The Alfred Step Test Exercise Protocol (A-STEP), for Adults With Cystic Fibrosis.

Study Overview
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Brief Summary
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Exercise testing has become clinically important in the management and ongoing evaluation of patients with Cystic Fibrosis (CF) with higher rates of exercise tolerance and participation previously linked to lower mortality risk (1). Lower exercise capacity generally correlates with more severe lung disease (2,3) and landmark studies suggest that low exercise capacity as measured by peak oxygen capacity (VO2peak) and rate of decline in lung function (FEV1) are strong predictors of mortality (1,4). However not all studies have found pulmonary function tests (PFTs) to be reliable predictors of maximal exercise capacity (5), especially in relatively well preserved lung function (6,7). The wide distribution in physical capacity between fit individuals and end stage disease adds to complexity of assessment. Independent factors of age, genetics, habitual exercise, nutritional status and musculoskeletal conditions are all known to influence physical capacity in patients with CF (8,9). Maximal exercise testing places additional stress on cardiovascular, respiratory and peripheral systems providing more information around multiple influences on disease progression including degree of limitation in these major systems (10,11) and is useful for assessment of exercise desaturation, more common (but not always present) in advanced lung disease (5,12). With prediction of exercise performance and functional capacity from PFTs unreliable and the understanding that health status correlates better with exercise tolerance there has been an increase in maximal exercise testing for patient management (13). Many international centers now regard exercise testing as highly important with many assessing maximal exercise capacity annually to monitor disease progression, identify physical status and drive changes in medical, physiotherapy or nutritional management (14,15). The main vision is to develop a standardized incremental step test protocol suitable for adults with Cystic Fibrosis (CF), all ages, levels of fitness and disease state that is in line with current exercise testing recommendations (15). To develop a more useful field test to assess exercise tolerance and a more user friendly test than the currently available laboratory exercise test to allow for early detection of decline in physical function in the day-to-day clinical setting. To date no studies have been published in adults with CF where an incremental exercise step test has been investigated to assess exercise tolerance or determine maximum oxygen uptake (VO2max).

Detailed Description
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Many international centers now regard exercise testing as highly important with many measuring maximal exercise capacity annually to monitor disease progression, identify physical status and to drive changes in medical, physiotherapy or nutritional management (14,15). Cardiopulmonary Exercise Testing (CPET): The current best practice for assessing VO2max in adults with CF is a CPET using the Godfrey Protocol, a progressive and incremental maximal test performed on a cycle ergometer (13,14,15). Exercise testing should aim to achieve a maximal response within a time frame of 8-12 min and incremental protocols with stage duration of 1 minute are considered more efficient in eliciting the desired response within this time frame (14). During CPET, VO2max is determined while breath-by-breath gas analysis allows for a comprehensive assessment of exercise ventilation and circulation. This information can identify reasons for low exercise capacity and whether exercise limitation is due to deconditioning, or primarily within the respiratory, cardiovascular or peripheral systems. CPET is performed using a specialist ergometer, and requires specialist clinical expertise, monitoring and reporting equipment for interpretation of the test. The cost, space and expertise to carry out CPET in CF units around the world may limit its use for the regular assessment of exercise capacity in adults with CF (16). Field Tests: Field tests generally cannot determine absolute maximal exercise capacity, but do provide valuable information about the patient's functional abilities and limitations and compared to laboratory tests are inexpensive and easy to administer. Field tests that use a single step for assessment of exercise tolerance in patients with chronic lung disease include: 3-Minute Step Test (3MST): The 3MST is a feasible and acceptable measure of sub-maximal exercise performance in children and adults and a useful tool in the assessment of oxygen desaturation (17,18). The test is short in duration, simple to carry out, and has low cost and minimal space and equipment requirements however the sub-maximal nature and ceiling effect of the 3MST limits its usefulness clinically across the age spectrum (18,19). The Chester Step Test (CST): The CST is a 10-minute sub-maximal standardized multistage test and like the 3MST has minimal space and equipment requirements. The CST was originally designed for workplace screening and is now widely used for exercise prescription in the UK cardiac population (20). In healthy individuals one study reported a ceiling effect and a positive relationship between predicted VO2max using the CST and measured VO2max (21) however a subsequent study questioned this prediction validity (22). The CST has been found to be highly reproducible in patients with chronic obstructive lung disease (COPD) and reliable in patients with Bronchiectasis, but too challenging for both groups (23,24). The Modified Incremental Step Test (MIST): The MIST was designed to be more suitable for COPD patients and modeled from the CST(25). A reduction in work rate was not found to result in a difference in cardiopulmonary stress and exertion effort at peak exercise but did result in a higher exercise tolerance in patients with COPD. The MIST is reliable and better tolerated than the CST in patients with Bronchiectasis (23,24). The CST and CF: One study (published in abstract form) has shown the CST to be a useful field test when compared to the 3MST and 6MWT for those with mild to moderate CF. The authors commented this was likely due to the progressive nature being more representative of adult physical activity (26). The main vision is to develop a standardized incremental step test protocol suitable for adults with Cystic Fibrosis (CF), all ages, levels of fitness and disease state that is in line with current exercise testing recommendations (15). The test should be a more useful than the already available field tests and more user friendly test than the currently available laboratory exercise test to assess exercise tolerance and allow for early detection of decline in physical function in the day-to-day clinical setting. To date no studies have been published in adults with CF where an incremental exercise step test has been investigated to assess exercise tolerance or determine VO2max. To design a standardized externally paced incremental step test that is portable, easy to administer, simple to perform, time, cost and space efficient (A-STEP). Study A: To assess feasibility and reliability of the A-STEP to objectively assess exercise tolerance. To determine if the A-STEP is a more useful tool than the 3-Minute Step Test. Study B: To develop an alternative tool to determine maximum oxygen uptake (VO2max) to the gold standard CPET that is feasible across the whole spectrum of lung disease. To determine if the A-STEPmax is a valid tool when compared to the VO2max achieved from a CPET performed on a cycle ergometer using the Godfrey Protocol. The principle investigator hypothesizes that the A-STEP will be a feasible tool to assess exercise capacity; and the A-STEP max will be a valid tool for the assessment of VO2max across the age range and disease spectrum in adults with CF.

