The design of this study is a noninferiority, triple-blinded, parallel, multi-center, randomized clinical trial. The blinded groups are the patients and their caregivers, nurses and the research group.
The null hypothesis of this study is that the difference in the appearance of pressure ulcers in immobilized patients at home who receive olive oil (G
o), in contrast to those patients applying HOFA (G
h) is higher than the delta value established at 10% (H
0 = G
o − G
h > 10%), that is to say, that the lower bound of the confidence intervals includes that 10%. In the event that it is possible to reject the null hypothesis, the alternative hypothesis of this study will be that olive oil is not lower than 10%, compared with the HOFA (H
1 = G
o − G
h < 10%); in other words, the lower bound of the confidence interval of the difference between both products is lower than 10%.
Two procedures will be performed: usual care and application of HOFA to the control group and usual care and application of an olive-oil composition to the target group. The main outcome will be the appearance of grade 2 pressure ulcers. The accuracy of the trial with regard to the control medicine (HOFA) is widely supported, owing to the favorable historical results of such medicine against placebo  as per recommendations of the International Conference of Harmonization and also because the efficiency conditions of the mentioned medicine will be met for the purpose of this trial.
The target population will be patients included in the immobilized-patients program within the nursing care at home service provided in Health Centers in Andalucía (Spain), and more specifically in the regions of Malaga, Granada, Seville, and Cadiz.
The inclusion criteria will be: patients over 18 years; not having pressure ulcers; patients supported by a family or a remunerated caregiver for the application of the treatment; diagnosed by a nurse as a ‘risk for impaired skin integrity’, by applying the Braden Scale for prediction of pressure ulcer risk, showing a high risk (score ≤ 12) or moderated risk (score 13 to 16), and; patients with nutritional status assessed according to the Mini Nutritional Assessment scale scoring 10 or less.
As exclusion criteria, the following were established: the patient declines to take part in the trial; patients with a usual address different from the area of the health center where the study is carried out, or plans to be away from the usual address during the follow-up period; those patients who have been hospitalized during the sampling period; terminally ill patients or those who already have pressure ulcers.
All the patients included in the trial will receive the information concerning the aim of the trial in writing, which will be duly signed by the researchers. The patients will confirm their participation in the trial and sign an informed consent form. In those cases when the patients have cognitive impairment, the legal guardian will be the one who signs the informed consent form. Patients who do not confirm their consent will be substituted by other patients selected by the same procedure of general randomized selection, thus, extending the selection process as long as necessary.
The directors and care service coordinators of each health center will be duly informed about the trial, and they will be asked for their availability as well as their consent to take part in the trial. Nursing staff of each health center who so desire will be able to take part, being in such case responsible for the research study implementation and follow-up in their respective health center.
Records of patients included in the nursing at home program for immobilized patients will be assessed to determine whether patients comply with the inclusion requirements. At this point, such patients will sign the informed consent form and subsequently, their details will be randomized by a computer system independent of the professional staff, which will be processed at the clinical trial control center.
To achieve a power rate of 80.00% to reject the null hypothesis (H
0: the difference between proportions p1 and p2 is lower than the noninferiority bound), using a normal asymptotic analysis test (noninferiority), unilateral proportions for two independent samples, taking into account that the level of statistical significance is 5.00%, and assuming that the proportion in the reference (control) group is 45.00% and the proportion in the experimental group is 45.00% , the proportion of experimental units in the reference group is 50% related to the total and the noninferiority bound (delta) is 10.00%, then, it will be necessary to include 306 experimental units in the reference group and 306 units in the experimental group, totalling 612 units in the study. Taking into account that the expected withdrawal rate is 15.00%, it will be necessary to enroll 360 experimental units in the reference group and 360 units in the experimental group, totalling 720 experimental units in the trial.
