Brevetti 1992.

Study characteristics
Methods	Randomized double‐blind controlled trial; cross‐over study
Participants	12 intermittent claudication patients in the preliminary study (dose‐finding study), 14 intermittent claudication patients in the comparative study (iv 600 mg PLC vs iv 500 mg LC). Patients were referred to the outpatient clinic of the study authors
Interventions	Preliminary study: first iv placebo for all participants, 4 days later followed by intervention: iv 300 mg PLC or 600 mg PLC (cross‐over after 4 days between the 2 PLC dose arms) Comparative study: first iv placebo for all participants, 4 days later followed by intervention: iv 600 mg PLC iv or 500 mg LC (cross‐over after 4 days between the 2 intervention arms) There was a washout period between the different phases
Outcomes	Maximal walking distance (meters) on treadmill (2.5 mph, slope 7%) Initial (pain‐free) claudication distance (meters) on treadmill (2.5 mph, slope 7%) Hemodynamic assessment: CSA common femoral artery, blood flow velocity (cm/s), blood flow rate (mL/min), pulsatility index, resistance index, ABI
Notes	Quote in the discussion: "an increase in MWD of 30% was accepted as clinically relevant" Disease specific: short study duration and follow‐up Small number of participants No washout period in the comparative study Funding by Sigma Tau
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information about random generation of the sequence of phases and groups (cross‐over study)
Allocation concealment (selection bias)	Unclear risk	No description of the method of allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "double‐blind, double‐dummy cross‐over study"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome assessment assumed, hence no influence on outcome assessment
Incomplete outcome data (attrition bias) All outcomes	Low risk	All results and P values reported; no reported withdrawals
Selective reporting (reporting bias)	Unclear risk	Quote in the discussion: "only an increase in MWD of 30% over baseline was accepted as clinically relevant": 8/14 on PLC and 5/14 on LC. It is not fully clear which numbers were used for analysis
Other bias	Unclear risk	Possible conflict of interest (funding by Sigma Tau), short duration and follow‐up, small number of participants