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

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

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)

Study Overview

• Status: Completed
• Conditions: Plaque; Tuberous Sclerosis; Angiofibroma; Hypomelanotic Macule
• Intervention / Treatment: Drug: NPC-12G gel; Drug: Placebo gel

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.

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Suita, Osaka, Japan, 565-0871
    • Graduate School of Medicine, Osaka University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 three or more papules of angiofibroma ( >= 2 mm in diameter with redness in each) on the face at screening tests
4. Patients who are not suitable for therapy with laser or surgery, or who do not want therapy with laser or surgery
5. 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 are hard to apply the test drug topically with keeping compliance
2. 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
3. Patients who are hard to be taken pictures of their lesions adequately in such cases that they may not follow instruction of stillness
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. Patients who have taken drugs with mTOR inhibitory action including sirolimus, everolimus or temsirolimus within 12 months before the initial registration
8. Patients who have applied topical tacrolimus on the lesion of angiofibroma within 3 months before the initial registration
9. Patients who have received therapy with laser or surgery to the lesion of angiofibroma within 6 months before the initial registration
10. Female patients who may be pregnancy or are lactating
11. 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
12. Patients who have participated in other clinical trial and have taken a trial drug within 6 months before the initial registration
13. Others, patients who are considered by the investigator as unsuitable for participation in the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Nobelpharma
• Investigators: Principal Investigator: Mari Wataya-Kaneda, MD, PhD, Department of Dermatology, Graduate School of Medicine, Osaka University

Publications and helpful links

General Publications

• Wataya-Kaneda M, Ohno Y, Fujita Y, Yokozeki H, Niizeki H, Ogai M, Fukai K, Nagai H, Yoshida Y, Hamada I, Hio T, Shimizu K, Murota H. Sirolimus Gel Treatment vs Placebo for Facial Angiofibromas in Patients With Tuberous Sclerosis Complex: A Randomized Clinical Trial. JAMA Dermatol. 2018 Jul 1;154(7):781-788. doi: 10.1001/jamadermatol.2018.1408.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2015
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: December 15, 2015
• First Submitted That Met QC Criteria: December 16, 2015
• First Posted (Estimate): December 21, 2015

Study Record Updates

• Last Update Posted (Estimate): February 2, 2017
• Last Update Submitted That Met QC Criteria: February 1, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Tuberous Sclerosis Complex; Sirolimus; Plaque; TSC; Skin lesions; NPC-12G; Angiofibroma; Hypomelanotic macule
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Congenital Abnormalities; Genetic Diseases, Inborn; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Neoplasms, Vascular Tissue; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neurocutaneous Syndromes; Hamartoma; Neoplasms, Multiple Primary; Sclerosis; Tuberous Sclerosis; Angiofibroma
• Other Study ID Numbers: NPC-12G-1