Phase III Trial of Topical Formulation of Sirolimus to Skin Lesions in Patients With Tuberous Sclerosis Complex (TSC)

Study Overview
=================
Brief Summary
-----------------
The purpose of this trial is to evaluate the efficacy and safety of NPC-12G gel (topical formulation of sirolimus) versus placebo gel to facial angiofibroma and other skin lesions in patients with tuberous sclerosis complex (TSC)

Detailed Description
-----------------
Tuberous Sclerosis Complex (TSC) is an autosomal dominant hereditary disease that causes benign tumors on the almost whole body (including skin, brain, kidney, lung and heart), behavior disorder as autism, mental retardation and neurologic symptom as epilepsy. Angiofibroma is TSC-specific facial skin lesions, and hamartoma caused by increase of the component of skin connective tissues and blood vessels. Other skin lesions due to TSC are white macule(hypomelanotic macule), plaque, shagreen patch and ungual fibromas. Current therapeutic methods for angiofibroma are laser or surgical treatments, but there are problems as many relapses, deficiency of evidence, change of pigment, scar and risk of infection. This will be a multicenter, double-blind, randomized, placebo-controlled parallel group trial. The trial has three phases; the screening phase, double-blinded treatment phase, and post-treatment phase. The screening phase comprises a screening visit where subject's initial eligibility will be evaluated. During double-blinded treatment phase, patients who meet all entry criteria for the trial will be randomized into two groups, and they will apply 0.2% NPC-12G gel or placebo gel topically twice a day for 12 weeks.

Official Title
-----------------
A Double-blind, Randomized, Placebo-controlled Phase III Trial to Investigate the Efficacy and Safety of NPC-12G Gel (Topical Formulation of Sirolimus) to Angiofibroma and Other Skin Lesions in Patients With Tuberous Sclerosis Complex

Conditions
-----------------
Tuberous Sclerosis, Angiofibroma, Hypomelanotic Macule, Plaque

Intervention / Treatment
-----------------
* Drug: NPC-12G gel
* Drug: Placebo gel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female patients 3 years old or greater at the time of informed consent Patients who are diagnosed as definite diagnosis according to diagnostic criteria for tuberous sclerosis complex (International Tuberous Sclerosis Complex Consensus Conference 2012) Patients with three or more papules of angiofibroma ( >= 2 mm in diameter with redness in each) on the face at screening tests Patients who are not suitable for therapy with laser or surgery, or who do not want therapy with laser or surgery Patients or his/her guardian who give a written informed consent in understanding and willingness after having received enough explanation of the test drug and the current trial plan Exclusion Criteria: Patients who are hard to apply the test drug topically with keeping compliance Patients with clinical findings such as erosion, ulcer and eruption on or around the lesion of angiofibroma, which may affect assessment of safety or efficacy Patients who are hard to be taken pictures of their lesions adequately in such cases that they may not follow instruction of stillness Patients with a history of hypersensitivity to alcohol or allergy to sirolimus Patients who have complications such as malignant tumor, infection, serious heart disease, hepatic function disorder, renal function disorder or blood disorders which severity are considered by investigator as grade 2 or more severe with reference to ''Concerning classification criteria for seriousness of adverse drug reactions of medical agents'' Patients who have complications such as diseases unsuitable for the trial participation, for examples, uncontrolled diabetes (fasting blood glucose level >140 mg/dL or postprandial blood glucose level > 200 mg/dL), dyslipidemia (cholesterol level > 300 mg/dL or > 7.75 mmol/L, triglycerides level > 300 mg/dL or > 3.42 mmol/L), etc. Patients who have taken drugs with mTOR inhibitory action including sirolimus, everolimus or temsirolimus within 12 months before the initial registration Patients who have applied topical tacrolimus on the lesion of angiofibroma within 3 months before the initial registration Patients who have received therapy with laser or surgery to the lesion of angiofibroma within 6 months before the initial registration Female patients who may be pregnancy or are lactating Patients who cannot agree to take appropriate measures of contraception until completion of post-treatment phase or follow-up period after discontinuation from informed consent Patients who have participated in other clinical trial and have taken a trial drug within 6 months before the initial registration Others, patients who are considered by the investigator as unsuitable for participation in the trial

Ages Eligible for Study
-----------------
Minimum Age: 3 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NPC-12G gel<br>NPC-12G gel is containing 0.2% Sirolimus | Drug: NPC-12G gel<br>* NPC-12G gel is administered topically twice a day for 12 weeks<br>|
| Placebo Comparator: Placebo gel<br>Placebo gel is matched ingredient with NPC-12G gel | Drug: Placebo gel<br>* NPC-12G gel placebo is administered topically twice a day for 12 weeks<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvements in angiofibroma | Improvements comparing with baseline is assessed using photograph by the central photo-judgement committee | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvements in angiofibroma | Improvements comparing with baseline is assessed using photograph by the central photo-judgement committee | Week 4 and 8 and follow-up Week 16 | 
| Improvements in angiofibroma | Improvements comparing with baseline is assessed by the investigator | Week 4, 8, 12 and follow-up Week 16 | 
| Improvements in redness of angiofibroma | Improvement comparing with baseline is assessed by the central photo-judgement committee and the investigator | Week 4, 8, 12 and follow-up Week 16 | 
| Improvements in hypomelanotic macule and plaque of upper neck | Improvement comparing with baseline is assessed by the central photo-judgement committee and the investigator | Week 4, 8, 12 and follow-up Week 16 | 
| The rate of patients who are evaluated as ''improvement'' or more (improvement rate) in primary outcome measure and in secondary outcome measures above outcome 1 to 5 |  | Week 4, 8, 12 and follow-up Week 16 | 
| Change in total score from baseline for DLQI and CDLQI | DLQI for subjects 16 years old and greater, or CDLQI for children of less than 16 years old is assessed by patients | Week 4, 8, 12 and follow-up Week 16 | 
| Adverse events | Adverse events during the study period | 16 weeks | 
| Serious adverse events | Serious adverse events during the study period | 16 weeks | 
| Laboratory findings | Laboratory findings during the study period | 16 weeks | 
| Vital sign | Vital sign during the study period | 16 weeks | 
| Sirolimus blood concentration | Blood concentration of Sirolimus is assessed by drug monitoring | Baseline, Week 4 and Week 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sirolimus, Skin lesions, TSC, Tuberous Sclerosis Complex, NPC-12G, Angiofibroma, Hypomelanotic macule, Plaque