Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Use Of The Levonorgestrel-releasing Intrauterine System In Women With Endometriosis, Chronic Pelvic Pain And Dysmenorrhea.

This report is a review of the medical literature on the use of the levonorgestrel-releasing intrauterine system (LNG-IUS) in women with endometriosis, adenomyosis, cyclic pelvic pain and dysmenorrhea. A review was carried out using the MEDLINE and EMBASE databases to evaluate the use of LNG-IUS in women with endometriosis and adenomyosis. Nine studies were identified, only two of which were randomized clinical trials. One compared the insertion of LNG-IUS after surgery with expectant conduct and the other compared the use of the device with a GnRH analogue (GnRH-a). All studies reported an improvement in pelvic pain and dysmenorrhea, and a reduction in menstrual bleeding. One study found an improvement in the staging of the disease at 6 months of use, and the studies that evaluated the use of LNG-IUS in women with adenomyosis reported a reduction in uterine volume. Furthermore, the only study in which women were followed up for 3 years after insertion found improvement in pelvic pain at 12 months of use. However, there was no improvement after that period. The use of LNG-IUS is an alternative for the medical treatment of women suffering from endometriosis, adenomyosis, chronic pelvic pain or dysmenorrhea, but experience is limited and long-term studies are necessary to reach definitive conclusions. However, for women who do not wish to become pregnant, this device offers the possibility of at least 5 years of treatment following one single intervention.75S134-

Práticas e condutas em relação a sintomas de endometriose: pesquisa com ginecologistas brasileiros

OBJECTIVE: The purpose is to assess current medical practice in the diagnosis of endometriosis by Brazilian gynecologists. METHODS: A Cross-sectional study using questionnaires was sent to all gynecologists of the São Paulo State Ob/Gyn Association. RESULTS: A total of 1,660 (31.8%) replies was received. Multiple logistic regression showed that physicians who stated that endometriosis can affect women of all ages was the variable significantly associated with suspicion of endometriosis. Diagnosis was delayed less than 12 months after the first consultation when patients complained of: infertility (OR = 1.81, 95% CI 1.01-3.22), dysmenorrhea (OR = 2.16, 95% CI 1.18-3.93) or chronic pelvic pain (CPP) (OR = 2.17, 95% CI 1.17-4.00). Time until diagnosis was shorter when the complaint was dysmenorrhea (OR = 1.33, 95% CI 1.05-1.69) or CPP (OR = 1.51, 95% CI 1.19-1.91) and when physicians had participated in congresses and lectures on gynecological endoscopy and endometriosis. CONCLUSION: Gynaecologists who are better informed suspect and diagnose endometriosis at an early stage.OBJETIVO: O objetivo deste estudo é conhecer as práticas de ginecologistas brasileiros em relação ao diagnóstico da endometriose. MÉTODOS: Estudo de coorte transversal utilizando questionários enviados a ginecologistas do Estado de São Paulo. RESULTADOS: Um total de 1.660 respostas foram recebidas (31,8%). A análise de regressão logística mostrou que médicos que acreditam que a endometriose pode ocorrer em qualquer idade foi a variável, associada a suspeita precoce de endometriose por parte do médico quando a paciente se queixa de: infertilidade (OR = 1.81, 95% IC 1.01-3.22), dismenorréia (OR = 2.16, 95% IC 1.18-3.93) ou dor pélvica crônica (OR = 2.17, 95% IC 1.17-4.00). O tempo até a indicação de um procedimento diagnóstico foi menor para médicos que participaram em congressos e aulas sobre endoscopia ginecológica e endometriose, e quando a queixa da paciente era de dismenorréia (OR = 1.33, 95% IC 1.05-1.69) ou dor pélvica crônica (OR = 1.51, 95% IC 1.19-1.91). CONCLUSÃO: Ginecologistas mais informados suspeitam de endometriose mais precocemente.52552

Current practice in the management of symptoms of endometriosis: a survey of Brazilian gynecologists

