Drug development in ultra-rare diseases is challenging because small sample sizes and heterogeneity hamper the ability of randomized, placebo-controlled trials with a single primary endpoint to demonstrate treatment effects. To overcome these challenges, a novel randomized Blind Start design was used in a Phase 3 study of vestronidase alfa in mucopolysaccharidosis VII, an ultra-rare lysosomal disease with heterogeneous presentation and severity spectrum. 12 subjects were randomized to 1 of 4 blinded groups, each crossing over to active treatment in a blinded fashion at different timepoints. To capture improvement in subject-specific domains, a Multi-Domain Responder Index (MDRI) was used, summing the minimal important difference scores from 6 domains (6-minute walk test, forced vital capacity, shoulder flexion, visual acuity, and Bruininks-Oseretsky test of fine motor and gross motor proficiency). MDRI showed overall improvement (mean[SD]=0.5 [0.8]). The Blind Start and MDRI design improve statistical power enhancing detection of a treatment effect in this rare disease, while maintaining objectivity and eliminating potential bias by incorporating a variable blinded placebo period.