Long-term Trial of Topical Sirolimus to Angiofibroma in Patient With Tuberous Sclerosis Complex

Study Overview
=================
Brief Summary
-----------------
The purpose of this trial is to evaluate the safety and efficacy of long-term treatment with NPC-12G gel (0.2% sirolimus gel) to angiofibroma and other skin lesions in patients with tuberous sclerosis complex in the open-label trial.

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 a TSC-specific facial skin lesion, 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 and surgical treatments, but there are problems as many relapses, deficiency of evidence, change of pigment, scar and risk of infection. This is a multicenter and open-label trial. The trial consists of two phase. In the first trial phase for 52 weeks, the efficacy as well as the safety is evaluated. For the second trial phase the trial will be continued until the date of approval of NDA for NPC-12G. The safety is evaluated during the second trial phase, but not the efficacy. Patients who meet all entry criteria for the trial apply 0.2% NPC-12G gel twice a day. Patients will visit at 4 to 5-week intervals for the first 6 months of the first trial phase, and then 3 months intervals thereafter.

Official Title
-----------------
A Long-term, Single-arm, Open-label Trial of NPC-12G (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


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 skin lesions such as angiofibroma, white macules or plaque upper neck associated with tuberous sclerosis complex at the screening visit or the baseline visit Patients or his/her guardian who agree to use the test drug (NPC-12G gel) or who want to participate in the trial again following participation in Phase III trial (NPC-12G-1) Patient who are considered to be an appropriate patient to participate in the trial by investigator 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 have offered to withdraw from Phase III trial (NPC-12G-1) and have been discontinued Patients who have not applied the test drug topically more than 25% of whole applications without appropriate reason for Phase III trial (NPC-12G-1) 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 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. Female patients who may be pregnancy or are lactating Patients who cannot agree to take appropriate measures of contraception until completion of the trial or follow-up period after discontinuation from informed consent Patients who have participated in other clinical trial other than Phase III trial (NPC-12G-1) and have taken a trial drug within 6 months before informed consent 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


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 52 weeks or longer<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The discontinuation rate due to adverse events | The first discontinuation in each patient due to adverse events is assessed.Completion of week 26 and 52 are cut-off points for interim-analyses by Kaplan-Meier method | 52 weeks and longer | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events and adverse events related to the test drug | The number of discontinuation/ resume due to adverse events are evaluated. Completion of week 26 and 52 are cut-off points for interim-analyses | 52 weeks and longer | 
| Adverse events related to the test drug leading to the discontinuation permanently | The incidence of adverse events are evaluated. Completion of week 26 and 52 are cut-off points for interim-analyses | 52 weeks and longer | 
| Serious adverse events and serious adverse events related to the test drug | The incidence of serious adverse events are evaluated. Completion of week 26 and 52 are cut-off points for interim-analyses | 52 weeks and longer | 
| Adverse events and adverse events related to the test drug leading to modification of dosage and administration | The incidence of adverse events are evaluated. Completion of week 26 and 52 are cut-off points for interim-analyses | 52 weeks and longer | 
| Significant adverse events and significant adverse events related to the test drug | The incidence of significant adverse events such as local irritation are evaluated. Completion of week 26 and 52 are cut-off points for interim-analyses | 52 weeks and longer | 
| Laboratory tests, vital signs | Completion of week 26 and 52 are cut-off points for interim-analyses | Baseline and every 3 months for laboratory tests, every scheduled visit for vital sign] | 
| Blood level of sirolimus | Whole blood level of sirolimus are measured any day time at baseline and every 3 months visit | Baseline and every 3 months only for the first trial phase | 
| Improvements in angiofibroma | Improvements comparing with baseline is assessed using photograph by the investigator and the central photo-judgement committee. Completion of week 26 is a cut-off point for interim-analysis. | Week 4, 8, 12, 26, 39 and 52 | 
| Improvements in sizes of angiofibroma | Improvements comparing with baseline is assessed using photograph by the investigator and the central photo-judgement committee. Completion of week 26 is a cut-off point for interim-analysis. | Week 4, 8, 12, 26, 39 and 52 | 
| Improvements in redness of angiofibroma | Improvements comparing with baseline is assessed using photograph by the investigator and the central photo-judgement committee. Completion of week 26 is a cut-off point for interim-analysis. | Week 4, 8, 12, 26, 39 and 52 | 
| Improvements in white macule and plaque upper neck | Improvements comparing with baseline is assessed using photograph by the investigator and the central photo-judgement committee. Completion of week 26 is a cut-off point for interim-analysis. | Week 4, 8, 12, 26, 39 and 52 | 
| The rate of patients evaluated ''improvement'' or more (improvement rate) in above the efficacy measures. | Completion of week 26 is a cut-off point for interim-analysis. | Week 4, 8, 12, 26, 39 and 52 | 
| Change in total score of DLQI and CDLQI from baseline | DLQI for subjects 16 years old and greater, or CDLQI for children of less than 16 years old is assessed by patients. Completion of week 26 is a cut-off point for interim-analysis. | Week 4, 8, 12, 26, 39 and 52 | 
| Degree of patient's satisfaction | Patient's satisfaction is assessed by patient. Completion of week 26 is a cut-off point for interim-analysis. | Week 12, 26, 39 and 52 | 

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