OBJECTIVE: The purpose is to assess current medical practice in the diagnosis of endometriosis by Brazilian gynecologists. METHODS: A Cross-sectional study using questionnaires was sent to all gynecologists of the São Paulo State Ob/Gyn Association. RESULTS: A total of 1,660 (31.8%) replies was received. Multiple logistic regression showed that physicians who stated that endometriosis can affect women of all ages was the variable significantly associated with suspicion of endometriosis. Diagnosis was delayed less than 12 months after the first consultation when patients complained of: infertility (OR = 1.81, 95% CI 1.01-3.22), dysmenorrhea (OR = 2.16, 95% CI 1.18-3.93) or chronic pelvic pain (CPP) (OR = 2.17, 95% CI 1.17-4.00). Time until diagnosis was shorter when the complaint was dysmenorrhea (OR = 1.33, 95% CI 1.05-1.69) or CPP (OR = 1.51, 95% CI 1.19-1.91) and when physicians had participated in congresses and lectures on gynecological endoscopy and endometriosis. CONCLUSION: Gynaecologists who are better informed suspect and diagnose endometriosis at an early stage.OBJETIVO: O objetivo deste estudo é conhecer as práticas de ginecologistas brasileiros em relação ao diagnóstico da endometriose. MÉTODOS: Estudo de coorte transversal utilizando questionários enviados a ginecologistas do Estado de São Paulo. RESULTADOS: Um total de 1.660 respostas foram recebidas (31,8%). A análise de regressão logística mostrou que médicos que acreditam que a endometriose pode ocorrer em qualquer idade foi a variável, associada a suspeita precoce de endometriose por parte do médico quando a paciente se queixa de: infertilidade (OR = 1.81, 95% IC 1.01-3.22), dismenorréia (OR = 2.16, 95% IC 1.18-3.93) ou dor pélvica crônica (OR = 2.17, 95% IC 1.17-4.00). O tempo até a indicação de um procedimento diagnóstico foi menor para médicos que participaram em congressos e aulas sobre endoscopia ginecológica e endometriose, e quando a queixa da paciente era de dismenorréia (OR = 1.33, 95% IC 1.05-1.69) ou dor pélvica crônica (OR = 1.51, 95% IC 1.19-1.91). CONCLUSÃO: Ginecologistas mais informados suspeitam de endometriose mais precocemente

Correlation Between Endometrial Histology, Microvascular Density And Calibre, Matrix Metalloproteinase-3 And Bleeding Pattern In Women Using A Levonorgestrel-releasing Intrauterine System.

The main reason for discontinuation of the levonorgestrel-releasing intrauterine system (LNG-IUS) is unpredictable bleeding pattern. The objective of the study was to evaluate the endometrial histology, microvascular density and calibre, and the quantification of matrix metalloproteinase (MMP-3) in long-term users of LNG-IUS, with and without bleeding. Endometrial biopsies were obtained from 58 healthy women, 29 who maintained some degree of endometrial bleeding and 29 who were amenorrhoeic. In the histological analysis, the majority of samples displayed a progestin-modified appearance. The major glandular diameter and the perimeter were significantly greater in the group of women with amenorrhoea. A significantly higher number of leukocytes was found in the group with bleeding (P = 0.014). No significant correlation was observed between the microvascular density or calibre and the bleeding pattern. MMP-3 showed a significantly higher number of reactive cells (P = 0.005) in the group who maintained some degree of bleeding. Women using LNG-IUS who maintained endometrial bleeding during its use presented a higher number of leukocytes and MMP-3 in the endometrium when compared to women using LNG-IUS who became amenorrhoeic. However, the results did not provide evidence for microvascular pattern changes.191778-8

Levonorgestrel-releasing Intrauterine System (mirena) As A Therapy For Endometrial Hyperplasia And Carcinoma.

82580-

Endometrial Chemokines, Uterine Natural Killer Cells And Mast Cells In Long-term Users Of The Levonorgestrel-releasing Intrauterine System.

The objective was to assess endometrial chemokines in users of the levonorgestrel-releasing intrauterine system (LNG-IUS) and correlate them with leucocyte populations, uterine natural killer cells (uNK) and mast cells (MCs). Endometrium was obtained from two groups of women who had been using LNG-IUS for 3 years or more: 11 amenorrhoeic women formed the non-bleeding group and 15 women who maintained some form of cyclic bleeding comprised the bleeding group. Specific antibodies were used for the assessment of neutrophils, uNK cells and MCs. Immunohistochemistry was performed to locate the chemokines 6Ckine and interleukin-8 (IL-8). Neutrophils were few and without differences between the two groups. uNK cells were significantly higher in the bleeding group (P < 0.0001). There was no difference between the total number of MCs and activated MCs, but there was a greater extracellular area stained for MC tryptase (P < 0.05). Chemokines 6CKine and IL-8 were abundant in the stroma and in the epithelium, and there was no difference between the groups. We observed more uNK cells in users with bleeding and a greater extracellular area stained for MC tryptase, although there were no differences between the number of MCs and activated MCs or the chemokines 6CKine and IL-8. uNK cells and MC products may play a role in provoking breakthrough bleeding in long-term users of the LNG-IUS.211129-3