Physical activity and exercise training in cystic fibrosis

Thomas Radtke; Sherie Smith; Sarah J Nevitt; Helge Hebestreit; Susi Kriemler

doi:10.1002/14651858.CD002768.pub5

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Figure 1

Methodological quality summary: review authors' judgments about each methodological quality item for each included study.

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Figure 2

Methodological quality graph: review authors' judgments about each methodological quality item presented as percentages across all included studies.

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Figure 3

Study flow diagram.

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Comparison 1: Physical activity versus control, Outcome 1: Change in VO2 peak (mL/min per kg bodyweight)

Analysis 1.1

Comparison 1: Physical activity versus control, Outcome 1: Change in VO₂ peak (mL/min per kg bodyweight)

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Comparison 1: Physical activity versus control, Outcome 2: Change in VO2 peak (mL/min per kg bodyweight): sensitivity analysis

Analysis 1.2

Comparison 1: Physical activity versus control, Outcome 2: Change in VO₂ peak (mL/min per kg bodyweight): sensitivity analysis

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Comparison 1: Physical activity versus control, Outcome 3: Change in VO2 peak (% predicted)

Analysis 1.3

Comparison 1: Physical activity versus control, Outcome 3: Change in VO₂ peak (% predicted)

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Comparison 1: Physical activity versus control, Outcome 4: Change in VO2 peak (mL/min per kg bodyweight): combined subgroups

Analysis 1.4

Comparison 1: Physical activity versus control, Outcome 4: Change in VO₂ peak (mL/min per kg bodyweight): combined subgroups

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Comparison 1: Physical activity versus control, Outcome 5: Change in VO2 peak (mL/min per kg bodyweight): combined subgroups – sensitivity analysis

Analysis 1.5

Comparison 1: Physical activity versus control, Outcome 5: Change in VO₂ peak (mL/min per kg bodyweight): combined subgroups – sensitivity analysis

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Comparison 1: Physical activity versus control, Outcome 6: Change in FEV1 (% predicted)

Analysis 1.6

Comparison 1: Physical activity versus control, Outcome 6: Change in FEV₁ (% predicted)

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Comparison 1: Physical activity versus control, Outcome 7: Change in FEV1 (% predicted): sensitivity analysis

Analysis 1.7

Comparison 1: Physical activity versus control, Outcome 7: Change in FEV₁ (% predicted): sensitivity analysis

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Comparison 1: Physical activity versus control, Outcome 8: Change in FEV1 (mL)

Analysis 1.8

Comparison 1: Physical activity versus control, Outcome 8: Change in FEV₁ (mL)

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Comparison 1: Physical activity versus control, Outcome 9: Change in FEV1 (z‐score)

Analysis 1.9

Comparison 1: Physical activity versus control, Outcome 9: Change in FEV₁ (z‐score)

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Comparison 1: Physical activity versus control, Outcome 10: Change in FEV1 (% predicted): combined subgroups

Analysis 1.10

Comparison 1: Physical activity versus control, Outcome 10: Change in FEV₁ (% predicted): combined subgroups

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Comparison 1: Physical activity versus control, Outcome 11: Change in FEV1 (% predicted): sensitivity analysis

Analysis 1.11

Comparison 1: Physical activity versus control, Outcome 11: Change in FEV₁ (% predicted): sensitivity analysis

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Analysis 1.12

Comparison 1: Physical activity versus control, Outcome 12: Change in HRQoL: CFQ‐R physical functioning domain

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Analysis 1.13

Comparison 1: Physical activity versus control, Outcome 13: Change in HRQoL: CFQ‐R physical functioning domain: sensitivity analysis

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Analysis 1.14

Comparison 1: Physical activity versus control, Outcome 14: Change in HRQoL: CFQ‐R physical functioning domain: combined subgroups

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Analysis 1.15

Comparison 1: Physical activity versus control, Outcome 15: Change in HRQoL: CFQ‐R physical functioning domain: combined subgroups – sensitivity analysis

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Analysis 1.16

Comparison 1: Physical activity versus control, Outcome 16: Change in HRQoL: CFQ‐R respiratory symptoms

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Analysis 1.17

Comparison 1: Physical activity versus control, Outcome 17: Change in HRQoL: CFQ‐R respiratory symptoms: combined subgroups

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Analysis 1.18

Comparison 1: Physical activity versus control, Outcome 18: Change in HRQoL: Quality of Well‐Being scale

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Analysis 1.19

Comparison 1: Physical activity versus control, Outcome 19: Change in peak work capacity (W/kg bodyweight) during maximal exercise

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Analysis 1.20

Comparison 1: Physical activity versus control, Outcome 20: Change in peak work capacity (W) during maximal exercise

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Analysis 1.21

Comparison 1: Physical activity versus control, Outcome 21: Change in peak work capacity (% predicted) during maximal exercise

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Analysis 1.22

Comparison 1: Physical activity versus control, Outcome 22: Change in time to symptom limitation (T_lim in sec) during constant work submaximal exercise

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Comparison 1: Physical activity versus control, Outcome 23: Change in VO2 (mL/min per kg bodyweight and % predicted) during constant work submaximal exercise

Analysis 1.23

Comparison 1: Physical activity versus control, Outcome 23: Change in VO₂ (mL/min per kg bodyweight and % predicted) during constant work submaximal exercise

