Table of Contents
Study setting {9}
Data will be collected at the CF specialized clinic of the Children’s Medical Center Hospital, Tehran, Iran. Patients diagnosed with CF will be referred by a pediatric pulmonologist (MRME) or called among the previous files available.
Eligibility criteria {10}
Table 1 summarizes the inclusion and exclusion criteria for the groups. Participants must meet all the eligibility criteria to be included.
The age range considered for inclusion criteria is 6–18. Based on the review and study of patient archives and registrations in the center, most of the patients who are referred to the CF specialized clinic are between the ages of 6 and 18, and this age range is the most accessible. In addition, those who are outpatients mostly have the same stage of chest disease; otherwise, patients with higher and more acute stages of chest disease are hospitalized and those with better conditions and in milder stages usually do not have routine clinical visits and are referred only for check-ups. Thus, participants will be among patients with more similar conditions.
Who will take informed consent? {26a}, additional consent provisions for collection and use of participant data and biological specimens {26b}
The informed consent form will be created following the guidelines provided by the Ethics Committee of Iran University of Medical Sciences. The hospital’s secretary will be in charge of collecting the consent form from the patients, their parents, or caregivers. Before signing the consent form, all eligible patients or their parents will be fully informed about the interventions and possible adverse events. For more information regarding the consent form, please refer to Supplemental file 2.
Interventions {11a}
The treatment session will commence 30 min after the first examination. Group A will first include the main treatment of CPT and then a placebo of aerobic exercise; group B will first include the main treatment of aerobic exercise and then a placebo of CPT (the inverse of Group A). The study will be conducted over 6 weeks, 3 times a week, with a total of 18 sessions. Make-up sessions will be allowed if a session is missed. The duration of the entire treatment session will last approximately 70 min.
Group A (CPT and sham aerobic exercise)
At first, the participants will be placed in six standard postural drainage positions for a total of 30 min (Additional file 1: Supplemental Fig. 1A to F). Manual percussion and vibration will be performed on draining segments, in each position for 3–5 min. After completing the previous steps, the patient will be asked to sit down and cough for 1–2 min to expel the extracted secretions. In the following, in order to keep the patients blinded, the placebo aerobic exercise will be applied using a motorized stationary bike in two 15-min sections (Additional file 1: Supplemental Fig. 2). Between the two parts, 1–2 min will be allocated for rest. Throughout the exercise, the heart rate and percentage of arterial oxygen saturation (SpO2) of the patients will be monitored by a pulse oximeter. In this group, in order to eliminate the aerobic effects of the exercises, based on the method of previous studies [37], increasing the respiratory demands and breathing ventilation will be avoided until the end of the study. Therefore, the heart rate of the subject will not exceed 40% of HRmax during 30 min [38]. The total time of the exercises is 30 min, and at the end, 1–2 min will be given for coughing, if needed.
Group B (aerobic exercise and sham CPT)
Progressive aerobic exercises will be conducted in two parts; the first will be 15 min on the treadmill and then a further 15 min on a stationary bike. Between the two sets, rest will be given for 1–2 min. A warm-up of 3 min with a gradual increase in speed will take place, and then 24 min of aerobic exercise with determined intensity (12 min on the treadmill and 12 min on a stationary bike), and finally a 3-min cool-down with a gradual decrease in speed will be conducted (Additional file 1: Supplemental Fig. 3A and B).
Throughout the training, the heart rate and SpO2 of patients will be monitored by a pulse oximeter. If there is a sharp drop in SpO2 below 85%, the heart rate is disproportionate to the conditions, and symptoms of severe shortness of breath or any other warning signs appear, the exercise will be stopped. During 24 min of aerobic exercises, the intensity of the exercise will be controlled through the heart rate of the patients (Table 2).
In order to keep patients blinded, Sham CPT will be done by the experienced conductor (NH) exactly like the main CPT in group A, considering draining areas and hand placements. Modifications are made to the postural drainage positions and the applied manual force. To perform postural drainage, in order to remove the effect of gravity, only 2 positions of supine and prone without inclination will be used; the treated areas and procedures will be similar to group A. In order to eliminate the effect of manual percussion, these strikes will be done very gently with pressure just like touching the skin. In order to eliminate the effects of vibration and pressure, hands will be placed on the desired areas and no vibration or pressure will be applied during exhalation. The total duration will last approximately 30 min. At the end, 1–2 min will be allocated for any coughing, if needed.
Criteria for discontinuing or modifying allocated interventions {11b}
The medical recommendations of individuals, such as drug treatments and airway clearance methods, will not be changed. Due to the risk of cross-infection, two infected patients will not be in the same environment at the same time [3]. Participants are asked to use their 7% sodium chloride nebulizer at home before their treatment session, to prepare the airways [39].
Strategies to improve adherence to interventions {11c}
To improve patient motivation, the comprehensive rehabilitation protocol will be offered completely free of charge, ensuring a seamless connection between the patients and their dedicated team of healthcare professionals including the physiotherapist (NH) and physicians. This regular contact will enable patients to promptly communicate any symptoms they may experience. Participants will be given gifts like toys, edibles, and accessories for more encouragement and cooperation. These gifts will be of equal value and given to the patients at the end of the treatment session, in packages. Also, the treatment room has been well designed in colors and music will be accompanied, to provide a better environment for children. In addition, patient adherence to home ACT, ACBT, will be checked at the beginning of every session and marked in a provided checklist. Participants will be called adherent if at least 90% of the prescribed ACT is successfully performed.
