fezolinetant 30 mg, or fezolinetant 45 mg. Completers were rerandomized to fezolinetant 30/45 mg for 40 additional weeks. Coprimary efficacy endpoints were mean daily change from baseline to week 4 (W4) and W12 in VMS frequency and severity. Safety was also assessed. RESULTS: Both fezolinetant doses statistically significantly reduced VMS frequency/severity at W4 and W12 vs placebo. For VMS frequency, W4 least squares mean (SE) reduction vs placebo: fezolinetant 30 mg, -1.82 (0.46; P < .001); 45 mg, -2.55 (0.46; P < .001); W12: 30 mg, -1.86 (0.55; P < .001); 45 mg, -2.53 (0.55; P < .001). For VMS severity, W4: 30 mg, -0.15 (0.06; P < .05); 45 mg, -0.29 (0.06; P < .001); W12: 30 mg, -0.16 (0.08; P < .05); 45 mg, -0.29 (0.08; P < .001). Improvement in VMS frequency and severity was observed by W1 and maintained through W52. Serious treatment-emergent adverse events were infrequent, reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo, respectively. CONCLUSION: Daily fezolinetant 30 and 45 mg were efficacious and well tolerated for treating moderate to severe VMS associated with menopause.

Effects of Flibanserin on Subdomain Scores of the Female Sexual Function Index in Women With Hypoactive Sexual Desire Disorder.

INTRODUCTION: Flibanserin treatment increases sexual desire and satisfying sexual events while decreasing distress in certain women diagnosed with acquired, generalized hypoactive sexual desire disorder (HSDD). Additional aspects of sexual function and the time course of response have not been fully characterized. AIM: To evaluate changes in sexual function assessed by the subdomains of the Female Sexual Function Index (FSFI) in women with HSDD treated with flibanserin. METHODS: FSFI data pooled from 3 pivotal flibanserin trials in premenopausal women (flibanserin = 1,165; placebo = 1,203) and FSFI data from one complete flibanserin trial in postmenopausal women (flibanserin = 432; placebo = 463) were subjected to post-hoc analyses. For each FSFI subdomain, least squares mean change from baseline was calculated at each assessment visit (treatment weeks 4, 8, 16, 24) and treatment groups were compared using analysis of covariance. Standardized effect size (Cohen's d) was also determined for each FSFI subdomain. MAIN OUTCOME MEASURE: Changes from baseline in FSFI subdomains. RESULTS: Compared to placebo, both premenopausal (P < .02) and postmenopausal (P < .045) patients in the flibanserin group reported significantly greater increases over baseline in the FSFI subdomain scores of desire, arousal, lubrication, orgasm, and satisfaction. In premenopausal patients, significant improvements were observed at the first assessment of response (week 4) and were maintained through week 24. In postmenopausal patients, significant improvements were observed at week 4 for desire and arousal, while significant improvements in lubrication, orgasm, and satisfaction were observed at week 8. At week 24, excluding the pain subdomain, standardized effect sizes ranged from 0.18 to 0.28 in the premenopausal cohort and 0.12 to 0.29 in the postmenopausal cohort. In both pre- and postmenopausal patients, improvements in pain were smaller and largely undifferentiated between treatment groups. CLINICAL IMPLICATIONS: While variations in time to response should be taken into consideration, on average, the beneficial impact of flibanserin on overall sexual function occurs within the first month of treatment. The data also suggest that the response to flibanserin is sustained for the duration of treatment. STRENGTHS AND LIMITATIONS: Sexual function assessments were performed in a large cohort of 2,368 premenopausal women and 895 postmenopausal women. However, the FSFI assesses changes over a 1-month period and time points earlier than 4 weeks could not be assessed. CONCLUSION: These analyses suggest that assessment of benefit of flibanserin in HSDD should include improvements across all domains of sexual function, not only desire. Simon JA, Clayton AH, Goldstein I, et al. Effects of Flibanserin on Subdomain Scores of the Female Sexual Function Index in Women With Hypoactive Sexual Desire Disorder. Sex Med 2022;10:100570.

A Master Class in Family Doctor Leadership: Evaluating an Innovative Program.

