Rabe 2015.

Study characteristics
Methods	Study design: randomised, multi‐centre, double‐blind, placebo‐controlled Method of randomisation: not specified Exclusions post randomisation: 48% of patients (no symptoms) Losses to follow‐up: not specified.
Participants	Countries: Argentina, Austria, Czech Republica, France, Germany, Hungary, Italy, Poland, Portugal, Russia, Slovakia, Spain and Switzerland Setting: ambulatory outpatients Number: 1137 (579 to experimental and 558 to placebo group); 592 (52.1%) patients had CVI with symptoms Age: mean 48.9.2 ± 11.1 years old (symptomatic patients) Gender: 87.3% women (symptomatic patients) Inclusion criteria: ambulatory outpatients, adults, with CEAP C3 or C4A, and at least one venous reflux and vesper leg oedema Exclusion criteria: BMI ≥ 30, dermatoliposclerosis, leg ulcer, idiopathic oedema, lymphoedema, a recent (< 1 year) DVT, dermal infection or inflammation of the leg, recent sclerotherapy or surgical treatment of varicose veins. Treatment with anti‐inflammatories, calcium channel blockers, diuretics, thymoanaleptics, hormones or venous‐active drugs
Interventions	Treatment: micronized purified flavonoid fraction 1000 mg (2 tablets 500 mg) per day Control: matching placebo Duration: 4 months Follow‐up post treatment: 2 months Elastic stockings: not specified
Outcomes	Primary Signs ‐ leg edema measured by water displacement volumetry Secondary Symptoms ‐ subjective symptoms (pain, heaviness assessed by 10‐cm visual analogue scale, and quality of life was assessed by CIVIQ Tolerance to treatments assessed on recording adverse events and vital signs (blood pressure, heart rate and body weight)
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: The authors did not describe the process of random sequence generation
Allocation concealment (selection bias)	Unclear risk	Comment: The authors did not describe the process of allocation concealment
Blinding (patients)	Unclear risk	Comment: The authors did not describe the placebo characteristics (colour and taste). The patient received two tablets of 500 mg of placebo at lunch time as the experimental group that received micronized purified flavonoid fraction
Blinding (study researchers)	Unclear risk	Comment:The study used placebo
Blinding (outcome assessment)	Unclear risk	Comment: The study used placebo
Incomplete outcome data	Low risk	The baseline characteristics were described only for symptomatic patients (52% of the sample size) and were balanced between groups. Although there is not a flowchart about the total patients included, the authors reported a 4.1% of losses in the overall patients and a 3.6% of losses in the symptomatic subgroup
Selective reporting	High risk	The main outcome "improvement on leg oedema" was not reported adequately. The authors only referred that there were not significant differences between groups when oedema was assessed using water displacement volumetry. This is a posthoc analysis for only symptomatic patients
Other bias	Low risk	Comment: none detected