Official Title
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Development; Feasibility/Safety and Validation of the Alfred Step Test Exercise Protocol (A-STEP) Developed for Adults With Cystic Fibrosis:

Conditions
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Cystic Fibrosis, Fibrosis, Lung Diseases, Respiratory Diseases, Genetic Diseases, Pancreatic Diseases

Intervention / Treatment
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* Other: A-STEP
* Other: A-STEP (New Protocol)
* Other: Comparator: CPET cycle ergometer (Gold Standard)


Participation Criteria
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Eligibility Criteria
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INCLUSION Confirmed Diagnosis of CF (by genotype or positive sweat test) Aged 18yrs and older FEV1 ≥20% (Forced expiration in 1 sec) Stable baseline state. (Stable baseline state is defined as: clinically stable respiratory status, for at least 30 days, characterized by the absence of hospitalization and no changes in maintenance therapy during this period (Yankaskas et al 2004)). EXCLUSION Febrile Haemoptysis Uncontrolled asthma Pneumothorax Cardiac issues Unreliable readings on pulse oximetry Pulmonary hypertension Unstable CF related diabetes (CFRD) Vascular issues Renal disease Pregnancy Body mass index (BMI) <18.0 Significant musculoskeletal issues Unable to safely follow instructions (ATS/ACCP 2003; Hebestreit 2015)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A-STEP<br>Study A) A-STEP Study Development of new exercise test protocol and Observational Feasibility/Safety Study (no comparator). | Other: A-STEP<br>* Study A) Study A) Development of new exercise test protocol and Observational Feasibility/Safety Study (no comparator). Feasibility/safety of a newly designed, incremental, maximal, standardised step test in adults with Cystic Fibrosis.<br>* Other names: Alfred Step Test Exercise Protocol (A-STEP);|
| Experimental: A-STEP (New Protocol)<br>Study B) A-STEPmax Study Validity Study (random allocation of test order). | Other: A-STEP (New Protocol)<br>* Study B) Validation Study (random allocation of test order). Validity of an incremental, maximal, standardised incremental step test with breath-by-breath gas analysis using portable metabolic measurement equipment against CPET.<br>* Other names: Alfred Step Test Exercise Protocol;|
| Active Comparator: CPET cycle ergometer (Gold Standard)<br>Study B) A-STEPmax Study Validity Study (random allocation of test order). | Other: Comparator: CPET cycle ergometer (Gold Standard)<br>* Study B) Validation study (random allocation of test order) Gold standard CPET. An incremental, maximal standardised cycle ergometer exercise test (performed as per published protocol) using portable metabolic measurement equipment.<br>* Other names: Cardiopulmonary Exercise Test Protocol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study B) Maximum oxygen uptake (VO2max) | The highest oxygen uptake achieved during the exercise test taken from inspired gas in a given period of time. Body weight is used to calculate this from oxygen consumption during the test. VO2peak may be used as a surrogate if VO2max is not achieved. Criteria for reaching maximum effort is not included in this document. | Measured during the incremental test for a maximum of 15 minutes. | 
