Impact of Copper Compression Stockings on Venous Insufficiency and Lipodermatosclerosis: a Randomised Controlled Trial
Phase: NA
Conditions: Lipodermatosclerosis, Chronic Venous Insufficiency, Venous Insufficiency, Varicose Veins
Sponsor: Croydon Health Services NHS Trust

 
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Protocol 
 
 
CIVIL study 
Copper Impact on Venous Insufficiency and Lipodermatosclerosis 
 
Version 3 (25/03/2015) 
 
 
 
 
 
Authors: 
L.P. Arendsen MD, Research Fellow in Urogynaecology 
S. Vig FRCS, Consultant Vascular Surgeon 
E. Mallon, Consultant Dermatologist 
R. Thakar FRCOG, Consultant Gynaecologist, Urogynaecology subspecialist 
A.H. Sultan FRCOG, Consultant Gynaecologist 
 
Croydon University Hospital 
530 London Road, CR7 7YE  
Croydon, United Kingdom 
Telephone number: 020 8401 3000

 
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Full title: Randomised Controlled Trial on the Impact of Copper Impregnated Stockings on 
lipodermatosclerosis secondary to venous insufficiency 
 
Background 
Chronic venous disease (CVD) has various clinical presentations and the most commonly 
known symptom is varicose veins. Other symptoms include pain, oedema, and cutaneous 
changes of the lower legs such as hyperpigmentation, eczema, atrophie blanche (white scar 
tissue) and lipodermatosclerosis (induration caused by the fibrotic process of the 
subcutaneous fat). Chronic venous disease can be classified with the clinical, aetiologic, 
anatomical, and pathophysiological classification (CEAP-classification) in which the clinical 
signs are graded into six classes; C0-C6 (Table 1). CVD includes all symptoms and signs, 
whereas chronic venous insufficiency (CVI) refers to a more advanced stage of CVD (i.e. 
C4-C6) (12). 
 
CEAP Clinical classification of chronic venous disease 
C0 
No visible or palpable signs of venous disease 
C1 
Telangiectasies or reticular veins 
C2 
Varicose veins 
C3 
Oedema without skin changes 
C4a` 
Pigmentation or eczema 
C4b 
Lipodermatosclerosis or atrophie blanche 
C5 
Healed venous ulcer 
C6 
Active venous ulcer 
 
The prevalence of CVD varies among the different stages of the disease. A large worldwide 
study of the Vein Consult Program showed a prevalence of clinically significant CVD of more 
than 60% in the general population (4). Varicose veins are the most common manifestation 

 
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of CVI with a prevalence up to 30% in adult population (1,2,3). The prevalence of active and 
healed ulcers is approximately 1% of the adult population (5). Since delayed healing and 
recurrence are very common, the prognosis of venous ulceration is poor (6).  
 
The high prevalence and the chronic nature of venous disease have a considerable socio-
economic impact. A study conducted in the United States and the United Kingdom showed 
that venous ulcers cause a decrease of 2 million working days per year (7) and the National 
Health Service (NHS) spends approximately 1-3% of the total health care budget on the 
treatment of CVD (8,9).  
 
Graded compression stockings are the primary conservative treatment in patients with CVI. 
A significant improvement can only be achieved with a good compliance (10). Reduced 
adherence to compression therapy is a well-known and major issue in the treatment of 
patients with CVD (13). Patients with clinical CEAP classification C4 venous disease, or 
higher, have an increased risk of venous ulceration. Non-compliance with compression 
hosiery and deterioration of the skin condition increases this risk. In literature the non-
compliance ranged from 22%-67% (13 - 17). The most common reasons for non-compliance 
are inapplicability, the perception of inefficacy and the lack of comfort (13). However,the 
strategy to properly address non-compliance remains unknown. 
 
Standard compression stockings reduce the symptoms of pain and oedema, facilitate the 
healing of ulcers, and prevent the recurrence of venous ulcers (11), but they do not improve 
the skin condition. Copper has been shown to promote angiogenesis and therefore it could 
support wound healing and possibly improve skin condition. Copper has also been shown to 
have strong antimicrobial properties. It has been shown in observational, non-randomised 
trials that improvement of the skin condition could be seen within two weeks (33,34). When 
no change in skin condition is seen within four weeks, it is unlikely to be seen at all. 
 

