Serra 2015a.

Methods	Doxycycline arm of RCT (doxycycline vs control) Setting: single clinical centre Country: Italy Duration of follow‐up: 5 months Treatments: all participants had basic treatment, including vein surgery if appropriate and compression stockings. Randomised to receive 3 months' course of doxycycline or standard care
Participants	32 participants with VLUs Mean age: 50.5 (SD 8) years, range 41‐60 years Sex (M:F): 9:23 Stage of ulcer: class 6 of CEAP (inclusion criterion) Ulcer duration: ≥ 6 weeks (inclusion criterion) Ulcer size at baseline median (range): 12.9 (2.9‐19.5) cm² Wound infection: no infection within 6 weeks (inclusion criterion) Number of wounds: unclear Inclusion criteria: aged 20‐70 years, VLU (class 6 CEAP), duration at least weeks, ABPI > 0.9 Exclusion criteria: arterial disease, infection within 6 weeks, connective tissue disorder, blood disorder, cancer, gastroenteritis, allergy to tetracyclines
Prognostic factors	MMP‐9 (continuous data). Measurement method ELISA: kit from Amersham Pharmacia Biotech; same approach as Serra 2013 Time of measurement: baseline, 4 weeks, 3 months, 5 months Wound fluid sampling method: not stated
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Selection bias	Unclear risk	Moderate: insufficient information to assess this domain. RCT, so may be less representative
Attrition bias	Low risk	No missing data
Prognostic factor measurement	Unclear risk	Moderate: unclear if ELISA was adequate method and unclear if active or latent protease
Outcome measurement	High risk	Not adjusted for baseline; unclear if blinded
Adjustment factors	High risk	None of the key adjustment factors taken into account in the design or analysis
Analysis and reporting	High risk	Experimental arm may have interacted with protease levels. Not taken into account. Number of participants healing not reported, so SMD could not be applied
Overall risk of bias	High risk