BACKGROUND AND OBJECTIVES: In family medicine, leadership is critical for health care delivery, advancing curricula, research, and quality improvement. Systematic reviews of leadership development programs in health care identify limitations, calling for innovative designs and rigorous assessment. Our objective was to evaluate the impact of applying master class principles to leadership development in academic family medicine. METHODS: We used mixed methods to assess the impact of an innovative master class program on 15 emerging leaders in a large academic department of family medicine. The program consisted of five sessions where family physician masters shared their wisdom, techniques, and feedback with promising leaders. Quantitative evaluation involved participants' ratings of each session's content and delivery using a 5-point Likert scale. We assessed postcourse semistructured interviews with participants qualitatively using descriptive thematic content analysis. RESULTS: Individual sessions were highly evaluated, with a combined mean of 4.82/5. Qualitative thematic analysis identified self-perceived increased effectiveness in leadership activities; increased confidence as a leader; increased motivation to be a leader; and perceptions of value from the program, contributing to what participants described as unexpected potential change within themselves. Themes related to effectiveness of the program were practical advice; networking; diverse topics; accessible speakers sharing personal stories; and small-group, informal, early-evening format. CONCLUSIONS: Master class concepts can be adapted to leadership development in academic family medicine, with evidence of early positive impact on participants' self-perception of leadership skills and confidence. Further research is warranted to assess organizational impact and applicability to other settings.

Vaccine strategies for prevention of community-acquired pneumonia in Canada: Who would benefit most from pneumococcal immunization?

OBJECTIVE: To describe the burden of pneumococcal disease and associated risk factors in the Canadian adult population, delineate available pneumococcal vaccines and associated efficacy and effectiveness data, and review current pneumococcal vaccine recommendations and community-acquired pneumonia (CAP) prevention strategies in Canada. QUALITY OF EVIDENCE: Pneumococcal vaccination guidelines from the Canadian National Advisory Committee on Immunization in 2013 and 2016 constitute level III evidence for CAP prevention in the Canadian adult population. MAIN MESSAGE: It is recommended that immunosuppressed adults of all ages receive the 13-valent pneumococcal conjugate vaccine (PCV13) (grades A and B recommendations). In 2016, the National Advisory Committee on Immunization also recommended that all adults aged 65 years and older receive PCV13 (grade A recommendation) on an individual basis, followed by the 23-valent pneumococcal polysaccharide vaccine (grade B recommendation). This update is based on a large clinical study that demonstrated PCV13 efficacy against vaccine-type CAP in this population. CONCLUSION: Physicians should focus on improving pneumococcal vaccination rates among adults, which remain low. Vaccination with PCV13 should also be considered for adults with chronic conditions, whose baseline risk is often higher than that for healthy individuals aged 65 years and older.

An individualized approach to the management of vaginal atrophy in Latin America.

OBJECTIVE: In the absence of guidelines specific for Latin America, a region where the impact of menopause is becoming increasingly important, an evidence-based specialist opinion on management of vaginal atrophy will help improve outcomes. METHODS: An advisory board meeting was convened in São Paulo, Brazil, to discuss practical recommendations for managing vaginal atrophy in women in Latin America. Before the meeting, physicians considered various aspects of the condition, summarizing information accordingly. This information was discussed during the meeting. The expert consensus is now summarized. RESULTS: In Latin America, given the relatively early age of menopause, it will be beneficial to raise awareness of vaginal atrophy among women before they enter menopause, considering cultural attitudes and involving partners as appropriate. Women should be advised about lifestyle modifications, including attention to genital hygiene, clothing, and sexual activity, and encouraged to seek help as soon as they experience vaginal discomfort. Although treatment can be started at any time, prompt treatment is preferable. A range of treatments is available. By addressing the underlying pathology, local estrogen therapy can provide effective symptom relief, with choice of preparation guided by patient preference. An individualized treatment approach should be considered, giving attention to patients' specific situations. CONCLUSIONS: It is critical that women are empowered to understand vaginal atrophy. Educating women and healthcare providers to engage in open dialogue will facilitate appreciation of the benefits and means of maintaining urogenital health, helping to improve outcomes in middle age and beyond. Women should receive this education before menopause.

