A randomized,double-blind,placebo-controlled,clinical study on the efficacy and safety of calcium dobesilate in the treatment of chronic venous insufficiency

Abstract

Objective

To show the superiority of 500 mg calcium dobesilate vs. placebo in reduction of edema of the lower limbs in patients with chronic venous insufficiency, Clinical, Etiological, Anatomical and Pathophysiological classes C3/C4.

Methods

A total of 351 patients were randomized (n = 174 calcium dobesilate, n = 177 placebo). Active treatment was 500 mg calcium dobesilate, three times daily for 12 weeks, with a 12-week follow-up.

Results

At the end of treatment, the relative volume change in the most pathological leg was −0.6 ± 4.8% with calcium dobesilate compared to −0.3 ± 3.3% with placebo (p = 0.09). At the end of follow-up, this was −1.01 ± 5.4% for calcium dobesilate vs. −0.08 ± 3.5% for placebo (p = 0.002).

Conclusions

Calcium dobesilate treatment resulted in no significant volume change in the most pathological leg between baseline and end of treatment. However, the calcium dobesilate group showed a significantly greater volume decrease in the most pathological leg at the end of follow-up. Calcium dobesilate was well-tolerated, with a safety profile consistent with previously published data.

Keywords

Chronic venous insufficiency calcium dobesilate leg volume CEAP CIVIQ score

Introduction

Chronic venous disease (CVD) is a highly prevalent but underestimated disease.¹ The underlying cause of the venous pathology is an increase in venous pressure and impairment in the return of blood from the peripheral venous system to the central circulation. This may be due to one or a combination of factors such as venous and valve incompetence in the axial superficial or deep veins, valve incompetence in the perforator veins, or obstruction of the veins.² Chronic venous insufficiency (CVI) is a term that describes disease of greater severity, in general the condition of inadequate venous return and hypertension when an individual is in an upright position.¹ According to the Clinical, Etiological, Anatomical and Pathophysiological (CEAP) classification, CVI is defined as clinical classes C3 to C6.³ CVI manifests as a range of pathologies including swelling, skin changes and ulcerations and is frequently associated with venous symptoms such as pain.² One of the most frequent signs is edema in the leg, the result of accumulation of fluid due to a combination of fluid extravasation from the capillary bed and defective uptake by lymphatic vessels.^4,5

The estimated prevalence of CVI ranges from 1 to 40% in women and 1 to 17% in men.^1,2,6 Recent studies suggest a CVI prevalence between 17.0 and 20.6%.^7,8 For CVI, the risk factors include age, hereditary factors, female gender, pregnancy and obesity.⁹ The disease is graded according to the descriptive CEAP classification, which provides the main framework for guiding clinical decision making.^3,10 Treatment of CVI focuses on reducing venous valve reflux, thereby attenuating the development of inflammation and pathological tissue changes.^10,11

Calcium dobesilate (Doxium®; OM Pharma/Vifor Pharma, Meyrin, Switzerland) is a synthetic venoactive drug that has been demonstrated to be effective for the treatment of microcirculatory disorders, including CVI, and is recommended by the international guidelines.¹² Calcium dobesilate is registered and marketed in over 60 countries for the treatment of CVI. At the cellular level, calcium dobesilate inhibits serotonin-, bradykinin- and histamine-induced capillary permeability.¹³ Furthermore, it has antioxidant properties,¹⁴ inhibits the synthesis of prostaglandins and thromboxanes, reduces platelet and erythrocyte aggregation, and lowers blood viscosity.^15,16 In vivo, calcium dobesilate has been shown to reduce experimental lymphedema¹⁷ and intralymphatic pressure,¹⁸ increase lymphatic flow¹⁹ and decrease angiogenesis,²⁰ as well as vascular endothelial cell growth factor overexpression and albumin leakage.²¹ The safety and efficacy of calcium dobesilate have been demonstrated in several double-blind, placebo-controlled clinical trials in patients with CVI.^22,23 Use of calcium dobesilate resulted in improvement in clinical symptoms, as well as reduction in leg volume. The benefits of calcium dobesilate were particularly evident in moderate to severe cases of CVI, including CEAP classes C3, C4 and C5.^24–26

The goal of the present study was to demonstrate the efficacy and safety of calcium dobesilate in CVI patients within CEAP Classes C3 or C4 assessed using the method of water displacement volumetry (WDV).

Methods

Study design

This was a randomized, double-blind, placebo-controlled, multi-center Phase IV study. The study consisted of a 12-week double-blind treatment period and a 12-week follow-up period without treatment. Between 20 April 2010 and 10 November 2011, 397 subjects were screened and 351 were randomized in a 1:1 ratio to treatment with calcium dobesilate or placebo. The study was conducted at 26 sites in four countries: Germany (19 sites, 287 subjects, 81.8%), Poland (five sites, 60 subjects, 17.1%), Portugal (one site, three subjects, 0.9%), and Italy (one site, one subject, 0.3%).

