Topical Sirolimus Ointment for Cutaneous Angiofibromas in Subjects With Tuberous Sclerosis Complex

Sponsor

Aucta Pharmaceuticals, Inc (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03363763

Collaborator

(none)

Enrollment

Locations

Arms

70.6

Anticipated Duration (Months)

5.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The objective of this study is to evaluate the safety and efficacy of sirolimus (0.2% and 0.4% formulations) and its vehicle when applied topically once daily for 12 weeks for the treatment of cutaneous angiofibromas in pediatric subjects with tuberous sclerosis complex (TSC).

Condition or Disease	Intervention/Treatment	Phase
Angiofibroma of Face Tuberous Sclerosis	Drug: Sirolimus 0.2% Drug: Sirolimus 0.4% Drug: Placebo ointment	Phase 2

Detailed Description

This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study designed to assess the safety and efficacy of topically-applied sirolimus for the treatment of cutaneous angiofibromas in pediatric subjects with TSC. Approximately 45 subjects will be enrolled at investigational sites in the United States (US) and China, though other countries may be added in the future. Approximately 45 subjects who meet the study entry criteria will randomly be assigned in a 1:1:1 ratio to receive 1 of 3 treatments: sirolimus 0.2% ointment, sirolimus 0.4% ointment, or placebo ointment. The randomization is stratified by site. Subjects, or a parent/guardian, will apply the study medication topically to the cutaneous angiofibromas on the face once daily at night before going to bed for 12 weeks. Subjects who complete the double-blind phase of the study, with an overall compliance rate >80% as determined by the dosing diary, will be offered entry into an open-label period for an additional 12 weeks.

The maximum study duration for each subject will be approximately 30 weeks and includes a screening period of up to 4 weeks, a blinded treatment period of 12 weeks, optional open-label period of 12 weeks, and a follow-up period of 2 weeks.

An interim analysis will be performed when all subjects have completed the double-blind phase (Visit 5 - Week 12). The data will be unblinded to assess for efficacy and results reported.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

45 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Subjects will be randomly assigned in a 1:1:1 ratio to receive 1 of 2 treatments or placebo. The randomization is stratified by site. Subjects who complete the double-blind phase of the study with an overall compliance rate >80% and <120%, as determined by weight of returned study medication, will be offered entry into an open-label period for an additional 12 weeks.Subjects will be randomly assigned in a 1:1:1 ratio to receive 1 of 2 treatments or placebo. The randomization is stratified by site. Subjects who complete the double-blind phase of the study with an overall compliance rate >80% and <120%, as determined by weight of returned study medication, will be offered entry into an open-label period for an additional 12 weeks.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Phase 2 Multi Center Prospective Rand. Double Blind Placebo Cont. Parallel Design Study to Evaluate Safety & Efficacy of Topical Sirolimus for Cutaneous Angiofibromas in Subjects W/ Tuberous Sclerosis Complex Followed by Opt. Open Label

Actual Study Start Date :

Apr 12, 2017

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Mar 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm 1 Sirolimus 0.2% ointment applied topically hs x 12 weeks	Drug: Sirolimus 0.2% Ointment for topical administration hs x 12 weeks Other Names: Rapamune rapamycin mTOR inhibitor
Active Comparator: Arm 2 Sirolimus 0.4% ointment applied topically hs x 12 weeks	Drug: Sirolimus 0.4% Ointment for topical administration hs x 12 weeks Other Names: Rapamune rapamycin mTOR inhibitor
Placebo Comparator: Arm 3 Placebo ointment applied topically hs x 12 weeks	Drug: Placebo ointment Placebo ointment comparator for topical administration hs x 12 weeks Other Names: Placebo

Arm

Intervention/Treatment

Active Comparator: Arm 1

Sirolimus 0.2% ointment applied topically hs x 12 weeks

Drug: Sirolimus 0.2%

Ointment for topical administration hs x 12 weeks

Other Names:

Rapamune

rapamycin

mTOR inhibitor

Active Comparator: Arm 2

Sirolimus 0.4% ointment applied topically hs x 12 weeks

Drug: Sirolimus 0.4%

Ointment for topical administration hs x 12 weeks

Other Names:

Rapamune

rapamycin

mTOR inhibitor

Placebo Comparator: Arm 3

Placebo ointment applied topically hs x 12 weeks

Drug: Placebo ointment

Placebo ointment comparator for topical administration hs x 12 weeks

Other Names:

Placebo

Outcome Measures

Primary Outcome Measures

The proportion of subjects with a clinical response of treatment success. [Week 12]
At least a 2-grade improvement on the Week 12 Investigator Global Assessment (IGA) of the facial skin lesions assessed by the investigator.

