A study to evaluate safety and efficacy of topical sirolimus to treat plantar keratoderma in adults with PC. Subjects may receive either placebo or treatment with at least 1 foot receiving topical sirolimus at some time. For certain phases of the study treatment assignment to the right and left foot will be randomized in a double blind fashion. Blood levels will test systemic absorption of sirolimus. Other safety and efficacy measures will be taken through the 39-week study duration. Funding Source - FDA OOPD

Inclusion Criteria:

Subjects must:

• Be capable of understanding the purpose and risks of the study and sign a written Informed Consent Form (ICF)
• Be male or female ≥ 16 years of age at the time of the screening visit
• Have a confirmed diagnosis of PC by genotyping (e.g., familial) and clinically correlated painful keratoderma.
• Have roughly symmetrical calluses of similar severity on the plantar surface of both feet
• Women of childbearing potential must have a negative serum pregnancy test
• Subjects, whether male or female, with reproductive potential and who are sexually active must agree to use double-barrier contraception methods

Exclusion Criteria:

A Subject with any of the following criteria is not eligible for inclusion in this study:

• Use of other investigational drugs within 30 days of the screening visit and/or has not recovered from any side effects of prior investigational drugs or procedure in the affected area (e.g., a biopsy)
• Significant condition in the dermatologic treatment area such as trauma, or nonhealing chronic wound
• Pregnant or nursing (lactating) female, or a positive serum pregnancy test
• Active infection either systemic or local near the site of treatment requiring chronic or prolonged use of antimicrobial agents
• Known immunodeficiency including: Hepatitis A; Hepatitis B; Hepatitis C; Human Immunodeficiency Virus (HIV)

Prior and Current Treatment

• Unable to be discontinued from drugs known to either be inducers or inhibitors of CYP3A4/5 enzymes
• Unable to be discontinued from drugs known to be P-glycoprotein inhibitors

This is a split-body design. After a 2-week run in phase in which both feet were treated with placebo, feet were randomized and one foot received 1% sirolimus and the other placebo ("randomized phase") for 8 weeks. Following the randomized phase, patients applied 1% sirolimus to both feet ("open label phase") for an additional 8 weeks.

Duration of the study, up to 39 weeks

This study was primarily concerned with safety endpoints. Efficacy endpoints need to be improved for follow on studies.