| Study A) Oxygen Saturation | Standard objective outcome measures of field exercise testing. Measured via pulse oximetry. | Measured for 3 min prior to exercise (recorded at baseline sitting and standing), monitored during the test (recorded at minute intervals) and for at least 2 min of recovery up to a maximum of 10 minutes. | 
| Study A) Heart Rate | Standard objective outcome measures of field exercise testing. Measured via pulse oximetry. | Measures for 3 min prior to exercise (recorded at baseline sitting and standing), monitored during the test (recorded at minute intervals) and for at least 2 min of recovery up to a maximum of 10 minutes. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study B) Carbon Dioxide Production | Standard secondary outcome measure of maximal exercise testing using breath- by-breath gas analysis with portable metabolic measurement equipment. | Measured during the test incremental tests for a maximum 15 minutes and 5 mins of recovery. | 
| Study B) Respiratory Exchange Ratio | Standard secondary outcome measure of maximal exercise testing using breath- by-breath gas analysis. The ratio of carbon dioxide production to oxygen consumption. | Measured during the test incremental tests for a maximum 15 minutes and 5 mins of recovery. | 
| Study B) Minute Ventilation | Standard secondary outcome measure of maximal exercise testing using breath- by-breath gas analysis. The product of tidal volume and respiratory rate. | Measured during the test incremental tests for a maximum 15 minutes and 5 mins of recovery. | 
| Study B) Oxygen Pulse | Standard secondary outcome measure of maximal exercise testing using breath- by-breath gas analysis. Calculated by dividing the oxygen consumption by heart rate. | Measured during the test incremental tests for a maximum 15 minutes and 5 mins of recovery. | 
| Study B) Tidal Volume | Standard secondary outcome measure of maximal exercise testing using breath- by-breath gas analysis. The volume of each breath taken. | Measured during the test incremental tests for a maximum 15 minutes and 5 mins of recovery. | 
| Study B) Oxygen Saturation | Standard objective outcome measures of exercise testing. Measured via pulse oximetry. | easures are taken at baseline (post 5 mins), monitored during the test (recorded at minute intervals) and for min 5 mins of recovery | 
| Study B) Heart rate | Standard objective outcome measures of exercise testing. Measured via pulse oximetry. | easures are taken at baseline (post 5 mins), monitored during the test (recorded at minute intervals) and for min 5 mins of recovery | 
| Study B) Measures from Electrocardiogram | Used to monitor the patient's cardiac rhythm (CPET only) | easures are taken at baseline (post 5 mins), monitored during the test (recorded at minute intervals) and for min 5 mins of recovery | 
| Study A & B) Breathlessness and Leg Fatigue | Standard subjective outcome measures of exercise testing. Modified Borg 0-10. | Measures are taken at baseline (post 5 mins), monitored during the test (recorded at minute intervals) and for min 5 mins of recovery | 
| Study A & B) Blood pressure | Standard outcome measure of exercise testing. | Measures are takenpre/post A-STEP, pre/every 2 mins during/post CPET | 
| Study A & B) Duration of test; Highest level (mins and sec)/stage achieved; Reason for test termination. | Parameters of exercise test. | Measured during or on completion of the test. Maximum 15 minutes. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exercise Testing, Maximal Exercise Testing, Maximal Exercise Capacity, Peak Exercise Capacity, Adults, Step Tests