Topical Sirolimus in Chemoprevention of Facial Squamous Cell Carcinomas in Solid Organ Transplant Recipients (SiroSkin)

Study Overview
=================
Brief Summary
-----------------
01.21 SiroSkin is a phase 3, double-blind, multi-centre, parallel-arm, randomised, placebo-controlled trial to evaluate the use of topical 1% sirolimus in the chemoprevention of skin cancer, versus placebo, applied every night for 6 months in solid organ transplant recipients.

Detailed Description
-----------------
Keratinocyte carcinomas are a major burden affecting mortality and morbidity in solid organ transplant recipients (SOTRs). Due to an increased prevalence of skin cancers, SOTRs require recurrent skin checks and frequent skin cancer surgery. The gold standard of treatment is surgery, enabling complete remission and a cure in the majority of cases. Despite this, there is no effective way of preventing new cancers from developing in the same area. Oral sirolimus is a selective immunosuppressant agent which has proven to reduce the burden of skin cancer; however, it is poorly tolerated due to side effects. Topical sirolimus has proven effective in reducing the skin cancer burden in animal models and is safe on the face of patients with tuberous sclerosis. An initial 12-week phase II clinical trial recently conducted by the research team suggested topical sirolimus to be safe and effective, as it reduced the early signs of skin cancer without any major side effects. In this phase III randomised, double-blind, placebo-controlled study, we propose using 1% topical sirolimus applied to the face on a regular basis for 6 months. We aim to determine whether this topical cream can fill a major gap in our current therapies by reducing the onset of new skin cancers and therefore reduce the burden of disease in terms of number of biopsies and surgeries, and potential hospitalisations and death.

Official Title
-----------------
A Randomised Double-blind Placebo-controlled Trial of Topical Sirolimus in Chemoprevention of Facial Squamous Cell Carcinomas in Solid Organ Transplant Recipients

Conditions
-----------------
Solid Organ Transplant Recipients, Skin Cancer

Intervention / Treatment
-----------------
* Drug: Sirolimus Topical Cream
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Be aged 18 years or older and able to provide consent Have received an organ transplant 12 months ago or earlier Have had at least 1 SCC/BCC in the past 5 years Have at least 5 keratotic lesions on their face at inclusion Exclusion Criteria: Are currently receiving sirolimus or everolimus orally* Have a skin cancer on their face requiring excisional surgery** Have an open wound on their face requiring treatment Are pregnant or planning to become pregnant in the next 6 months Anticipate elective medical events which may prevent daily cream application. Are unable to provide informed consent, complete questionnaires and attend trial site for visits Are participating in another clinical trial with an investigational drug/device aiming to reduce skin cancers or affect level of immunosuppression Planning to move overseas (*)Patients are eligible to join the study after ceasing treatment and after a washout period of 16 days for sirolimus and 8 days for everolimus. (**) Once treatment of the lesion is completed these patients can be re-screened.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topical Sirolimus<br>Topical 1% sirolimus cream applied daily to the face for 6 months | Drug: Sirolimus Topical Cream<br>* The intervention topical cream consists of sirolimus 1% in a vehicle. Patients randomised to the intervention will be required to apply the sirolimus topical cream to their face for 6 months<br>* Other names: Rapamycin;|
| Placebo Comparator: Placebo<br>Topical placebo cream applied daily to the face for 6 months | Other: Placebo<br>* Cream containing only the base, or vehicle.<br>* Other names: Vehicle alone;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| KC development | The percentage of patients who develop keratinocyte carcinomas on the treated area at completion of 6 months of topical 1% sirolimus, then at 12 and 24 months follow up. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of biopsy-proven SCC | The percentage of patients who develop biopsy-proven SCC on the treated area at the completion of 6 months of topical 1% sirolimus, then at 12 and 24 months follow up. | 4 years | 
| Occurrence of biopsy-proven SCC | The occurrence of biopsy-proven SCC at the completion of 6 months of topical 1% sirolimus, then at 12 and 24 months follow up on the treated area. | 4 years | 
| The number of intraepidermal carcinomas | The percentage of patients who develop intraepidermal carcinomas (IECs), BCCs and subtypes of SCCs or BCCs at each of the aforementioned time-points on the treated area. | 4 years | 
| The occurrence of intraepidermal carcinomas | The occurrence of intraepidermal carcinomas (IECs), BCCs and subtypes of SCCs or BCCs at each of the aforementioned time-points on the treated area. | 4 years | 
| Number of facial actinic keratosis | The percentage of patients who experience a reduction in the number of facial actinic keratosis from recruitment to the end of the study (6 months) on photographic images and counts. | 4 years | 
| Cost-effectiveness | The cost-effectiveness of utilizing topical sirolimus therapy on SOTRs measured by the ratio of the cost of the intervention to the improvement in the primary outcome. | 4 years | 
| Intervention-related side effects | Number and occurrence of intervention-related side effects, by type | 3.5 years | 
| Number of doses | The average number of doses of topical sirolimus (or placebo for the placebo arm) applied during the 24 weeks. | 6 months | 
| Completion rate | The percentage of patients who complete the 24-week course of treatment. | 6 months | 
| Intervention completion | The percentage of patients who complete the 24-week course of treatment. The percentage of patients who complete the 24-week course of treatment | 6 months |