Paul Harmatz1, Chester B Whitley2, Raymond Y Wang3, Mislen Bauer4, Wenjie Song5, Christine Haller5, Emil Kakkis5. 1. UCSF Benioff Children's Hospital Oakland, Oakland, CA, United States. Electronic address: Pharmatz@mail.cho.org. 2. University of Minnesota, Minneapolis, MN, United States. 3. Children's Hospital of Orange County, Orange, CA, United States. 4. Miami Children's Hospital, Miami, FL, United States. 5. Ultragenyx Pharmaceutical Inc., Novato, CA, United States.
Abstract
BACKGROUND: Drug development for ultra-rare diseases is challenging because small sample sizes and heterogeneous study populations hamper the ability of randomized, placebo-controlled trials with a single primary endpoint to demonstrate valid treatment effects. METHODS: To overcome these challenges, a novel Blind Start design was utilized in a study of vestronidase alfa in mucopolysaccharidosis VII (Sly syndrome), an ultra-rare lysosomal disease, that demonstrates the strengths of this approach in a challenging drug-development setting. Twelve subjects were randomized to 1 of 4 blinded groups, each crossing over to active treatment in a blinded fashion at different timepoints with efficacy analysis comparing the last assessment before cross over to after 24 weeks of treatment. Study assessments included: Percentage change from baseline in urinary GAG (uGAG); a Multi-Domain Responder Index (MDRI) using prespecified minimal important differences (6-Minute Walk Test, Forced Vital Capacity, shoulder flexion, visual acuity, and Bruininks-Oseretsky Test of Motor Proficiency); fatigue as assessed by the Pediatric Quality of Life Inventory™ Multidimensional Fatigue Scale; and safety. RESULTS: Vestronidase alfa treatment for 24 weeks significantly reduced uGAG excretion (dermatan sulfate: 64.8%, p < 0.0001). Most subjects (10/12) had a clinically meaningful improvement in at least one MDRI domain with an overall mean change (±SD) of +0.5 (±0.8) at Treatment Week 24 (p = 0.0527). Exposure-adjusted incidence rates of adverse events were similar between groups. CONCLUSIONS: The Blind Start study and MDRI design improve statistical power that enhances detection of a positive treatment effect in this rare heterogeneous disease and could be utilized for other ultra-rare diseases.
RCT Entities:
BACKGROUND: Drug development for ultra-rare diseases is challenging because small sample sizes and heterogeneous study populations hamper the ability of randomized, placebo-controlled trials with a single primary endpoint to demonstrate valid treatment effects. METHODS: To overcome these challenges, a novel Blind Start design was utilized in a study of vestronidase alfa in mucopolysaccharidosis VII (Sly syndrome), an ultra-rare lysosomal disease, that demonstrates the strengths of this approach in a challenging drug-development setting. Twelve subjects were randomized to 1 of 4 blinded groups, each crossing over to active treatment in a blinded fashion at different timepoints with efficacy analysis comparing the last assessment before cross over to after 24 weeks of treatment. Study assessments included: Percentage change from baseline in urinary GAG (uGAG); a Multi-Domain Responder Index (MDRI) using prespecified minimal important differences (6-Minute Walk Test, Forced Vital Capacity, shoulder flexion, visual acuity, and Bruininks-Oseretsky Test of Motor Proficiency); fatigue as assessed by the Pediatric Quality of Life Inventory™ Multidimensional Fatigue Scale; and safety. RESULTS: Vestronidase alfa treatment for 24 weeks significantly reduced uGAG excretion (dermatan sulfate: 64.8%, p < 0.0001). Most subjects (10/12) had a clinically meaningful improvement in at least one MDRI domain with an overall mean change (±SD) of +0.5 (±0.8) at Treatment Week 24 (p = 0.0527). Exposure-adjusted incidence rates of adverse events were similar between groups. CONCLUSIONS: The Blind Start study and MDRI design improve statistical power that enhances detection of a positive treatment effect in this rare heterogeneous disease and could be utilized for other ultra-rare diseases.
Authors: Sun H Peck; John W Tobias; Eileen M Shore; Neil R Malhotra; Mark E Haskins; Margret L Casal; Lachlan J Smith Journal: Bone Date: 2019-08-20 Impact factor: 4.398
Authors: Roberto Giugliani; Anneliese Lopes Barth; Melissa Rossi Calvão Dumas; José Francisco da Silva Franco; Liane de Rosso Giuliani; Carlos Henrique Paiva Grangeiro; Dafne Dain Gandelman Horovitz; Chong Ae Kim; Emilia Katiane Embiruçu de Araújo Leão; Paula Frassinetti Vasconcelos de Medeiros; Diego Santana Chaves Geraldo Miguel; Maria Espírito Santo Almeida Moreira; Helena Maria Guimarães Pimentel Dos Santos; Luiz Carlos Santana da Silva; Luiz Roberto da Silva; Isabel Neves de Souza; Tatiele Nalin; Daniel Garcia Journal: Orphanet J Rare Dis Date: 2021-05-22 Impact factor: 4.123