Rabe 2016.

Study characteristics
Methods	Study design: randomized, double‐blind, placebo‐controlled, multi‐center Phase IV study Method of randomisation: not specified Exclusions post randomisation: the analysis was per ITT but 149 (45.4%) participants presented major protocol violations Losses to follow‐up: 52 (14.8%) participants
Participants	Countries: Germany, Italy, Poland, Portugal Setting: ambulatory outpatients Number: 351 (177 calcium dobesilate, 177 placebo) Age: mean 54.9 ± 10.7 years Gender: 280 (79.8%) female Inclusion criteria: participants of both sexes, with moderate CVI, as defined by CEAP classification C3 or C4,3 and assessed by clinical evaluation and duplex sonography. Eligible patients presented with a pitting oedema and at least one of the following: discomfort or pain in at least one leg at both the screening and baseline visits. In addition, all patients had to have chronic but stable edema. Exclusion criteria: participants with diseases that mimicked CVI (such as cardiac, hepatic or renal disease or other causes of leg oedema), those with other vascular system disorders (such as cardiac insufficiency, diabetes mellitus, non‐controlled hypertension, recent phlebitis/deep leg vein thrombosis) and those with primary or secondary lymphoedema
Interventions	Treatment: capsules containing 500 mg of calcium dobesilate (Doxium; batch number 23843) Control: placebo Dose: 3 capsules per day of calcium dobesilate or matching placebo Duration: 12 weeks Follow‐up post treatment: 12 weeks Elastic stockings: not specified
Outcomes	Primary Relative volume change in the MPL assessed by WDV between baseline and end of the treatment period Secondary Relative volume change in the MPL assessed by WDV between baseline and end of study Absolute volume change of the MPL measured by WDV after the end of the treatment period and after the end of the follow‐up period Relative volume change of the MPL from baseline to the end of treatment and end of study assessed by a volumetric measurement with a calibrated spring metered tape and calculated by assimilating the leg volume to a truncated cone Change in the score from the CIVIQ tool, comprising 20 questions that were given a score from 1 to 5 (lowest to greatest intensity) from baseline to the end of treatment Safety
Notes	EudraCT (number 2009‐013391‐44). clinicaltrialsregister.eu/ctr‐search/trial/2009‐013391‐44/IT. Recruitment between 20 April 2010 and 10 November 2011
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "351 were randomized in a 1:1 ratio to treatment with calcium dobesilate or placebo" Comment: There was no information about the generation of the random sequence
Allocation concealment (selection bias)	Unclear risk	Quote: "351 were randomized in a 1:1 ratio to treatment with calcium dobesilate or placebo" Comment: There was no information about the allocation concealment
Blinding (patients)	Low risk	Quote: "Capsules containing 500 mg of calcium dobesilate (Doxium; batch number 23843) were used. The treatment regimen consisted of three capsules per day of calcium dobesilate or matching placebo" Comment: Placebo were capsules administered at the same posology as Dobesilate
Blinding (study researchers)	Low risk	Quote: "Capsules containing 500 mg of calcium dobesilate (Doxium; batch number 23843) were used. The treatment regimen consisted of three capsules per day of calcium dobesilate or matching placebo" Comment: Placebo were capsules administered at the same posology as Dobesilate
Blinding (outcome assessment)	Low risk	Quote: "Capsules containing 500 mg of calcium dobesilate (Doxium; batch number 23843) were used. The treatment regimen consisted of three capsules per day of calcium dobesilate or matching placebo" Comment: Placebo were capsules administered at the same posology as Dobesilate
Incomplete outcome data	High risk	Comment: 14.8% of the randomised participants were lost during follow‐up and major protocol violations were reported for 42.4% of the randomised participants.
Selective reporting	Low risk	Comment: The outcomes specified in the protocol were reported
Other bias	Low risk	Comment: none detected