Comparison 1. Protease activity continuous.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 t‐test assocation of protease level and healing (dichotomous)	6		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.1 Completely healed vs non‐healed	2		Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Degrading MMPs: (gelatinases/metalloelastase) healing vs non‐healing	3		Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Reparative MMPs: (collagenases/matrilysin) healing vs non‐healing	2		Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 t‐test association of protease level and healing: high (≥ 1 cm²/week) vs low (< 1 cm²/week) healing	3		Mean Difference (Fixed, 95% CI)	Totals not selected
2.1 With doxycycline treatment	1		Mean Difference (Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 With standard care treatment	1		Mean Difference (Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Treatment not reported (other than compression)	1		Mean Difference (Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Correlation coefficients: protease levels and change in size	3		Correlation coefficient (Fixed, 95% CI)	Totals not selected
3.1 Change in MMP‐2 level vs reduction in ulcer size	1		Correlation coefficient (Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Change in MMP‐9 level vs reduction in ulcer size	1		Correlation coefficient (Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 MMP‐8 level at 4 weeks vs % reduction in size at 8 weeks	1		Correlation coefficient (Fixed, 95% CI)	0.0 [0.0, 0.0]
3.4 Elastase level at 4 weeks vs % reduction in size at 8 weeks	1		Correlation coefficient (Fixed, 95% CI)	0.0 [0.0, 0.0]
3.5 Elastase at 4 weeks vs % change in size at 9 months	1		Correlation coefficient (Fixed, 95% CI)	0.0 [0.0, 0.0]