A phase IV clinical trial of gastrointestinal motility in adult patients with migraine before and after initiation of a calcitonin gene-related peptide ligand (galcanezumab) or receptor (erenumab) antagonist.

OBJECTIVE: To compare effects of an initial dose of calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) antagonists on gastrointestinal (GI) motility in patients with migraine and to explore if the mechanistic difference contributes to GI adverse events (AEs). BACKGROUND: Different frequencies of constipation have been observed between CGRP mAbs that target the ligand (galcanezumab [GMB]) or receptor (erenumab [ERE]). METHODS: Patients (n = 65) with migraine without significant GI symptoms were enrolled in a multi-center, single-blind phase IV clinical trial (NCT04294147) and randomized 1:1 to receive GMB (240 mg; n = 33) or ERE (140 mg; n = 32). GI whole and regional transit times were assessed using a wireless motility capsule 1 week before and 2 weeks after mAb administration. The primary endpoint was change from baseline in colonic transit time (CTT) within each treatment group. Other measures included GI Symptom Rating Scale (GSRS), Bristol Stool Form Scale (BSFS), and spontaneous bowel movement (SBM) evaluation. AEs were monitored throughout the study. RESULTS: Baseline characteristics indicated significant GI transit time variability with minimal GI reported symptoms. While not statistically significant, a numerical mean increase in CTT was observed in ERE patients (n = 28, mean [SD] at baseline: 33.8 [29.4] h; least square [LS] mean [SE] change: 5.8 [5.7] h, 95% confidence interval [CI] -5.7 to 17.2, p = 0.320), while GMB decreased CTT (n = 31, mean [SD] at baseline: 29.3 [24.5] h; LS mean [SE] change: -5.4 [5.4] h, 95% CI -16.2 to 5.5, p = 0.328) compared to baseline. No meaningful changes were observed in other regional transit times. ERE significantly reduced BSFS (LS mean [SE] score -0.5 [0.2], p = 0.004) and SBM (LS mean [SE] -1.2 [0.5], p = 0.0120), and increased GSRS-constipation compared to baseline (LS mean [SE] score 0.3 [0.1], p = 0.016). GMB increased GSRS-constipation (LS mean [SE] score 0.4 [0.1], p = 0.002). There were no discontinuations due to or serious AEs. A higher percentage of treatment-emergent AEs were reported with ERE than GMB (ERE: nine of 32 [28.1%] versus GMB: three of 33 [9.1%]), with constipation the most frequently reported (ERE: five of 32 [15.6%] versus GMB one of 33 [3.0%]). CONCLUSION: While the primary endpoint of this study was not met, secondary and tertiary endpoints support a within- and between-treatment change in GI effects suggesting possible mechanistic differences between ligand (GMB) and receptor (ERE) antagonism.

Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension.

OBJECTIVE: Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension. METHODS: A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day. RESULTS: There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks. CONCLUSIONS: This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

Memantine and functional communication in Alzheimer's disease: results of a 12-week, international, randomized clinical trial.

Post hoc analyses suggest that memantine treatment may provide communication-related benefits in patients with Alzheimer's disease (AD). In this 12-week, international, randomized, double-blind, placebo-controlled trial of memantine (10 mg bid), the functional communication abilities of patients with AD (MMSE range: 10-19) were assessed using the Functional Linguistic Communication Inventory (FLCI; primary measure). Two combined subscales (Social Communication and Communication of Basic Needs) from the American Speech-Language-Hearing Association Functional Assessment of Communication Skills for Adults (ASHA FACS; secondary measure) were administered to caregivers. Treatment-emergent adverse events were also recorded. After 12 weeks, memantine-treated patients (n = 133) demonstrated a non-significant improvement on the FLCI (placebo: -0.6; memantine: 0.7; p = 0.070, LOCF) and a significant improvement on the ASHA FACS (placebo: -5.3; memantine: 0.5; p = 0.022), compared with placebo-treated patients (n = 124). Memantine had a low incidence of adverse events. In patients with moderate AD, memantine treatment improved functional communication, as recognized by caregivers.

Magnetic resonance imaging and neuropsychological results from a trial of memantine in Alzheimer's disease.

BACKGROUND: This study was designed to assess changes in brain volume and cognitive abilities in memantine-treated patients with Alzheimer's disease (AD) by using an exploratory, single-arm, delayed-start design. METHODS: Cholinesterase inhibitor-treated patients with AD (N = 47; Mini-Mental State Examination score range: 15-23) were enrolled in an observational lead-in period (weeks: 1-24), followed by an open-label period of add-on memantine treatment (weeks: 25-48). The patients underwent magnetic resonance imaging at weeks 0 (baseline), 24 (immediately before memantine initiation), and 48 (endpoint), and a battery of neuropsychological tests at weeks 0, 24, 28, 36, and 48. The primary outcome measure was the annualized rate of change (%) in total brain volume (TBV) between the two study periods. Data were analyzed using paired t-tests. RESULTS: There were no statistically significant differences in the rates of change in TBV, ventricular volume, or left hippocampal volume between the study periods; however, the memantine treatment period was associated with a significantly slower right hippocampal atrophy (-5.5% ± 12.0% vs -10.8% ± 7.2%; P = .038). Memantine treatment was also associated with superior performances on the Boston Naming Test (P = .034) and the Trail Making Test, Part B (P = .001), but also with a higher number of errors (i.e., repetitions and intrusions) on the California Verbal Learning Test. Memantine was found to be safe and well tolerated. CONCLUSIONS: In this study, no difference in the rates of TBV change between the two periods was observed; however, memantine treatment was found to be associated with slowing of right hippocampal atrophy, and with improvement on one test of executive functioning as well as a test of confrontation naming ability. Trials using structural magnetic resonance imaging and a delayed-start design may be a feasible option for the assessment of treatments for AD.