The study protocol was approved by the Ethics Committee (Ethik-Kommission an der Medizinischen, Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn, Biomedizinisches Zentrum, Sigmund-Freud-Str. 25, 53105 Bonn, Germany) and all study procedures were conducted according to the principles of Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent. This study was registered at EudraCT (number 2009-013391-44).

Patients

Main inclusion and exclusion criteria

All patients included in the study (males or females aged 18–70 years) had 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 edema 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.

Patients with diseases that mimicked CVI (such as cardiac, hepatic or renal disease or other causes of leg edema), 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 lymphedema were excluded.

Study treatment

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 for 12 weeks.

Study assessments

The primary efficacy variable was the relative volume change of the most pathological leg (MPL) from baseline to the end of the 12-week treatment period, as measured by WDV.^10,27 At the study visits, each patient had to have all measurements taken at the same time of day within a 2-h timeframe.

The main secondary efficacy variables included the following:

Relative volume change of the MPL using WDV, from baseline to the end of the 24-week 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 chronic venous insufficiency questionnaire (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.

Additional post-hoc analyses were performed in order to examine the population of responders, as well as the effects of disease severity at baseline and seasonality on the response to treatment.

Safety parameters assessed were general physical status, vital signs, adverse events (AEs), serious adverse events (SAEs), safety laboratory variables and global assessment of tolerability by patients and investigators. All AEs were coded according to system organ classes (SOCs) as defined by the MedDRA dictionary (version 15.1).

Statistics/data analysis

Calculation of the biometrical sample size was performed using NQuery® (Version 7.0) with the following assumptions:

Approximate normal distribution for the primary variable,

Two-sided level of significance α = 5.0%,

Power 1-β = 90%,

Standardized difference δ = Δ/SD = 0.38.

With these assumptions, it was necessary to include 147 patients per group. Accordingly, we planned to enroll a total of 328 patients assuming a 10% dropout rate.

The primary endpoint was analysed using analysis of covariance (ANCOVA; including the variables treatment, baseline value, centre and treatment-centre interaction) on the intent-to-treat (ITT) and per-protocol (PP) sets. A two-sided overall level of significance was set at α = 5.0%. All other efficacy and safety variables were analysed by means of descriptive and exploratory statistical methods.

Results

Study populations

Of the 351 randomized subjects (ITT population), 174 were assigned to the calcium dobesilate group and 177 to placebo. A total of 299 (85.2%) completed the study (Figure 1).

Figure 1.

Disposition of study patients.

All randomized subjects received at least one dose of study medication and were evaluable for the safety analysis. Among the 351 randomized subjects, 328 (93.4%) presented at least one protocol violation, considered to be minor for 321 subjects, and major for 149 subjects (i.e., a deviation which may impact the primary endpoint). Major protocol violations were reported for 74 subjects (42.5%) in the calcium dobesilate group and 75 subjects (42.4%) in the placebo group. The main protocol violations included the following: wrong timing between the baseline and end of treatment visits (31 patients [17.8%] in the calcium dobesilate group and 37 patients [20.9%] in the placebo group), the MPL not defined according to the study protocol at screening (18 patients [10.3%] in the calcium dobesilate group and 13 patients [7.3%] in the placebo group) and duration of treatment <11 weeks (15 patients [8.6%] in the calcium dobesilate group and 21 patients [11.9%] in the placebo group).

The PP population included therefore only 202 patients (n = 100 in the calcium dobesilate group and n = 102 in the placebo group; Figure 1).

Demographics and baseline characteristics

The demographics and baseline disease characteristics of the study population were evenly balanced across both study arms (Table 1). The majority (79.8%) of the patients were female, mean age was 54.9 ± 10.7 years, and mean weight at inclusion was 84.5 ± 16.6 kg for a mean height of 169.6 ± 8.2 cm, leading to a mean body mass index (BMI) of 29.4 ± 5.0 kg/m². A relatively large proportion of patients received concomitant medications during the treatment period: 12.0% received an antithrombotic agent, 9.4% received analgesics and 4.6% received corticosteroids.

Table 1.

Demographic and disease characteristics at baseline (ITT population).

