Overview
Shortness of breath (dyspnea) during exercise is a major source of distress and is a commonly reported symptom in patients with cystic fibrosis (CF). A recent drug treatment option known as Trikafta, which contains elexacaftor, tezacaftor, and ivacaftor, may be used in patients with CF to help improve lung health. However, the effects of this combination therapy on dyspnea and exercise performance, a known predictor of survival in CF, are not clear. The investigators aim to understand the effects of Trikafta on these symptoms and to gain new insight into the potential health improvements in CF from using this treatment option.
Description
Justification: Advances in therapies and patient care have led to dramatic improvements in 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, elexacaftor/tezacaftor/ivacaftor (Trikafta), a combination drug therapy, was approved by Health Canada for use in CF patients. Exercise capacity is an important outcome parameter in CF and is a strong predictor of disease prognosis including survival. Although previous research in patients on elexacaftor/tezacaftor/ivacaftor combination therapy reported improved respiratory symptoms and lung function, it remains uncertain as to whether this translates into improvements in exercise performance. Stressing the respiratory system to its physiologic limits through exercise might provide a more sensitive outcome measure to evaluate the response to cystic fibrosis transmembrane regulator (CFTR) modulator therapy. Studies on another CFTR modulator therapy combining lumacaftor and ivacaftor, have shown inconclusive results on exercise tolerance in patients with CF when evaluated using an incremental work rate exercise test protocol. However, a far more clinically and physiologically relevant protocol in evaluating treatment effects is to use constant work rate exercise tests and to evaluate dyspnea at standardized submaximal exercise times. Additionally, changes in body composition shown to result from CFTR modulator therapy may also have contributed to these inconclusive findings; however, body composition has not been evaluated in previous CFTR studies.
Purpose: The purpose of this study is to determine the various factors that cause shortness of breath (or dyspnea) in patients with cystic fibrosis (CF) and to determine how treatment with Trikafta can manipulate these factors to improve shortness of breath and exercise capacity.
Hypothesis: The investigators hypothesize that Trikafta will reduce dyspnea intensity ratings and improve exercise capacity. These improvements will be associated with improvements in the ventilatory response to exercise.
Objectives: To perform detailed cardiopulmonary exercise testing before and after the initiation of Trikafta to evaluate its effect on exertional dyspnea and exercise capacity, and to evaluate potential physiological mechanisms of improvement and the impacts of changes in body composition.
Research Design: Observational study conducted over 4 visits. Participants with CF will report to the Cardiopulmonary Exercise Physiology (CPEP) Laboratory on four separate occasions. Visit 1 and 2 will occur before the participants go on drug (Trikafta) and will be separated by a minimum of 48 hours between visits. Visit 3 and 4 will occur at 12 months and 24 months after initiating drug, respectively. On visit 1, participants will complete medical history screening, anthropometric measurements, and a symptom limited incremental cycle exercise test to determine peak incremental work rate. On visit 2, participants will undergo a dual-energy X-ray absorptiometry (DEXA) scan, chronic activity-related dyspnea questionnaires, quality of life questionnaires, physical activity questionnaires, pulmonary function testing, and a constant-load cycle exercise test at 80% of peak incremental work rate. Visits 3 and 4 will include chronic activity-related dyspnea questionnaires, quality of life questionnaires, physical activity questionnaires, a DEXA scan, pulmonary function testing, and a constant-load cycle exercise test at 80% of peak incremental work rate. Data from the constant-load cycle exercise tests performed on visits 2, 3, and 4 will address our hypothesis.
Eligibility
Inclusion Criteria:
- Confirmed diagnosis of CF and at least one copy of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
- Plan to initiate Trikafta by the treating physician within 30 days of the enrolment visit
- Aged 19 years or older
- Stable clinical status based on clinical judgment of the treating physician
- Forced Expiratory Volume in 1 second (FEV1.0) < 90% predicted
- Body mass index greater than 16 or less than 30 kg/m^2
- Currently non-smoking or a past smoking history of less than 20 pack-years
- Able to read and understand English
- Fully vaccinated (at least 2 doses) for Covid-19
Exclusion Criteria:
- A disease other than CF that could importantly contribute to dyspnea or exercise limitation
- Chronic airway infection with Mycobacterium abscessus, Burkholderia cepacia complex, or other organisms with infection control implications based on the treating physicians
- Contraindications to clinical exercise testing
- Use of supplemental oxygen or desaturation less than 85% with exercise
- Diagnosis of pneumothorax in the past 4 weeks
- History of organ transplantation