Rationale, design, and methods of a randomized, controlled, open-label clinical trial with open-label extension to investigate the safety of vosoritide in infants, and young children with achondroplasia at risk of requiring cervicomedullary decompression surgery

Abstract

Achondroplasia causes narrowing of the foramen magnum and the spinal canal leading to increased mortality due to cervicomedullary compression in infants and significant morbidity due to spinal stenosis later in adulthood. Vosoritide is a C-natriuretic peptide analogue that has been shown to improve endochondral ossification in children with achondroplasia. The objective of this trial is to evaluate the safety of vosoritide and whether vosoritide can improve the growth of the foramen magnum and spinal canal in children that may require decompression surgery. An Achondroplasia Foramen Magnum Score will be used to identify infants at risk of requiring decompression surgery. This is a 2-year open label randomized controlled trial of vosoritide in infants with achondroplasia ages 0 to ≤12 months. Approximately 20 infants will be randomized 1:1 to either open label once daily subcutaneous vosoritide combined with standard of care or standard of care alone. The primary and secondary aims of the study are to evaluate the safety and efficacy of vosoritide in children with cervicomedullary compression at risk of requiring decompression surgery. The trial will be carried out in specialized skeletal dysplasia treatment centers with well established multidisciplinary care pathways and standardized approaches to the neurosurgical management of cervicomedually compression. After 2 years, infants randomized to standard of care alone will be eligible to switch to vosoritide plus standard of care for an additional 3 years. This pioneering trial hopes to address the important question as to whether treatment with vosoritide at an early age in infants at risk of requiring cervicomedullary decompression surgery is safe, and can improve growth at the foramen magnum and spinal canal alleviating stenosis. This in turn may reduce compression of surrounding structures including the neuraxis and spinal cord, which could alleviate future morbidity and mortality.Trial registrations: ClinicalTrials.gov, NCT04554940; EudraCT number, 2020-001055-40.

Keywords: Clinical trials; achondroplasia; genetics; precision therapy; skeletal dysplasia.

Figure 1.

Study design. This is a stratified, randomized, controlled, open-label clinical study to investigate the safety of vosoritide treatment in infants and young children with achondroplasia at risk of requiring cervicomedullary decompression surgery. Approximately 20 patients, aged 0 to ≤12 months who have documented achondroplasia confirmed by genetic testing and who meet the study eligibility criteria will be eligible to enroll. Enrolled patients will be stratified based on age (0 to ≤6 months, >6 months to ≤12 months) and will be randomized 1:1 to either open-label, once daily, subcutaneous vosoritide combined with standard of care (vosoritide + standard of care) or standard of care alone. After 104 weeks of randomized treatment, all patients will be eligible to complete an additional 156 weeks on-study receiving open-label vosoritide treatment + standard of care. All patients will complete a safety follow-up visit approximately 4 weeks after the end of treatment.