Variable	Statistic	Calcium dobesilate (n = 174)	Placebo (n = 177)	Total (n = 351)
Age (years)^a	n	174	177	351
	Mean ± SD	54.91 ± 10.58	54.90 ± 10.79	54.91 ± 10.67
	Min; Max	23.0; 70.0	23.0; 70.0	23.0; 70.0
Sex [n (%)]	n	174	177	351
	Male	37 (21.3)	34 (19.2)	71 (20.2)
	Female	137 (78.7)	143 (80.8)	280 (79.8)
Height at inclusion (cm)	n	174	177	351
	Mean ± SD	169.86 ± 8.77	169.37 ± 7.67	169.61 ± 8.23
	Min; Max	146.0; 195.0	153.0; 196.0	146.0; 196.0
Weight at inclusion (kg)	n	174	177	351
	Mean ± SD	85.05 ± 16.67	83.91 ± 16.53	84.47 ± 16.58
	Min; Max	54.0; 133.0	50.0; 138.0	50.0; 138.0
Body mass index at inclusion (kg/m²)	n	174	177	351
	Mean ± SD	29.49 ± 5.04	29.25 ± 5.06	29.37 ± 5.04
	Min; Max	18.0; 40.5	20.0; 40.0	18.0; 40.5
Heart rate (beats/min)	n	174	177	351
	Mean ± SD	72.34 ± 9.46	73.19 ± 9.72	72.77 ± 9.59
	Min; Max	54.0; 102.0	56.0; 100.0	54.0; 102.0
Systolic blood pressure (mmHg)	n	174	177	351
	Mean ± SD	127.90 ± 14.04	127.24 ± 14.75	127.56 ± 14.38
	Min; Max	94.0; 170.0	96.0; 180.0	94.0; 180.0
Diastolic blood pressure (mmHg)	n	174	177	351
	Mean ± SD	78.70 ± 8.64	79.15 ± 9.00	78.92 ± 8.82
	Min; Max	60.0; 100.0	50.0; 106.0	50.0; 106.0
Disease characteristics
Symptomatology at inclusion: pain [n (%)]	n	174	177	351
	Right leg	50 (28.7)	42 (23.7)	92 (26.2)
	Right and Left leg	61 (35.1)	66 (37.3)	127 (36.2)
	Left leg	46 (26.4)	51 (28.8)	97 (27.6)
	NA	17 (9.8)	18 (10.2)	35 (10.0)
Symptomatology at inclusion: discomfort [n (%)]	n	174	177	351
	Right leg	41 (23.6)	44 (24.9)	85 (24.2)
	Right and left leg	79 (45.4)	87 (49.2)	166 (47.3)
	Left leg	50 (28.7)	42 (23.7)	92 (26.2)
	NA	4 (2.3)	4 (2.3)	8 (2.3)

^aFrom the year of the birth date to the year of the screening visit.

Primary endpoint: relative volume change in the MPL assessed by WDV between baseline and end of the treatment period

There were no significant differences between the two study groups with respect to the primary endpoint. At baseline, the mean WDV leg volume in the MPL for the ITT population was 2368.9 ± 414.7 g, with 2352.1 ± 386.5 g in the calcium dobesilate group vs. 2385.5 ± 441.2 g in the placebo group (p = 0.8). At end of the treatment period, the mean overall value was 2357.3 ± 417.8 g, with 2336.0 ± 389.6 g in the calcium dobesilate group vs. 2378.2 ± 443.9 g in the placebo group (p = 0.7). This corresponded to an overall relative volume change of −0.4 ± 4.1% in the MPL, slightly higher in the calcium dobesilate group (−0.6 ± 4.8%) compared to placebo (−0.3 ± 3.3%), though not statistically significant (p = 0.09). Similar findings were obtained for the PP population (data not shown).

Secondary endpoint: relative volume change in the MPL assessed by WDV between baseline and end of study

The relative volume change measured by WDV was assessed at the end of the study, 12 weeks after last intake of the study drug. At that time-point, the relative volume change in the calcium dobesilate group was significantly higher compared to that in the placebo group (−1.01 ± 5.4% compared to −0.08 ± 3.5% for placebo; p = 0.002; Table 2). These findings were also confirmed in the PP population, with a mean relative volume change of −1.78 ± 5.1% in the calcium dobesilate group compared to −0.03 ± 3.7% in the placebo group (p < 0.001; Table 2).

Table 2.

Relative change in leg volume of the most pathological leg measured by water displacement volumetry between baseline and end of the study in the ITT (n = 351) and PP (n = 202) populations.

Between end of the study^a and baseline	Statistic	Calcium dobesilate (n = 174)	Placebo (n = 177)	P^b	Total (n = 351)
ITT population
Relative change in WDV in the most pathological leg (%)	N	174	177	0.002^c	351
	Mean ± SD	−1.01 ± 5.40	−0.08 ± 3.46		−0.54 ± 4.55
	Q1; Q3	−2.93; 0.94	−1.54; 1.78		−2.54; 1.33
	Median	−0.79	0.00		−0.27
	Min; Max	−34.7; 28.4	−14.1; 11.0		−34.7; 28.4
		Calcium dobesilate (N = 100)	Placebo (N = 102)	P[a]	Total (N = 202)
PP population
Relative change in WDV in the most pathological leg (%)	N	100	102	<0.001^c	202
	Mean ± SD	−1.78 ± 5.14	−0.03 ± 3.69		−0.90 ± 4.54
	Q1; Q3	−3.52; 0.11	−1.52; 1.91		−2.65; 1.31
	Median	−1.38	0.03		−0.68
	Min; Max	−34.7; 14.0	−14.1; 11.0		−34.7; 14.0

Assessed using last observation carried forward (LOCF) where applicable.

Exploratory tests.

P-value, Wilcoxon-Mann-Whitney test (two-sided), t-approximation due to Non-Gaussian variable.

Secondary endpoint: absolute leg volume change assessed by WDV between baseline and end of the treatment period or end of the study

As expected, there was no significant difference between the two treatment groups for the absolute volume change when comparing the end of treatment and baseline (Table 3). The mean values were −16.1 ± 109.5 g in the calcium dobesilate group compared to −7.2 ± 84.0 in the placebo group (p = 0.08). However, in line with the relative volume change, when comparing the results from end of study vs. baseline, the mean value for the absolute volume change was significantly higher in the calcium dobesilate group (−25.7 ± 127.4 g, compared to −1.1 ± 88.3 g for placebo; p = 0.002; Table 3).

