A phase 2a study investigating the effects of ritlecitinib on brainstem auditory evoked potentials and intraepidermal nerve fiber histology in adults with alopecia areata.

Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9-month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50-mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double-blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4-week loading dose of 200 mg QD or placebo for 9 months (placebo-controlled phase); they then entered the active-therapy extension and received ritlecitinib 50 mg QD (with a 4-week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I-V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans.

Efficacy and Safety of Ertugliflozin in Patients With Diabetes Mellitus Inadequately Controlled by Sulfonylurea Monotherapy: a Substudy of VERTIS CV.

INTRODUCTION: Sulfonylureas (SU) are commonly used antihyperglycemic agents. VERTIS CV was the cardiovascular outcome study for the sodium-glucose cotransporter 2 inhibitor ertugliflozin. Enrollment of patients in VERTIS CV occurred in two sequential cohorts (Cohort 1 and Cohort 2). METHODS: This substudy assessed the efficacy and safety of adding ertugliflozin to SU monotherapy. The primary endpoint was the change in HbA1c from baseline at 18 weeks. RESULTS: Among the 8246 patients who were randomized in VERTIS CV, 157 patients in Cohort 1 and 135 patients in Cohort 2 were on SU monotherapy at baseline. In the prespecified analysis (Cohort 1 only), the least squares (LS) mean HbA1c change from baseline for placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg was -  0.56%, -  0.91%, and -  0.78%, respectively (placebo-adjusted LS mean [95% CI] change: - 0.35% [-  0.72%, 0.02%]; -  0.22% [-  0.60%, 0.16%] for ertugliflozin 5 and 15 mg, respectively; p > 0.05 for both). In a post-hoc analysis that included Cohorts 1 and 2 (N = 292), the LS mean HbA1c change from baseline at week 18 for placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg was -  0.31%, - 0.77%, and -  0.68%, respectively (placebo-adjusted change: -  0.46% [-  0.73%, -  0.18%]; -  0.37% [-  0.66%, -  0.09%]; p = 0.001 and 0.01 for ertugliflozin 5 and 15 mg, respectively). In Cohort 1, adverse events were reported in 45.8%, 47.3%, and 25.9% of patients with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg. The incidence rates of symptomatic hypoglycemia were 0.0%, 5.5%, and 3.7%, respectively, with no cases of severe hypoglycemia. The safety profile was similar for Cohorts 1 and 2 combined. CONCLUSION: The addition of ertugliflozin to SU monotherapy reduced HbA1c but did not result in significant placebo-adjusted reductions from baseline according to the prespecified primary analysis (n = 157); however, in a post-hoc analysis with a larger patient population (n = 292), significant and clinically relevant HbA1c reductions were observed. Ertugliflozin was generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01986881.

Clinical presentation and course of bleeding events in patients with venous thromboembolism, treated with apixaban or enoxaparin and warfarin. Results from the AMPLIFY trial.

Apixaban, a direct acting oral anticoagulant (DOAC), was found to be non-inferior to and safer as enoxaparin followed by warfarin for treatment of venous thromboembolism (VTE) in the AMPLIFY trial. Information is needed on how bleeding events with DOACs present and develop. In this post-hoc analysis, the clinical presentation and course of all major and clinically relevant non major (CRNM) bleeding events in the AMPLIFY trial were blindly classified by three investigators, using pre-designed classification schemes containing four categories. Odds ratios (OR) for classifying as category three or four (representing a more severe clinical presentation and course) were calculated between apixaban and enoxaparin/warfarin. In total, 63 major and 311 CRNM bleeding events were classified. Of the major bleeds, a more severe clinical presentation occurred in 28.5 % of apixaban versus 44.9 % of enoxaparin/warfarin related recipients (OR 0.49, 95 % confidence interval [CI] 0.14-1.78). A severe clinical course was observed in 14.3 % and in 12.2 %, respectively (OR 1.19, 95 %CI 0.21-6.69). Of the CRNM bleeding events, a more severe clinical presentation and extent of clinical care was found in 25 % of apixaban recipients compared to 22.7 % in the enoxaparin/warfarin group (OR 1.13, 95 %CI 0.65-1.97). The clinical presentation and course of major and CRNM bleeds were similar in apixaban and enoxaparin/warfarin treated patients. This finding should reassure physicians and patients that even in the absence of a specific reversal agent, apixaban is a convenient and safe choice for VTE.

Expression of angiogenic chemokines in ovarian clear cell carcinoma.