The main outcome will be the incidence of grade 2 pressure ulcers in patients during the 16-weeks of follow-up (112 days). We have selected this grade because when the patient has grade 2 pressure ulcers, prevention can no longer be carried out, and prevention is the intended outcome. We are only able to conduct this trial on intact skin, therefore it is only possible to conduct the trial when the patients have no pressure ulcer or have grade 1 pressure ulcers, when there are just erythemas. Therefore, patients who develop grade 2 pressure ulcers with breaks in the skin are excluded from the trial, as we cannot keep using the products because prevention is not useful anymore. Such patients will be treated again by the nurse who will cure the pressure ulcer, although this will be done out of the trial. When preventing the patient from developing grade 2 pressure ulcers, we are also preventing greater stages of ulcer. The 112 days of follow-up are higher than trials carried out up to now, 7 days , 9 days , and 30 days , which is more than enough for the appearance of pressure ulcers at any stage. The appearance of grade 2 pressure ulcers will be confirmed by the inspection of those areas where the product has been applied (sacrum, hips, and heels).
As secondary endpoints, cost measures will be applied that will allow us to assess the cost-effectiveness balance of the new product (olive-oil formula) against the HOFA-based products. As inputs of this model, the cost of each treatment will be used and defined as the number of units (NE
) necessary to carry out 16 weeks’ treatment (112 days) multiplied by the price of one unit (P
) (the price of each unit will be achieved from the information provided by each supplier according to the market price). The number of units will be the result of dividing the treatment period (DT
) (112 days) by the number of days (d
) the recipient used, according to the dose established in the trial protocol in each branch of the treatment. The resulting amount achieved shall be rounded up, even if the whole number of units has not been fully used:
As a variable cost, the number of visits of the nurse to the patient’s home during the trial period (VE
) will be used, which will act as a proxy measure of the level of care required. The mean time spent on each visit will be estimated according to the standard value of time within the community-health nurse working hours spent during a nursing care at home visit (this information will be obtained from the human resources management divisions of the different health districts and an assessment test will be carried out on the length of 30 visits to patients with the characteristics complying with the inclusion criteria, randomly selected among the health centers included in the study, prior to the commencement of the trial). Structural fixed costs will not be included, as in all cases the care assistance is provided at the patient’s home and the services are already included in the aforementioned variable. It will not be possible to assess the cost derived from the family care, since this is quite difficult to achieve and has a high variability. Therefore, this will not be included in the model. In those cases when there is a remunerated caregiver, such cost will not be included in the total costs either, as it would create a bias in the estimation when comparing them with those patients who are not assisted by a remunerated caregiver. Furthermore, the intangible costs derived from certain aspects, such as the pain level derived from the process will not be included either. Therefore, the estimation of total costs (CT) in the model will remain as follows:
The effectiveness variable will be the appearance of pressure ulcers. A limited number of states will be taken into account: appearance of pressure ulcers (U
1) and nonappearance of pressure ulcers (U
0). The incidence will be estimated in percentages, which will be used for the incremental estimations on cost-effectiveness.
Furthermore, variables on characterization of patients and caregivers will be included to assess sociodemographic data, such as the time registered in the care service for immobilized patients, information about previous cases of pressure ulcers, comorbidity, nutritional and cognitive status, and dampness (incontinence), apart from taking into account the ulcer location as well as the availability of technical support items (mattress and cushions to avoid bedsores, adjustable beds, and so on). With regard to the caretaker, the age, sex and whether he or she is a family or remunerated caregiver will be taken into account.
A basal-assessment will be performed on all patients at the beginning of the trial and this will be repeated each week up to the conclusion of the follow-up period, or until a pressure ulcer appears in patients. All the information concerning the application of the products will be registered in the weekly evaluations.
The new procedure consists of the application of a formula, in either liquid or spray, which contains 95% extra virgin olive oil. This product will have the same appearance as the hyperoxygenated fatty acid, using the same presentation, which will make it appear identical to both patients and nurses. This intervention will be applied to both groups (control and target group). Both the patients of the control group and those patients who are part of the target group will receive the preventative instructions stated in the clinical practice guidelines on deterioration of skin integrity issued by the Health District of Malaga. For such purposes, the caregivers of both groups will be trained in the mentioned procedures. In addition to these preventative measures, the patients included in the control group will receive two applications per day of the HOFA-based product in the skin, more specifically, in the sacral area, the hips, and the heels. For the purpose of this trial, we will use a HOFA product bearing the CE marking, IIb Class, with a higher classification than other products existing in the market. The product is to be applied topically and includes hyperoxygenated fatty acids, Equisetum Arvense, Hypericum Perforatum, and perfume. On their part, the target group will receive, as well as the preventative measures mentioned above, two daily applications of the olive-oil-based formula in the skin areas of sacrum, hips, and heels. The appearance of pressure ulcers will be registered in the weekly follow-up report, which will include an assessment of whether the skin integrity is maintained or not. In the event that there is any adverse effect during the follow-up period, the research group will be informed and such events will be notified by means of a specific document designed for such purposes.