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Analysis 1.24

Comparison 1: Physical activity versus control, Outcome 24: Change in 6MWT distance (m)

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Analysis 1.25

Comparison 1: Physical activity versus control, Outcome 25: Change in modified shuttle walk distance (m)

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Analysis 1.26

Comparison 1: Physical activity versus control, Outcome 26: Change in quadriceps muscle strength (Nm)

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Analysis 1.27

Comparison 1: Physical activity versus control, Outcome 27: Change in FVC (% predicted)

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Analysis 1.28

Comparison 1: Physical activity versus control, Outcome 28: Change in FVC (mL)

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Analysis 1.29

Comparison 1: Physical activity versus control, Outcome 29: Change in objectively measured physical activity (steps per day)

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Analysis 1.30

Comparison 1: Physical activity versus control, Outcome 30: Change in objectively measured physical activity (aerobic steps per day)

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Analysis 1.31

Comparison 1: Physical activity versus control, Outcome 31: Change in objectively measured moderate‐to‐vigorous physical activity (hours per week)

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Analysis 1.32

Comparison 1: Physical activity versus control, Outcome 32: Change in self‐reported vigorous physical activity (hours per week)

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Analysis 1.33

Comparison 1: Physical activity versus control, Outcome 33: Change in BMI (kg/m²)

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Analysis 1.34

Comparison 1: Physical activity versus control, Outcome 34: Change in BMI (z‐score)

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Study	Physical activity (n)	Control (n)	Incidence rate ratio	95% CI	P value
Number of pulmonary exacerbations
Number of exacerbations at end of 6 months' partially supervised active intervention (mixed Poisson regression model)
Hebestreit 2022	27	23	1.07	0.60 to 1.90	0.83
Number of exacerbations after 12 months: 6 months' partially supervised activity followed by 6 months unsupervised activity with access to study resources (mixed Poisson regression model)
Hebestreit 2022	61	53	1.28	0.85 to 1.94	0.24

Analysis 1.35

Comparison 1: Physical activity versus control, Outcome 35: Number of pulmonary exacerbations

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Study	Hazard ratio	95% CI	P value
Time to first pulmonary exacerbation
Hebestreit 2022	1.34	0.65 to 2.80	0.43

Analysis 1.36

Comparison 1: Physical activity versus control, Outcome 36: Time to first pulmonary exacerbation

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Analysis 1.37

Comparison 1: Physical activity versus control, Outcome 37: Number of hospitalisations

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Analysis 1.38

Comparison 1: Physical activity versus control, Outcome 38: Change in whole body bone mineral density (g/cm²)

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Analysis 1.39

Comparison 1: Physical activity versus control, Outcome 39: Change in lumbar spine bone mineral density (g/cm²)

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Analysis 1.40

Comparison 1: Physical activity versus control, Outcome 40: Change in metabolic parameters (HbA1c (%))

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Analysis 1.41

Comparison 1: Physical activity versus control, Outcome 41: Change in metabolic parameters (glucose AUC)

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Analysis 1.42

Comparison 1: Physical activity versus control, Outcome 42: Change in metabolic parameters (total insulin AUC)

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Analysis 1.43

Comparison 1: Physical activity versus control, Outcome 43: Change in metabolic parameters (insulin sensitivity index)

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Analysis 1.44

Comparison 1: Physical activity versus control, Outcome 44: Change in plasma glucose (mmol/L) during an oral glucose tolerance test: end of active intervention ≤ 6 months

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Analysis 1.45

Comparison 1: Physical activity versus control, Outcome 45: Change in plasma insulin (µIU/mL) during an oral glucose tolerance test: end of active intervention ≤ 6 months

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Analysis 1.46

Comparison 1: Physical activity versus control, Outcome 46: Change in blood glucose (mmol/L) during an oral glucose tolerance test: end of active intervention > 6 months

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Analysis 1.47

Comparison 1: Physical activity versus control, Outcome 47: Adverse events and serious adverse events

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Summary of findings 1. Physical activity compared with no physical activity for cystic fibrosis