Management of genitourinary syndrome of menopause in women with or at high risk for breast cancer: consensus recommendations from The North American Menopause Society and The International Society for the Study of Women's Sexual Health.

The objective of The North American Menopause Society (NAMS) and The International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel was to create a point of care algorithm for treating genitourinary syndrome of menopause (GSM) in women with or at high risk for breast cancer. The consensus recommendations will assist healthcare providers in managing GSM with a goal of improving the care and quality of life for these women. The Expert Consensus Panel is comprised of a diverse group of 16 multidisciplinary experts well respected in their fields. The panelists individually conducted an evidence-based review of the literature in their respective areas of expertise. They then met to discuss the latest treatment options for genitourinary syndrome of menopause (GSM) in survivors of breast cancer and review management strategies for GSM in women with or at high risk for breast cancer, using a modified Delphi method. This iterative process involved presentations summarizing the current literature, debate, and discussion of divergent opinions concerning GSM assessment and management, leading to the development of consensus recommendations for the clinician.Genitourinary syndrome of menopause is more prevalent in survivors of breast cancer, is commonly undiagnosed and untreated, and may have early onset because of cancer treatments or risk-reducing strategies. The paucity of evidence regarding the safety of vaginal hormone therapies in women with or at high risk for breast cancer has resulted in avoidance of treatment, potentially adversely affecting quality of life and intimate relationships. Factors influencing decision-making regarding treatment for GSM include breast cancer recurrence risk, severity of symptoms, response to prior therapies, and personal preference.We review current evidence for various pharmacologic and nonpharmacologic therapeutic modalities in women with a history of or at high risk for breast cancer and highlight the substantial gaps in the evidence for safe and effective therapies and the need for future research. Treatment of GSM is individualized, with nonhormone treatments generally being first line in this population. The use of local hormone therapies may be an option for some women who fail nonpharmacologic and nonhormone treatments after a discussion of risks and benefits and review with a woman's oncologist. We provide consensus recommendations for an approach to the management of GSM in specific patient populations, including women at high risk for breast cancer, women with estrogen-receptor positive breast cancers, women with triple-negative breast cancers, and women with metastatic disease.

Understanding modern-day vaccines: what you need to know.

Vaccines are considered to be one of the greatest public health achievements of the last century. Depending on the biology of the infection, the disease to be prevented, and the targeted population, a vaccine may require the induction of different adaptive immune mechanisms to be effective. Understanding the basic concepts of different vaccines is therefore crucial to understand their mode of action, benefits, risks, and their potential real-life impact on protection. This review aims to provide healthcare professionals with background information about the main vaccine designs and concepts of protection in a simplified way to improve their knowledge and understanding, and increase their confidence in the science of vaccination ( Supplementary Material ). KEY MESSAGE Different vaccine designs, each with different advantages and limitations, can be applied for protection against a particular disease. Vaccines may contain live-attenuated pathogens, inactivated pathogens, or only parts of pathogens and may also contain adjuvants to stimulate the immune responses. This review explains the mode of action, benefits, risks and real-life impact of vaccines by highlighting key vaccine concepts. An improved knowledge and understanding of the main vaccine designs and concepts of protection will help support the appropriate use and expectations of vaccines, increase confidence in the science of vaccination, and help reduce vaccine hesitancy.

Is It Time for Vaccination to "Go Viral"?

To promote and sustain excellent vaccination coverage, while preserving the key core values of ethics, truth, transparency and trust, the vaccine community should adopt modern digital communication strategies. This article summarizes our views-as experts in multidisciplinary field of vaccinology (consisting of an anthropologist, a public health policy advisor, a vaccine industry expert, a health care journalist and a practicing physician)-which were presented at a satellite symposium held at the 33rd European Society of Paediatric Infectious Disease conference in Leipzig, Germany, in May 2015. This article aims to suggest and recommend strategies to promote vaccination awareness, and highlight proactive measures for building, maintaining and enhancing trust in vaccination through innovative communication and evidence-based interaction with the end user. We believe that converting the results of vaccine research into a successful vaccination program, and replacing misinformation with evidence-based communication, will require a multidisciplinary approach that embraces modern digital and tailored applications to reach out to all populations.

