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.

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.

How 4 Companies Became One: Co-development Under an Outsourced Model With Focus on Phase 3 Analysis and Reporting Deliverables.

With the growth in co-development deals between pharmaceutical companies and the increased use of contract research organizations (CROs) in drug development, more and more employees are encountering projects that require working across different companies. Navigating the mix of corporate cultures as well as variations in standards and procedures can lead to unanticipated challenges and delays. The development of ertugliflozin, a recently approved medicine for type 2 diabetes mellitus, involved both co-development and CRO engagement across 4 companies. Challenges to combining processes and systems across the 4 companies were encountered and resolved. Early decisions for adoption of standards and processes as well as the organization of committees and communication pathways were key to the success of this ambitious program. Here we share our experiences and lessons learned with respect to the analysis and reporting of clinical trial results.

Impact of new-onset diabetes mellitus on development of atrial fibrillation and heart failure in high-risk hypertension (from the VALUE Trial).

Hypertension and diabetes mellitus (DM) are known risk factors for atrial fibrillation (AF). We investigated the influence of new-onset DM on developing AF in the VALUE trial population of high-risk hypertensive patients. Five thousand two hundred fifty patients of the 15,245 participants in the VALUE trial had DM at baseline and 1,298 of the initially nondiabetic patients developed DM during the average 4.2-year follow-up. The presence of AF was determined by central analyzed electrocardiograms at baseline and changes were assessed yearly. Patients without AF at baseline and with any AF by later electrocardiograms were defined as patients with new-onset AF. Patients with new-onset and baseline DM were compared with patients without DM by a Cox regression model with adjustment for prespecified covariates. Five hundred fifty-one patients developed new-onset AF during the trial. Patients with new-onset DM had a significantly higher event rate of new-onset AF with a hazard ratio of 1.49 (1.14 to 1.94, p = 0.0031) compared with patients without DM, and there was a trend toward more AF in patients with DM at baseline. Patients with new-onset DM had also more persistent AF (hazard ratio 1.87, 1.28 to 2.74, p = 0.0014). Patients with new-onset DM and AF had a hazard ratio of 3.56 for heart failure (2.86 to 4.44, p <0.0001) compared with patients with new-onset DM without AF. In conclusion, hypertensive patients who developed DM during the VALUE trial had more AF than did patients without DM, and this may explain some of their concomitant high risk of hospitalization for heart failure.