A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known. METHODS: We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients. RESULTS: In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed. CONCLUSIONS: This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.).

Mediation analysis of time-to-event endpoints accounting for repeatedly measured mediators subject to time-varying confounding.

In this article, we will present statistical methods to assess to what extent the effect of a randomised treatment (versus control) on a time-to-event endpoint might be explained by the effect of treatment on a mediator of interest, a variable that is measured longitudinally at planned visits throughout the trial. In particular, we will show how to identify and infer the path-specific effect of treatment on the event time via the repeatedly measured mediator levels. The considered proposal addresses complications due to patients dying before the mediator is assessed, due to the mediator being repeatedly measured, and due to posttreatment confounding of the effect of the mediator by other mediators. We illustrate the method by an application to data from the LEADER cardiovascular outcomes trial.

Evaluation of Bayesian models of substitution rate evolution--parental guidance versus mutual independence.

We have evaluated the performance of two classes of probabilistic models for substitution rate variation over phylogenetic trees. In the first class, branch rates are considered to be independent and identically distributed (i.i.d.) stochastic variables. Three versions with respect to the underlying distribution (Gamma, Inverse Gaussian, and LogNormal) are considered. The i.i.d. models are compared with the autocorrelated (AC) model, where rates of adjacent nodes in the tree are AC, so that a node rate is LogNormal distributed around the rate of the parent node. The performance of different models is evaluated using three empirical data sets. For all data sets, it was clear that all tested models extracted substantial knowledge from data when posterior divergence time distributions were compared with the prior distributions and, furthermore, that they clearly outperformed a molecular clock. Moreover, the descriptive power of the i.i.d. models, as evaluated by Bayes factors, was either equal to or clearly better than that of the AC model. The latter effect increased with extended taxon sampling. Likewise, under none of the models could we find compelling evidence, in any of the data sets, for rate correlation between adjacent branches/nodes. These findings challenge previous suggestions of universality of autocorrelation in sequence evolution. We also performed an additional comparison with a divergence time prior including calibration information from fossil evidence. Adding fossil information to the prior had negligible effect on Bayes factors and mainly affected the width of the posterior distribution of the divergence times, whereas the relative position of the mean divergence times were largely unaffected.

Semaglutide for the treatment of non-alcoholic steatohepatitis: Trial design and comparison of non-invasive biomarkers.

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease. There is a clear need to develop pharmacological treatment for patients with NASH as well as biomarkers that can diagnose the disease. We describe a trial of semaglutide treatment for NASH, identify key patient characteristics and compare the relationship of patient characteristics and non-invasive biomarkers/scores. NCT02970942 is a randomised, double-blind, placebo-controlled, multi-national Phase 2 trial of daily subcutaneous semaglutide (0.1 mg, 0.2 mg, 0.4 mg) in patients with biopsy-confirmed NASH, F1-F3 fibrosis, NAFLD Activity Score ≥ 4, and body mass index (BMI) > 25 kg/m2. Exploratory analyses were performed to evaluate correlations between baseline parameters and biomarkers in NASH. Mean (standard deviation [SD]) age of 320 randomised patients was 55 (11) years, mean BMI was 36 (6) kg/m2, and 199 (62%) had type 2 diabetes. Of the total patients, 28% had F1 fibrosis, 23% had F2 fibrosis and 49% had F3 fibrosis. The highest area under the receiver operating characteristic curve (0.69) for accuracy in classifying fibrosis stage, F2-3 versus F1, was observed for Fib-4 and Enhanced Liver Fibrosis (ELF). No substantial correlation between BMI or other clinical or biochemical parameters and fibrosis stage was observed. In this large Phase 2 trial of semaglutide treatment for NASH, the clinical profile of enrolled patients was typical for patients with NASH. Of the investigated biomarkers/scores, ELF and Fib-4 showed the most apparent correlation in classifying fibrosis stage, but had only moderate predictive value.

Cardiovascular Risk Reduction With Liraglutide: An Exploratory Mediation Analysis of the LEADER Trial.

OBJECTIVE: The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (ClinicalTrials.gov reg. no. NCT01179048) demonstrated a reduced risk of cardiovascular (CV) events for patients with type 2 diabetes who received the glucagon-like peptide 1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial. RESEARCH DESIGN AND METHODS: We performed exploratory analyses to identify potential mediators of the effect of liraglutide on major adverse CV events (MACE; composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) from the following candidates: glycated hemoglobin (HbA1c), body weight, urinary albumin-to-creatinine ratio (UACR), confirmed hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure, and LDL cholesterol. These candidates were selected as CV risk factors on which liraglutide had an effect in LEADER such that a reduction in CV risk might result. We used two methods based on a Cox proportional hazards model and the new Vansteelandt method designed to use all available information from the mediator and to control for confounding factors. RESULTS: Analyses using the Cox methods and Vansteelandt method indicated potential mediation by HbA1c (up to 41% and 83% mediation, respectively) and UACR (up to 29% and 33% mediation, respectively) on the effect of liraglutide on MACE. Mediation effects were small for other candidates. CONCLUSIONS: These analyses identify HbA1c and, to a lesser extent, UACR as potential mediators of the CV effects of liraglutide. Whether either is a marker of an unmeasured factor or a true mediator remains a key question that invites further investigation.