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
Physical activity compared with no physical activity for cystic fibrosis
Patient or population: adults and children with cystic fibrosis Settings: at home or in hospital Intervention: physical activity Comparison: no physical activity (usual care)
	Assumed risk	Corresponding risk
	Usual care	Physical activity
Exercise capacity: change in VO₂ peak (mL/min per kg bodyweight) Active intervention: > 6 months	VO₂ peak was 1.60 mL/min per kg bodyweight higher in the physical activity group than in the control group (0.16 mL/min per kg bodyweight higher to 3.05 mL/min per kg bodyweight higher).		—	348 (6)	⊕⊕⊕⊝ Moderate^a,b	P = 0.005 Sensitivity analysis which removed 1 small outlying study did not alter the results. Other time points: Active intervention ≤ 6 months 8 studies reported the effect of physical activity for periods of up to and including 6 months (MD 2.10 mL/min per kg bodyweight, 95% CI 0.06 to 4.13; n = 323; P = 0.04). There was a high level of heterogeneity in the results. Follow‐up (no active intervention) This was reported by 3 out of 9 studies. VO₂ peak was higher in the physical activity versus control groups (MD 3.27 mL/min per kg bodyweight, 95% CI 1.37 to 5.18; n = 125; P < 0.001).
FEV₁ % predicted (change from baseline) Active intervention: > 6 months	The mean change in FEV₁ % predicted was 2.41% higher in the physical activity group than in the control group (0.49% lower to 5.31% higher).		—	367 (6)	⊕⊕⊝⊝ Low^a,c	P = 0.1 Sensitivity analysis which removed 1 small outlying study with wide CIs changed the effect slightly towards a beneficial effect of physical activity (MD 1.71 % predicted, 95% CI 0.15 to 3.26; P = 0.02). Other time points: Active intervention ≤ 6 months 8 studies found no difference between the physical activity group and control group (MD 1.30 % predicted, 95% CI ‒3.01 to 5.61; n = 356; P = 0.56). Follow‐up (no active intervention) 3/9 studies reported this outcome and found no difference between groups (MD 5.68 % predicted, 95% CI ‒1.88 to 13.23; n = 128; P = 0.14).
HRQoL: change in CFQ‐R physical functioning domain score Active intervention: > 6 months	The mean change in CFQ‐R score was 2.19 points higher in the physical activity group than in the control group (3.42 points lower to 7.80 points higher).		—	247 (4)	⊕⊕⊝⊝ Low^d	P = 0.44 Other time points: Active intervention ≤ 6 months 6 studies reported that there was no difference in HRQoL CFQ‐R scores between groups (MD 4.67, 95% CI ‒2.55 to 11.90; n = 217; P = 0.21). Follow‐up (no active intervention) No studies reported CFQ‐R after a period off training.
HRQoL: change in CFQ‐R respiratory symptoms domain score Active intervention: > 6 months	The mean change in CFQ‐R score was 0.05 points lower in the physical activity group than in the control group (3.61 points lower to 3.51 points higher).		—	251 (4)	⊕⊕⊝⊝ Low^d	P = 0.98 Other time points: Active intervention ≤ 6 months 5 studies reported that there was no difference in HRQoL CFQ‐R scores between groups (MD ‒1.87, 95% CI ‒5.66 to 1.92; n = 212; P = 0.33). Follow‐up (no active intervention) No studies reported CFQ‐R after a period off training.
Pulmonary exacerbations: number of exacerbations occurring in the study period Active intervention: 12 months	There was no difference in the number of pulmonary exacerbations between the physical activity and control group. The incidence rate ratio was 1.28 (95% CI 0.85 to 1.94).		—	117 (1)	⊕⊕⊕⊕ High	P = 0.24 There was also no difference in the time to first exacerbation between the groups, HR 1.34 (95% CI 0.65 to 2.80). Other time points: Active intervention ≤ 6 months 1 study reported no difference in the number of exacerbations between groups at the 6‐month time point (incidence rate ratio 1.07, 95% CI 0.60 to 1.90), or in the time to first exacerbation (HR 1.34, 95% CI 0.65 to 2.80). Follow‐up (no active intervention) No studies reported this outcome after a period off training.
Diabetic control: change in blood glucose levels at rest, at 60 and 120 minutes after a glucose ingestion (mmol/L) Active intervention: 9 months	There were no differences between the physical activity and control groups with regard to blood glucose. At rest: MD ‒0.16 mmol/L (95% CI ‒0.44 to 0.12) After 60 minutes: MD ‒0.04 mmol/L (95% CI ‒1.11 to 1.03) After 120 minutes: MD ‒0.44 mmol/L (95% CI ‒1.43 to 0.55)		—	91 (1)	⊕⊕⊕⊝ Moderate^e	Participants included for this outcome did not have a diagnosis of CFRD on entry to the study. Other time points: Active intervention ≤ 6 months 1 study (n = 14, including 2 people with CFRD at study entry) assessed HbA1c, plasma glucose and insulin response to an oral glucose tolerance test. There was no difference in HbA1c (MD ‒0.00%, 95% CI ‒0.01 to 0.00). There was no difference in plasma glucose values between groups at any time point apart from at 120 minutes postglucose test when there was a significant difference favouring the exercise group (Beaudoin 2017). Follow‐up (no active intervention) No studies reported this outcome after a period off training.
Adverse events: number of adverse events Active intervention: 12 months	1 study reported no adverse events in either the physical activity or control group during the 12‐month study period (Kriemler 2013). A larger study reported no difference in the number of participants experiencing an adverse event or serious adverse event related to the intervention between the physical activity and no physical activity group (adverse events: OR 6.22, 95% CI 0.72 to 53.40; serious adverse events: OR 0.95, 95% CI 0.06 to 15.54) (Hebestreit 2022).		—	156 (2)	⊕⊕⊝⊝ Low^f,g	Other time points: Active intervention ≤ 6 months 2 studies reported adverse events: in the first study there was muscle stiffness (common after active video games) and in the second study there was an ankle injury in the physical activity group and haemoptysis in 1 participant in the control group. 1 further study reported no adverse events during the 6‐week intervention period. Follow‐up (no active intervention) In 1 study it was not clear if the earlier reported muscle stiffness continued in the follow‐up period. The study that reported no adverse events in the 6‐week intervention period, also observed no adverse events in the follow‐up period.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; CFQ‐R: Cystic Fibrosis Questionnaire – Revised; CFRD: cystic fibrosis‐related diabetes; FEV₁: forced expiratory volume in 1 second; HbA1c: glycated haemoglobin; HR: hazard ratio; HRQoL: health‐related quality of life; MD: mean difference; n: number of participants; OR: odds ratio; VO₂ peak: peak oxygen uptake.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.
^aDowngraded once due to high or unclear risk of bias across many of the domains for the included studies. Two studies contributing data to this outcome were at high risk of bias due to concerns around randomisation and allocation concealment. ^bThere was moderate heterogeneity in the results, but this was due to an outlying study (Kriemler 2013). When this study was removed from the analysis, the result remained significant and therefore we did not downgrade the certainty of evidence due to inconsistency. The outlying study included small numbers and had wide CIs around the effect. ^cThere was moderate heterogeneity in the results due to a small outlying study with wide CIs (Kriemler 2013); downgraded once. ^dDowngraded twice due to risk of bias across several domains in the studies included in this analysis. There were particular concerns around randomisation and allocation concealment in three of the four included studies. ^eDowngraded once due to imprecision caused by a small number of participants. ^fDowngraded once due to risk of bias in one of the two included studies for this outcome. ^gDowngraded once for imprecision (low event rates and wide CIs).

