Materials and Methods
Design and Objectives
This was a confirmatory, prospective, multicenter, multinational, parallel-group, randomized, double-blind clinical investigation comparing the HA cream (0.2% HA) and a neutral comparator. The objective of the study was to confirm the superiority of a local application of HA cream as compared to a neutral comparator cream in the treatment of subjects with chronic leg ulcers of venous or mixed (venous and arterial) origin.
The trial was conducted in accordance with the Declaration of Helsinki and its modifications, the rules of Good Clinical Practice, and the International Organization for Standardization (EN) 14155 requirements as well as conformed to the Consolidated Standards of Reporting Trials (CONSORT) 2010 extension for randomized controlled trials. Approval for the protocol and protocol amendments was obtained from the Bioethics Committee of the Regional Medical Chamber, Lodz (Poland), and written informed consent was obtained from all subjects before starting the trial.
Project management and monitoring of the study were carried out by the local contract research organization, CROMSOURCE, in Poland.
Adult males and females 18 years or older were eligible for inclusion in the study if the following criteria were met: one or more chronic leg ulcers of venous (varicose or postthrombotic) or mixed (venous and arterial) origin with a predominance of venous origin, with a duration of at least 2 months but less than 4 years; the target ulcer area was at least 5 cm2 but no more than 40 cm2, with less than 50% of necrotic tissue; an arteriovenous Doppler examination showing superficial or profound venous reflux; and/or a well-documented history of deep venous thrombosis and/or clinical evidence of postthrombotic syndrome with chronic edema and lipodermatosclerosis. Other inclusion criteria included daily use of an appropriate compression system, albuminemia of 25 g/L or higher, and a negative pregnancy test together with the use of reliable contraception for women of childbearing age.
The main exclusion criteria were as follows: the presence of a nonvascular ulcer or a general cause (eg, hematologic cause), ankle-brachial index less than 0.8 or higher than 1.2 and/or dominant significant arterial insufficiency, diabetes mellitus of any type, hepatic or renal failure, presence of wound infection, an ulcer with exposed tendon or bone or due to malignancy, a recent history of venous thrombosis, and ongoing treatment with drugs known to adversely affect the healing process.
Subjects were randomized in a 1:1 ratio using a centralized randomization system to have an investigator-selected target ulcer treated once daily locally with either a cream containing HA 0.2% or a neutral comparator cream for a maximum period of 20 weeks (active treatment period) or until complete ulcer healing was achieved, whichever occurred first. The trial was stratified on target ulcer size (≤ 20 cm2 or > 20 cm2).
The active treatment (HA cream) contained HA 0.2% intended for topical use and was supplied for the study in 100-g tubes. The neutral comparator cream contained the same ingredients, with the exception of HA, and had visual and physical characteristics identical to those of the active cream.
The randomization list was prepared using validated software (SAS Institute Inc) by the Data Management and Statistics Department of the sponsor and stored in electronic form in a secure directory to ensure confidentiality in full respect of standard operating procedures. The study was double-blind; treatment allocation was kept hidden to the subject, investigator, sponsor, contract research organization team, and central assessor. Strict procedures were followed throughout the study to maintain blinding.
Treatments under scope were used in conjunction with standard local therapy for both groups, with standard of care as recommended by the French National Health Authority; that is, sterile saline was used before each application to clean the target ulcer, together with the use of surgical debridement or local anesthesia if necessary. Wound debridement, dressing, and optimized compression were only applied by experienced personnel with knowledge of the assessment and treatment of subjects with leg ulcers. Subjects with nontarget ulcers were treated according to the same standard-of-care procedures. If clinical evidence of infection was present, therapy with systemic antibiotics was considered. However, the use of topical antimicrobial drugs and antiseptic agents was prohibited.
After wound cleansing, the HA cream or neutral comparator cream was applied directly to the target ulcer once daily by the study nurse or authorized study personnel either at the subject's home or clinic. Following cream application, the wound area was covered with a sterile gauze dressing and an appropriate long-stretch graduated elastic bandage with stirrup (BIFLEX 16+ PRACTIC bandage), which was provided to all sites; this regimen was applied to all subjects according to the standard of care. Adapted and efficient compression was required to be worn daily during the entire investigation period. The compression was set up before subjects arose in the morning and was removed in the evening prior to going to bed. Its daily usage was confirmed by the study nurse when visiting the subjects at home or by the study personnel at each in-clinic visit. Standard of care (compression socks or compression bandages) was continued for subjects discontinuing the trial.