Vigilance and sustained attention in children and adults with ADHD.

OBJECTIVE: The present article tests the hypothesis of a sustained attention deficit in children and adults suffering from ADHD. METHOD: Vigilance and sustained attention of 52 children with ADHD and 38 adults with ADHD were assessed using a computerized vigilance task. Furthermore, the attentional performance of healthy children (N = 52) and healthy adults (N = 38) was examined. RESULTS: Children and adults with ADHD performed significantly less well in the vigilance task than healthy participants (main effect for group). Furthermore, children and adults showed a significant decrease of performance over time (time-on-task effects). However, there was no greater decrement of performance with the passage of time in patient groups than in control groups (group-by-time interaction). CONCLUSION: The present results do not support the hypothesis of a sustained attention deficit in children and adults with ADHD.

Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity.

BACKGROUND: Obesity and type 2 diabetes are drivers of non-alcoholic fatty liver disease (NAFLD). Glucagon-like peptide-1 analogues effectively treat obesity and type 2 diabetes and may offer potential for NAFLD treatment. AIM: To evaluate the effect of the glucagon-like peptide-1 analogue, semaglutide, on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD. METHODS: Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight. RESULTS: Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end-of-treatment ALT reductions were 6%-21% (P<0.05 for doses≥0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%-46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end-of-treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change. CONCLUSIONS: Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.

[Intensive outpatient group treatment for adolescents with eating disorders]. / trEATit - Intensive ambulante Gruppentherapie von Jugendlichen mit Essstörungen.

We present an intensive outpatient group treatment for girls with eating disorders (anorexia nervosa, bulimia nervosa, binge eating disorder) additionally to/instead of inpatient treatment or individually treatment by psychotherapists. The therapy concept is primarily behaviour therapy oriented, encouraging the self-management-abilities of the patients thereby learning self-determination and responsibility in dealing with their illness. The slow-open group concept provokes group cohesion, solidarity and support among girls, who share similar age-related development-stages and eating disorders. Other than cognitive behaviour therapy and the principles of self-management we use client-centered therapy, art-, dance- and nutritional therapy. For each patient an individual treatment plan is adapted depending on age, individual symptoms, problems and motivation. Each member of the group has to accept defined group rules during the group sessions. The group takes place twice a week and on one Saturday per month. The adolescents stay in their social environment. Transfer of therapeutic success into daily life therefore is immediate and longlasting. Duration of therapy is between four months and one year, longer only in complex cases. Parallel to the parent/patient cooperation a parental psycho-educative group is available.

Effects of methylphenidate on multiple components of attention in children with attention deficit hyperactivity disorder.

RATIONALE: Methylphenidate (MPH) has been shown to be effective in the treatment of attention deficits in children with attention deficit hyperactivity disorder (ADHD). Although a variety of studies have been performed, there is little available information as to which components of attentional functioning are disturbed in ADHD. OBJECTIVES: The aim of the present study was to monitor the effect of MPH on various measures of attention in children with ADHD. METHODS: In a double-blind, placebo-controlled, crossover study, the attentional functioning of 58 children diagnosed with ADHD without psychiatric comorbidity was examined. Assessment of attention was performed on their usual MPH treatment and following withdrawal of the drug. Furthermore, the attentional performance of 58 healthy children was assessed. The test battery consisted of reaction time tasks, including measures of alertness, vigilance, divided attention, flexibility, and aspects of selective attention such as focused attention, inhibition, and integration of sensory information. RESULTS: In comparison to the test performance of healthy children, children with ADHD displayed impairments of vigilance, divided attention, flexibility, and aspects of selective attention including focused attention, inhibition, and integration of sensory information. Statistical comparison of attentional functioning of children with ADHD on and off MPH treatment revealed that the medication resulted in an improved task accuracy regarding vigilance, divided attention, inhibition, focused attention, integration of sensory information, and flexibility. CONCLUSION: The present findings indicate that various aspects of attention are markedly impaired in children with ADHD. Treatment with MPH was accompanied by improvements in attention functions of small to moderate sizes. Although MPH-induced improvements were observed in a broad range of attention measures, children with ADHD who were on MPH treatment nevertheless displayed serious deficits in a number of components of attention.