AIMS: The aim of this study was to assess the expression of angiogenic chemokines (CXCR4/CXCL12) and the vascular endothelial growth factor in ovarian clear cell carcinoma, comparing levels against those in ovarian high-grade serous carcinoma. MATERIAL AND METHODS: Tissue microarray samples from 136 cases of epithelial ovarian carcinoma (108 high-grade serous carcinoma and 28 clear cell carcinoma) were reviewed with World Health Organization histological criteria strictly applied to categorize cases according to histological subtype. Only cases without prior exposure to chemotherapy were included. Sections were stained with vascular endothelial growth factor, CXCR4, CXCL12 and assessed using conventional histological scoring (H-scoring). RESULTS: Patients with clear cell carcinoma presented at an early stage of the disease (74% stage 1 and 2) and had a significantly better progression-free (P=0.042) survival than those with high-grade serous carcinoma. Low expression profile of the tested markers was seen in cases of clear cell carcinoma contrary to that seen in high-grade serous carcinoma. CONCLUSION: The current study reports, for the first time, the difference in expression of a set of angiogeneic prognostic markers between clear cell carcinoma and high-grade serous carcinoma, offering a possible explanation for the apparent chemotherapy resistance. These results are relevant for the design of future clinical studies of first-line treatment for patients with ovarian clear cell carcinoma.

Evidence for the involvement of free light chain immunoglobulins in allergic and nonallergic rhinitis.

BACKGROUND: Allergic rhinitis is characterized by mast cell degranulation induced by antigen cross-linking of IgE. It has been proposed that some patients with rhinitis show nasal allergy in the absence of systemic markers of atopy, termed entopy. Recent murine studies suggest the existence of an IgE-independent hypersensitivity response involving antigen-induced mast cell activation, mediated by immunoglobulin free light chains (FLCs). OBJECTIVES: To determine whether FLC is associated with mast cell-mediated nasal hypersensitivity and its relationship with eosinophilic activity in allergic and nonatopic rhinitis. METHODS: Patients with allergy and nonallergic rhinitis with eosinophilia syndrome (NARES) had levels of soluble FLC measured in nasal secretions and serum. In addition, levels of the nasal inflammatory mediators mast cell tryptase and eosinophil cationic protein were quantified. Cellular expression of kappa and lambda FLC was characterized in the nasal mucosa of allergic and nonatopic idiopathic rhinitis and control subjects by using immunohistochemistry. Immunopositive cells were phenotyped by using laser microdissection and PCR. RESULTS: Free light chain was significantly increased in nasal secretions of subjects with allergy and NARES, and in serum of patients with NARES. Nonatopic patients with allergy showed significantly increased nasal mast cell tryptase and eosinophil cationic protein. FLC-positive cells were significantly increased in allergic and nonatopic mucosa, and were shown to be mast cells and plasma cells. CONCLUSION: Nasal FLC is significantly increased in allergic and nonatopic rhinitis nasal mucosa, suggesting a role in nasal hypersensitivity. Further studies are needed to identify which allergens trigger FLC-mediated responses in nonatopic rhinitis.

Mucosal thickening in allergic and idiopathic rhinitis mucosa and its probable mechanism.

BACKGROUND: Rhinitis is a prevalent condition characterized by nasal mucosal irritation. Conflicting studies suggest that the mucosa of patients with allergic and nonallergic rhinitis undergoes thickening. OBJECTIVES: To investigate mucosal epithelial thickening in allergic and idiopathic rhinitis and to determine if the mechanism is a consequence of altered proliferation or apoptosis. METHODS: Interactive image analysis was performed on histologic sections of inferior nasal turbinate tissue to measure epithelial thickness in 3 patient groups. Patients with allergic rhinitis (n = 15), patients with idiopathic rhinitis (n = 15), and a healthy control group (n = 10) were compared. Immunohistochemical and morphometric analyses were used to quantify cell proliferation (Mib-1), apoptosis (terminal uridine nick end labeling technique), and the antiapoptotic factor Bcl-2. RESULTS: Idiopathic epithelium was found to be significantly thickened compared with healthy epithelium (P = .04). Epithelial thickening occurred in some allergic patients, but the findings did not reach statistical significance (P = .22). No statistically significant difference in proliferation as evidenced by Mib-1 staining was seen among the 3 patient groups. Allergic mucosa differed statistically significantly to that of patients with idiopathic rhinitis (P = .01) and healthy controls (P = .005) in showing increased Bcl-2 staining, suggesting reduced apoptosis. CONCLUSIONS: Allergic epithelium shows significantly decreased apoptosis, which might explain the increased epithelial thickening seen in some study participants. This mechanism does not, however, appear to explain the significantly increased thickening seen in the idiopathic epithelium. Furthermore, both allergic and nonallergic epithelium showed regional thinning and thickening possibly involving an inflammatory infiltrate.

Methods to determine the minimum important difference for a sexual event diary used by postmenopausal women with hypoactive sexual desire disorder.