Medications or therapies prohibited during the entire trial period included treatment known to delay the healing process (eg, high-dose systemic corticosteroids, cytostatic drugs, immunosuppressants), the use of proteolytic enzymes for wound debridement, other topical treatments of the target ulcer, vein surgery of the affected leg, and any other systemic or general therapy that could positively or negatively influence the healing of the target ulcer.
A total of 8 visits were carried out by the same investigator for each subject, consisting of screening/inclusion (visit 0); randomization and first treatment (visit 1); weeks 4, 8, 12, 16, and 20 of treatment (visits 2–6); and a final evaluation (follow-up) visit (visit 7) at day 162 (week 23) or 3 weeks after complete healing if it occurred before week 20. An unscheduled visit to confirm healing could be arranged by request of the study nurse if that person thought complete healing had been achieved between scheduled visits. The healing status of the target ulcer was assessed and recorded at each study visit after treatment was initiated. The target ulcer was evaluated by the investigator and documented using standardized digital photography after cleansing and wound preparation were completed at randomization and before the Investigational Medical Device (IMD) was applied at each study visit and at the follow-up visit. During each evaluation visit, the aspect of periulcerous skin was assessed by the investigator, and evidence of edema, purpura, erythema, oozing, and/or maceration was identified on a four-grade scale of intensity: none (0), mild (1), moderate (2), and severe (3).
Adherence with the study treatment, defined as the number (%) of daily applications of the IMD as compared with the theoretical number, was checked at each visit during the treatment phase. This was based on the subject's and nurse's records in study-dedicated diaries in which daily medication renewal, compression bandage, and any oral analgesic use were recorded.
Primary and Secondary Endpoints
The primary efficacy endpoint was ulcer healing, defined as 100% reepithelialization of the wound area at 20 weeks or at any earlier visit if healing occurred before week 20, as evaluated by the central blinded assessor and confirmed 3 weeks after initial healing achievement. The clinical assessment of the primary efficacy variable was centralized and independently performed by an experienced, blinded assessor judging via standardized photography of the target ulcer.
Secondary efficacy endpoints included the percentage of completely healed target ulcers as assessed by the investigator, and at all other scheduled study visits as assessed by the central blinded assessor, the target ulcer area relative to baseline at each study visit, the condition of the periulcerous skin, the total amount of analgesics used, the rate of infection of the target ulcer, the adherence with treatment, the time to achieve complete healing as centrally assessed, and pain intensity as self-assessed by the subject on a visual analog scale (VAS) at each study visit.
The incidence of adverse events (AEs) and treatment-emergent AEs (TEAEs) occurring at any time during the trial, regardless of relationship to the IMD, were recorded, together with vital signs at each study visit, and physical examination at screening, randomization, and final visit. Adverse events and serious adverse events (SAEs) were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1. The frequency of TEAEs, as well as serious TEAEs, and the proportion of subjects experiencing TEAEs, were calculated.
It was estimated that the percentage of subjects expected to have completely healed target ulcers at week 20 or the earliest visit when healing was complete and confirmed after 3 weeks was 43% for the HA cream group and 20% for the neutral comparator group. Therefore, a sample size of 84 evaluable subjects in each group (168 in total) was calculated to have greater than 90% power to detect a difference of 23% between the HA cream group and the neutral comparator group in terms of successes, according to the assessment of the central blinded assessor judging in favor of the HA cream group (superiority study), when using a χ2 test with a two-sided α set to equal .05.
The proportion of completely healed target ulcers in the primary analysis was compared between treatment groups by means of the Cochran-Mantel-Haenszel χ2 test, considering target ulcer size at baseline (≤ 20 cm2 or > 20 cm2) as a stratification factor. For the safety analysis, the difference between the proportions of subjects in treatment groups was analyzed using the χ2 test.
Wounds. 2021;33(11):285-295. © 2021 HMP Communications, LLC