Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00243620 |
| Other study ID # |
CB/jd/01.259 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
October 21, 2005 |
| Last updated |
January 12, 2017 |
| Start date |
May 2001 |
| Est. completion date |
May 2004 |
Study information
| Verified date |
May 2001 |
| Source |
Maastricht University Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Current treatment modalities for chronic leg ulcers are time consuming, expensive, and only
moderately successful. Recent data suggest that creating a sub-atmospheric pressure by
Vacuum Assisted Closure (V.A.C.®) therapy supports the wound healing process. Here, we
studied the efficacy of V.A.C.® in the treatment of chronic leg ulcers prospectively.
Description:
PROTOCOL
I. INTRODUCTION:
In the last 25 years we have entered an area where patients are living longer with more
complex systemic pathology. The number of patients with chronic non-healing wounds continues
to increase, despite many recent advances in the basic science of wound healing.
Although, the chronic leg ulcers approximately affect 1 % of the adult population of
developed countries and chronic wound care consumes 1-2% of the health care budgets of
European countries. It is still probably true to say that leg ulcer disease is not
sufficiently recognised as a problem either by the population at large or by the medical
community. Recent socio-economic and quality of life data showed the importance of this
long-neglected health care problem.
In recent years, many new wound care products were developed. We have learned that a moist
wound bed, without maceration of wound borders, gives faster wound healing. So, wound care
products need a high absorption capacity and at the same time, they need to create a moist
wound climate. However, many of these new wound care products resulted in divergent results.
Complications are described like enlargement of the wounds, maceration, infections, sepsis
and loss of grafts. These results in delayed hospitalisation and increased costs.
In 1989 Prof. Argenta and Dr. Morykwas developed a sub-atmospheric pressure technique: "
Vacuum Assisted Closure". This technique was introduced to our hospital by the department of
surgery in the treatment of large complicated surgical wounds.
We are employing this new technique at our department of dermatology in treating lower leg
ulcers since 1997, by placing a foam dressing into the wound, seal it with tape and applying
a sub-atmospheric pressure to the wound.
The meaning of Vacuum Assisted Closure is, first to clean the ulcer in a quick and
non-invasive way until a vital red wound is produced (first stage). When a wound is too big
to close primarily, secondary surgery is needed. By using the V.A.C.-technique in
combination with transplantation, the skin grafts will be supported in adhering to the wound
surface (second stage).
Before the PVA (Polyvinylalcohol) or PU (Polyurethane ether) foam is placed into the wound,
the border has to be protected by hydrocolloïd foam, which will be trimmed to the
appropriate size and geometry for each individual wound. After that, The PVA or PU foam can
be placed into the wound defect. We employed especially a reticulated polyvinyl alcohol
dressing with a pore size of 400-600 h-meters depending of the appearance of the wound bed.
The Polyurethane ether foams were often used in the past. The PVA or PU foams are embedded
with a non-collapsible evacuation tube, having side ports that allow communication of the
lumen to the space of the reticulated foam. In large wounds, multiple foams may be placed in
close contact to one another. The surface of the foam dressing is covered by an adhesive
drape, extending 5 cm, beyond the hydrocolloid dressings. The proximal end of the evacuation
tube leads to a collection canister localised on the V.A.C. pump into which the wound fluid
will be drawn when a permanent sub-atmospheric pressure is applied. So an open wound is now
converted to a controlled closed wound.
First a permanent subatmospheric pressure was applied to the chronic ulcus cruris until a
vital red wound was produced (first stage). Subsequently, these ulcers were treated by a
combination of transplantation and vacuum sealing to support the skin grafts (the second
stage). The therapy was monitored weekly.
The V.A.C. is the first active, non-invasive wound care product, used by a secure local
regulated sub-atmospheric pressure technique.
The exact mechanisms to explain this treatment are not known yet. Researches by Prof.
Argenta et al. postulated that interrelated factors are the basis for the success of the
technique. These factors can be devised in 3 subgroups: (1) Removing, (2) Improving, (2)
Reducing
1. Tissues surrounding the chronic wounds are characterised by localised collection of
interstitial or third-space fluid. This collection of third-space fluid contains
factors which inhibits or suppresses mitosis, protein synthesis and fibroblasts
collagen synthesis. An active withdrawal of this fluid removes the excess of third
space wound fluid and its inhibitory factors. The active withdrawal also results in the
removing of wound debris.
