Long-term safety of glycopyrrolate: A randomized study in patients with moderate-to-severe COPD (GEM3).

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the United States. Long-acting muscarinic antagonists (LAMAs) are a class of medications used as maintenance therapy for COPD. The GEM3 (Glycopyrrolate Effect on syMptoms and lung function) study assessed the long-term safety and efficacy of a LAMA, glycopyrrolate (GLY) 15.6 µg twice daily (b.i.d.), compared with an approved long-acting ß2-agonist (LABA), indacaterol (IND) 75 µg once daily (q.d.) in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation. METHODS: This 52-week, multicenter, double-blind, parallel-group study randomized patients (1:1) of the United States to receive GLY 15.6 µg b.i.d. or IND 75 µg q.d. both delivered via the Neohaler(®) device. The primary objective was to assess the safety and tolerability in terms of adverse event (AE) reporting rates over 52 weeks. Safety was also determined by evaluating multiple secondary endpoints, including vital signs, electrocardiograms (ECGs), and time to first moderate or severe exacerbation. Efficacy-related secondary endpoints included pre-dose forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). RESULTS: Of the 511 randomized patients (GLY, n = 254; IND, n = 257), 81.6% completed the study. The overall incidences of AEs (GLY, 77.3%; IND, 77.0%) and serious AEs (GLY, 13.1%; IND, 13.3%) were comparable between the groups. The incidence of major adverse cardiovascular events was low and comparable between the groups. No clinically relevant differences for vital signs or ECG parameters were observed between the treatment groups. The three sudden deaths reported within 30 days of the treatment (GLY, n = 2; IND, n = 1) were adjudicated as unrelated to the study medication. In terms of efficacy, GLY 15.6 µg b.i.d. showed improvements in pre-dose FEV1 and FVC from baseline, which was comparable to those with IND 75 µg q.d., with no statistically significant differences. No significant differences were observed between the treatment groups in the time to first moderate or severe COPD exacerbation. CONCLUSION: GLY 15.6 µg b.i.d. showed a long-term safety profile comparable to that of IND 75 µg q.d. and provided rapid and sustained bronchodilation over 52 weeks in patients with COPD with moderate-to-severe airflow limitation. CLINICAL TRIAL REGISTRATION NUMBER: NCT01697696.

Modified constraint-induced movement therapy after childhood stroke.

The aim of this pilot study was to investigate feasibility, tolerability, and effect of modified constraint-induced movement therapy (mCIT) in children with hemiparesis after arterial ischaemic stroke (AIS). Children with chronic hemiparesis and impaired hand function after AIS had mCIT for 2 hours a day, 5 days a week for 4 weeks. Pre- and post-therapy assessments included indices of sensorimotor function, quality of upper limb movement, functional therapy goals, and child and parent interviews. Of eight participants initially recruited, six (one male, five females) completed mCIT (median age 12y 3mo; range 6y 10mo-15y 2mo). Hemiparesis was predominantly spastic in three participants and dystonic in the others; all had severely impaired hand function. After mCIT there were no significant improvements in sensorimotor function or quality of upper limb movement. However, all children improved in individual therapy goals related to functional performance. Children and parents were positive about mCIT. The use of mCIT is a promising intervention for children with chronic acquired hemiparesis. In this severely impaired group functional improvements were seen after therapy despite unchanged sensorimotor measures.