Memantine efficacy and safety in patients with acute mania associated with bipolar I disorder: a pilot evaluation.

OBJECTIVE: Evaluate the efficacy and tolerability of memantine (20, 30, and 40 mg/d) in the acute treatment of adults with bipolar I disorder hospitalized for mania. METHODS: This multicenter, open-label, pilot trial included adults with bipolar I disorder (manic or mixed episode, with and without psychotic features). Patients were assigned to 21 days of treatment: cohort 1, 20 mg/d (range, 20-30 mg/d); cohort 2, 30 mg/d (range, 30-40 mg/d); cohort 3, 40 mg/d (range, 30-50 mg/d). Efficacy measures included the Young Mania Rating Scale (YMRS) and the Mania Rating Scale (>or=50% reduction in total score from baseline). The change from baseline was also assessed using the Positive and Negative Syndrome Scale in patients with psychiatric symptoms, Positive and Negative Syndrome Scale-Excited Component, Clinical Global Impression Severity and Improvement scores, and Montgomery Asberg Depression Rating Scale. RESULTS: A total of 35 patients were enrolled; 33 patients received at least 1 dose of memantine and had at least 1 postbaseline assessment using YMRS. Greatest improvement occurred in cohort 1 where half of the patients responded to memantine based on YMRS and Mania Rating Scale. At day 21, a response was observed in all patient cohorts. Treatment-emergent adverse events were reported in 19 patients (54.3%). The most frequently reported adverse events (>or=4 patients) included constipation, nausea, and headache. CONCLUSIONS: The response to memantine combined with its tolerability support conducting large-sized randomized controlled trials to investigate further the use of memantine monotherapy in the treatment of mania.

Healthy Growth: project description and baseline findings.

OBJECTIVES: The purpose of the study was to describe the physical activity, blood pressure, and body fat patterns of sixth-grade, African-American girls (N = 82), who participated in the Healthy Growth Study. The purpose of the primary study questions was to determine which sets of variables best predict blood pressure, physical activity, and body fat. DESIGN AND METHODS: This paper is a cross sectional analysis of the first assessment of a 5-year longitudinal project. Standard procedures were used to assess height, weight, skinfolds, blood pressure, physical activity, predictors of physical activity, maturation, dietary intake, fitness level, and health behaviors. RESULTS: The average age of the subjects was 12.3 years; almost two-thirds of the girls had reached menarche. Fifty-two percent of the 13-year-olds had body mass index (BMI) values greater than the 85th percentile for their age and sex compared to 32% of the 12-year-olds. None of the variables were significantly related to diastolic or systolic blood pressure. Physical activity was significantly and negatively related to total percent of calories from fat and to breast stages and positively related to waist/thigh ratio. Body mass index (BMI) was significantly and positively related to breast stages. CONCLUSIONS: Important developmental differences between 12- and 1 3-year-olds were evident. Body mass index (BMI) was mainly dependent on physical maturity. No relationship was found between BMI and blood pressure. The relationship between physical activity and waist/thigh ratio merits further study. The importance of BMI and physical inactivity as potential indicators of cardiovascular risk in adolescent girls is discussed. Developmentally appropriate and culturally competent interventions are recommended to increase physical activity and healthy eating behaviors among adolescents.

Precision of measuring body fat distribution in adolescent African American girls from the 'healthy growth study'.

Precision estimates are given for anthropometric assessment of body fat distribution in participants (n = 86) of the Healthy Growth Study (total n = 154). This five year longitudinal study explored the psychosocial and biologic influences on activity levels in urban adolescent African American girls. The basic anthropometric data include height, weight, four body and limb circumferences, and five skinfold measurements. It is proposed that ratio indices of body fat distribution are likely to have poorer precisions than the single variables which they comprise, and that ratios based on skinfolds may be particularly sensitive to this problem. The precision of the body mass index (BMI) and principal components of skinfold fatness and fat distribution are also considered. Precisions were greater than 0.95 (intraclass correlation from a random-effects analysis of variance) for most anthropometric dimensions and indices, including the BMI and the first principal component of fatness. However, three of the five skinfolds had lower precisions (0.84-0.93). In contrast, the precisions of all indices of body fat distribution were 0.90 or less (range: 0.57-0.87 skinfold ratios; 0.83-0.90 circumference ratios). Of the ratios, conicity was most stable at 0.90 for repeated measures by both the same and different observers. A second principal component of central fat did not have precisions noticeably better than skinfold ratios (0.79-0.82). Indices of fat distribution may have lower reliabilities than the single variables that they comprise, because errors may be compounded when dividing one variable by another or in linear combinations of measurements other than the first principal component. This problem should be taken into account in clinical and epidemiologic investigations of body fat distribution. © 1996 Wiley-Liss, Inc.