Summary of findings 1. Physical activity compared with no physical activity for cystic fibrosis

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Table 1. Study results for Santana‐Sosa 2012

Variable	Group	Pretraining	Post‐training	Detraining^a	P value	Comments
Age (mean (SEM)) years	Intervention	11 (3)	—	—	—	—
Age (mean (SEM)) years	Control	10 (2)	—	—	—	—
Sex (% boys)	Intervention	55	—	—	—
Sex (% boys)	Control	64	—	—	—
VO₂ peak (mean (95% CI)) mL/min per kg bodyweight	Intervention	N/A	3.9 (1.8 to 6.1)	‒3.4 (‒5.7 to 1.7)	0.036	Higher in controls at baseline (P = 0.023). Data were presented in a figure in the original publication.
VO₂ peak (mean (95% CI)) mL/min per kg bodyweight	Control	N/A	‒2.2 (‒5.3 to 0.1)	‒0.7 (‒4.4 to 5.9)	0.036
Leg press (mean (95% CI)) kg	Intervention	N/A	24.9 (14.3 to 34.4)	‒1.0 (‒4.1 to 3.3)	< 0.001	Data are reported in a figure in the original publication. Significantly higher in controls at baseline (P = 0.014).
Leg press (mean (95% CI)) kg	Control	N/A	N/A	N/A	< 0.001
Bench press (mean (95% CI)) kg	Intervention	N/A	10.5 (7.0 to 14.0)	‒1.2 (‒3.6 to 3.0)	< 0.001	Significantly higher in controls at baseline (P = 0.007). Data presented in a figure in the original publication.
Bench press (mean (95% CI)) kg	Control	N/A	N/A	N/A	< 0.001
Seated row (mean (95% CI)) kg	Intervention	N/A	12.7 (9.2 to 16.0)	‒0.2 (‒3.6 to 3.2)	< 0.001	Significantly higher in controls at baseline (P = 0.009). Data presented in a figure in the original publication.
Seated row (mean (95% CI)) kg	Control	N/A	N/A	N/A	< 0.001
Oxygen saturation at peak exercise (mean (SEM)) %	Intervention	94.9 (0.9)	95.6 (0.8)	94.5 (1.2)	N/A	—
Oxygen saturation at peak exercise (mean (SEM)) %	Control	95.7 (0.5)	96.4% (0.4)	96.1 (0.5)	N/A	—
FEV₁ (mean (SEM)) L	Intervention	1.87 (0.24)	1.94 (0.23)	1.90 (0.25)	0.769	—
FEV₁ (mean (SEM)) L	Control	1.77 (0.17)	1.87 (0.15)	1.79 (0.19)	0.769	—
FVC (mean (SEM)) L	Intervention	2.41 (0.24)	2.49 (0.25)	2.56 (0.29)	0.920	—
FVC (mean (SEM)) L	Control	2.29 (0.19)	2.36 (0.20)	2.40 (0.24)	0.920	—
PI_max (mean (SEM)) cmH₂O	Intervention	64.0 (5.5)	69.8 (6.8)	75.2 (6.2)	0.797	—
PI_max (mean (SEM)) cmH₂O	Control	61.5 (6.9)	72.2 (7.2)	76.4 (7.5)	0.797	—
HRQoL score – children's report (median (range))	Intervention	696 (495–741)	719 (550–734)	—	0.257	HRQoL was assessed before and after the intervention. P value for comparison pre versus post‐training.
HRQoL score – children's report (median (range))	Control	649 (578–768)	638 (461–791)	—	0.257
HRQoL score – parents' report (median (range))	Intervention	896 (688–1011)	889 (811–973)	—	0.143	HRQoL was assessed before and after the intervention.
HRQoL score – parents' report (median (range))	Control	911 (842–1028)	978 (684–1059)	—	0.143	HRQoL was assessed before and after the intervention.
Weight (mean (SEM)) kg	Intervention	39.9 (3.5)	40.5 (3.4)	41.4 (3.4)	0.723	—
Weight (mean (SEM)) kg	Control	34.0 (2.6)	35.1 (2.8)	36.2 (3.0)	0.723	—
BMI (mean (SEM)) kg/m²	Intervention	18.4 (1.0)	18.3 (0.7)	18.5 (0.7)	0.959	—
BMI (mean (SEM)) kg/m²	Control	17.2 (0.8)	17.1 (0.8)	17.4 (0.9)	0.959	—
Fat‐free mass (mean (SEM)) %	Intervention	78.1 (2.7)	79.4 (2.8)	78.8 (2.9)	0.115	—
Fat‐free mass (mean (SEM)) %	Control	81.1 (2.5)	80.9 (2.1)	81.1 (2.2)	0.115	—
Body fat (mean (SEM)) %	Intervention	21.9 (2.7)	20.6 (2.8)	21.2 (2.9)	0.115	—
Body fat (mean (SEM)) %	Control	18.9 (2.5)	19.1 (2.1)	18.9 (2.2)	0.115	—
Compliance with physical training (mean (SEM)) %	Intervention	—	95.1 (7.4)	—	—	73% of children completed all training sessions.
Compliance with physical training (mean (SEM)) %	Control	—	—	—	—	73% of children completed all training sessions.
Adverse effects	Intervention	—	—	—	—	No adverse effects occurred during training or maximal exercise testing.
Adverse effects	Control	—	—	—	—
^aDescribed in the original papers as "detraining" but corresponding to our definition of 'off training'. BMI: body mass index; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; HRQoL: health‐related quality of life; N/A: not applicable; PI_max: maximum inspiratory mouth pressure; SEM: standard error of the mean; VO₂ peak: peak oxygen consumption.

Table 1. Study results for Santana‐Sosa 2012

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Table 2. Study results for Santana‐Sosa 2014

Variable	Group	Pretraining	Post‐training	Detraining^a	P value	Comments
Age (mean (SEM)) years	Intervention	11 (1)	—	—	—	—
Age (mean (SEM)) years	Control	10 (1)	—	—	—	—
Sex (% boys)	Intervention	60	—	—	—	—
Sex (% boys)	Control	60	—	—	—	—
VO₂ peak (mean (95% CI) mL/min per kg bodyweight	Intervention	N/A	6.9 (3.4 to 10.5)	‒1.5 (‒2.7 to ‒0.4)	< 0.001	Significantly higher in controls at baseline (P = 0.034).
VO₂ peak (mean (95% CI) mL/min per kg bodyweight	Control	N/A	N/A	N/A	< 0.001	Significantly higher in controls at baseline (P = 0.034).
Leg press (mean (SEM)) kg	Intervention	62.5 (6.5)	89.5 (9.3)	88.6 (9.2)	< 0.001	Higher in controls at baseline (P = 0.046).
Leg press (mean (SEM)) kg	Control	45.2 (4.7)	43.9 (5.1)	43.9 (5.4)	< 0.001	Higher in controls at baseline (P = 0.046).
Bench press (mean (SEM)) kg	Intervention	26.4 (2.7)	38.4 (3.2)	35.9 (2.9)	< 0.001	—
Bench press (mean (SEM)) kg	Control	23.2 (2.9)	21.6 (3.2)	21.7 (3.6)	< 0.001	—
Lateral row (mean (SEM)) kg	Intervention	30.5 (3.6)	43.0 (4.2)	35.9 (2.9)	< 0.001	—
Lateral row (mean (SEM)) kg	Control	23.2 (3.0)	22.0 (3.1)	21.7 (3.6)	< 0.001	—
Oxygen saturation at peak exercise (mean (SEM)) %	Intervention	94.7 (0.7)	94.5 (0.7)	93.1 (0.8)	N/A	—
Oxygen saturation at peak exercise (mean (SEM)) %	Control	96.4 (0.4)	96.2 (0.5)	96.1 (0.6)	N/A	—
FEV₁ (mean (SEM)) L	Intervention	1.65 (0.19)	1.74 (0.23)	1.69 (0.24)	0.486	—
FEV₁ (mean (SEM)) L	Control	1.57 (0.26)	1.55 (0.26)	1.59 (0.26)	0.486	—
FVC (mean (SEM)) L	Intervention	2.23 (0.27)	2.34 (0.29)	2.28 (0.28)	0.156	—
FVC (mean (SEM)) L	Control	1.90 (0.33)	1.85 (0.32)	1.92 (0.32)	0.156	—
PI_max (mean (SEM)) cmH₂O	Intervention	68.3 (6.3)	107.6 (8.4)	103.2 (8.1)	< 0.001	—
PI_max (mean (SEM)) cmH₂O	Control	69.5 (9.7)	71.8 (10.0)	66.7 (9.4)	< 0.001	—
HRQoL score (median (range))	Intervention	629 (505–701)	688 (609–791)	—	0.071	HRQoL was assessed before and after the intervention.
HRQoL score (median (range))	Control	636 (626–745)	638 (626–737)	—	0.071	HRQoL was assessed before and after the intervention.
Weight (mean (SEM)) kg	Intervention	36.4 (3.1)	37.8 (3.2)	38.3 (3.1)	0.342	—
Weight (mean (SEM)) kg	Control	31.5 (4.6)	32.4 (4.7)	32.7 (4.5)	0.342	—
Fat‐free mass (mean (SEM)) % of total	Intervention	81.6 (1.3)	82.6 (1.0)	82.5 (1.0)	0.001	—
Fat‐free mass (mean (SEM)) % of total	Control	82.9 (1.8)	82.8 (1.8)	82.5 (1.9)	0.001	—
Body fat (mean (SEM)) % of total	Intervention	18.4 (1.3)	17.4 (1.2)	17.5 (1.1)	0.023	—
Body fat (mean (SEM)) % of total	Control	17.1 (1.8)	17.2 (1.8)	17.5 (1.9)	0.023	—
Compliance with physical training (mean (SEM)) %	Intervention	—	97.5 (1.7)	—	—	70% of children completed all training sessions.
Compliance with physical training (mean (SEM)) %	Control	—	—	—	—	70% of children completed all training sessions.
Adverse effects	Intervention	—	—	—	—	No adverse effects occurred during training or exercise testing.
Adverse effects	Control	—	—	—	—
^aDescribed in the original papers as "detraining" but corresponding to our definition of 'off training'. CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; HRQoL: health‐related quality of life; N/A: not applicable; PI_max: maximum inspiratory mouth pressure; SEM: standard error of the mean; VO₂ peak: peak oxygen consumption.

Table 2. Study results for Santana‐Sosa 2014

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Table 3. Health‐related quality of life (HRQoL) results for Rovedder 2014

Health‐related quality of life	Exercise group (n = 19) (median (IQR))	Control group (n = 22) (median (IQR))	P value
HRQoL scale – physical	6.1 (‒4 to 8)	2.4 (‒10 to 13)	0.742
HRQoL scale – respiratory	3.8 (0 to 11)	‒4.7 (‒1 to 7)	0.925
SF‐36 – functional capacity	2.8 (‒10 to 15)	2.0 (‒11 to 10)	0.916
SF‐36 – physical aspects	11.8 (‒25 to 50)	6.8 (‒6 to 31)	0.705
SF‐36 – pain	‒7.2 (‒28 to 11)	8.0 (7 to 17)	0.100
SF‐36 – general health	3.7 (‒5 to 10)	‒3.5 (‒11 to 5)	0.197
SF‐36 – vitality	1.2 (‒15 to 20)	7.5 (‒1 to 21)	0.416
SF‐36 – social aspects	15.2 (0 to 33)	21.2 (0 to 66)	0.989
SF‐36 – emotional aspects	4.7 (‒12 to 37)	4.5 (‒12 to 25)	0.914
SF‐36 – mental health	‒0.8 (‒12 to 12)	0.9 (‒9 to 13)	0.752
Pre–post changes in HRQoL measured using the CFQ and SF‐36. CFQ: Cystic Fibrosis Questionnaire; HRQoL: health‐related quality of life; IQR: interquartile range; n: number of participants; SF‐36: Medical Outcomes Study 36‐Item Short‐Form Health Survey.

Table 3. Health‐related quality of life (HRQoL) results for Rovedder 2014

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Comparison 1. Physical activity versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Change in VO₂ peak (mL/min per kg bodyweight) Show forest plot	11		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1.1 End of active intervention ≤ 6 months	8	323	Mean Difference (IV, Random, 95% CI)	2.10 [0.06, 4.13]
1.1.2 End of active intervention > 6 months	6	348	Mean Difference (IV, Random, 95% CI)	1.60 [0.16, 3.05]
1.1.3 Follow‐up (no active intervention)	3	125	Mean Difference (IV, Random, 95% CI)	3.27 [1.37, 5.18]
1.2 Change in VO₂ peak (mL/min per kg bodyweight): sensitivity analysis Show forest plot	10		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.2.1 End of active intervention ≤ 6 months	7	287	Mean Difference (IV, Random, 95% CI)	1.30 [‐0.17, 2.78]
1.2.2 End of active intervention > 6 months	5	318	Mean Difference (IV, Random, 95% CI)	1.38 [0.08, 2.69]
1.2.3 Follow‐up (no active intervention)	2	99	Mean Difference (IV, Random, 95% CI)	3.21 [1.27, 5.14]
1.3 Change in VO₂ peak (% predicted) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.3.1 End of active intervention ≤ 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.4 Change in VO₂ peak (mL/min per kg bodyweight): combined subgroups Show forest plot	11	496	Mean Difference (IV, Random, 95% CI)	1.52 [0.31, 2.73]

1.5 Change in VO₂ peak (mL/min per kg bodyweight): combined subgroups – sensitivity analysis Show forest plot	10	466	Mean Difference (IV, Random, 95% CI)	1.38 [0.22, 2.55]