Initially, a descriptive analysis of the variables included in the trial will be performed. Continuous variables will be summarized with mean, standard deviation, median, and interquartile range. Categorical variables will be shown in absolute and relative frequencies. An analysis of the normal distribution by the Kolmogorov-Smirnov test, symmetry analysis, and kurtosis will be performed.
With the aim of assessing the noninferiority of the olive oil for the prevention of pressure ulcers, a contrast of association between the appearance of pressure ulcers and the kind of treatment received (olive-oil-based cream or conventional treatment) will be carried out, by absolute and relative measures of effect sizes (complete reduction of risk, number needed to treat, relative risk, and relative reduction of risk), with their respective confidence intervals at 95%. It will be determined whether the confidence interval includes the estimated delta value from the sample or not, so as to reject or accept the null hypothesis.
A bivariate analysis will be carried out using the Student’s t and chi-squared tests according to the characteristics of the variables analyzed in the event that these are normally distributed. Otherwise, nonparametric tests will be applied, such as the Wilcoxon and Man-Whitney U tests. Likewise, analysis of variance (ANOVA) will be applied for the association of quantitative and qualitative variables in the necessary cases, as well as robust measures of central tendency in cases of homoscedasticity (which will be tested by Levene’s test) by means of the Welch and Brown-Forsythe test.
An analysis according to the Kaplan-Meier curves and log-rank test will be carried out to determine the progress of the appearance of pressure ulcers in both groups, taking into account the treatment applied, the sex, age, nutritional status, and functional degree of the patient and the caregiver’s age.
For the analysis on cost-effectiveness, the effectiveness measures previously established (U
1 and U
0) will be obtained. The increase in cost for each option (ΔC
) will be estimated, as well as the increase of effectiveness rate, when comparing the two options, the cost-efficiency ratio of each treatment and the incremental cost-effectiveness ratio of each option. These values will enable us to assess the necessary cost to increase by 1% the possibilities of success when preventing pressure ulcers in these patients by using each product.
The analysis will be carried out according to the protocol, as established for the noninferiority studies, to ensure the difference conditions between the treatments and increase the rejection conditions of the null hypothesis. Nevertheless, an analysis will be carried out that is intended to compare both analyses and assess, if the analyses differ, the subgroups of patients who did not comply with the trial protocol with the aim of identifying the possible reasons for the withdrawal from the trial, before accepting or rejecting the null hypothesis. The confidence intervals of the main result variable will be analyzed to determine whether the difference found is within the bound established for the delta value. Statistical analysis will be performed using SSPS 20 software.
Ethical and legal issues
The Ethics and Research Committee of Malaga (Northwest District) granted the approval for this trial. The regulations on Good Clinical Practice will be observed at all times, as well as the ethical principles established for the research on human beings stipulated in the Declaration of Helsinki and further amendments thereto. The clinical information will remain separate from the identification details and the databases will be coded and stored in specific computers solely intended for the project. All the records will be made observing all the dispositions from the legislation in force with regard to personal data protection according to the Act 15/1999 dated 13 December, as well as on safety of computerized files which may store personal data information, and more specifically, with regard to the access through communication networks (Royal Decree 994/1999 dated 11 June) and access to confidential information for scientific purposes from the Commission Regulation CE No. 831/2002 by the European Union and Act 41/2002 dated 14 November, which is considered the legal standard on Patient’s Autonomy and Rights and Duties in terms of Clinical Information and Documentation.
The staff responsible for such purpose will manage the data according to the instructions provided by the person responsible for the treatment. Such data will not be applied or used for a different purpose than those stated in the respective authorization; neither will they be reproduced to other people even for registration purposes. Once the aim of the trial has been carried out, the personal data collected will be destroyed, deleted, or given back to the person responsible for the treatment, along with any other media or documents containing any personal data related to the project. Every patient will be informed verbally and in writing about the objectives of the project and its methodology. Each individual will sign the respective informed consent form.