 
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Antimicrobial copper 
Copper was primarily known for its antimicrobial effect and has been used for hygienic 
purposes for centuries (18). With the increase in antibiotic resistant bacteria causing 
nosocomial infections, copper has become a popular subject of recent research. There are 
many laboratory studies showing the biocidal effect of copper on a wide range of microbes 
such as bacteria, fungi and viruses (21,22). Copper has also been proven to be effective 
against Methicillin-resistant Staphylococcus aureus (MRSA) (19) and Vancomycin-resistant 
Enterococci (VRE) (20). The use of copper surfaces in the hospital has been evaluated in 
several clinical studies showing significant reductions in bacterial colonisation on copper 
surfaces compared to standard materials (23). After the use of copper as a biocidal contact 
surface, the use of copper impregnated textiles was explored. Currently, there is a great 
variety in products available containing copper impregnated textiles such as socks, pyjamas, 
underwear, bed linen, face masks, stockings and wound dressings, but there is a paucity of 
clinical research. There has been a clinical study on the effect of copper impregnated socks 
in patients suffering from tinea pedis showing a significant improvement or resolution of the 
infection after wearing these socks for two weeks (24). 
 
Wound healing 
It has also been proven that copper is essential for the process of wound healing.  Copper is 
assumed to be involved in several processes crucial for wound healing (25). A key role in 
wound healing is angiogenesis. It has been shown that copper induces the production of 
vascular endothelial growth factor (VEGF) and therefore stimulates angiogenesis (26). 
Furthermore, copper promotes wound healing due to an elevation in integrin expression 
(27); enhancement of fibrinogen stabilisation (28) and up-regulation of several enzymes 
essential for matrix remodelling and cell growth (29). Several laboratory studies have 

 
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demonstrated an association between a copper dependant enzyme, lysyl oxidase (LOX), 
and skin ageing and pathological skin conditions (30).  
 
Safety 
The dermal exposure to copper is considered safe as copper is not only an essential 
element for normal skin function but also essential for the immune system and blood 
coagulation (31). In contrast to microorganisms, human skin cells have the ability to 
metabolise and utilise copper (32) and therefore the development of adverse reactions are 
unlikely (33,35).  
 
Our hypothesis is that copper impregnated stockings promotes wound healing and improves 
the skin condition in patients with lipodermatosclerosis secondary to CVI. 
 
Aim 
To investigate the impact of copper impregnated stockings on subjective and objective 
outcomes in patients with lipodermatosclerosis secondary to venous insufficiency. 
 
Objectives 
Primary:  
To assess the effect of copper stockings on symptoms in patients with lipodermatosclerosis 
secondary to venous insufficiency. 
 
Secondary:  
To assess the effect of copper stockings on skin condition in patients with 
lipodermatosclerosis secondary to venous insufficiency.  
 
Methodology 

 
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This is a randomised controlled pilot study to assess the feasibility of copper impregnated 
stockings. All patients with CEAP classification 4 in both legs and venous disease identified 
by venous duplex will be recruited from the vascular clinics within Croydon Health Services 
over a period of three months. All patients will be given a patient information sheet 
describing the study prior to consent (Appendix 1 Patient Information Sheet). Patients will be 
giving adequate time to read the information. Informed consent and the agreement for 
photography of their legs will be obtained (Appendix 2 Informed Consent). Patients will be 
assessed at baseline and at 2, 4 and 8 weeks follow-up. 
 
The inclusion criteria are: 
- 
Male or female patients 
- 
CEAP classification 4 in both legs 
- 
Venous disease identified by venous duplex 
- 
Ability to understand and read the patient information sheet (in English) 
- 
Ability to give informed consent 
 
The exclusion criteria are: 
- 
Inability to give consent 
- 
Pregnancy 
- 
Current ulceration 
- 
Wilson’s disease 
- 
Allergy to copper 
- 
Arterial insufficiency of the lower extremities  
 
Copper impregnated stockings 
All patients will be asked to wear compression stockings (14-18mmHg). These closed-toe 
and below-the-knee stockings are made of 88% nylon, 5% elastin, and 7% spandex and 
come in various sizes. One of the pair will have copper oxide ions permanently attached to 

 
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the nylon fibres and these stockings will contain 2-3% copper ions. The patients will wear a 
copper stocking on one leg (study leg) and a non-copper stocking on the other (control leg). 
Both the patients and the clinicians will be blinded to the copper impregnated stocking. 
 
