Topical sirolimus 0.1% for treating cutaneous microcystic lymphatic malformations in children and adults (TOPICAL): protocol for a multicenter phase 2, within-person, randomized, double-blind, vehicle-controlled clinical trial

Abstract

BackgroundCutaneous microcystic lymphatic malformations (CMLMs) are rare conditions in children and adults. They present as clusters of vesicles full of lymph and blood to various extents, inducing maceration, esthetic impairment, pain, and impaired quality of life. The treatment is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) involved in angio-lymphangiogenesis. Topical sirolimus has recently been reported as effective in a few reports of patients with CMLMs. The objective is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults.MethodsThis French blinded multicenter within-person randomized controlled phase 2 trial aims to include 55 patients aged ≥ 6 years who have a primary CMLM. The CMLM will be divided into two equal areas that will be randomly allocated to 0.1% topical sirolimus or topical vehicle applied for 12 weeks. At the end of the 12-week period, the patient/parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for eight more weeks. Patients will be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy. The primary outcome will be improvement of the CMLM in the area treated with topical sirolimus compared to the area treated with topical vehicle by the investigator physician (blinded to the treatment) with the Physician Global Assessment score at week 12. Secondary outcomes will include: assessment of efficacy by independent experts on the basis of standardized photographs; impact on quality of life; efficacy for oozing, bleeding, erythema, and thickness evaluated by the investigators; and global efficacy as well as efficacy for functional and aesthetic impairment evaluated by the patient. Systemic passage of sirolimus will be measured at weeks 6, 12, and 20, and at week 16 for CMLMs ≥ 900 cm2.DiscussionFor patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment.Trial registrationClinicalTrials.gov, NCT03972592. Registered on 3 June 2019. EU Clinical Trials Register EudraCT, 2018–001359-11.

Validation of measurement scores for evaluating vascular anomaly skin lesions

“…It is known that evaluating this score using clinical photographs is useful 12 . In an ongoing phase 2, randomized, double‐blind, controlled clinical trial of topical sirolimus for microcystic LM, the 6‐point PGA score will be used to evaluate cutaneous microcystic LM as a primary outcome 11 . Although the score is not specified in skin VA, our results show excellent correlation between scores evaluated by two external evaluators and patients’ objective data.…”

“…The assessment criteria for treatment depended on the degree of target lesion resolution after propranolol treatment. Furthermore, the latest clinical trials of voluminous and complicated superficial slow‐flow vascular malformations with sirolimus (PERFORMUS) and topical sirolimus 0.1% for treating cutaneous microcystic LM in children and adults (TOPICAL) are planning to assess digital photographs at baseline and after treatment 10,11 . In these studies, photographs will be qualitatively assessed by two blinded independent trained readers without informative data.…”

“…Furthermore, the latest clinical trials of voluminous and complicated superficial slow‐flow vascular malformations with sirolimus (PERFORMUS) and topical sirolimus 0.1% for treating cutaneous microcystic LM in children and adults (TOPICAL) are planning to assess digital photographs at baseline and after treatment. 10 , 11 In these studies, photographs will be qualitatively assessed by two blinded independent trained readers without informative data. However, the details of these evaluation methods and criteria of ongoing these trials have not yet been officially announced.…”

Vulval lymphangiectasia in pregnancy—a rare case report

“…Other modalities of treatment include electrodesiccation, laser therapy, sclerotherapy, and cryotherapy. OK‐432 (a corn‐based alcohol derivative), doxycycline, 3% polidocanol, and sirolimus 0.1% are the sclerotherapy agents used in treatment 3,4 . Carbon dioxide lasers vaporize superficial lesions 5 .…”

Research Techniques Made Simple: Randomized Controlled Trials for Topical Drugs in Dermatology: When and How Should We Use a Within-Person Design?

“…Methods to limit and detect the carry-across effect should be described in protocols. When a plasma dosage of the drug is feasible, blood samples for this dosage must be included in the protocol (Leducq et al, 2019).…”