Hebestreit 2022.

Study characteristics
Methods	Design: parallel‐group design; block randomisation stratified by FEV1 (< 70% predicted, ≥ 70% predicted) and country; computer‐generated list of random numbers; randomisation within the REDCap database at each study centre to allow complete allocation concealment Location: international multicentre RCT conducted in 27 centres across Europe and North America Inclusioncriteria: males and females aged 12 years and older with a confirmed diagnosis of CF; FEV1 ≥ 35% predicted and access to Internet Exclusioncriteria: participation in another clinical trial up to 4 weeks prior to the first baseline visit; pregnant or breastfeeding; inability to exercise; > 4 hours of reported vigorous physical activities per week currently or up to 3 months prior to baseline measurements and not already planned within the coming 6 months; unstable condition precluding exercise (major haemoptysis or pneumothorax within the last 3 months, acute exacerbation and IV antibiotics during the last 4 weeks, planned surgery, listed for lung transplantation, major musculoskeletal injuries such as fractures or sprains during the last 2 months, others according to the impression of the treating physician); cardiac arrhythmias with exercise; requiring additional oxygen with exercise; recent diagnosis of CF‐related diabetes 3 months prior to screening or at screening; recent changes in medication ≤ 1 month prior to screening (systemic steroids, ibuprofen, inhaled antibiotics, mannitol, dornase alfa, hypertonic saline); ≥ 1 G551D mutation and not on ivacaftor (VX770) yet but planned start or planned stop of ivacaftor during the trial and colonisation with Burkholderia cenocepacia. Duration: 12 months
Participants	117 participants with CF Group demographics Intervention group (n = 60): 65 (56%) female; mean age 25.3 (SD 11.4) years; FEV1 74 (SD 22) % predicted; BMI 22.0 (SD 4.1) kg/m²; VO2 peak 71 (SD 17) % predicted Control group (n = 57): 52 (56%) female; mean age 22.8 (SD 10.8) years; FEV1 74 (SD 21) % predicted; BMI 20.8 (SD 3.5) kg/m²; VO2 peak 69 (SD 15) % predicted
Interventions	Interventiongroup: participants were advised to add 3 hours of vigorous physical activities per week to baseline activities. Weekly exercises included ≥ 30 min of strength‐building activities and ≥ 2 hours of aerobic activities. Exercise bouts lasting ≥ 20 min were counted with respect to total weekly training time. Participants were given exercise counselling to boost motivation towards an active lifestyle, strategies included face‐to‐face information, motivational interviewing, goal setting, a written "activity contract" with specific information on which activities were scheduled for which day and for how long, a pedometer, a web‐based activity diary (www.activate-cf.org) providing feedback on missing time in vigorous activities to reach the weekly goal, and repeated counselling via telephone contacts and during clinic visits. A full manual describing the intervention and all intervention materials including the website was available in 4 languages: Dutch, English, French and German. Controlgroup: usual care. Group was advised to keep their physical activity level constant during the 12‐month study.
Outcomes	Primary outcome Change in FEV1 (% predicted) from baseline to 6 months Secondary outcomes Change in VO2 peak (% predicted) from baseline to 6 months and baseline to 12 months Change in maximal aerobic power (% predicted change from baseline to 6 months and baseline to 12 months) Change in daily steps from baseline to 6 months and baseline to 12 months Change in daily exercise steps from baseline to 6 months and baseline to 12 months Change in self‐reported physical (hours) activity from baseline to 6 months and baseline to 12 months Change in FEV1 (% predicted) from 6 months to 12 months and baseline to 12 months Change in FVC (% predicted) from baseline to 6 months and baseline to 12 months Change in RV (% of TLC) from baseline to 6 months and baseline to 12 months Time to first exacerbation from baseline to 6 months and baseline to 12 months Number of upper respiratory tract infections (diary) from baseline to 6 months and baseline to 12 months Days on additional oral or IV antibiotics (questionnaire) from baseline to 6 months and baseline to 12 months Change in BMI from baseline to 6 months and baseline to 12 months Change in muscle mass (estimated from skinfold thickness) from baseline to 6 months and baseline to 12 months Change in body fat (estimated from skinfold thickness) from baseline to 6 months and baseline to 12 months Change in HRQoL (CFQ‐R) from baseline to 6 months and baseline to 12 months Change in depression, anxiety and stress (Depression Anxiety Stress Scales) from baseline to 6 months and baseline to 12 months Change in plasma glucose concentrations 1 and 2 hours after a standardised glucose load (standardised OGTT only for participants without CFRD from baseline to 9 months Adverse events possibly or likely related to exercise (causality as judged by investigator, from baseline to 6 months and baseline to 12 months) Severe adverse events and serious adverse events from baseline to 6 months and baseline to 12 months Other outcomes Compliance with the exercise goal based on questionnaire and diary entries from baseline to 6 months and baseline to 12 months Substudy: change in time spent in moderate‐to‐vigorous physical activity (accelerometry, in selected centres only) from baseline to 6 months and baseline to 12 months Substudy: change in LCI based on nitrogen multiple breath washout (in selected centres only) from baseline to 6 months and baseline to 12 months Substudy: change in bone mineral density and body composition based on dual energy x‐ray absorptiometry (in selected centres only) from baseline to 6 months and baseline to 12 months Substudy: change in mucociliary clearance with exercise based on nuclear medicine scans (US centres only) from baseline to 6 months
Notes	The review authors Thomas Radtke, Helge Hebestreit and Susi Kriemler were lead investigators of the ACTIVATE‐CF trial and had full access to the data before the publication of the main manuscript. The data were included in this review, and during the process of preparing the review update, the paper was accepted for publication and appropriately cited. Author Sherie Smith and Sarah Nevitt performed data extraction and risk of bias assessment for this study. Data from substudies were not published in the main manuscript. The substudy on bone health and body composition using dual energy x‐ray absorptiometry was stopped due to insufficient recruitment.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Stratified block randomisation (1:1 ratio) within REDCap database, computer‐generated randomisation list generated by a statistician. Randomisation was stratified by country and lung disease severity (i.e. moderate‐to‐severe lung disease (FEV1 value < 70% predicted) or mild lung disease (FEV1 ≥ 70% predicted)).
Allocation concealment (selection bias)	Low risk	Randomisation within each study site conducted centrally via a database. Study investigators had no access to the randomisation list.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not possible to blind participants to intervention. Unclear whether personnel were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Outcome assessors were not blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All outcomes detailed in methods were reported in results. Data reported for all time points. All randomised participants who received allocated intervention were included in a (modified) intention‐to‐treat analysis. Losses to follow‐up were reported with reasons.  Data from substudies were not reported in the main publication (see comment in original report).  The study was registered with ClinicalTrials.gov (identifier: NCT01744561) and a study protocol was published (Hebestreit et al. BMC Pulmonary Medicine 2018;18(1):31).
Selective reporting (reporting bias)	Low risk	No indication of selective reporting.
Other bias	High risk	The estimated sample size of 292 participants was not achieved; 155 individuals were assessed for eligibility, and 117 individuals were randomised. Consequently, the analysis of the primary endpoint (i.e. change in FEV1 % predicted from baseline to 6 months) was underpowered and the unexpected finding of a significant difference favouring the control group might be due to chance.