Rapamycin Dose-Ranging Efficacy Study in Port Wine Stains

This is a single-centre, double-blind, randomized withdrawal design, parallel group, placebo-controlled, dose-response clinical study investigating the efficacy and safety of two concentrations of topical rapamycin cream in the treatment of port wine stain as an adjunct to pulsed dyed laser (PDL) in paediatric patients. 30 participants will be enrolled into the study.

The study hypothesis is that topical rapamycin, as an adjunct to PDL, will show a dose-dependent increase in the blanching of port wine birthmarks, compared to PDL with placebo after 12 weeks.

Eligible participants will undergo PDL treatment of their entire port wine birthmark. Patients that respond positively to PDL within 5 days will be enrolled and randomized, before the first application of the study drug. Participants will be randomly assigned to one of three possible treatments in a 1:1:1 ratio:

• Rapamycin cream, topical (0.6% rapamycin)
• Rapamycin cream, topical (1.0% rapamycin)
• Placebo The stain will be divided into two parts. One part will be treated only with PDL and the other will be treated with both PDL and the assigned cream. Cream will be applied once daily for 12 weeks.

During this phase of the study, four clinical visits will occur, one every 4 weeks for 12 weeks. Assessment of the extent and severity of birthmark size and colour will be performed at randomization, at each clinical visit, and at follow-up using photography and percentage improvement ratings. Safety will be assessed by recording all adverse events experienced and testing blood rapamycin concentration at prior to treatment and at the last clinical visit.

Follow-up will be performed 28 days after the last cream application. An extra PDL session will be optionally provided at the follow-up appointment. If PDL treatment occurs at the follow-up visit, a further follow-up phone call will occur 7±2 days after the second PDL session to assess concomitant medications and adverse events.

Inclusion criteria

• Male and female patients aged ≤ 10 years on the day informed consent is obtained
• Patients presenting either facial, neck, or upper trunk port-wine stains
• Port wine stain size of at least 5 cm tall x 2.5 cm wide (2x1 inches)
• Patients (or their legal representatives) capable of understanding the explanation of the clinical trial, and who give written informed consent for participation
• Patients (or their legal representatives) able to maintain patient diaries following the instructions of the investigator or sub-investigator
• Patients (or their guardians) are willing and able to follow instructions to only apply cream to part of their port-wine stain
• Skin type classified as either I, II, III or IV on the Fitzpatrick scale
• Patients who are indicated for PDL treatment and accept this treatment
• Patients who respond to PDL with purpura or blanching

Exclusion criteria

• Skin type classified as either V or VI on the Fitzpatrick scale
• Patients with PWS in extremities and/or acral areas
• Patients unwilling or unable to carry out the treatment plan or follow-up assessment
• Patients with serious skin lesions such as erosions or ulcers
• Patients with known hypersensitivity to any component of the study product
• Patients who have received rapamycin/sirolimus, everolimus, or temsirolimus within 3 months of enrolment
• Patients who have received laser therapy or surgical therapy to treat PWS within 3 months prior to trial enrolment
• Patients who have received 5 or more PDL treatments previously
• Patients who participated in any other clinical trial within 3 months prior to the day of enrolment
• Patients judged unsuitable for this clinical trial by the investigator or sub-investigator
• Pregnant or lactating females
• Sexually active females of childbearing potential not using adequate contraception and sexually active males not using adequate contraception*
• Patients with immune dysfunction or receiving any form of immunosuppression