Primary biliary cholangitis (PBC) is typically associated with elevated serum bile acid levels and pruritus, but pruritus is often refractory to treatment with existing therapies. This phase 2 study assessed the efficacy and safety of maralixibat, a selective, ileal, apical, sodium-dependent, bile acid transporter inhibitor, in adults with PBC and pruritus. Adults with PBC and pruritus who had received ursodeoxycholic acid (UDCA) for ≥6 months or were intolerant to UDCA were randomized 2:1 to maralixibat (10 or 20 mg/day) or placebo for 13 weeks in combination with UDCA (when tolerated).
View Article and Find Full Text PDFFragile X syndrome (FXS) is the most common monogenic cause of inherited intellectual and developmental disabilities. Mavoglurant, a selective metabotropic glutamate receptor subtype-5 antagonist, has shown positive neuronal and behavioral effects in preclinical studies, but failed to demonstrate any behavioral benefits in two 12-week, randomized, placebo-controlled, double-blind, phase IIb studies in adults and adolescents with FXS. Here we report the long-term safety (primary endpoint) and efficacy (secondary endpoint) results of the open-label extensions.
View Article and Find Full Text PDFBackground: A phase II randomized, placebo-controlled, double-blind study and subsequent open-label extension study evaluated the efficacy, safety, and tolerability of mavoglurant (AFQ056), a selective metabotropic glutamate receptor subtype-5 antagonist, in treating behavioral symptoms in adolescent patients with fragile X syndrome (FXS). A novel method was applied to analyze changes in symptom domains in patients with FXS using the narratives associated with the clinician-rated Clinical Global Impression-Improvement (CGI-I) scale.
Methods: In the core study, patients were randomized to receive mavoglurant (25, 50, or 100 mg BID) or placebo over 12 weeks.
Fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autistic spectrum disorder, is typically caused by transcriptional silencing of the X-linked FMR1 gene. Work in animal models has described altered synaptic plasticity, a result of the up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling, as a putative downstream effect. Post hoc analysis of a randomized, placebo-controlled, crossover phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes.
View Article and Find Full Text PDFExpert Opin Investig Drugs
January 2014
Introduction: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. With no curative treatment available, current therapeutic approaches are aimed at symptom management. FXS is caused by silencing the FMR1 gene, which encodes FMRP; as loss of FMRP leads to the development of symptoms associated with FXS.
View Article and Find Full Text PDFPsychopharmacology (Berl)
March 2014
Rationale: Advances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement.
Objectives: We review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders.
Dysregulation of the neuronal nicotinic acetylcholine receptor (NNR) system has been implicated in attention-deficit/hyperactivity disorder (ADHD), and nicotinic agonists improve attention across preclinical species and humans. Hence, a randomized, double-blind, placebo-controlled, crossover study was designed to determine the safety and efficacy of a novel α4β2 NNR agonist (ABT-894 (3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.
View Article and Find Full Text PDFObjective: ABT-089, an α4β2 neuronal nicotinic receptor partial agonist (generic name pozanicline), has demonstrated efficacy in adults with attention-deficit/hyperactivity disorder (ADHD) at doses of 40 mg once daily and 40 mg twice daily. The purpose of this exploratory pilot study was to obtain initial safety, tolerability, and efficacy data for an ABT-089 80-mg once-daily regimen to inform a decision of whether to include an 80-mg once-daily dose regimen in subsequent, definitive (phase 3) efficacy studies.
Method: This phase 2, randomized, double-blind, parallel-group, placebo-controlled pilot study was conducted at 12 sites from March to August 2008.
Rationale: α(4)β(2) Neuronal nicotinic receptors (NNRs) are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD).
Objectives: This study examined the efficacy and safety of the α(4)β(2) NNR partial agonist ABT-089 versus placebo in adults with ADHD.
Methods: In this multicenter, randomized, double-blind, placebo-controlled crossover study, subjects received placebo followed by ABT-089 (2 mg once daily [QD], 5 mg QD, 15 mg QD, 40 mg QD, or 40 mg twice daily [BID]), or vice versa, in a 2 × 2 crossover design.
Objective: To assess the safety and efficacy of ABT-089, a novel α(4)β(2) neuronal nicotinic receptor partial agonist, vs. placebo in children with attention-deficit/hyperactivity disorder (ADHD).
Method: Two multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of children 6 through 12 years of age were conducted.
Background: Genome-wide association studies in European Americans have reported several single-nucleotide polymorphisms (SNPs) in the lipoprotein lipase gene associated with plasma levels of high-density lipoprotein cholesterol (HDL-C) and triglycerides. However, the influences of the lipoprotein lipase SNPs on longitudinal changes of these lipids have not been systematically examined.
Methods And Results: On the basis of data from 2045 African Americans and 2116 European Americans in the Coronary Artery Risk Development in Young Adults study, we investigated cross-sectional and longitudinal associations of lipids with 8 lipoprotein lipase SNPs, including the 2 that have been reported in genome-wide association studies.
Objective: The objective of this long-term open-label study in adolescents was to assess the safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches.
Background: Two formulations of divalproex sodium have demonstrated efficacy in the prevention of migraine headaches in adults. However, no medications are currently approved for this indication in adolescents, and long-term safety data on agents for migraine prevention are lacking for this younger population.
Objective: To evaluate the long-term safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches in adolescents.
Background: Divalproex sodium has been approved for migraine prophylaxis in adults. A previous double-blind, placebo-controlled study of the efficacy and safety of divalproex sodium extended-release for prevention of migraine in adolescents was followed by the present long-term extension trial, which was designed to collect additional safety and tolerability data.
Objective: To evaluate the efficacy, tolerability, and safety of 3 different doses of divalproex sodium extended-release vs placebo in the prophylaxis of migraine headaches in adolescents.
Background: Divalproex sodium has been approved for migraine prophylaxis in adults, and previous uncontrolled data suggest divalproex sodium may be effective in preventing migraine in children and adolescents with acceptable tolerability.
Methods: This was a 12-week, phase 3, randomized, placebo-controlled, double-blind, parallel-group, multicenter study in approximately 300 adolescents aged 12 to 17 years with migraine headaches.
Background: Lung function at the end of life depends on its peak and subsequent decline. Because obesity is epidemic in young adulthood, we quantified age-related changes in lung function relative to body mass index (BMI).
Methods: The Coronary Artery Risk Development in Young Adults (CARDIA) study in 1985-86 (year 0) recruited 5,115 black and white men and women, aged 18-30.
Background: We hypothesized that fibrinogen, as a marker of chronic inflammation, is inversely associated with forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV(1)) in healthy persons.
Methods: The CARDIA cohort started in 1985 and included black and white men and women, aged 18-30, from the general population. Spirometry testing conducted at years 5 and 10 [FVC, FEV(1), and their ratio (FEV(1)/FVC)] was studied relative to plasma fibrinogen levels measured at year 5 (cross-sectional n = 4,040) and at year 7 (longitudinal n = 3,001), controlling for race, sex, age, height, smoking, asthma, body mass index, physical activity, birth control pill use, and alcohol intake.
Early life factors may influence pulmonary function. We measured forced expiratory volume in 1 second (FEV(1)) in 1985-1986 and 2, 5, and 10 years later in approximately 4,000 black and white men and women initially aged 18-30 years. We estimated the age pattern of FEV(1) according to family smoking status, early diagnosis of asthma, early smoking initiation, adult asthma, and cigarette smoking.
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