Clinical trial NCT02634931: Long-term Trial of Topical Sirolimus to Angiofibroma in Patient With Tuberous Sclerosis Complex
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tuberous Sclerosis
Angiofibroma
Hypomelanotic Macule
Plaque
Keywords: Sirolimus
Skin lesions
TSC
Tuberous Sclerosis Complex
NPC-12G
Angiofibroma
Hypomelanotic Macule
Plaque
Lead sponsor: Nobelpharma
Sponsor class: INDUSTRY
First posted: 2015-12-18
Enrollment: 94
Sex: ALL
Minimum age (years): 3
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Male or female patients 3 years old or greater at the time of informed consent
2. Patients who are diagnosed as definite diagnosis according to diagnostic criteria for tuberous sclerosis complex (International Tuberous Sclerosis Complex Consensus Conference 2012)
3. 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
4. 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)
5. Patient who are considered to be an appropriate patient to participate in the trial by investigator
6. 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:

1. Patients who have offered to withdraw from Phase III trial (NPC-12G-1) and have been discontinued
2. 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)
3. 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
4. Patients with a history of hypersensitivity to alcohol or allergy to sirolimus
5. 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''
6. 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.
7. Female patients who may be pregnancy or are lactating
8. Patients who cannot agree to take appropriate measures of contraception until completion of the trial or follow-up period after discontinuation from informed consent
9. 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
10. Others, patients who are considered by the investigator as unsuitable for participation in the trial

Primary outcomes:
measure: The discontinuation rate due to adverse events
timeFrame: 52 weeks and longer
Secondary outcomes:
measure: Adverse events and adverse events related to the test drug
timeFrame: 52 weeks and longer
measure: Adverse events related to the test drug leading to the discontinuation permanently
timeFrame: 52 weeks and longer
measure: Serious adverse events and serious adverse events related to the test drug
timeFrame: 52 weeks and longer
measure: Adverse events and adverse events related to the test drug leading to modification of dosage and administration
timeFrame: 52 weeks and longer
measure: Significant adverse events and significant adverse events related to the test drug
timeFrame: 52 weeks and longer
measure: Laboratory tests, vital signs
timeFrame: Baseline and every 3 months for laboratory tests, every scheduled visit for vital sign]
measure: Blood level of sirolimus
timeFrame: Baseline and every 3 months only for the first trial phase
measure: Improvements in angiofibroma
timeFrame: Week 4, 8, 12, 26, 39 and 52
measure: Improvements in sizes of angiofibroma
timeFrame: Week 4, 8, 12, 26, 39 and 52
measure: Improvements in redness of angiofibroma
timeFrame: Week 4, 8, 12, 26, 39 and 52
measure: Improvements in white macule and plaque upper neck
timeFrame: Week 4, 8, 12, 26, 39 and 52
measure: The rate of patients evaluated ''improvement'' or more (improvement rate) in above the efficacy measures.
timeFrame: Week 4, 8, 12, 26, 39 and 52
measure: Change in total score of DLQI and CDLQI from baseline
timeFrame: Week 4, 8, 12, 26, 39 and 52
measure: Degree of patient's satisfaction
timeFrame: Week 12, 26, 39 and 52
Other outcomes:
Locations:
city: Suita, Osaka
country: Japan
facility: Graduate School of Medicine, Osaka University
Study officials:
affiliation: Department of Dermatology, Graduate School of Medicine, Osaka University
name: Mari Wataya-Kaneda,, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wataya-Kaneda M, Nagai H, Ohno Y, Yokozeki H, Fujita Y, Niizeki H, Yoshida K, Ogai M, Yoshida Y, Asahina A, Fukai K, Tateishi C, Hamada I, Takahata T, Shimizu K, Shimasaki S, Murota H. Safety and Efficacy of the Sirolimus Gel for TSC Patients With Facial Skin Lesions in a Long-Term, Open-Label, Extension, Uncontrolled Clinical Trial. Dermatol Ther (Heidelb). 2020 Aug;10(4):635-650. doi: 10.1007/s13555-020-00387-7. Epub 2020 May 8.