Randomisation 
All stockings are marked with an ‘L’ for the left or ‘R’ for the right foot. The manufacturer has 
randomly marked the copper stockings with an ‘L’ or ‘R’ and paired these with a non-copper 
stocking. A closed envelope will contain the unique numbers of all the pairs of stockings and 
the information on which sock contains the copper. This envelope will remain closed for the 
whole recruitment period.  
 
Patient data, history and physical examination: 
Demographic data such as age, ethnicity, height and weight will be collected (Appendix 3 
Datasheet). Past medical history such as concomitant (chronic) diseases and the use of 
medications will be obtained. At each visit, subjective symptoms will be obtained using the 
Aberdeen Varicose Veins Questionnaire (AVVQ). For obtaining objective signs, the CEAP 
classification and the Venous Clinical Severity Scoring (VCSS) will be performed for grading 
the severity of the venous insufficiency per leg individually, and photographs with the 
Eykona® 3D camera will be taken. All datasets will be coded and anonymised. The data will 
be stored in a secure room within the Trust. All electronic data will be stored within password 
protected IT system within the Trust, which is only accessible by the clinical and research 
team. 
 
Aberdeen Varicose Veins Questionnaire 
This questionnaire is specific for varicose vein disease but it also addresses important 
elements of venous insufficiency in general. The AVVQ (appendix 4 Datasheet) is a 
validated questionnaire and it consists of 13 questions on signs and symptoms such as pain, 
oedema, itching, purple discoloration, eczema and skin ulceration. It also addresses social 

 
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issues such as compression stocking usage and the effect of the disease on daily life. The 
AVVQ is the only validated questionnaire on vascular disease where most questions 
address each leg separately and therefore provides the ability to compare the two legs. The 
scoring of the questionnaire is from 0, which indicates no effect on the patient, to 100, which 
indicates a severe effect.  
 
CEAP 
Chronic venous disease can be classified with the clinical, aetiologic, anatomical, and 
pathophysiological (CEAP) classification (appendix 4 Datasheet). The clinical element is 
scored from 0 to 6 with increasing disease severity. The aetiological element indicates if the 
venous disease has a congenital, primary or secondary origin. The anatomical element 
denotes if the veins involved are superficial, deep or perforating. The pathophysiological 
element indicates the presence of reflux or obstruction. 
 
Venous Clinical Severity Scoring (VCSS) 
The VCSS is an extension of the CEAP classification and has been designed as an 
evaluative tool for the assessment of CVD. The VCSS (appendix 4 Datasheet) consists of 10 
categories, pain, varicose veins, oedema, skin pigmentation, inflammation, induration, 
ulceration (number, size and duration) and use of compression therapy, which are scored on 
a severity scale from 0 to 3.  
 
Eykona® Wound Measurement System 
Skin changes associated with lipodermatosclerosis such as erythema, induration, 
hyperpigmentation and white atrophy, will be measured using the Eykona® Wound 
Measuring System (Type EYK10001). This system (Appendix 4 Datasheet) contains a 3D 
portable camera with software that enables precise measurements of wound size and tissue 
condition. Photographs will be taken at each visit. The length and width are measured and 
the surface area of the different skin changes will be calculated.  

 
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Statistical analysis 
Statistical analysis will be performed using SPSS version 20.0 or higher. The CEAP 
classification, the Venous Clinical Severity Score and the AVVQ score at the 2, 4, and 8 
weeks assessment will be compared with the baseline scores. The length, width and surface 
area of the skin condition from the leg with the copper will be compared with the control leg 
and the measurements at the 2, 4, and 8 weeks assessment will be compared with the 
baseline measurements. Paired t-test will be used for continuous data at baseline and a 
multilevel (mixed) regression model will be used to analyse the change over time. 
 
Sample size calculation 
The sample size for this study will be 15. This number is based on the prevalence of the 
disease in this hospital over three months’ time. There is no existing data available to allow a 
sample size calculation. The data collection of this pilot study will enable power calculation 
for a larger multicentre study. 
 
 

 
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