Abstract: We found no trials comparing the effectiveness and safety of enzyme replacement therapy to another intervention, no intervention or placebo. We found one trial (18 participants) that fulfilled the selection criteria, comparing different doses of alglucosidase alfa. The trial provided low-quality evidence (this was a small trial, there were no numerical results available by dose group, random sequence generation and allocation concealment were unclear, and there was a lack of blinding). The duration of alglucosidase alfa treatment ranged from 52 weeks (the length of the original study) to up to three years (including the extended phase of the trial), with a median duration of treatment being 2.3 years. The trial only reported that clinical responses including cardiac function and motor development, as well as the proportion of children that were free of invasive ventilation, were similar in the 20 mg/kg every two weeks and the 40 mg/kg every two weeks groups (low-quality evidence). Long-term alglucosidase alfa treatment markedly extended survival as well as ventilation-free survival and improved cardiomyopathy (low-quality evidence). In relation to the number of children experiencing one or more infusion-related events, there was no significant difference between dose groups, risk ratio 0.83 (95% confidence interval 0.40 to 1.76) (low-quality of evidence). However, of note, at 52 weeks, five children in the 20 mg/kg every two weeks dose group experienced a total of 41 mild or moderate (none severe) infusion-related events and the six children in the 40 mg/kg every two weeks dose group experienced a total of 123 infusion-related events. By the end of the extended phase of the trial, five children in the 20 mg/kg every two weeks dose group experienced a total of 47 infusion-related events and the six children in the 40 mg/kg every two weeks dose group experienced a total of 177 infusion-related events. The trial was supported by the Genzyme Corporation. The search found no trials comparing the effectiveness and safety of enzyme replacement therapy to another intervention, no intervention or placebo. One small randomized controlled trial provided no robust evidence for which dosing schedule of alglucosidase alfa was more effective to treat infantile-onset Pompe disease. It is not deemed ethical to proceed with new placebo-controlled trials, therefore a randomized controlled trial with a large sample size comparing different dosing schedules of enzyme replacement therapy is needed. The main clinical outcomes (i.e. cardiac function, invasive ventilation, survival, motor development, adverse events (e.g. the development of antibodies)) should be standardized when evaluated and reported.

Plain-language summary: We searched medical databases for clinical trials of enzyme replacement therapy in children with Pompe disease. We found no randomised trials (where people taking part in the trial have equal chances of being in the treatment or the control group) comparing the effectiveness and safety of enzyme replacement therapy to another intervention, no intervention or placebo (a 'dummy' drug). We found one trial (18 children) that compared two doses of recombinant human alglucosidase alfa (an enzyme replacement therapy): 20 mg/kg every two weeks (low dose) and 40 mg/kg every two weeks (high dose). The duration of treatment ranged from 52 weeks (the length of the original study) to up to three years (including the extension phase of the study), with a median (the middle number) duration of treatment being 2.3 years. There were very limited numerical results available by dose group, the trial showed no evidence in favour of a high dose as opposed to a low dose. It described that the clinical responses including cardiac function, motor development (development of a child's muscles and their ability to move around and manipulate their environment), as well as the proportion of children that were free of invasive ventilation,were similar in the two groups (low-quality evidence). Long-term alglucosidase alfa treatment markedly extended survival as well as ventilation-free survival (time without requiring a machine to help with breathing) and improved cardiomyopathy (heart disease) (low-quality evidence). In relation to the number of children experiencing one or more infusion-related events, there was no significant difference between the different dose groups (low-quality evidence), although, of note, at 52 weeks, five children in the low-dose group experienced a total of 41 mild or moderate (none were severe) infusion-related events and the six children in the high dose-group experienced a total of 123 infusion-related events. By the end of the extension phase, five children in the low-dose group experienced a total of 47 infusion-related events and the six children in the high-dose group experienced a total of 177 infusion-related events. New trials should be undertaken with adequate number of participants to detect effectiveness and safety at different doses of alglucosidase alfa. The main clinical outcomes (i.e. cardiac function, time to ventilation, survival, motor development and side effects) should be standardized when evaluated and reported. The evidence that this small trial provided to the review was of low quality. The trial was supported by the Genzyme Corporation.