Secondary Outcome Measures

The proportion of subjects with at least 30% improvement at Week 12 as compared to Baseline in the Facial Angiofibromas Severity Index (FASI) score. [Week 12]
Based on lesion erythema, size, and extension
The time to reach at least 30% improvement from Baseline in the Facial Angiofibromas Severity Index (FASI) score [Week 12]
Based on lesion erythema, size, and extension
The proportion of subjects with at least 2-grade improvement as compared to Baseline in categorical lesion counts [Week 12]
Based on number of lesions
The proportion of subjects with at least 2-grade improvement as compared to Baseline in lesion elevation score [Week 12]
Based on elevation over normal skin
The proportion of subjects with at least 2-grade improvement as compared to Baseline in the subject self-assessment survey [Week 12]
Based on redness and disease-related lesions
The proportion of subjects with an investigator assessed IGA score of clear or almost clear with at least a 2-grade improvement on the Week 12 IGA of the facial skin lesions [Week 12]
Based on IGA score
Overall response of angiofibroma assessed by the investigator at Week 12 as compared to baseline based on Modified Nobel Scoring System [Week 12]
Based on target and non-target lesions. Minimum value of -2 and maximum value of 4 with higher score indicating better outcome.
Overall response of angiofibroma assessed by the IRC at Week 12 compared to baseline based on Modified Nobel Scoring System [Week 12]
Based on target and non-target lesions Minimum value of -2 and maximum value of 4 with higher score indicating better outcome.
The proportion of subjects with at least Moderate Improvement on Modified Nobel Scoring System assessed by the investigator at Week 12 [Week 12]
Based on target and non-target lesions
The proportion of subjects with at least Moderate Improvement on Modified Nobel Scoring System assessed by the IRC at Week 12 [Week 12]
Based on target and non-target lesions
The proportion of subjects with at least a 2-grade improvement on the Week 12 Investigator Global Assessment (IGA) of the facial skin lesions assessed by the IRC [Week 12]
Based on IGA Score

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Generally healthy males or non-pregnant females aged 2 to 21 years, inclusive, at the time of screening.
Diagnosis of TSC with visible facial angiofibromas of at least grade 3 up to grade 5, inclusive, based on the IGA.
Subjects with 3 or more isolated, measurable lesions of facial angiofibroma, with color grading score ≥2 for each of the 3 lesions.
Females of childbearing potential must have a negative urine pregnancy test (or a negative serum pregnancy test if a urine pregnancy test cannot be obtained) (For China, different pregnancy test would be followed) and if sexually active or become sexually active during the study, must agree to use an effective form of birth control for the duration of the study. Females using oral contraceptives must also use a barrier method of contraception during the study. Sexually active male subjects and/or their female partners should also use appropriate contraception.

Effective contraception is defined as follows:

Oral/implant/injectable/transdermal/estrogenic vaginal ring contraceptives, intrauterine device, condom with spermicide, diaphragm with spermicide.
Abstinence or partner's vasectomy are acceptable if the female agrees to implement one of the other acceptable methods of birth control if her partner changes.

The subject and/or their parent or guardian must be willing and able to provide written informed consent/assent.
Willing and able to comply with all trial requirements.
Subject or parent/guardian must be able to complete the subject self-assessment survey and subject diary in English or another language into which the documents have been officially translated.
Subjects should be in good general health based on the subject's medical history, physical exam, and impression of the study doctor.

Exclusion Criteria:

Has any chronic or acute medical condition, that in the opinion of the investigator, may pose a risk to the safety of the subject during the trial period, or may interfere with the assessment of safety or efficacy in this trial.
Has received oral therapy or topical therapy of an mTOR inhibitor (sirolimus, temsirolimus, or everolimus) within 1 month of Baseline or other dermatological treatment to facial angiofibromas within 1 month of baseline. (Sunscreen is expected to be used in this patient population and is not considered treatment.)
Is currently receiving any form of immunosuppression therapy or has previously experienced significant immune dysfunction.
Has a history of sensitivity to any component of the investigational product.
Is pregnant, plans to become pregnant during the course of the study, or is breastfeeding.
Has other dermatologic conditions, pigmentation, scarring, pigmented lesions or sunburn in the treatment area that would preclude or prevent adequate assessment of changes to their facial angiofibromas.
Has facial hair (e.g., beard, sideburns, mustache) that could interfere with study assessments.
Has had laser surgery or cryotherapy to facial angiofibromas within 6 months preceding study entry.
Requires the use of any concomitant medication that, in the investigator's opinion, has the potential to cause an adverse effect when given with the investigational product or will interfere with the interpretation of the study results (see Section 16.1 Appendix 1 for Potential Drug Interactions).
Has participated in another clinical trial or received an investigational product within 3 months prior to screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Translational Genomics Research	Phoenix	Arizona	United States	85004
2	Children's Hospital of Los Angeles, Division of Neurology	Los Angeles	California	United States	90027
3	Children's Clinical Research Organization, Children's Hospital Colorado	Aurora	Colorado	United States	80045
4	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30329
5	Boston Children's Hospital	Boston	Massachusetts	United States	02115
6	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
7	LeBonheur Children's Hospital	Memphis	Tennessee	United States	38103
8	Children's Hospital of Fudan University	Shanghai		China	201102