The wounds were primarily trophic ulcers caused by pancreatic diabetes and venous insufficiency of the lower extremities, carbuncles, furuncles, infected third- and fourth-degree heat burns, and infiltrations of postoperative wounds.
All included wounds were exuding and critically colonized to infected with remaining necrotic tissue or slough. The comparators were therefore chosen to be Gentaxane, a gel-forming polydimethylsiloxane powder containing the antibiotic gentamicin (Gentaksan, Borshchagovsky CCP, Kyiv, Ukraine) and iodine in combination with dimethyl sulfoxide (DMSO), where the DMSO is used to improve tissue penetration (Ioddicerin; Farmak, Kyiv, Ukraine). Iodine has antimicrobial properties and is used for minor wound debridement. All products were applied once daily until the wound was clean (ie, the wound was free of necrosis, pus, and fibrinogenous thickenings). Measurements for all patients included time to reach clean wound stage, time to onset of granulation, time to onset of epithelialization, and number of hospitalization days from start of application until hospital discharge. In addition, for a subgroup of patients with acute infected wounds, the wound surface area was measured on days 1 (start of application), 5, 7, and 10.
Number of participants. The study included a total of 266 patients; eTable 1 shows the inclusion/exclusion criteria. For measurements of the wound surface area, each group included 30 patients.
Follow-up period. Patients were monitored during their hospital stay; minimum duration of monitoring was 10 to 15 days after the last application of the product.
Ethical permissions. The study was approved by the Ethical Board of the Shupik National Medical Academy of Postgraduate Education and the Ethics Committee at the Clinical Hospital of Zaporizhzhia Station in Zaporizhzhia, Ukraine, in accordance with Ukrainian laws. All patients provided oral and written informed consent prior to participation in the study and signed medical reports to indicate their agreement with the treatment protocol. The trial was conducted in accordance with Good Clinical Practice principles, with the Declaration of Helsinki, and with relevant Ukrainian legislation. The study was performed in accordance with the protocol, and no amendments were required.
Comparators. Comparators included Gentaxane and an iodine/DMSO combination. Gentaxane is polydimethylsiloxane powder containing the antibiotic gentamicin, L-tryptophan, and zinc sulphate (gentamicin 24 mg/g, L-tryptophan 14 mg/g, zinc sulphate 10 mg/g in polydimethylsiloxane ad 1 g). Gentaxane is used for treating wound infections, and it has been shown to promote wound healing.5 The iodine/DMSO is a topical antiseptic containing 0.5% iodine, 30% dimexide (DMSO), and 69.5% glycerine. Iodine has bactericidal effects and is commonly used for minor wound debridement, while DMSO improves tissue penetration. The 3 products used herein are different in use and appearance, and it was not possible to blind the trial. To minimize observer bias, the end-points were chosen to be quantitative measures. All measurements were taken with daily dressing changes.
Patient allocation. The goal of the study was to evaluate the effects of MPPT across a wide range of wounds in an exploratory manner. It was therefore not possible to use a traditional randomization scheme in this study. Instead, patients were allocated based on wound type to treatment groups in a sequential manner as the order of patient hospital arrival can be assumed to be random and unlikely to introduce a systematic error.
The process began with patient arrival at the Clinical Hospital of Zaporizhzhia, where the patient’s pathology was determined. If suitable for inclusion in the study (eTable 1) and the patient agreed to participate, the patient was placed into the group with the fewest cases of that wound type, ie, sequentially to ensure an equal number of cases (eg, foot ulcers) were present in each group and the distribution of age, sex, and concomitant pathology was equal in the 3 groups. Due to the small size of the hospital, it was not possible to recruit sufficient numbers of patients for the group of acute wounds measured for the wound surface area during the study period (goal was 30/group), and for that reason historical data were included for the Gentaxane (17 cases) and the iodine/DMSO (15 cases) groups to have equal numbers in each group. These patients were selected from hospital files based on primary pathology, concomitant diseases, and age with the primary pathology as the principal criterion. Patients were treated and evaluated under identical conditions and by the same doctors in connection with a similar unpublished study conducted internally. A statistical analysis confirmed that the findings were unchanged if the retrospective cases were omitted from the analysis.
Parameters. For all wounds, the number of days to reach the clean wound stage, onset of granulation, and onset of epithelialization were recorded. These measurements can be used across wound types as they are independent of any underlying pathology and initial wound size, thus allowing comparison across wound types.
For abscesses, carbuncles, and infected wounds, the study also recorded wound surface area to determine the rates of wound closure. This measurement, to be meaningful, requires that the wounds have the same underlying pathology and same initial size. Acute infected wounds with a surface area ranging from 5 cm2 to 15 cm2 were included, and the rate of closure was measured for the first 10 days. Polyethylene film was applied on top of the wound, and wound circumference was copied onto the film. Lengths of all sides were measured in centimeters. Data were entered into a computer program (Sigma ScanPro; Systat Software, Inc, San Jose, CA), and wound surface area was calculated.