2. The collection of third space fluid mechanically comprises the micro-vascularisation
and lymphatic system. By removing the third space fluid and its inhibitory factors,
this result in increased vascularisation, reduced venous afterload and an increased
delivery of oxygen and nutrients as well. These changes improve the rate of granulation
formation and the concentration of growth factors. An additional mechanism of the
V.A.C. is the mechanical stimulation of cells migration by tensile forces placed on the
surrounding tissues.
3. Besides reducing of third space fluid, we know that successful wound healing correlates
with bacterial counts of less than 100 000 organism per gram of tissue.
Bacterial counts of human wounds treated by V.A.C. have demonstrated a significant decrease
after 3-4 days usually until less than 1000 per gram of tissue. Last but not least, the
V.A.C. technique also reduces the infection chances, because the creation of a controlled
closed wound.
Recently socio-economic and quality of life evaluation showed the impact of this
long-neglected health care problem. Phillips et al shows a strong correlation between time
spent on ulcer care and feelings of anger and the quality of life. Besides that, there is no
doubt that ulcer care consumes a substantial proportion of the health care budgets. The
retrospective results of V.A.C. therapy compared to the conventional therapy showed a
reduction up tot 39% in hospitalisation time. These outcomes may be result in a better
quality of life and a reduction of the health care costs.
Summarised V.A.C. treatment has a positive effect to wound cleaning and increases the
survival chance of transplanted skin, which will minimise hospitalisation time and costs,
compared to the conventional wound care techniques. It must be emphasised that the
Vacuum-assisted Closure technique was developed as an adjunct to wound care. It is not meant
to, and will never, replace surgical procedures. Despite the positive effects, this method
needs more and further investigation.
A randomised, prospective, comparative cost/ effect balance and quality of life
investigation will be starting soon in co-operation with Prof. H.A.M. Neumann (University
Hospital Maastricht), comparing the V.A.C. treatment versus conventional therapy.
II. AIMS OF THIS MULTI-CENTRE STUDY:
To demonstrate V.A.C. therapy is a more quick and cheap option in the treatment of chronic
arteriolosclerotic, chronic venous en combined venous /arterial leg ulcers.
III. PATIENTS AND METHODS:
3.1 Patients: The study is conducted in the departments of Dermatology at the University
Hospital Maastricht and the Atrium Medical Centre Heerlen. All patients in which extensive
ambulatory treatment in an out-patient-clinic according to the Scottish Intercollegiate
Guideline Network (SIGN) had failed and who are hospitalized due to chronic venous (venous
insufficiency of the deep or superficial system without an arterial incompetence), combined
venous/arterial (venous insufficiency of the deep or superficial system with an
ankle/brachial index of 0·60 - 0·85) or arteriolosclerotic (Martorell's ulcer) leg ulcers,
are evaluated for eligibility in this study.
3.2 Methods: Patients are randomly assigned to the VAC® therapy group or to the control
group (conventional wound care) by a computer program using random permuted blocks of 8.
Randomisation was carried out within 3 strata, one for each ulcer type: venous, combined
venous/arterial, and arteriolosclerotic ulcers, respectively. Treatment allocation occurred
through telephone calls to the coordinating centre.
In both study groups and both study centres an initial necrotectomy was performed by sharp
debridement of slough and nonviable tissue.
I.Vacuum Assisted Closure-techniques:
Before the PVA (Polyvinylalcohol) or PU (Polyurethane ether) foam is placed into the wound,
the border has to be protected by a hydrocolloïd foam, which will be trimmed to the
appropriate size and geometry for each individual wound. After that, The PVA or PU foam can
be placed into the wound defect. We employed especially a reticulated polyvinyl alcohol
dressing with a pore size of 400-600 h-meters depending of the appearance of the wound bed.
