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

Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study

“…Other, ongoing clinical trials (ClinicalTrials.gov numbers NCT03583697, and NCT04554940) of vosoritide will investigate its safety and efficacy in children with achondroplasia aged 3 months to 60 months, and in infants at risk of requiring cervicomedullary decompression surgery [ 8 ]. These trials will provide further insights into the long-term treatment effects on skeletal growth, body proportions, and functionality, as well as how treatment might ameliorate the most significant medical complications in achondroplasia, specifically foramen magnum stenosis with brainstem compression and sudden death.…”

Literature review and expert opinion on the impact of achondroplasia on medical complications and health-related quality of life and expectations for long-term impact of vosoritide: a modified Delphi study

“…These data will be provided by the ongoing open-label extensions of the phase 2 and phase 3 clinical trials. In addition, data regarding the long-term impact of vosoritide in children < 5 years of age at treatment initiation, who were excluded from the initial phase 2 and phase 3 clinical trials, are expected from two ongoing studies in young children aged 0 to 60 months (clinicaltrials.gov NCT03583697) and infants aged 0 to 12 months (clinicaltrials.gov NCT04554940) [ 14 , 15 ].…”

“…Treatment studies of infants with vosoritide are needed to verify if these early complications are targetable in infancy. The effect of treatment on foramen magnum stenosis is being investigated in an ongoing study including infants 0–12 months (clinicaltrials.gov NCT04554940) [ 15 ]. On the other hand, symptomatic spinal stenosis and kyphosis, and related back pain, are most prevalent in adults with achondroplasia and may still be altered if treatment is started at a later age, when spinal growth can still be improved.…”

“…Because of the clinical importance of symptomatic spinal stenosis, kyphosis, foramen magnum stenosis and obstructive sleep apnea, evaluation of the impact of vosoritide on these complications in future clinical trials should be considered. As previously mentioned, the ongoing infant study will answer the question regarding the impact of early treatment on foramen magnum stenosis [ 15 ]. It should be noted that the perceived impact of a complication on HRQoL depends on individual patient-specific factors, such as the presence or absence and severity of other complications and their wider social environment.…”

Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review

“…In 2020, a clinical trial was launched to test the effectiveness of vosoritide in reducing foramen magnum stenosis (NCT0455494) and compression of the spinal cord at the craniocervical junction site, therefore potentially reducing the need for surgical decompression [ 59 ] (see Table 1 , Table 2 and Table 3 ).…”