Finally, health economic parameters were determined by recording the number of hospitalization days for each patient in the study from the start of treatment until the patient was discharged and could continue treatment at an outpatient clinic or at his/her own general practitioner. Calculating the number of days a patient requires a hospital bed (during hospitalization) is a simple and reliable indicator of the economic toll, as it is a key factor in determining the overall costs of wound care for hospital inpatients.
Wound healing stages (eFigure 1):
- Clean wound: Wounds entering the study were in the suppurative necrotic phase, which consists of alteration and exudation stages and is characterized by the presence of necrotic tissues and purulent contents, edema, and high-microbial seeding. Wounds were determined to have reached the clean wound stage when they were free from necrosis, pus, and fibrinogenous thickenings.
- Onset of granulation: The granulation phase consists of wound cleansing, normalization of microcirculation and metabolic processes in tissues, and granulation formation. Wounds were determined to have reached this stage when the first presence of granulation tissue was detected.
- Onset of epithelialization: In this stage, the wound shows stable progressive epithelialization and active reduction of size. Wounds were determined to have reached this stage when the first presence of young skin (ie, epithelial tissue growth) was detected.
Bacteriological measurements. For patients with carbuncles in the MPPT group, samples were taken and analyzed at the hospital laboratory. Due to costs, hospitals do not routinely perform this analysis; therefore, it was only performed for the MPPT group.
Adverse events. Adverse events (AEs) were collected at each inspection of the wound and included events spontaneously reported by the patient, reported by the patient upon questioning, and events directly observed. Abnormal laboratory values or vital sign abnormalities were recorded as AEs only if they were medically relevant (ie, symptomatic, requiring corrective treatment, leading to discontinuation, or fulfill a criterion for a serious adverse event [SAEs]). In the case of chronic diseases, if the disease is known and documented when the patient entered the study, only increased frequency or intensity of the episodes were documented as an AE.
Adverse events were evaluated and categorized based on their intensity as follows: 1) mild: awareness of sign or symptom but easily tolerated (acceptable); 2) moderate: discomfort interferes with usual activities (disturbing); and 3) severe: incapable to work or to perform usual activities (unacceptable). To distinguish severe AEs from SAEs, the term severe is used to describe the intensity of the event and does not necessarily need to be considered serious. The assessment of causality of an AE was based on the following considerations: associative connections (time or place), explanations related to the MPPT, presence of clinical or pathological characteristic phenomena, exclusion of other causes, or absence of alternative explanations.
All AEs related to the application of MPPT occurring during the study were reported. No SAEs occurred. The follow-up of the patient who had experienced an AE continued until resolution of the event. All withdrawals due to an AE were recorded.
Procedure. As the patient entered the hospital, wound type and any underlying pathology were determined. Patient then was approached with the purpose of the study and its implications were explained. If the patient agreed to participate and provided written informed consent, he/she was placed into a group based on the previously described randomization scheme.
Prior to start of application, carbuncles were opened surgically; for other wounds, surgical necrectomy was performed if needed.
For all patients, if the wound was coated with necrotic and purulent tissue, the perimeter was cleaned with 2.5% iodine solution and the wound itself with 3% hydrogen peroxide; surgical necrectomy was performed if required. Wound was washed with physiological saline solution. Treatment included either a 1-mm to 3-mm layer of MPPT, a 1-mm to 3-mm layer of Gentaxane, or a bandage laced with 3 mL to 5 mL of iodine/DMSO applied to the wound. The MPPT and the Gentaxane layers then were covered with a gauze dressing.
Wounds were cleaned and redressed daily. The 3 products were applied once daily to the wound surface and edges until the wound was clean (ie, free from necrosis, pus, and fibrinogenous thickenings). After removing the old dressing, the wound was rated and measured, and any AEs were recorded.
Further care after reaching a clean wound and termination of application consisted, if needed, of bandages with methyluracil ointment (Metiluracil; Darnitsa, Kyiv, Ukraine) (100 g methyluracil ointment contains 5 g methyluracil, 0.5 g MIRAMISTIN [“Infamed” LLC, Moscow, Russia], and adjuvants [propylene glycol, macrogol 400, proxanol 268, cetyl alcohol, stearyl alcohol, and water]). The ointment and bandages were applied every 24 hours either until full wound closure or until the formation of active granulations and marginal epithelialization (ie, active tendency to heal).
Criteria for withdrawal and discontinuation of subjects. The withdrawal and discontinution of treatment for the study patients included the patient’s request to be withdrawn from the study, the development of any SAE that could be attributed to MPPT, and the development of any severe AE, which could be attributed to MPPT and could not immediately be remedied.
If a patient was withdrawn from the study, the date and reason were recorded. Any measurements originating from the patient remained part of the dataset.
Statistical analysis. Data were analyzed statistically by two-way analysis of variance (ANOVA) with Fisher’s least significant difference post-hoc test using the program package Systat 8.0 (Systat Software, Inc, San Jose, CA). The level for statistically significant differences was P = .05.