Table 3.

Absolute change in leg volume of the most pathological leg as measured by water displacement volumetry, between baseline, end of treatment, and end of the study (ITT population; n = 351).

Absolute change in the WDV in the most pathological leg (g)	Statistic	Calcium dobesilate (n = 174)	Placebo (n = 177)	P^a	Total (n = 351)
Between end of treatment^b and baseline	n	174	177	0.083 (NS)^c	351
	Mean ± SD	−16.14 ± 109.46	−7.24 ± 84.03		−11.65 ± 97.43
	Q1; Q3	−60.50; 24.00	−43.50; 32.00		−50.00; 28.50
	Median	−10.50	0.00		−4.50
	Min; Max	−696.0; 498.0	−522.0; 229.5		−696.0; 498.0
Between end of the study^b and baseline	n	174	177	0.002^c	351
	Mean ± SD	−25.68 ± 127.44	−1.08 ± 88.33		−13.28 ± 110.01
	Q1; Q3	−74.17; 21.00	−38.00; 39.00		−56.00; 31.33
	Median	−17.75	0.00		−6.00
	Min; Max	−919.0; 601.0	−363.0; 330.5		−919.0; 601.0

Exploratory tests.

Assessed using last observation carried forward (LOCF) where applicable.

P value, Wilcoxon-Mann-Whitney test (two-sided), t-approximation due to Non-Gaussian variable.

Other secondary endpoints

There was no significant difference in the relative leg volume change using truncated cone measurements between baseline and end of treatment. There was a decrease of 1.8 ± 7.0% in the calcium dobesilate group compared to a decrease of 2.0 ± 6.5% in the placebo group, leading to a non-adjusted difference of 0.19% (p = 0.79). Likewise, no difference was seen for the relative change in calf circumference between baseline and end of treatment (mean decrease of 0.9 ± 3.3% in the active treatment group versus a decrease of 1.0 ± 3.2% in the placebo group, p = 0.71).

Measurement of pain and discomfort

Patients in both groups reported a decrease in total CIVIQ score between baseline and end of treatment, reflecting an improvement of disease status. However, the differences in total CIVIQ scores were not statistically significant (baseline scores: 50.5 ± 14.8 for the calcium dobesilate group vs. 51.0 ± 14.7 for placebo; end of treatment scores: 39.9 ± 14.9 for the calcium dobesilate group vs. 40.3 ± 16.4 for placebo, p = 0.9).

At the end of the treatment period, patients in the calcium dobesilate group reported a statistically significant reduction in the CIVIQ sub-score “pain or discomfort in ankles or legs during the past 4 weeks” (baseline scores: 3.0 ± 0.9 for the calcium dobesilate group versus 3.1 ± 0.9 for placebo; end of treatment scores: 2.1 ± 0.9 for the calcium dobesilate group vs. 2.3 ± 1.0 for the placebo group, p = 0.03). These findings were also reflected in the scores for pain and discomfort in the patients’ questionnaire. Amongst the patients treated with calcium dobesilate, 53.2% (51.9%) did not suffer from pain (discomfort) at end of the treatment period, compared to 11.5% (5.7%) at baseline. In contrast, 36.8% (43.2%) of patients treated with placebo did not suffer from pain (discomfort) at the end of the treatment period, compared to 11.9% (5.1%) at baseline. The severity of pain and discomfort also decreased during the study, as reflected by scores with a severity of >4. Amongst the patients treated with calcium dobesilate, 17.5% (29.3%) suffered from pain (discomfort) with a severity of >4 at end of treatment, compared to 51.8% (68.4%) at baseline. In patients who received placebo, however, 21.3% (37.1%) suffered from pain (discomfort) with a severity of >4 at end of treatment, compared to 52.0% (62.7%) at baseline. There were no differences in the other parameters for both the CIVIQ and patient questionnaires throughout the study.

Post-hoc analyses

There was a significantly higher proportion of responders to treatment, defined post-hoc as patients who had a negative relative change in WDV measurements in the MPL at the end of the treatment period compared to baseline, in the calcium dobesilate group compared to the placebo group (59.2% vs. 48.6%, respectively). Further exploratory analyses of the data were performed in order to understand the effects of disease severity at baseline, and the treatment effect according to the seasons.

