Sleep and pulmonary outcomes for clinical trials of airway plexiform neurofibromas in NF1

Objective: Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN. Methods: The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials. Results: For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R10) or forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV0.75) as primary pulmonary endpoints. The group defined minimum changes in AHI, R10, and FEV1 or FEV0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows. Conclusions: These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs.