Ethics statement
The trial protocol, investigators, and consent documents for each clinical trial were reviewed and approved by accredited Institutional Review Boards. The 4 studies were conducted in accordance with the ethical principles originating in the Declaration of Helsinki and with the applicable regulatory requirements in the Good Clinical Practice guidelines by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). All patients participating in the 4 clinical trials provided written informed consent. The 4 clinical trials evaluated in this study are registered at ClinicalTrials.gov: NCT01143714; NCT01143727; NCT01408277; and NCT01056198.
Trial participants
In brief, eligible patients were 18 years or older and diagnosed with type 1 or type 2 diabetes and a neuropathic nonischemic foot ulcer of at least 1 month’s duration between 0.5 cm2 to 10 cm2 in area, with the exception of trial 2 (NCT01143727) (area > 1.5 cm2; no upper limit). Wound size for eligibility into the study was determined at the screening visit. Baseline visits and start of treatment were about 1 week later to allow for the results of eligibility labs. During this time period, some subjects’ wounds decreased in size while others increased, causing the wound area to range in size from 0.1 cm2 to 24 cm2 at the start of treatment.
Trial 1 (NCT01143714)
The primary objective of this randomized, double-blind, CCO versus vehicle-controlled trial was to assess the percentage of wound area change from baseline at the end of 4-week treatment and 12-week trial periods. Secondary objectives were proportion of closed wounds within 12 weeks, rate of wound area reduction over the 4-week treatment phase, periwound skin status, and incidence of wound infection. For this trial, the test articles were supplied in prenumbered kits given in sequential order to eligible subjects as they entered the study. Study personnel and subjects remained blinded as to treatment.
Trial 2 (NCT01143727)
This randomized, open-label trial was a comparison of CCO and hydrogel on mildly inflamed DFUs (defined as the presence of 2 or more of the following symptoms: purulence, erythema, pain, tenderness, warmth, or indurations). The primary objective of the trial was to describe the weekly wound appearance assessed by a standardized wound assessment tool. The secondary objectives were to assess the percentage of wound area change from baseline and measurement of wound fluid levels of endogenous proteolytic enzymes and inflammatory factors.18
The study site was provided with a set of envelopes, numbered in sequential order, to randomize eligible subjects into 1 of the 2 treatment groups (CCO or hydrogel). An envelope was only opened, revealing the treatment assignment, once the baseline measurements had been taken for an eligible subject. The eligible subject was assigned the randomization number printed on the envelope. Within each envelope was a card containing the identification of the treatment to be given to the subject; the contents of the envelopes had previously been determined by a randomization sequence. All site personnel and subjects were aware of the test article received by each subject.
Trial 3 (NCT01408277)
This was an open-label trial in which patients were randomized to debridement with either CCO applied daily (after a single sharp debridement at baseline) or mechanical debridement using saline-moistened gauze (SMG) plus intermittent elective sharp debridement. The primary objective of the trial was to describe changes in the wound status total score using a standardized wound assessment tool (a modified Bates-Jensen Wound Assessment Tool [BWAT]) and 8 subscale scores at the end of the 4-week treatment and 12-week trial periods, while the secondary objective was the percentage of wound area change from baseline19 at the same time points.
For this study, central randomization across all sites was used to assign the test article. Once a subject was eligible, the site called a central number to receive the next sequential test article for that subject according to the schedule held by the randomization center. Both the clinician and the patient were aware of the test article received.
Trial 4 (NCT01056198)
This was a randomized, parallel group, open-label trial comparing CCO, used as an adjunct to sharp surgical debridement, to sharp surgical debridement with various SC regimens (at the discretion of the principal investigator). The primary objective was to assess the percent of wound area change from baseline at the completion of the 6-week and 12-week trial periods. The secondary objectives were assessment of the wound status, measured using the standardized wound assessment tool including 8 subscale scores, and the number of sharp debridements required during the trial period, measured at the same time points. The time to wound closure for each group was also assessed.20,21
For this study, central randomization across all sites was used to assign the test article. Subjects qualifying for enrollment were issued a randomization number and assigned to treatment by the electronic data capture system, which had access to the randomization code.
Trial design
All trials were conducted at a mixed panel of academic wound care programs, outpatient wound care facilities, or private practices located in the United States. All study visits, procedures, and data collection were performed at the individual study sites. Patients were randomly assigned to treatment (allocation ratio, 1:1) to prevent treatment allocation bias. The randomization sequences for each study were generated by a consultant biostatistician in blocks of 2, using the SAS Version 9.1.3 random number generator (SAS Institute Inc, Cary, NC). The subjects at each site were enrolled by the Investigator and the site study coordinator, with treatment assignments made according to the procedures outlined in the appropriate protocol (see specific trial above).
eFigure 1 illustrates the overall trial design of each trial included in this report. A double-blind design was used for Trial 1 but not in the other 3 due to the obvious dissimilarities in the treatments. With the exception of Trial 2, each trial entailed a screening visit followed by a 5- to 9-day screening period before randomization to treatment for 4 weeks (Trials 1–3) or 6 weeks (Trial 4) with a follow-up interval terminating 12 weeks after randomization. Trial 2 had the same design but did not have a follow-up period (eFigure 1). In general, all studies incorporated some component of autolytic debridement in the SC cohort, whether this was a hydrogel or a moisture-retentive primary layer such as silver sulfadiazine.