We selected the subpopulation of patients with severe disease amongst the ITT population, defined according to disease duration (>7 years) and a CIVIQ score ≥3 for the item “pain or discomfort in the ankles or legs during the past 4 weeks” at baseline. In this subpopulation (n = 59 in the calcium dobesilate group and n = 72 in the placebo group), the leg volume as assessed by WDV in the MPL at baseline was 2344.79 ± 341.76 g in the calcium dobesilate group vs. 2405.50 ± 468.15 g in the placebo group. At the end of treatment, these values were 2310.17 ± 337.39 g and 2404.13 ± 471.48 g, respectively. This corresponded to a statistically significant difference in mean relative volume change in the MPL between baseline and the end of treatment, in favour of calcium dobesilate (−1.28 ± 6.75% in the calcium dobesilate group vs. −0.01 ± 2.95% in the placebo group; p = 0.005). This difference persisted at the end of the study, with absolute leg volumes of 2320.80 ± 344.88 g and 2399.28 ± 473.34 g for the calcium dobesilate and placebo groups, respectively. This corresponded to a statistically significant difference in mean relative volume change in the MPL between baseline and the end of the study in favour of calcium dobesilate (−0.86 ± 6.75 vs. −0.24 ± 2.75 for the calcium dobesilate and placebo groups, respectively; p = 0.005).

Another question we attempted to answer was related to the seasonal WDV changes, since for some patients the treatment period started in the cold season and ended in the warm season. This would suggest that the level of edema would be more pronounced in warmer temperatures, potentially enhancing any differences between calcium dobesilate and placebo during the warmer season. In the subpopulation of patients who were randomized and treated in the autumn/winter (i.e. between 21 September and 21 March the following year; n = 75 in the calcium dobesilate group and n = 65 in the placebo group), there was a difference in WDV in the MPL between the end of treatment and baseline that approached statistical significance. At baseline, the mean absolute values obtained in the MPL were 2291.21 ± 305.50 g for the calcium dobesilate group compared to 2402.25 ± 439.87 g for the placebo group. At the end of treatment, the corresponding values were 2260.65 ± 324.02 g and 2398.48 ± 454.76 g, respectively. These values corresponded to a mean relative change in WDV of −1.32 ± 4.91% in the calcium dobesilate group, vs. −0.13 ± 4.09% in the placebo group (p = 0.066).

Safety

Of the 351 patients included in the safety analysis, 188 (53.6%) presented with 427 AEs during the study; 91 (52.3%) reporting 210 AEs in the calcium dobesilate group and 97 (54.8%) with 217 AEs in the placebo group (Table 4). There was one death in the study in the calcium dobesilate group. The patient was a 66-year-old female, who died during the follow-up period from complications from a gastroscopy due to underlying Crohn's disease. The death was assessed by the investigator as unrelated to the study drug.

Table 4.

Overview of safety findings (n = 351).

	Calcium dobesilate n = 174		Placebo n = 177		Total n = 351
	n (%)	# events	n (%)	# events	n (%)	# events
Any AE	91 (52.3)	210	97 (54.8)	217	188 (53.6)	427
Any treatment-related AE	26 (14.9)	128	23 (13.0)	131	49 (14.0)	259
Any severe treatment-related AE	4 (2.3)	8	6 (3.4)	8	10 (2.8)	16
Any AE with outcome of death	1 (0.6)	1	0 (0.0)	0	1 (0.3)	1
Any serious AE	6 (3.4)	13	9 (5.1)	10	15 (4.3)	23
Any serious treatment-related AE	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0
Any AE leading to permanent discontinuation	17 (9.8)	35	23 (13.0)	35	40 (11.4)	70
Any AE leading to dose reduction	1 (0.6)	2	0 (0.0)	0	1 (0.3)	2
Any treatment-related AE leading to permanent discontinuation	6 (3.4)	12	7 (4.0)	12	13 (3.7)	24

Note: Only treatment-emergent adverse events (AE) are summarised.

Patients are counted only once, even if they experienced multiple events in that category.

Fifteen patients (4.3%) experienced at least one SAE (6 [3.4%] treated with calcium dobesilate and nine [5.1%] treated with placebo). None of these SAEs were deemed by the investigator to be related to the study treatment.

The most frequently reported AEs by SOC (>2%) during the study included infections and infestations (19.1%), musculoskeletal and connective tissue disorders (14.5%), gastrointestinal disorders (10.3%), nervous system disorders (7.1%), skin and subcutaneous tissue disorders (6.8%), vascular disorders (6.3%) and investigations (5.1%) (Table 5). Of the total AEs, 16 severe AEs were assessed by the investigator as related to treatment (6 patients [3.4%], eight AEs in the placebo group, compared to four patients [2.3%], eight AEs in the calcium dobesilate group).

Table 5.

Adverse events reported by ≥2% of subjects in the safety population (n = 351).