INTRODUCTION: Recently, there has been much discussion in the literature about how to determine the meaningfulness of results generated from a patient-reported outcome measure. A number of reviews have shown that there are two main approaches: anchor- and distribution-based approaches for determining the minimum important difference (MID) for a new measure. There are issues with calculating an MID using each method: Will the two approaches give the same estimate? If the estimates differ, how do you decide on one estimate? Would asking patients directly be more beneficial? AIM: A case study was presented to address these issues based on a newly developed diary assessing number of satisfactory sexual events (SSEs) per week in women with hypoactive sexual desire disorder (HSDD). METHODS: Anchor- and distribution-based estimates were generated from data gathered in two double-blind, placebo-controlled, parallel group trials for the treatment of HSDD (N = 788). A novel interview study was used to ask women directly about an MID for SSEs (N = 77). MAIN OUTCOME MEASURES: Defining the MID for an SSE diary in women with HSDD. RESULTS: The estimates varied, producing a range of mean MID estimates between 0.04 and 0.46 SSEs per week. CONCLUSION: We recommend that rather than defining the MID, a range should be selected from the set of estimates formed by the limits of the 95% confidence intervals.

A methodology study to develop and validate a screener for hypoactive sexual desire disorder in postmenopausal women.

INTRODUCTION: Current methods for diagnosing hypoactive sexual desire disorder (HSDD) can be complicated and time-consuming. A previous study reported validity and reliability of a structured diagnostic method created for clinical trials that can be performed in approximately 1 hour. METHODS: A more succinct tool is needed for incorporation into busy physician practices. Therefore, a brief HSDD screening tool was developed consisting of four self-report questions with an interpretable cut-score and concise confirmatory physician interview. MAIN OUTCOME MEASURES: Accuracy of the HSDD screener cut-score alone, and in combination with physician interview, was then separately evaluated when compared with in-depth interview diagnosis. RESULTS. The results showed good agreement between the two diagnoses (kappa of 0.669 and 0.562 for cut-score alone and cut-score in combination with physician interview, respectively). CONCLUSIONS: The HSDD screener can reliably detect the likely presence of HSDD in postmenopausal women.

A methodology study to validate a structured diagnostic method used to diagnose female sexual dysfunction and its subtypes in postmenopausal women.

The currently accepted gold standard for diagnosis of female sexual dysfunction (FSD) is a nonstandardized interview by a clinician whose field of expertise is FSD. However, the limited number of experts in the field has implications for running efficient large-scale clinical trials. Therefore, we developed a structured diagnostic method (SDM) to enable diagnosis of FSD in postmenopausal women by health care professionals who are not FSD experts. Our study objectives were to evaluate both convergent validity and intrarater reliability of the SDM. The results showed that the method had good convergent validity and excellent intrarater reliability. Thus, we conclude that the SDM can reliably diagnose FSD status and FSD subtypes in postmenopausal women.

Current perspectives on the clinical assessment and diagnosis of female sexual dysfunction and clinical studies of potential therapies: a statement of concern.

INTRODUCTION: The assessment and diagnosis of female sexual dysfunction (FSD) are in a state of transition because of evolving concepts of female sexuality and suggested changes to the FSD diagnostic framework. AIM: To review the problems with current FSD diagnosis. METHODS: Multidisciplinary experts from five countries were assembled to convene a "Postmenopausal FSD Roundtable on specific topics related to FSD." MAIN OUTCOME MEASURE: Expert opinion was based on a review of evidence-based medical literature, presentation, and internal discussion. RESULTS: Current FSD diagnosis is challenging because of poorly defined distinctions between normal and abnormal, a limited ability to integrate subjective and objective findings and an inability to incorporate contextual factors that play a significant role in sexual behavior. The availability of self-administered questionnaires (SAQs) that assess various domains of female sexual function, as well as those developed specifically for postmenopausal women, suggests that a more structured approach to assessment and diagnosis may be possible. Several SAQs reflecting proposed changes to the FSD diagnostic framework by the American Foundation for Urologic Disease (AFUD), including the Sexual Function Questionnaire (SFQ) and the Female Sexual Distress Scale (FSDS), have been introduced and recently incorporated into a Structured Diagnostic Method (SDM). Recent regulatory decisions and events affecting the development of FSD interventions have highlighted the lack of consensus with regard to clinically meaningful FSD outcomes, as well as shortcomings in a U.S. Food and Drug Administration draft document that provides the primary guidance for conducting FSD clinical studies in the United States. CONCLUSIONS: Given the high cost and inherent risk of clinical studies, continued development efforts toward FSD therapies are unlikely to proceed in the absence of significant changes in regulatory guidance that reflect the current understanding of FSD and incorporate validated assessment tools.