Wound care during the 5- to 9-day screening interval was at the discretion of the local Investigator with certain restrictions (no CCO, topical antibiotics, or engineered tissue constructs). Dressings were changed once daily throughout trial participation (screening, treatment, and follow-up). In patients assigned to CCO, a 2-mm thick layer of ointment was applied to the wound surface once daily. Direct contact SC regimens employed for the control groups in all trials were also applied once daily. The specific topical therapy for SC was petrolatum in Trial 1, hydrogel (Tegaderm; 3M, St Paul, MN) in Trial 2, and SMG in Trial 3. In Trial 4, SC was selected at the discretion of the investigators and included hydrogel, SMG, alginate, or silver-impregnated dressings.
During the posttreatment follow-up period of Trials 1, 3, and 4, subjects whose wounds remained open (following either CCO or SC treatment) were treated in parallel fashion. For Trials 1 and 3, a silicone screen (Mepitel; Mölnlycke Health Care, Norcross, GA) was used to cover the wound bed and secured with dry gauze. Allevyn foam (Smith & Nephew) secured with dry gauze and Coban (3M) was employed in Trial 4. All of these therapies obviously incorporate a component on autolytic debridement that, although not standardized for the outlined reasons, does represent autolytic debridement nonetheless.
Offloading and debridement
In all trials, patients were required to use offloading shoes and were provided with a Darco MedSurg (Darco International, Huntington, WV) padded shoe with an accommodative insert containing removable pegs (removal of pegs was discretionary). Debridement of the wounds with sharp instruments, such as scalpels and curettes, was governed by protocol-specific rules that differed by trial. The same rule was applied to both treatment groups in each trial except Trial 3 where sharp debridement was not permitted post baseline for patients assigned to CCO unless medically required and, if performed, the CCO patient exited the trial. Sharp debridement was performed in Trial 4 if any undermining, necrotic tissue type, necrotic tissue amount, exudate type, or exudate amount scored ≥ 3 on the subscales of the modified BWAT at baseline or any subsequent visit.
Wound measurements
Digital cameras coupled with laser imaging devices (ARANZ Medical Ltd, Christchurch, New Zealand) were used to measure wound area for Trials 1, 2, and 4. Wound area was measured manually (length x width) for Trial 3. The criteria for the target wound to be considered as closed included full (100%) epithelialization, no drainage, and no requirement for a dressing. Wound bed assessment was performed using an 8-category tool modified from BWAT22 for Trials 2–4; wound bed of Trial 1 was not assessed using any numeric tool. The wound status total score incorporates various factors ascertained before debridement if debridement was performed. The factors scored individually included wound edge appearance, undermining, necrotic tissue type, necrotic tissue amount, exudate type, exudate amount, periwound skin color, and granulation tissue amount.
Pooled data assessments
Since all 4 randomized trials had similar treatment designs (eFigure 1) with comparable inclusion and exclusion criteria (eTable 1), data were pooled to assess the overall clinical effectiveness of CCO in comparison with SC in patients with DFUs. The variables assessed in the pooled data analysis included wound area and wound closure at the completion of 4 weeks of treatment as well as at end of study (EOS). In addition, subgroup analyses were performed based on wound size (above and below median size), plantar versus nonplantar surface wounds, and baseline necrosis and granulation tissue wound assessment tool subscores.
Statistical procedures
The purpose of these pilot studies was to provide descriptive data regarding the outcomes achieved following 4 to 6 weeks of treatment with CCO used as indicated for the debridement of chronic DFUs. Because the intent of the studies was to generate rather than to test hypotheses, sample size was not based on statistical power calculations.
The intent-to-treat (ITT) population consisting of all patients randomized to treatment was the source of pooled data for all analyses. Data analysis was performed using SAS Version 9.1.3 (SAS Institute Inc). Summary statistics including distributions for single variables are provided for baseline data. Wound sizes at the randomization visit for each trial were defined as the baseline. The average percentage change from baseline in the wound area and status for the 2 treatment groups were compared at the end of treatment (EOT) (4 weeks in Trials 1–3 and 6 weeks in Trial 4) as well as at the EOS (Trials 1, 3, and 4 only) using a mixed-effects analysis of covariance (ANCOVA). Treatment and treatment week were defined as fixed effects and patient as a random effect. The corresponding wound area at baseline was used as a covariate. Missing values for any of the individual subscales were imputed with the mean score for that assessment (at that visit) or using the method of last observation carried forward as defined a priori in the respective protocols. Student’s t-test was used to compare the average percentage change from baseline in wound area, and Fisher’s exact test was used to compare the differences in proportions of wounds healed.
As noted above, these studies were planned as pilot studies to provide guidance to future studies with CCO and to define the best clinical criteria under which to use CCO in the treatment of DFUs. There was no expectation that data from the individual studies would provide significant statistical information.