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. 2022 Mar 31;10(4):826. doi: 10.3390/biomedicines10040826

Table 1.

Characteristics and included studies.

First Author, Year, Country Participants Interventions Outcomes
Wataya-Kaneda, 2017, [41] Japan
Settings: 1 center		 Inclusion:

  1. Age: 6–47 years

  2. Diagnosis: TSC and ≥3 isolated facial angiofibromas (≥2 mm in diameter)

Exclusion:

  1. mTOR inhibitors within the past 12 months

  2. Surgical treatments (including laser) within the past 6 months

  3. Topical tacrolimus within the past 3 months

 Randomization carried out by 2:1 to the following:

  • Placebo twice daily for 12 weeks (n = 12)

  • 0.05% sirolimus gel twice daily for 12 weeks (n = 8)

  • 0.1% sirolimus gel twice daily for 12 weeks (n = 8)

  • 0.2% sirolimus gel twice daily for 12 weeks (n = 8)

  • Ratio for the decrease in tumor volume (weeks 2, 4, 8, 12, 16)

  • Reduction in tumor color (weeks 2, 4, 8, 12, 16)

  • Improvement factor (variable composed of tumor volume reduction and lessening of the redness of the 3 target tumors) (weeks 2, 4, 8, 12, 16)

  • Photography (week 12)

  • General improvement (week 12)

  • Adverse event (no. of AEs):

  1. Dry skin (placebo, n = 1; 0.05%, n = 4; 0.1%, n = 3; 0.2%, n = 5)

  2. Irritated skin (placebo, n = 3; 0.05%, n = 2; 0.1%, n = 2; 0.2%, n = 4)
Koenig, 2018, [26]
USA
Settings: 9 clinical sites in the USA and 1 in Australia		 Inclusion criteria:

  1. Age: 3–61 years

  2. Diagnosis: TSC and visible facial angiofibromas

Exclusion:

  1. Sirolimus or immunosuppression receiverb

  2. Immune dysfunction or oral mTOR inhibitor receiverc

  3. Pregnant or nursingd

  4. Dermatologic condition that could interfere with study assessmentse

  5. Hypersensitivity to the topical formulation or sirolimusf

  6. Dermatologic treatment for their facial angiofibromas within the past 6 monthsg

  7. Participation in clinical trial within the past 30 days

 Randomization carried out by 1:1:1 to the following

  • Placebo every evening for 6 months (n = 57)

  • 0.1% sirolimus gel every evening for 6 months (n = 63)

  • 1% sirolimus gel every evening for 6 months (n = 59)

  • Change from baseline in the angiofibroma grading scale (in 6 months)

  • Photo readers’ rating of paired baseline and end of trial photographs for each patient (in 6 months)

  • Adverse event (no. of AEs):

  1. Irritated skin (placebo, n = 0; 0.1%, n = 2; 1%, n = 1)
Wataya-Kaneda, 2018, [24] Japan
Settings: multi-center (9 sites)		 Inclusion:

  1. Age: 3 years and older

  2. Diagnosis: TSC and ≥3 reddish papules facial angiofibromas (≥2 mm in diameter)

Exclusion:

  1. Erosions, ulcers, or other skin lesions associated with angiofibromas

  2. Inadequately photographed skin lesions

  3. Significant comorbidities including poorly controlled dyslipidemia

  4. mTOR inhibitor within 12 months prior to use of the investigational drug

  5. Laser therapy or surgery within 6 months

Randomization carried out by 1:1 to the following:

  • Placebo twice daily for 12 weeks (n = 32)

  • 0.2% sirolimus gel twice daily for 12 weeks (n = 30)

  • Composite improvement in angiofibromas based on the efficacy variables (size and color) (weeks 4, 8, 12, 16)

  • Adverse event (no. of AEs):

  1. Dry skin (placebo, n = 4; 0.2%, n = 11)

  2. Irritated skin (placebo, n = 9; 0.2%, n = 11)

Abbreviations: TSC: tuberous sclerosis complex; mTOR: mechanistic target of rapamycin.