Effects of Orkambi on Exertional Dyspnea, Exercise Performance, and Ventilatory Responses in Adults With Cystic Fibrosis

Advances in therapies and patient care have led to dramatic improvements in cystic fibrosis (CF) survival. Consequently, CF patients are living longer with varying degrees of lung function impairment. Dyspnea is a commonly reported symptom in CF that adversely impacts quality of life. Recently, lumacaftor/ivacaftor (Orkambi), a combination drug therapy, was approved by Health Canada for use in CF patients.

The purpose of this study is to determine the various factors that cause shortness of breath (or dyspnea) in patients with CF and to determine how treatment with Orkambi can manipulate these factors to improve shortness of breath and exercise capacity. The investigators hypothesize that lumacaftor/ivacaftor will reduce dyspnea intensity ratings and improve exercise capacity. These improvements will be associated with improvements in the ventilatory response to exercise.

Exercise capacity is an important outcome parameter in CF and is a strong predictor of disease prognosis including survival. While previous studies have reported improved respiratory symptoms in CF patients taking Orkambi, it remains uncertain as to whether this translates into improvements in exercise performance. Furthermore, the improvement in lung function parameters observed in these studies evaluating Orkambi in CF were modest compared to ivacaftor in CF and therefore stressing the respiratory system to its physiologic limits through exercise might provide a more sensitive outcome measure to evaluate the response to the Orkambi treatment option.

The objective of this study is to perform detailed cardiopulmonary exercise testing before and after the initiation of lumacaftor/ivacaftor to evaluate its effect on exertional dyspnea and exercise capacity, and to evaluate potential physiological mechanisms of improvement in patients with CF.

Experimental Overview: Participants with CF will report to the laboratory on four separate visits. Visit 1 and 2 will occur before the participants go on drug (Orkambi) and will be separated by a minimum of 2 days between visits. Visit 3 and 4 will occur at 1 month and 3 months after initiating full dose of drug, respectively. On visit 1, participants will complete medical history screening, anthropometric measurements, pulmonary function assessment, and a symptom limited incremental cycle exercise test to determine peak incremental work rate. On visit 2, participants will complete chronic activity-related dyspnea, quality of life, and physical activity questionnaires, perform pulmonary function testing followed by a constant-load cycle exercise test at 80% of peak incremental work rate. Visits 3 and 4 will include chronic activity-related dyspnea, quality of life, and physical activity questionnaires, pulmonary function testing, and a constant-load cycle exercise test at 80% of peak incremental work rate. Detailed physiological and sensory measurements will be obtained during the exercise test sessions. Data from the constant-load cycle exercise tests performed on visits 2, 3, and 4 will address our hypothesis.