Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial.

INTRODUCTION: This phase III, double-blind, randomised, placebo-controlled trial (and extension phase) was designed to assess the efficacy and safety of velmanase alfa (VA) in alpha-mannosidosis (AM) patients. METHODS: Twenty-five patients were randomised to weekly 1 mg/kg VA or placebo for 52 weeks. At study conclusion, placebo patients switched to VA; 23 patients continued receiving VA in compassionate-use/follow-on studies and were evaluated in the extension phase [last observation (LO)]. Co-primary endpoints were changes in serum oligosaccharide (S-oligo) and in the 3-min stair-climb test (3MSCT). RESULTS: Mean relative change in S-oligo in the VA arm was -77.6% [95% confidence interval (CI) -81.6 to -72.8] at week 52 and -62.9% (95% CI -85.8 to -40.0) at LO; mean relative change in the placebo arm was -24.1% (95% CI -40.3 to -3.6) at week 52 and -55.7% (95% CI -76.4 to -34.9) at LO after switch to active treatment. Mean relative change in 3MSCT at week 52 was -1.1% (95% CI -9.0 to 7.6) and - % (95% CI -13.4 to 6.5) for VA and placebo, respectively. At LO, the mean relative change was 3.9% (95% CI -5.5 to 13.2) in the VA arm and 9.0% (95% CI -10.3 to 28.3) in placebo patients after switch to active treatment. Similar improvement pattern was observed in secondary parameters. A post hoc analysis investigated whether some factors at baseline could account for treatment outcome; none of those factors were predictive of the response to VA, besides age. CONCLUSIONS: These findings support the utility of VA for the treatment of AM, with more evident benefit over time and when treatment is started in the paediatric age.

Formal training in general movement assessment is required to effectively evaluate infants with perinatal asphyxia in outpatient settings.

AIM: General movement assessment (GMA) can help to identify children with a high risk of developing neurological dysfunction, such as cerebral palsy, and certified training is provided in this specialism. The aim of this study was to investigate the feasibility and reliability of using video recordings to assess GMA, in a busy Danish outpatient clinic. METHODS: The study comprised 30-term infants born with perinatal asphyxia, who were video recorded at three months. They were assessed by two certified GMA observers and re-assessed two weeks later. Interobserver and intra-observer agreements were analysed using proportional agreement, and nominal kappa statistics were used to calculate 95% confidence intervals (95% CI). RESULTS: We found substantial and almost perfect interobserver and intra-observer reliability. Intra-observer agreement was 0.85 (95% CI: 0.65-1.00; p < 0.0001) and 0.85 (95% CI: 0.62-1.00; p < 0.0001), and interobserver agreement was 0.71 (95% CI: 0.45-0.96; p < 0.0001) at time point one and 0.85 (95% CI: 0.63-1.00; p < 0.0001) two weeks later. All video recordings were completed within our multidisciplinary outpatient clinic without delay. CONCLUSION: This study demonstrated the reliability of the GMA method in a busy multidisciplinary Danish paediatric outpatient setting, when assessors had been formally trained in the method and used it regularly.

Threshold electrical stimulation (TES) in ambulant children with CP: a randomized double-blind placebo-controlled clinical trial.

A randomized double-blind placebo-controlled clinical trial was carried out to determine whether a group of stable children with cerebral palsy (36 males, 21 females; mean age 10 years 11 months, range 5 to 18 years) would improve their motor skills after 12 months of threshold electrical stimulation (TES). Two thirds received active and one third received inactive stimulators. For the primary outcome we constructed a set of plausible motor function tests and studied the change in summary indices of the performance measurements. Tests were videotaped and assessed blindly to record qualitative changes that might not be reflected in performance measurements. We also judged range of motion, degree of spasticity, and muscle growth measured by CT. Fifty seven of 82 outpatients who were able to walk at least with a walker, completed all 12 months of treatment (hemiplegia n=25, diplegia n=32). There was no significant difference between active and placebo treatment in any of the tested groups, nor combined. Visual and subjective assessments favoured TES (ns), whereas objective indices showed the opposite trend. We conclude that TES in these patients did not have any significant clinical effect during the test period.