1.6 Change in FEV₁ (% predicted) Show forest plot	11		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.6.1 End of active intervention ≤ 6 months	8	356	Mean Difference (IV, Random, 95% CI)	1.30 [‐3.01, 5.61]
1.6.2 End of active intervention > 6 months	6	367	Mean Difference (IV, Random, 95% CI)	2.41 [‐0.49, 5.31]
1.6.3 Follow‐up (no active intervention)	3	128	Mean Difference (IV, Random, 95% CI)	5.68 [‐1.88, 13.23]
1.7 Change in FEV₁ (% predicted): sensitivity analysis Show forest plot	9		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.7.1 End of active intervention ≤ 6 months	6	255	Mean Difference (IV, Random, 95% CI)	‐2.16 [‐4.14, ‐0.17]
1.7.2 End of active intervention > 6 months	5	333	Mean Difference (IV, Random, 95% CI)	1.71 [0.15, 3.26]
1.7.3 Follow‐up (no active intervention)	1	31	Mean Difference (IV, Random, 95% CI)	‐0.32 [‐11.90, 11.26]
1.8 Change in FEV₁ (mL) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.8.1 End of active intervention > 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.9 Change in FEV₁ (z‐score) Show forest plot	1	67	Mean Difference (IV, Fixed, 95% CI)	0.12 [‐0.37, 0.61]

1.9.1 End of active intervention > 6 months	1	67	Mean Difference (IV, Fixed, 95% CI)	0.12 [‐0.37, 0.61]
1.10 Change in FEV₁ (% predicted): combined subgroups Show forest plot	11	536	Mean Difference (IV, Random, 95% CI)	1.37 [‐0.74, 3.47]

1.11 Change in FEV₁ (% predicted): sensitivity analysis Show forest plot	9	436	Mean Difference (IV, Random, 95% CI)	1.07 [‐0.36, 2.49]

1.12 Change in HRQoL: CFQ‐R physical functioning domain Show forest plot	7	464	Mean Difference (IV, Random, 95% CI)	3.57 [‐0.81, 7.95]

1.12.1 End of active intervention ≤ 6 months	6	217	Mean Difference (IV, Random, 95% CI)	4.67 [‐2.55, 11.90]
1.12.2 End of active intervention > 6 months	4	247	Mean Difference (IV, Random, 95% CI)	2.19 [‐3.42, 7.80]
1.13 Change in HRQoL: CFQ‐R physical functioning domain: sensitivity analysis Show forest plot	5		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.13.1 End of active intervention ≤ 6 months	5	197	Mean Difference (IV, Random, 95% CI)	0.10 [‐4.05, 4.25]
1.14 Change in HRQoL: CFQ‐R physical functioning domain: combined subgroups Show forest plot	7	295	Mean Difference (IV, Random, 95% CI)	4.76 [‐1.09, 10.61]

1.15 Change in HRQoL: CFQ‐R physical functioning domain: combined subgroups – sensitivity analysis Show forest plot	6	275	Mean Difference (IV, Random, 95% CI)	2.44 [‐1.43, 6.30]

1.16 Change in HRQoL: CFQ‐R respiratory symptoms Show forest plot	6	463	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐3.50, 1.69]

1.16.1 End of active intervention ≤ 6 months	5	212	Mean Difference (IV, Random, 95% CI)	‐1.87 [‐5.66, 1.92]
1.16.2 End of active intervention > 6 months	4	251	Mean Difference (IV, Random, 95% CI)	‐0.05 [‐3.61, 3.51]
1.17 Change in HRQoL: CFQ‐R respiratory symptoms: combined subgroups Show forest plot	6	279	Mean Difference (IV, Random, 95% CI)	0.22 [‐3.15, 3.58]

1.18 Change in HRQoL: Quality of Well‐Being scale Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.18.1 Follow‐up (no active intervention)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.19 Change in peak work capacity (W/kg bodyweight) during maximal exercise Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.19.1 End of active intervention ≤ 6 months	3	164	Mean Difference (IV, Random, 95% CI)	0.32 [0.12, 0.51]
1.19.2 End of active intervention > 6 months	3	155	Mean Difference (IV, Random, 95% CI)	0.18 [0.07, 0.29]
1.19.3 Follow‐up (no active intervention)	2	51	Mean Difference (IV, Random, 95% CI)	0.26 [‐0.03, 0.56]
1.20 Change in peak work capacity (W) during maximal exercise Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.20.1 End of active intervention ≤ 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.21 Change in peak work capacity (% predicted) during maximal exercise Show forest plot	3	285	Mean Difference (IV, Random, 95% CI)	5.12 [1.63, 8.61]