System organ class Preferred term	Calcium dobesilate (n = 174) n(%)	Placebo (n = 177) n(%)	Total (n = 351) n(%)
Any adverse event	91 (52.3)	97 (54.8)	188 (53.6)
Infections and infestations	36 (20.7)	31 (17.5)	67 (19.1)
Nasopharyngitis	12 (6.9)	16 (9.0)	28 (8.0)
Influenza	3 (1.7)	5 (2.8)	8 (2.3)
Upper respiratory tract infection	5 (2.9)	1 (0.6)	6 (1.7)
Musculoskeletal and connective tissue disorders	28 (16.1)	23 (13.0)	51 (14.5)
Arthralgia	6 (3.4)	4 (2.3)	10 (2.8)
Back pain	4 (2.3)	5 (2.8)	9 (2.6)
Muscle spasms	5 (2.9)	2 (1.1)	7 (2.0)
Pain in extremity	4 (2.3)	3 (1.7)	7 (2.0)
Gastrointestinal disorders	22 (12.6)	14 (7.9)	36 (10.3)
Diarrhea	6 (3.4)	3 (1.7)	9 (2.6)
Nausea	5 (2.9)	4 (2.3)	9 (2.6)
Nervous system disorders	9 (5.2)	16 (9.0)	25 (7.1)
Headache	7 (4.0)	9 (5.1)	16 (4.6)
Skin and subcutaneous tissue disorders	13 (7.5)	11 (6.2)	24 (6.8)
Eczema	3 (1.7)	4 (2.3)	7 (2.0)
Pruritus	5 (2.9)	2 (1.1)	7 (2.0)
Vascular disorders	10 (5.7)	12 (6.8)	22 (6.3)
Hypertension	2 (1.1)	6 (3.4)	8 (2.3)
Investigations	12 (6.9)	6 (3.4)	18 (5.1)
Gamma-glutamyltransferase increased	4 (2.3)	0 (0.0)	4 (1.1)
General disorders and administration site conditions	7 (4.0)	8 (4.5)	15 (4.3)
Edema peripheral	0 (0.0)	4 (2.3)	4 (1.1)
Injury, poisoning and procedural complications	6 (3.4)	6 (3.4)	12 (3.4)
Surgical and medical procedures	5 (2.9)	3 (1.7)	8 (2.3)
Cardiac disorders	2 (1.1)	5 (2.8)	7 (2.0)
Ear and labyrinth disorders	1 (0.6)	6 (3.4)	7 (2.0)
Metabolism and nutrition disorders	4 (2.3)	3 (1.7)	7 (2.0)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	0 (0.0)	4 (2.3)	4 (1.1)

Note: Adverse events are coded using MedDRA version 15.1 (2012).

For each system organ class and preferred term, subjects are included only once even if they experienced multiple events in that category.

A total of 26 patients (14.9%, 128 events) in the calcium dobesilate group experienced at least one AE that was considered by the investigator to be related to treatment, compared to 23 patients (13.0%, 131 events) in the placebo group. As expected, the most commonly reported treatment-related AEs in the calcium dobesilate group were gastrointestinal disorders (12 patients, 6.9%), followed by skin and subcutaneous tissue disorders (six patients 3.4%), whereas in the placebo group, the most frequently reported related AEs were gastrointestinal disorders (eight patients 4.5%), followed by skin and subcutaneous tissue disorders, musculoskeletal and connective tissue disorders and nervous system disorders (four patients 2.3% each).

Discussion

The results from our study showed no difference between the two study arms in the primary endpoint, the relative volume change in the MPL between baseline and end of treatment, although a trend towards a greater decrease in leg volume was observed in the calcium dobesilate group. When this parameter was assessed at the end of the study, 12 weeks after the last intake of study drug, the volume decrease in the MPL became statistically significant in the calcium dobesilate group. Not surprisingly, a similar pattern was observed for the absolute weight change of displaced water in the MPL. At the end of treatment, there was no significant difference between the two study arms for this parameter. However, at the end of the study (12 weeks after the end of treatment), the calcium dobesilate group showed a statistically significant higher absolute weight change in the MPL compared to baseline.

Our negative findings on the primary efficacy endpoint are in contrast with the results from previously published studies which demonstrated the efficacy of calcium dobesilate in 256 patients of both sexes, aged 20–70 years, with pitting edema due to CVI (C3–C5 according to the CEAP classification) and at least one symptom such as pain or discomfort.^{22,23,26,28,29} Several limitations of our study may have had an impact on the findings. First, a relatively large proportion of patients received concomitant medications during the treatment period: 12.0% received an antithrombotic agent, 9.4% received analgesics and 4.6% received corticosteroids. The most important limitation of our study, however, is the fact that 149 patients (42.5%) had major protocol violations related to the assessment of the primary efficacy endpoint and duration of treatment. These protocol violations could potentially affect the primary outcome of the study. Finally, although WDV of the lower leg is an accepted means of assessing edema, it only accounts for leg volume below the calf and not that of the whole leg. In combination, these factors may have affected the results of the primary efficacy endpoint in the ITT population.

At the end of the study (12 weeks after the last intake of study drug), the relative leg volume change was significantly higher in the calcium dobesilate group compared to that in the placebo group (−1.01 ± 5.4% compared to −0.08 ± 3.5% for placebo; p = 0.002). Although these percentages may seem small, it should be kept in mind that change in leg volume is not the same as change in edema. Edema is localized in subcutaneous fatty tissue and skin, whereas the majority of the leg volume consists of muscle and bone. These subcutaneous tissues represent approximately 20% of the total leg volume, and in this compartment, a reduction of 1% would translate into a clinically relevant reduction in edema.