Media and education of the consumer.

The landscape has changed in how consumers get their health information. A shift to the Internet and social media are now the way many consumers obtain their health and medical information. In addition, the highly complex information in medicine and science separates health journalism from other forms of journalism. In this article, the question of the role of media in educating consumers is examined. It is clear that knowledge translation is complex and begs the cooperation of scientists and journalists alike.

Denosumab, a new pharmacotherapy option for postmenopausal osteoporosis.

BACKGROUND: According to the 2010 Osteoporosis Canada Clinical Practice Guidelines, denosumab is a first-line option for the pharmacological management of postmenopausal osteoporosis (PMO), along with several therapeutics that may be more familiar to family practice doctors: bisphosphonates, raloxifene, teriparatide, and hormone therapy. Denosumab is indicated for postmenopausal patients at high risk for fracture or others who have failed, or are intolerant to, other osteoporosis therapies. SCOPE: We undertook a review of the efficacy and safety of denosumab in PMO, searching the English-language literature on this drug via PubMed queries as of July 2012. FINDINGS: Although established treatments reduce fracture risk among osteoporotic postmenopausal women in trials, their effectiveness in clinical practice is limited by patient adherence. Twice-yearly denosumab treatment is associated with markedly improved bone mineral density (BMD) and cortical and trabecular bone strength, and significantly reduced osteoporotic fracture. Inhibition of bone resorption is fully reversible following discontinuation. Placebo-controlled and open-label extension studies showed similar adverse event (AE) and serious AE rates, relative to placebo, over up to 5 years. Data indicate a potential advantage of denosumab over the bisphosphonate alendronate for BMD and patient adherence and preference. CONCLUSION: Owing to its efficacy, safety, and potential to improve adherence rates, denosumab is an appropriate first-line pharmacologic option for PMO management.

Multiple-component remediation for developmental reading disabilities: IQ, socioeconomic status, and race as factors in remedial outcome.

Results from a controlled evaluation of remedial reading interventions are reported: 279 young disabled readers were randomly assigned to a program according to a 2 × 2 × 2 factorial design (IQ, socioeconomic status [SES], and race). The effectiveness of two multiple-component intervention programs for children with reading disabilities (PHAB + RAVE-O; PHAB + WIST) was evaluated against alternate (CSS, MATH) and phonological control programs. Interventions were taught an hour daily for 70 days on a 1:4 ratio at three different sites. Multiple-component programs showed significant improvements relative to control programs on all basic reading skills after 70 hours and at 1-year follow-up. Equivalent gains were observed for different racial, SES, and IQ groups. These factors did not systematically interact with program. Differential outcomes for word identification, fluency, comprehension, and vocabulary were found between the multidimensional programs, although equivalent long-term outcomes and equal continued growth confirmed that different pathways exist to effective reading remediation.

Update on herpes zoster vaccination: a family practitioner's guide.

OBJECTIVE: To answer frequently asked questions surrounding the use of the new herpes zoster (HZ) vaccine. SOURCES OF INFORMATION: Published results of clinical trials and other studies, recommendations from the Canadian National Advisory Committee on Immunization, and the US Advisory Committee on Immunization Practices; data were also obtained from the vaccine's Health Canada-approved product monograph. MAIN MESSAGE: Herpes zoster results from reactivation of the varicella-zoster virus; postherpetic neuralgia (PHN) is its most common and serious complication. The incidence of PHN after HZ is directly related to age, with 50% of affected individuals older than 60 years experiencing persistent and unrelieved pain. The live virus HZ vaccine reduces the incidence of HZ by about 50% and the occurrence of PHN by two-thirds, with vaccinated individuals experiencing attenuated or shortened symptoms. The vaccine is contraindicated in many immunocompromised patients and might not be effective in patients taking antiviral medications active against the HZ virus. Physicians should be aware of the different recommendations for these groups. CONCLUSION: The HZ vaccine is a safe and effective preventive measure for reducing the overall burden and severity of HZ in older adults. The vaccine appears to be cost-effective when administered to adults aged 60 years and older.