1.21.1 End of active intervention ≤ 6 months	2	117	Mean Difference (IV, Random, 95% CI)	6.89 [3.94, 9.83]
1.21.2 End of active intervention > 6 months	2	168	Mean Difference (IV, Random, 95% CI)	3.59 [‐2.06, 9.24]
1.22 Change in time to symptom limitation (T_lim in sec) during constant work submaximal exercise Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.22.1 End of active intervention ≤ 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.23 Change in VO₂ (mL/min per kg bodyweight and % predicted) during constant work submaximal exercise Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.23.1 End of active intervention ≤ 6 months ‐ VO2 peakexpressed as mL/min per kg bodyweight	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.23.2 Active intervention ≤ 6 months ‐ VO2 peakexpressed as % predicted	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.24 Change in 6MWT distance (m) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.24.1 End of active intervention ≤ 6 months	2	81	Mean Difference (IV, Fixed, 95% CI)	25.32 [11.56, 39.08]
1.24.2 End of active intervention > 6 months	1	40	Mean Difference (IV, Fixed, 95% CI)	‐3.17 [‐35.27, 28.93]
1.25 Change in modified shuttle walk distance (m) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.25.1 End of active intervention ≤ 6 months	1	40	Mean Difference (IV, Fixed, 95% CI)	78.45 [18.18, 138.72]
1.25.2 End of active intervention > 6 months	2	107	Mean Difference (IV, Fixed, 95% CI)	131.91 [79.60, 184.22]
1.26 Change in quadriceps muscle strength (Nm) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.26.1 End of active intervention ≤ 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.26.2 Follow‐up (no active intervention)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.27 Change in FVC (% predicted) Show forest plot	10		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.27.1 End of active intervention ≤ 6 months	8	357	Mean Difference (IV, Random, 95% CI)	1.70 [‐1.95, 5.35]
1.27.2 End of active intervention > 6 months	5	299	Mean Difference (IV, Random, 95% CI)	2.51 [0.24, 4.78]
1.27.3 Follow‐up (no active intervention)	3	125	Mean Difference (IV, Random, 95% CI)	5.37 [‐1.69, 12.43]
1.28 Change in FVC (mL) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.28.1 End of active intervention > 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.29 Change in objectively measured physical activity (steps per day) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.29.1 End of active intervention ≤ 6 months	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.29.2 End of active intervention > 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.30 Change in objectively measured physical activity (aerobic steps per day) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.30.1 End of active intervention ≤ 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.30.2 End of active intervention > 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.31 Change in objectively measured moderate‐to‐vigorous physical activity (hours per week) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.31.1 End of active intervention ≤ 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.31.2 End of active intervention > 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.31.3 Follow‐up (no active intervention)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.32 Change in self‐reported vigorous physical activity (hours per week) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.32.1 End of active intervention ≤ 6 months	2	152	Mean Difference (IV, Fixed, 95% CI)	1.36 [0.86, 1.86]
1.32.2 End of active intervention > 6 months	2	148	Mean Difference (IV, Fixed, 95% CI)	1.71 [1.13, 2.29]
1.32.3 Follow‐up (no active intervention)	1	18	Mean Difference (IV, Fixed, 95% CI)	1.63 [0.02, 3.24]
1.33 Change in BMI (kg/m²) Show forest plot	5		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.33.1 End of active intervention ≤ 6 months	4	203	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.16, 0.20]
1.33.2 End of active intervention > 6 months	3	191	Mean Difference (IV, Fixed, 95% CI)	0.29 [‐0.04, 0.62]
1.33.3 Follow‐up (no active intervention)	2	60	Mean Difference (IV, Fixed, 95% CI)	0.61 [‐0.03, 1.26]
1.34 Change in BMI (z‐score) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.34.1 End of active intervention ≤ 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.35 Number of pulmonary exacerbations Show forest plot	1		Other data	No numeric data

1.35.1 Number of exacerbations at end of 6 months' partially supervised active intervention (mixed Poisson regression model)	1		Other data	No numeric data
1.35.2 Number of exacerbations after 12 months: 6 months' partially supervised activity followed by 6 months unsupervised activity with access to study resources (mixed Poisson regression model)	1		Other data	No numeric data
1.36 Time to first pulmonary exacerbation Show forest plot	1		Other data	No numeric data

1.37 Number of hospitalisations Show forest plot	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected

1.37.1 Hospitalisations during 12 months of active intervention	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected
1.38 Change in whole body bone mineral density (g/cm²) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.38.1 End of active intervention > 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.39 Change in lumbar spine bone mineral density (g/cm²) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.39.1 End of active intervention > 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.40 Change in metabolic parameters (HbA1c (%)) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.40.1 End of active intervention ≤ 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.41 Change in metabolic parameters (glucose AUC) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.41.1 End of active intervention ≤ 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.42 Change in metabolic parameters (total insulin AUC) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.42.1 End of active intervention ≤ 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.43 Change in metabolic parameters (insulin sensitivity index) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.43.1 End of active intervention ≤ 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.44 Change in plasma glucose (mmol/L) during an oral glucose tolerance test: end of active intervention ≤ 6 months Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.44.1 Change in fasting plasma glucose (mmol/L)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.44.2 Change in 1‐hour plasma glucose (mmol/L)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.44.3 Change in 2‐hour plasma glucose (mmol/L)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.45 Change in plasma insulin (µIU/mL) during an oral glucose tolerance test: end of active intervention ≤ 6 months Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.45.1 Pretest measurement	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.45.2 After 60 minutes	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.45.3 After 120 minutes	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.46 Change in blood glucose (mmol/L) during an oral glucose tolerance test: end of active intervention > 6 months Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.46.1 Change in fasting blood glucose (mmol/L)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.46.2 Change in blood glucose level (mmol/L) at 60 minutes	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.46.3 Change in blood glucose level (mmol/L) at 120 minutes	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.47 Adverse events and serious adverse events Show forest plot	2		Odds Ratio (IV, Fixed, 95% CI)	Subtotals only

1.47.1 Adverse events related to physical activity: end of active intervention > 6 months	2	156	Odds Ratio (IV, Fixed, 95% CI)	6.22 [0.72, 53.40]
1.47.2 Serious adverse events related to physical activity: end of active intervention > 6 months	1	117	Odds Ratio (IV, Fixed, 95% CI)	0.95 [0.06, 15.54]

Comparison 1. Physical activity versus control

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