Laterality judgments in people with low back pain--A cross-sectional observational and test-retest reliability study.

BACKGROUND: Disruption of cortical representation, or body schema, has been indicated as a factor in the persistence and recurrence of low back pain (LBP). This has been observed through impaired laterality judgment ability and it has been suggested that this ability is affected in a spatial rather than anatomical manner. OBJECTIVES: We compared laterality judgment performance of foot and trunk movements between people with LBP with or without leg pain and healthy controls, and investigated associations between test performance and pain. We also assessed the test-retest reliability of the Recognise Online™ software when used in a clinical and a home setting. DESIGN: Cross-sectional observational and test-retest study. METHODS: Thirty individuals with LBP and 30 healthy controls performed judgment tests of foot and trunk laterality once supervised in a clinic and twice at home. RESULTS: No statistically significant group differences were found. LBP intensity was negatively related to trunk laterality accuracy (p = 0.019). Intraclass correlation values ranged from 0.51 to 0.91. Reaction time improved significantly between test occasions while accuracy did not. CONCLUSIONS: Laterality judgments were not impaired in subjects with LBP compared to controls. Further research may clarify the relationship between pain mechanisms in LBP and laterality judgment ability. Reliability values were mostly acceptable, with wide and low confidence intervals, suggesting test-retest reliability for Recognise Online™ could be questioned in this trial. A significant learning effect was observed which should be considered in clinical and research application of the test.

Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE Treat-To-Target Randomized Trial.

OBJECTIVE: To investigate whether liraglutide added to treat-to-target insulin improves glycemic control and reduces insulin requirements and body weight in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A 52-week, double-blind, treat-to-target trial involving 1,398 adults randomized 3:1 to receive once-daily subcutaneous injections of liraglutide (1.8, 1.2, or 0.6 mg) or placebo added to insulin. RESULTS: HbA1c level was reduced 0.34-0.54% (3.7-5.9 mmol/mol) from a mean baseline of 8.2% (66 mmol/mol), and significantly more for liraglutide 1.8 and 1.2 mg compared with placebo (estimated treatment differences [ETDs]: 1.8 mg liraglutide -0.20% [95% CI -0.32; -0.07]; 1.2 mg liraglutide -0.15% [95% CI -0.27; -0.03]; 0.6 mg liraglutide -0.09% [95% CI -0.21; 0.03]). Insulin doses were reduced by the addition of liraglutide 1.8 and 1.2 mg versus placebo (estimated treatment ratios: 1.8 mg liraglutide 0.92 [95% CI 0.88; 0.96]; 1.2 mg liraglutide 0.95 [95% CI 0.91; 0.99]; 0.6 mg liraglutide 1.00 [95% CI 0.96; 1.04]). Mean body weight was significantly reduced in all liraglutide groups compared with placebo ETDs (1.8 mg liraglutide -4.9 kg [95% CI -5.7; -4.2]; 1.2 mg liraglutide -3.6 kg [95% CI -4.3; -2.8]; 0.6 mg liraglutide -2.2 kg [95% CI -2.9; -1.5]). The rate of symptomatic hypoglycemia increased in all liraglutide groups (estimated rate ratios: 1.8 mg liraglutide 1.31 [95% CI 1.07; 1.59]; 1.2 mg liraglutide 1.27 [95% CI 1.03; 1.55]; 0.6 mg liraglutide 1.17 [95% CI 0.97; 1.43]), and hyperglycemia with ketosis increased significantly for liraglutide 1.8 mg only (event rate ratio 2.22 [95% CI 1.13; 4.34]). CONCLUSIONS: Liraglutide added to insulin therapy reduced HbA1c levels, total insulin dose, and body weight in a population that was generally representative of subjects with type 1 diabetes, accompanied by increased rates of symptomatic hypoglycemia and hyperglycemia with ketosis, thereby limiting clinical use in this group.

A randomized, rater-blinded, crossover study comparing the clinical efficacy of Ritalin(®) LA (methylphenidate) treatment in children with attention-deficit hyperactivity disorder under different breakfast conditions over 2 weeks.

Several extended-release methylphenidate medications are available for treatment of children with ADHD. Pharmacokinetic investigations suggest that the serum levels of methylphenidate are partially altered when the medication is taken without breakfast. Clinical data comparing different breakfast situations are missing. In this study, different breakfast compositions and their influence on treatment with Ritalin LA are investigated. A total of 150 patients were enrolled in a rater-blinded, randomized crossover trial that compared a minimal breakfast with a standard breakfast in patients under stable treatment with Ritalin LA. Ratings for clinical efficacy were carried out after 1 week by teachers and parents (FBB-ADHS), as well as physicians (CGI). Additionally, a math test was administered to the patients. Of the total patients, 144 finished the trial with a breakfast compliance of 93%. All of the clinical rating scales showed consistently no difference between the two breakfast conditions. Non-inferiority of minimal breakfast versus standard breakfast was shown to be statistically significant (FBB-AHDS(Teacher): 0.97 with minimal breakfast, 1.01 with standard breakfast, P < 0.0001). The clinical efficacy of Ritalin LA is not influenced by breakfast and works independently of food intake.