The Polyurethane ether foams were often used in the past. The PVA or PU foams are embedded
with a non-collapsible evacuation tube, having side ports that allow communication of the
lumen to the space of the reticulated foam. In large wounds, multiple foams may be placed in
close contact to one another. The surface of the foam dressing is covered by an adhesive
drape, extending 5 cm, beyond the hydrocolloid dressings. The proximal end of the evacuation
tube leads to a collection canister localised on the V.A.C. pump into which the wound fluid
will be drawn when a permanent sub-atmospheric pressure is applied. So an open wound is now
converted to a controlled closed wound.
The meaning of Vacuum Assisted Closure is, first to clean the ulcer in a quick and
non-invasive way until a vital red wound is produced (first stage). When a wound is too big
to close primarily, secondary surgery is needed. By using the V.A.C.-technique in
combination with transplantation, the skin grafts (punch grafts) will be supported in
adhering to the wound surface (second stage). Once all skin grafts are well adhered, the
V.A.C. therapy can be stopped. Until 100% wound-closing patients will be hospitalised by
compression and local therapy.
Thereafter ambulant therapy (compression and local therapy) will be continued until complete
wound healing. Also therapy will be controlled once a week.
II.The conventional wound care techniques (control group):
Patients assigned to standard wound care receive daily local wound care according to the
SIGN guideline and a multiple-layer compression bandage (Smith and Nephew, Hoofddorp, the
Netherlands) until complete healing. Four basic types of commercially available wound
dressings will be used in this study including hydrogels (Johnson&Johnson, Amersfoort, the
Netherlands), alginates (Hartmann, Nijmegen, the Netherlands), hydrocolloids (Smith and
Nephew, Hoofddorp, the Netherlands), and films (Hartmann, Nijmegen, the Netherlands). The
choice of dressing most depended on the ulcer type, the amount of exsudate and the
physician's preference. Once 100% granulation was achieved, these patients also received
punch skin-graft transplantation in combination with topical therapy.
In both treatment groups, only toilet and basic hygiene mobility was permitted during the
wound bed preparation and transplantation stage. After complete wound healing,
community-grade elastic support stockings class 2 (Medi, Breda or Varodem, Horn; the
Netherlands) or 3 (Varodem, Horn; the Netherlands) were prescribed depending on the
underlying pathology.
3.3 Punch transplantation procedure The transplants will be taken of the upper-leg by
placing first a 'field-block' local anaesthetic (lidocaine 2% in NaCl). Epidermal grafts
will be created using a biopsy corer of 4 mm). The size of the field-block depends of the
ulcer size.
3.4 Evaluation criteria Because masking the interventions is not possible, patients will be
reviewed clinically by the same independent research physician and consultant dermatologist
twice a week until the ulcer is healed: description of the wound defect, surrounding tissue,
tracing the ulcer and taking a picture (Enclosure III), time investment forms (nurse and MD)
(Enclosure IV), evaluation of the used materials (Enclosure IV), evaluation of the V.A.C.
therapy and noting complications (Enclosure IV) and the quality of life evaluation of the
patient (Enclosure II). Using codes will anonymise all the patient information.
3.5 Selection criteria:
1. Patient groups (V.A.C.; n=30 / Conventional techniques; n=30):
I.chronic venous leg ulcer II. chronic combined venous /arterial leg ulcer III. chronic
arteriolosclerotic leg ulcer
2. Sex : either sex
3. Inclusion criteria:
a)patient with a chronic leg ulcer (> 6 months) without healing signs and satisfies to
one or more criteria:
- Venous (venous insufficiency of the deep or superficial system without an arterial
incompetence)
- Combined venous/arterial (venous insufficiency of the deep or superficial system
with an ankle/brachial index of 0·60 - 0·85)
- Arteriolosclerotic (Martorell's ulcer) leg ulcers (diagnose made by anamnesis,
clinical signs, exclusions of differential diagnosis's, venous/ arterial duplex
shows no signs of obstruction or major venous insufficiency, histology)
4. Exclusion criteria:
1) ulcer duration shorter than 6 months 2) age > 85 years 3) use of immune suppressive
medication 4) known type IV allergies against ingredients of the wound care products 5)
insulin-dependent diabetes mellitus type I 6) severe peripheral arterial disease
(ankle/brachial index <0·60) 7) vasculitic ulcers 8) neoplastic ulcers. In patients
presenting with multiple ulcerations, the clinically most severe ulcer was included in the
study whereas the other ulcers were treated conventionally.
