Design
The REOX study will conduct a multicentre, single blinded, randomized, controlled trial with parallel groups. Figure 1 presents an overview of the schedule for enrolment, intervention and assessment, according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (Additional File 1).
Setting
The REOX study will run in three primary health-care centres (one urban and two rural centres) of the Andalusian Health Service in Spain. The centres were selected based on having advanced-practice wound nurses working in them, who could participate in the study. (detailed in Additional File 2).
Participants
Patients are eligible according the inclusion and exclusion criteria presented in Table 1. The sample was recruited from patients with wounds treated in one of the healthcare centres engaged in the study.
Table 1. REOX trial inclusion and exclusion criteria
REOX trial inclusion and exclusion criteria
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Inclusion criteria
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Exclusion criteria
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- Patients over 18 years of age.
- Patients with leg ulcers (venous, ischemic, traumatic or diabetic foot ulcer).
- Patients with dehisced surgical wounds healing by second intention.
- Patients with pressure ulcers.
- Wound area between 1 and 250 cm2. (Wounds larger than 250 cm2 are quite infrequent and it was decided not to include because such a large wound could be more difficult to heal)
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-Systemic inflammatory disease or oncological disease.
- Wounds with clinical signs of infection.
- Terminal situation (life expectancy less than 6 months).
- Ulcers from other aetiologies: tumours, infectious.
- Wounds treated with negative pressure therapy.
- Pregnancy.
- History of sensitivity or allergy to any of the components of the study dressing.
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- Appearance of allergies or hypersensitivity to the dressing.
- Death.
- Hospital admission that interrupts the treatment in the primary healthcare centre.
-Changing the patient's residence, if the new residence is at a different health centre.
Sampling
Sample size was estimated based on 2 possible outcomes:
a) Detecting a mean difference of 2 points in the total score with the RESVECH 2.0 scale for chronic wound healing [37] between intervention group and control group with a standard deviation of 2.0 (5% type 1 error and 20% type 2 error) based on data published by Castro et al. who found a reduction of 8 points in RESVECH 2.0 at 4-weeks of treatment (this is a 23% reduction)[24]. We used a 2 points reduction for sample estimation, as minimum clinically significant difference; in order to have the study powered enough to detect just this small difference. The sample size needed is 17 patients per group.
b) Time for achieving a 50% reduction of the ulcer area; estimating an average of 49.5 days in the control group and 30.0 days in the intervention group with a standard deviation of 20.0 days (5% type 1 error and 20% type 2 error); based on the study by Lee [38]. The sample size needed is 18 patients per group.
An additional 30% is added to compensate possible lost patients in follow-up, so the final sample size is 54 patients (27 patients in each group). It is expected that each one of the three healthcare centres recruit 18 patients for the study.
Randomization and blinding
Patients (n=54) will be randomized into an intervention group (antioxidant dressing) or control group (standard clinical practice using dressings that create a moist environment). The block randomization scheme was generated by using the software EPIDAT. Participants will be randomized to receive antioxidant dressing or standard wound dressing with a 1:1 allocation ratio (Figure 2) using stratified block randomization with a fixed block size per centre. Once the patient has accepted to participate and meets the inclusion criteria, the clinical nurse will open an opaque, sealed envelopes sequentially numbered containing a sheep (folded 4 times) with the group allocation. Neither the patient nor the clinical nurse is blinded to the treatment received; data and wound photographs will be codified, the assessor who evaluates the photographs and the data analyst will be blinded to the treatment.
Intervention and control
The REOX study has two arms (see Fig.2). Both arms included cleansing with saline solution and debridement to remove devitalized tissues, if needed, according to recommendations from clinical practice guidelines.
In the intervention group, the antioxidant dressing will be applied over the wound bed and covered with a secondary adhesive dressing. The dressing will be kept in place for 2 to 3 days, according to the recommendations of the manufacturer.
In the control group (standard practice), a dressing that creates a moist environment will be applied over the wound bed (such as hydrocolloid, alginate, polyurethane foam or silver dressing, according to the nurse’s judgement and the availability of the products at the centre) and covered with a secondary adhesive dressing if necessary. The dressing will be kept in place for 2 to 3 days, according to the recommendations of the manufacturer.
To improve patient adherence to the treatment (both groups), the clinical nurse treating the patient will reinforce at each dressing change how important it is to keep the dressing in place until the next visit, and explain that if the patient is experiencing pain, itching or other wound related symptom, he/she should consult the nurse, but not remove the dressing. Any dressing related symptom will be recorded as a possible adverse effect.
Data collection and management
Each patient included in the study will be assessed by one clinical nurse at baseline and every 2 weeks (week 2, 4, 6 and 8). Figure 1 shows the variables collected at each assessment. The follow-up of patients in both groups will be prolonged until week 8 or complete healing of the wound, if it occurs earlier. A follow up of 8 weeks was considered as adequate for this study, because the main action of the antioxidant dressing tested is to reactivate the healing process by controlling the excess of ROS; according to the previous study by Castro et al. [35] at 4 weeks an significant number of wounds had improved. In order to promote participant retention and complete follow-up, the nurse will conduct the monitoring of patients in the healthcare centre. Furthermore, the principal investigator will have the primary responsibility for study monitoring; a formal data monitoring committee is not deemed necessary because there is not access to protected information and there is a limited amount of personal information.
To monitor wound healing, several variables will be used:
- Wound area, direct measurement of length and width with a graduated ruler (Kundin method) [39].
- Wound area estimated using a digital photography using the software Helcos [40,41]. This software is an integrated wound management system, which allows for estimation of the wound area and the relative percentage of tissue types in the wound bed (granulation, slough and necrotic tissue).
- Score in the RESVECH 2.0 scale for chronic wound healing [37].This scale assesses 6 aspects: wound size; depth/affected tissues; wound edges; type of tissue in the wound bed; exudate; and infection/inflammation. More score points means improvement in the healing process, so the score ranges from 0 (the worst possible status of the wound) to 35 point (wound healed).
Other variables to be recorded are demographic characteristics, anthropometric characteristics, pain level, concomitant medical diagnosis and clinical antecedents, nutritional status, consumption of drugs, tobacco habit, ankle-brachial index (ABI) and treatment with compressive therapy. No biological specimen will be collected or stored in this study.