This was an open-label, 6-month, interventional pilot study conducted in an expert centre. The study protocol was approved by the Institutional Ethics Committee (Comité de Protection des Personnes - Aquitaine, Bordeaux, France) and the French National Agency for Medicines and Health Products Safety, ANSM (Agence Nationale de Sécurité du Médicament et des produits de santé). The study was conducted in accordance with the principles of the 1975 Declaration of Helsinki, revised in 1983, and registered under the ClinicalTrials.gov identifier NCT02782702.
According to pilot study methodology (44), 30 patients were expected to be enrolled in this study. Eligible patients were aged ≥ 18 years and had a clinically and biopsy-proven diagnosis of DD or HHD. At baseline, patients were required to present at least one lesion located in the large fold areas (inguinal, axillary, mammary and abdominal), ranging from moderately severe to very severe (see section on outcomes). Exclusion criteria were provided as supplementary data (S1). Written consent was obtained from all patients.
Each patient was scheduled to attend four visits. At the first visit, each patient received intradermal BtxA injections (BotoxR) on selected areas presenting moderate to very severe lesions (see section on outcomes). These injections were performed under local anaesthesia (lidocaine prilocaine 5% cream, applied one hour earlier). Not more than one BtxA (200-unit) vial was used per patient. The BtxA vial was diluted with 8 mL of sterile, preservative-free physiological saline solution, resulting in a concentration of 2.5 units/0.1 ml. The areas to be injected were divided into a grid of 1 to 2 cm. Using a 30-gauge needle, 2 mL (50 units) were then administered intradermally, divided into a constant volume of 0.1 mL injected into the centre of each grid, resulting in approximately 20 intradermal injections over the entire treated area. The target concentration was 50 IU per 100 cm². There was two follow-up visits (1 and 3 months: M1 and M3), and one end-of-study visit (6 months: M6). Patients were instructed not to use any concomitant topical or systemic medication throughout the treatment period, except for emollients and antiseptics. In the event of relapse, defined as the occurrence of new skin lesions in the treated areas necessitating one of these prohibited treatments, the patient was excluded from the study (but still followed-up for tolerance outcomes).
Several parameters were evaluated at each visit: The first parameter was QOL, evaluated by the Dermatology Life Quality Index (DLQI) (45) (a score >10 is associated with a severe or very severe impact on QOL (46)). We also evaluated psychosocial impairment using HidroQoL (47); debilitating symptoms (itchiness, cutaneous pain, sweating and odour) using Visual Analogue Scales (VAS) (ranging from 0 (none) to 10 (worst case scenario)); and the number of infectious skin episodes (in the six months before and after the injections). The total surface area (cm²) was evaluated by totalling the surface of all selected areas. The severity of the lesions was evaluated on an individual basis using a 5-point photographic scale (0: no lesion, 1: mild, 2: moderate, 3: severe, 4: very severe), generated by the investigators and five other independent disease experts for the purpose of this study (see supplementary data S2). Global severity was defined as the average of the severity of each selected area. Clinical improvement was assessed by the treating investigator (AM) as well as a blinded investigator (ID) at M1, M3 and M6, using the IGA score (Improvement Global Assessment) (48), a validated 5-point scale, ranging from 0 to 4 (0: no improvement or exacerbation of the treated lesions / 1: slight improvement / 2: moderate improvement / 3: significant improvement or 4: complete disappearance of all lesions). In the event of discordance, mediation and moderation analysis were carried out. Patients were considered in treatment failure if the treated area did not improve throughout the study (non-responders to BtxA) or if they relapsed (occurrence of new skin lesions in the treated areas warranting the use of a prohibited treatment). Finally, tolerance was assessed during the injections using a VAS quoting pain from 0 to 10 (0: no pain, 10: maximal pain), and throughout the study period by reporting side effects. Patient satisfaction was recorded at the end-of-study visit according to a 4-point scale (very satisfied / satisfied / somewhat satisfied / dissatisfied).
A descriptive analysis was performed at each evaluation time (baseline, M1, M3 and M6) for each assessment criterion (mean, standard deviation, minimum – maximum for continuous variables; proportion for categorical variables). Before/after comparisons (each evaluation time vs. baseline, no comparison between the different follow-up evaluation times) were then performed using a Wilcoxon test for paired values. Disease severity at baseline (defined by the total surface area and the global severity) was compared between relapsing and non-relapsing patients using a Mann-Whitney test. For all tests, a p-value of <0.05 was considered statistically significant. All statistical tests were performed with STATA software.