Relevant concomitant care permitted or prohibited during the trial {11d}
Before the treatment starts, the ACBT technique, one of the main ACTs proven to be effective and safe [11], will be thoroughly taught to the patients and their parents and a guidance paper will be given to them. One week before the treatment starts, patients are asked to replace their sports activities with ACBT. Also, they are asked to do the technique on the days between their treatment days, twice a day, at home. The ACBT implementation is checked by the conductor every session. The steps to implement the technique are breathing control, chest expansion, and forced expiration technique (FET) [11].
Provisions for post-trial care {30}
There is no anticipated harm and compensation for trial participation and post-trial care is not applicable.
Outcomes {12}
All outcomes will be measured on two measurement time points: at baseline, and after 6 weeks.
Primary outcomes
Pulmonary function (FEV1): FEV1 will be assessed objectively using a spirometry test (Additional file 1: Supplemental Fig. 4). After recording a maximum of 8 trials, the maximum values recorded in liters and the predicted percentage will be reported as results. The minimal clinically important difference (MCID) for FEV1% in CF has been reported as 7.1% [36].
Functional capacity: 6MWT will be performed based on the recommendations of the ATS Association [40]. A 22.5-m corridor, in an enclosed space and flat surface, is marked by two cones. Patients will be asked to walk as fast as they can within 6 min and cover the greatest possible distance between the two points without running. In the end, the distance covered in 6 min will be measured as the test result. The MCID for this test in patients with CF has been calculated to be 33 m [36].
Key secondary outcome
Sputum culture: The test method will be based on the study of Marguet et al. [41]. Two respiratory mucus sampling methods are used according to the patient’s ability (expectorated sputum/swab method). The obtained samples will be sent to the laboratory within 2 h. The main and common pathogens of CF like Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepecia are cultured on the samples [42]. The culture test will be positive if pathogen culture is observed in the sample. In addition, in cases where the culture test is positive, the microbe colony count is also done and its amount is reported qualitatively (low/medium/high).
Secondary outcomes
Pulmonary function (FVC): FVC will be measured through a spirometry test, the same as FEV1.
Quality of life (CFQ-R): Quality of life will be subjectively assessed by the Persian version of the Cystic Fibrosis Questionnaire-revised (CFQ-R) [43, 44]. This questionnaire examines different domains (physical functioning, vitality, emotional state, social functioning, role functioning of the individual, body image, eating disorders, treatment burden, general perception of health, respiratory, and digestive symptoms) affecting the quality of life of the person in the last 2 weeks and has been prepared in 3 versions according to the age of the patient. The differing versions are for:
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1.
Children 6 to 13 years old
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2.
Parents of above-aged children
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3.
Adults 14 years old and older
The scale of answering questions is a 4-point scale. Total points are calculated and standardized in the range of 0 to 100. The closer the final score is to 100, the higher the quality of life. The MCID for the physical domain is 11.4 points increase, and for the respiratory domain, 7.3 has been calculated [36]. The validity and reliability of the Persian-translated version of the CFQ-R have been evaluated by Talebi et al. [43, 44]. The Cronbach-alpha for the CFQ-R was 0.65–0.91 for the children and parents versions, and ≥ 0.70 for the adult version, showing good internal consistency.
Other variables
In addition to the aforementioned outcomes, demographic and physiological variables such as age, sex, height, weight, medication history, physical activity level, and history of performing ACTs will be measured. These data will be reported as the baseline demographic information of the participants in Table 1 of the final paper, and they are balanced between the two groups by randomization method. There is no intention to do statistical analysis on these variables.
Participant timeline {13}
Participant timeline is presented in Fig. 1 and study’s time schedule is presented in Table 3.
Sample size {14}
The prevalence of CF disease is lower in the Asian continent [1] as reported as 1 per 100,000–350,000 in the Middle East and 1 per 100,000 in Iran [5]. Thus, the number of diagnosed CF patients is low. On the other hand, the coordinating center has dedicated the CF specialized clinic of the Children’s Medical Center Hospital to the trial team, for a limited short time frame. Considering these factors, we selected the randomized controlled trial study by Sosa et al. [45] which was closest to our trial in terms of methodology and variables, as the basis for sample size calculation. In this study, 22 participants, 11 in each group, were recruited. Adding a 30% drop-out rate probability to each group, we anticipate recruiting 15 participants in each trial arm. Using power analysis, the required sample size with a power of 0.8 and an α of 0.05, a total sample size of 30 children and adolescents is determined.
Recruitment {15}
In order to reach the target sample size, the pediatric pulmonologist from the CF specialized clinic will refer patients diagnosed with CF to the rehabilitation clinic of the Children’s Medical Center Hospital. The treatment course will be explained to the patients and their parents and they are encouraged to participate. Patients who are willing will enter the study based on the eligibility criteria. In addition, patients will be called among the previous files available at the center.