An interesting finding from our study was that calcium dobesilate had a prolonged effect in ameliorating leg volume in CVI, with more marked results evident 12 weeks beyond the end of the treatment period. These findings reflect those from a large, double-blind, placebo-controlled study by Martinez-Zapata et al.³⁰ After the three-month treatment period, no significant differences were evident; however, after a nine-month follow-up, the authors noted a statistically significant improvement in the progression of quality of life (the primary endpoint) in favor of calcium dobesilate.³⁰ In our study, patients in the calcium dobesilate group also showed a statistically significant improvement in the CIVIQ sub score “pain or discomfort in ankles or legs during the past four weeks” at the end of treatment, suggesting that the benefits of calcium dobesilate treatment were becoming apparent at the end of the treatment period. These findings suggest the possibility of a sustained and progressive therapeutic effect of calcium dobesilate in CVI, possibly due to its anti-inflammatory actions,^31,32 which would presumably result in a sustained effect over the long term even after drug intake has been stopped. It may also be hypothesized that pain or discomfort improved because of the primary effects of calcium dobesilate on the venous system, and that these effects did not immediately translate into a lower level of edema. Reduction in edema may have been a secondary consequence of the primary benefits of calcium dobesilate, and therefore would be observed after a time delay. At present, however, these points remain speculative and need to be formally demonstrated in clinical trials.

Post-hoc analyses of the ITT population revealed several key findings. First, in the subset of patients with severe disease (as defined by disease duration >7 years, and a CIVIQ score ≥3 for the item “pain or discomfort in ankles or legs during the past 4 weeks” at baseline), treatment with calcium dobesilate resulted in a significant improvement in leg volume in the MPL. It is noteworthy that even with the small number of patients used in the post-hoc analyses, statistically significant differences were observed. These findings suggest that patients who may benefit most from treatment with calcium dobesilate may have to be defined using additional criteria, and not only using the CEAP classification. Furthermore, we observed a seasonal effect in the reduction of leg volume in the MPL. Patients randomized and treated with calcium dobesilate during the autumn/winter season showed improvements on this endpoint compared to patients treated with placebo. Higher temperatures at the end of the treatment period or end of the study, in contrast to the lower temperatures at the beginning of the study, may have led to increased edema formation which would be better suppressed by calcium dobesilate in comparison with placebo. This suggests that climatic factors should also be considered and possibly controlled in future clinical studies in this indication because they could represent a confounding factor.³³

The most frequent AEs associated with calcium dobesilate in our study were fever, gastrointestinal disorders, and skin reactions, in line with previously published safety findings.³⁴ In general, there were no significant differences in AEs between the two study arms. The majority of AEs were of mild to moderate severity, and the overall safety findings were in line with the established safety profile of calcium dobesilate.

Conclusions

Treatment with calcium dobesilate did not result in a statistically significant difference in the relative volume change in the MPL (measured by WDV) between baseline and the end of the 12-week treatment period. However, when this parameter was assessed 12 weeks beyond the last intake of study drug, the calcium dobesilate group showed a statistically significant greater volume decrease in the MPL indicating a sustained and progressive therapeutic effect of calcium dobesilate in CVI. Calcium dobesilate was well tolerated, with a safety profile consistent with previously published data. No new safety signals emerged from this study.

Footnotes

Acknowledgements

We wish to thank Karine Pigache, Aude Chevalier and Sara Drago for their support with the administrative and operational aspects of the study.

Authors’ contributions

Stefania Ballarini and Lorenz Lehr contributed towards interpretation of the data and preparation of the manuscript.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Stefania Ballarini and Lorenz Lehr are employees of Vifor Pharma (Meyrin, Switzerland).

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Vifor Pharma (Meyrin, Switzerland).

References

Bergan

Schmid-Schonbein

Smith

. Chronic venous disease. N Engl J Med 2006; 355: 488–498.

Eberhardt

Raffetto

. Chronic venous insufficiency. Circulation 2005; 111: 2398–2409.

Eklof

Rutherford

Bergan

. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg 2004; 40: 1248–1252.

Bollinger

Pfister

Hoffmann

. Fluorescence microlymphography in chronic venous incompetence. Int Angiol 1989; 8: 23–26.

Bollinger

Herrig

Fischer

. Intravital capillaroscopy in patients with chronic venous insufficiency and lymphoedema: relevance to Daflon 500 mg. Int J Microcirc Clin Exp 1995; 15(Suppl 1): 41–44.

Beebe-Dimmer

Pfeifer

Engle

. The epidemiology of chronic venous insufficiency and varicose veins. Ann Epidemiol 2005; 15: 175–184.

Rabe

Pannier-Fischer

Bromen

. Bonner venenstudie der deutschen gesellschaft für phlebologie – Epidemiologische untersuchung zur frage der häufigkeit und ausprägung von chronischen venenkrankheiten in der städtischen und ländlichen wohnbevölkerung. Phlebologie 2003; 32: 1–14.

Rabe

Guex

Puskas

. Epidemiology of chronic venous disorders in geographically diverse populations: results from the Vein Consult Program. Int Angiol 2012; 31: 105–115.

Fowkes

Evans

Lee

. Prevalence and risk factors of chronic venous insufficiency. Angiology 2001; 52(Suppl 1): S5–15.

10.