3.6 Informed Consent :
Written informed consent will be obtained from all patients (volunteers). The investigator
will explain the nature of this study and its purpose, risks and duration.
Patients (volunteers) will advised that they are free to participate in, or to withdraw
from, the study at any time without prejudice to the doctor-patient relationship. The
medical care provided will not be affected or refusal to participate in this study.
This protocol will be submitted to the appropriate institutional Ethical Committee and their
approval obtained in writing will be awaited before starting the study.
3.7 Randomisation:
All volunteers first will underwent a complete intake. When the volunteer satisfy the
inclusion- and exclusion criteria, this multi-centre trial the randomisation procedure will
be carried out by the clinician being in contact with a central registration office, by
telephone. An independent person will use a computer program, which determine the therapy
(V.A.C. or Conventional therapy) by serial numbers. This centralisation helps the correct
implementation of each step and ensures that someone has an overview of how the trial is
going. Before randomisation, stratification into the ulcer type (3 strata: venous, combined
venous/ arterial and arteriolosclerotic ulcers) is needed. Using codes will anonymise all
patient information.
Data from a retrospective study showed that the mean duration of the preparation period was
24 days in conventional wound care (SD 11) versus 12 days in VAC® therapy (SD 5). In order
to detect a minimal difference of 10 days in preparation time with a power of 80% (α=5%) the
number of patients required in each treatment-group was 30, as derived from sample-size
calculations.
3.8 Masking: Because masking the interventions is not possible, patients were reviewed
clinically by the same independent research physician and consultant dermatologist twice a
week until the ulcer had healed. Thereafter, patients were prospectively followed up by one
and the same research physician at three months, six months and one year after discharge.
All participating clinicians completed standardised case record forms and checklists during
their control visits, treatments and follow-ups.
Decisions made during the treatment (V.A.C. and conventional therapy) are based on simple
and objective standards:
- Yellow debris and a necrotic tissue is bad climate for skin grafts.
- Only a red, vital granulated wound bed causes a successful transplantation
- Once all skin grafts are well adhered, the V.A.C. therapy can be stopped.
- 100% epithelialisation (wound closure) This approach seems to be authorised, because
scientific investigations showed these kinds of judgements are apparent equally
objective compared to other judgement methods (thesis of Dr. Mekkes; Amsterdam). To
have an external control, every intervention will be photograph.
3.9 outcome results:
Primary endpoints:
Time-to-complete-healing: i.e. the period between initial preparation of the wound and 100%
epithelialisation with the primary endpoint being time-to-complete-healing.
Secondary endpoints:
1. duration of the wound-bed preparation stage
2. percentage of leg ulcer recurrences within one year (i.e. an epithelial breakdown
anywhere along or within the index ulcer region)
3. skin-graft survival, where applicable (i.e. percentage of successfully adhered skin
grafts after 4 days of complete bed rest and compression or VAC® treatment)
Furthermore, we compared between both experimental groups i) the quality of life, ii)
pain scores, iii) the total time needed for wound care until complete wound closure,
and iv) the costs per ulcer.
3.10 Follow-up: Patients are followed up by one and the same research physician at three
months, six months and one year after discharge.
3.11 Statistical analysis: All data will be analysed using the SPSS 11.0 software package
and the results are analysed on an intention-to-treat basis. Time-to-complete-healing,
duration of wound-bed preparation, and recurrence rates are compared using the Kaplan-Meier
survival analysis. The log rank test is used to test for statistically significant
differences between both groups. Multivariate Cox's regression analysis is used to adjust
for imbalances in the baseline distribution of relevant prognostic factors. The regression
coefficient, expresses the independent contribution of potential determinants to duration of
cleaning and wound-healing. Hazard ratios and their 95% confidence intervals (95% CI) are
presented. A p-value of less than 0·05 was considered to be statistically significant.
Percentages are compared by the chi-square test and continuous variables are compared using
the independent samples t-test (for normally distributed variables) and the two-independent
sample test (for non-normally distributed variables).
LITERATURE:
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562-576
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1999; vol. 7, 55-57
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