A double-blind, randomized, placebo/active controlled crossover evaluation of the efficacy and safety of Ritalin ® LA in children with attention-deficit/hyperactivity disorder in a laboratory classroom setting.

OBJECTIVES: The primary objective of this study was to demonstrate efficacy of Ritalin(®) LA 20 mg by showing superiority to placebo and noninferiority to Medikinet(®) Retard in a laboratory classroom setting. Secondary objectives included safety/tolerability and further efficacy parameters. METHODS: A total of 147 children with attention-deficit/hyperactivity disorder (ADHD) diagnosed by the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) and aged 6-14 (81% males) and known to be methylphenidate (MPH) responders were enrolled in this multicenter, double-blind, randomized, placebo/active-controlled, three-period (7 days each) crossover study. The Swanson, Kotlin, Agler, M-Flynn, and Pelham (SKAMP) scale was used for efficacy ratings. The mean of SKAMP Combined ratings performed at 10:30 a.m., at 12:00 a.m., and at 1:30 p.m. was defined as the primary parameter. RESULTS: In all, 146 patients completed all treatment periods. Intensity and frequency of adverse events were comparable between the two formulations. Ritalin(®) LA demonstrated superiority compared to placebo (p<0.0001). The observed difference in the SKAMP scores between Ritalin(®) LA and Medikinet(®) Retard between the hours 1.5 until 4.5 did not exceed the noninferiority margin (p=0.0003); therefore, the difference is regarded as not clinically relevant. Similar results were obtained for the secondary efficacy variables. CONCLUSION: Ritalin(®) LA is an efficacious, well-tolerated treatment option for children aged 6-14 with ADHD.

[Analysis of comorbid psychiatric disorders in child and adolescent psychiatry using the standardised basic documentation]. / Analyse der komorbiden psychiatrischen Diagnosen anhand der Basisdokumentation der Kinder- und Jugendpsychiatrie.

A slightly modified version of the basic documentation of the Child and Adolescent Psychiatric Associations is used to record in a standardised way important characteristics of the patients consulting clinics in Munich and Regensburg. The focus of the instrument is on the diagnostic classification of the symptoms according to the multiaxial classification scheme. The data of 5166 patients were analysed for frequency and type of combined psychiatric disorder. The results showed, that more than 60 % of the patients had more than one psychiatric diagnosis. The type of the comorbid disorders are discussed.

[Evaluation of a group for parents of children with attention deficit hyperactivity disorder (ADHD)]. / Evaluation einer Elterngruppe für Eltern von Kindern mit Aufmerksamkeitsdefizit und Hyperaktivitätsstörung (ADHS).

OBJECTIVE: The curriculum of a group for parents of children with ADHD and its evaluation by the participants are presented. METHOD: A questionnaire was sent to the participants and answered anonymously. RESULTS: With a response rate of 59 %, mainly positive ratings were obtained. Information on the nature of the disorder, on behavioural strategies and the mutual exchange with other parents and the therapists were considered especially helpful. CONCLUSIONS: Information on ADHD, behavioural interventions and the exchange among co-parents contribute substantially to the success of a parent training group.

[Basic Documentation in Child and Adolescent Psychiatry: Preliminary Data Analysis and Practicability] / Die Basisdokumentation in der Kinder- und Jugendpsychiatrie: Erste Auswertungen und Erfahrungen.

A lightly modified version of the basic documentation of the Child and Adolescent Psychiatric Associations was introduced in three different clinics. Relevant items were analysed for about 5300 patients. The data of the 3 clinics were compared. There was a fair amount of agreement in the age structure and the distribution of the diagnoses between the clinics. A regular and detailed comparative analysis of the data will be developed as a measure of quality. The results of these analyses will be discussed in the 3 clinics and implemented in the daily routines.

[Basic documentation in child and adolescent psychiatry: first evaluations and experiences]. / Die Basisdokumentation in der Kinder- und Jugendpsychiatrie: Erste Auswertungen und Erfahrungen.

A lightly modified version of the basic documentation of the Child and Adolescent Psychiatric Associations was introduced in three different clinics. Relevant items were analysed for about 5300 patients. The data of the 3 clinics were compared. There was a fair amount of agreement in the age structure and the distribution of the diagnoses between the clinics. A regular and detailed comparative analysis of the data will be developed as a measure of quality. The results of these analyses will be discussed in the 3 clinics and implemented in the daily routines.