Nicolaides

Allegra

Bergan

. Management of chronic venous disorders of the lower limbs: guidelines according to scientific evidence. Int Angiol 2008; 27: 1–59.

11.

No authors listed. Management of chronic venous disorders of the lower limbs – guidelines according to scientific evidence. Int Angiol 2014; 33: 87–208.

12.

Ciapponi

Laffaire

Roque

. Calcium dobesilate for chronic venous insufficiency: a systematic review. Angiology 2004; 55: 147–154.

13.

Tejerina

Ruiz

. Calcium dobesilate: pharmacology and future approaches. Gen Pharmacol 1998; 31: 357–360.

14.

Brunet

Farine

Garay

. Angioprotective action of calcium dobesilate against reactive oxygen species-induced capillary permeability in the rat. Eur J Pharmacol 1998; 358: 213–220.

15.

Falkay

Kovacs

. Calcium dobesilate (Doxium) as a prostaglandin synthetase inhibitor in pregnant human myometrium in vitro. Experientia 1984; 40: 190–191.

16.

Suschek

Kolb

Kolb-Bachofen

. Dobesilate enhances endothelial nitric oxide synthase-activity in macro- and microvascular endothelial cells. Br J Pharmacol 1997; 122: 1502–1508.

17.

Casley-Smith

. The effects of calcium dobesilate on acute lymphedema (with and without macrophages), and on burn edema. Lymphology 1985; 18: 37–45.

18.

Casley-Smith

. The influence of tissue hydrostatic pressure and protein concentration on fluid and protein uptake by diaphragmatic initial lymphatics; effect of calcium dobesilate. Microcirc Endothelium Lymphatics 1985; 2: 385–415.

19.

Piller

. The lymphogogue action of calcium dobesilate on the flow of lymph from the thoracic duct of anesthetized and mobile guinea pigs. Lymphology 1988; 21: 124–127.

20.

Lameynardie

Chiavaroli

Travo

. Inhibition of choroidal angiogenesis by calcium dobesilate in normal Wistar and diabetic GK rats. Eur J Pharmacol 2005; 510: 149–156.

21.

Rota

Chiavaroli

Garay

. Reduction of retinal albumin leakage by the antioxidant calcium dobesilate in streptozotocin-diabetic rats. Eur J Pharmacol 2004; 495: 217–224.

22.

Pecchi

De Franco

Damiani

. Calcium dobesilate in the treatment of primary venous insufficiency of the lower limbs. A controlled clinical study. Clin Ter 1990; 132: 409–417.

23.

Widmer

Biland

Barras

. Doxium 500 in chronic venous insufficiency: a double-blind placebo controlled multicentre study. Int Angiol 1990; 9: 105–110.

24.

Labs

Degischer

Gamba

. Effectiveness and safety of calcium dobesilate in treating chronic venous insufficiency: randomized, double-blind, placebo-controlled trial. Phlebology 2004; 19: 123–130.

25.

Rabe

Jaeger

. on behalf of the study working group. Multicentre, double-blind, placebo-controlled, randomised clinical study to assess the efficacy and safety of Doxium® 500 three times daily in patients suffering from chronic venous insufficiency (CVI) CEAP Class C3, 4 or 5. Phlebologie 2006; 35: A37–A37.

26.

Rabe

Jaeger

Bulitta

. Calcium dobesilate in patients suffering from chronic venous insufficiency: a double-blind, placebo-controlled, clinical trial. Phlebology 2011; 26: 162–168.

27.

Perrin

Guex

. Edema and leg volume: methods of assessment. Angiology 2000; 51: 9–12.

28.

Jaeger

. the CVI Study Group. Efficacy and safety of Doxium in chronic venous insufficiency: double-blind, placebo-controlled multicenter study. Int Angiol 2001; 20: 239–239.

29.

Flota-Cervera

Flota-Ruiz

Trevino

. Randomized, double blind, placebo-controlled clinical trial to evaluate the lymphagogue effect and clinical efficacy of calcium dobesilate in chronic venous disease. Angiology 2008; 59: 352–356.

30.

Martinez-Zapata

Moreno

Gich

. A randomized, double-blind multicentre clinical trial comparing the efficacy of calcium dobesilate with placebo in the treatment of chronic venous disease. Eur J Vasc Endovasc Surg 2008; 35: 358–365.

31.

Alda

Valero

Pereboom

. In vitro effect of calcium dobesilate on oxidative/inflammatory stress in human varicose veins. Phlebology 2011; 26: 332–337.

32.

Piller

. Assessment of the anti-inflammatory action of calcium dobesilate. Effect on macrophages attaching to subcutaneously implanted coverslips in guinea pigs. Arzneimittelforschung 1990; 40: 698–700.

33.

Eklof

Perrin

Delis

. Updated terminology of chronic venous disorders: the VEIN-TERM transatlantic interdisciplinary consensus document. J Vasc Surg 2009; 49: 498–501.

34.

Allain

Ramelet

Polard

. Safety of calcium dobesilate in chronic venous disease, diabetic retinopathy and haemorrhoids. Drug Saf 2004; 27: 649–660.