Labs 2004.

Study characteristics
Methods	Study design: randomised, double‐blind, placebo‐controlled Method of randomisation: computerised random assignment method Exclusions post randomisation: 7/260 (0.3%), protocol violation Losses to follow‐up: 21/260 (8%)
Participants	Country: Switzerland Setting: university Number: 260 patients Age: 20 to 70 years Gender: 16 M:201 F Inclusion criteria: CVI class 1 to 4 (CEAP classification), oedema and symptoms Exclusion criteria: CVI class 5 to 6 (CEAP classification); other causes of oedema (cardiac, renal, etc.); hypertension with change in treatment within 6 weeks of study start; obesity; peripheral arterial occlusive disease; venous surgery in the past 12 months or sclerotherapy during the past 6 months; irregular menstrual cycle; elevated transaminases; neutropenia; significant renal insufficiency; gastrointestinal disease; allergy to study medication; pregnant or lactating women; unreliable patient (psychiatric disorders, alcoholism, etc.); compression stockings or bandages; diuretics; venotropic medication; antiphlogistic drugs; corticosteroids; analgesics
Interventions	Treatment: calcium dobesilate 1500 mg per day Control: placebo Duration: 28 days Follow‐up: 42 days
Outcomes	Primary Signs ‐ oedema, reduction in leg volume (≥ 25 mL/litre tissue), circumference of ankle and calf Secondary Symptoms ‐ pain and discomfort measured by a visual analogue scale Discomfort measured as the sum of frequencies of symptoms: heaviness, tingling and itching Pain measured as the sum of frequencies of symptoms: pain and cramps Total symptoms score (discomfort and pain) Overall efficacy assessed by physician and participant on a 7‐point scale Side effects
Notes	Reasons for withdrawal unknown
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The corresponding boxes were randomized in balanced blocks and were labelled by the sponsor with the study number, the dosage, the batch numbers, with the patient number and with the note 'for clinical trials only'. The randomization was done by BIOMETRIX S. A., CH‐1911 Gland, Switzerland, using appropriate software" Comment: computer‐generated list of random numbers accepted as a good method for generating a random sequence of participants
Allocation concealment (selection bias)	Low risk	Quote: "The allocation of the study treatment to each patient was done according to the next available consecutive patient number printed on the prescription card and on the label of the box. This number was recorded on each page of the CRF.¨ and ¨Each investigator was provided with a sealed envelope containing the code for each patients randomisation number" Comment: seems like a fair method of allocation concealment
Blinding (patients)	Low risk	Quote: "For the double‐blind treatment period, the boxes, labels, and capsules containing Doxium 500 and placebo were identical in appearance for each drug, to ensure patient and investigator blinding" Comment: Identical placebo ensures double‐blinding
Blinding (study researchers)	Low risk	Quote: "For the double‐blind treatment period, the boxes, labels, and capsules containing Doxium 500 and placebo were identical in appearance for each drug, to ensure patient and investigator blinding" Comment: Identical placebo ensures double‐blinding
Blinding (outcome assessment)	Low risk	Quote: "For the double‐blind treatment period, the boxes, labels, and capsules containing Doxium 500 and placebo were identical in appearance for each drug, to ensure patient and investigator blinding" Comment: Identical placebo ensures double‐blinding
Incomplete outcome data	Low risk	Comment: number of participants in each group described. Adverse events, participant experience, compliance and number of participants who dropped out prematurely reported (29/260 participants)
Selective reporting	Low risk	Comment: no published protocol identified, and no differences between outcomes reported in the methods section and those reported in the results section
Other bias	Low risk	Comment: none detected