Evaluating Sirolimus to Treat Autoimmune Blistering Dermatosis Pemphigus

• ClinicalTrials.gov Identifier: NCT01313923
• Recruitment Status: Terminated
• First Posted: March 14, 2011
• Results First Posted: March 25, 2016
• Last Update Posted: June 9, 2017
• Sponsor: University of California, Irvine
• Information provided by (Responsible Party): Sergei Grando, University of California, Irvine

Tracking Information

• First Submitted Date: March 10, 2011
• First Posted Date: March 14, 2011
• Results First Submitted Date: December 17, 2014
• Results First Posted Date: March 25, 2016
• Last Update Posted Date: June 9, 2017
• Study Start Date: February 2011
• Actual Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 24, 2016)

Improvement of ABSIS Score While Reducing Steroid Dosage [ Time Frame: Expected time line 24 months ]

Measurement of disease severity will be quantified using ABSIS (Autoimmune Bullous Skin Disorder Intensity Score). Improvement in disease control is quantified by the maintenance or improvement of ABSIS score while reducing steroid dosage. No results as study has been terminated early by the investigator.

Original Primary Outcome Measures (submitted: March 10, 2011)

Improvement of ABSIS Score while reduing Steroid Dosage [ Time Frame: 12 Months ]

Measurement of disease severity will be quantified using ABSIS (Autoimmune Bullous Skin Disorder Intensity Score). Improvement in disease control is quantified by the maintenance or improvement of ABSIS score while reducing steroid dosage.

Current Secondary Outcome Measures (submitted: May 8, 2017)

Statistical Measures [ Time Frame: Study early termination by investigator - no participant completed any visits of the study - no measurements taken ]

The statistical goal is to observe "success," an improvement in disease control while up-titrating sirolimus dosage. As there will be no control group, the subject or progress at the end of the study will be compared to their baseline at the beginning of the study. The subject and disease severity at the beginning of the study will be compared to the disease severity at each visit and be correlated with the dosage of sirolimus and corticosteroid. However, since no patient completed the study, the outcome and any data collected was not assessed.

Original Secondary Outcome Measures (submitted: March 10, 2011)

Statistical Measures [ Time Frame: 12 Months ]

The statistical goal is to observe "success," an improvement in disease control while uptitrating sirolimus dosage. As there will be no control group, the subject's progress at the end of the study will be compared to their baseline at the beginning of the study. The subject's disease severity at the beginning of the study will be compared to the disease severity at each visit and be correlated with the dosage of sirolimus and corticosteroid.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluating Sirolimus to Treat Autoimmune Blistering Dermatosis Pemphigus
• Official Title: Evaluation of Sirolimus for the Treatment of the Autoimmune Blistering Dermatosis Pemphigus
• Brief Summary: The purpose of this research is to study alternative treatments for the skin disease pemphigus (a rare autoimmune blistering disorder of the skin) by using sirolimus, an immunosuppressive drug. Immunosuppressive drugs inhibit or prevent the activity of the immune system and are commonly used to treat autoimmune diseases, inflammatory diseases, and organ transplantation rejection.

Detailed Description

The purpose of this study is to explore a new medication for the skin disease termed pemphigus. Our specific aim is to determine whether the use of sirolimus will allow for a decrease in the dosage or possibly eliminate the need for corticosteroids, which so far is the only type of drug that can control this disease.

Pemphigus is an autoimmune disease characterized by blistering, caused by autoantibodies against certain cells in the skin. This disease most commonly occurs in individuals ages 50 and older, and it presents as painful shallow erosions and/or blisters in the mouth and/or skin. Pemphigus is very painful and uncomfortable, associated with impaired quality of life and significant morbidity. Severe or untreated cases of pemphigus can become fatal if the involved surface area becomes large enough to cause dehydration and/or infection. The first line of therapy, and the standard of care, for pemphigus remain to be systemic corticosteroids. However, corticosteroids have many known side effects, especially when used for a long time. Many cases of pemphigus are insufficiently controlled with corticosteroids alone and require the addition of other immunosuppressive agents, such as azathioprine, cyclophosphamide, mycophenolate mofetil, or a variety of other therapies used off-label. All of these treatments are not always successful and have undesirable side effects, including increased risk of malignancy and infections. Although these treatments can offer some relief from the disease, they are also often the cause of many side effects.

Sirolimus (formerly known as rapamycin) is a drug commonly used after renal transplants to prevent organ rejection. In this study, pemphigus subjects with active disease will begin taking sirolimus in conjunction with corticosteroids, using a similar regimen used for organ transplantation to treat pemphigus. While increasing sirolimus and decreasing the corticosteroids, subjects will be monitored over a 12 month period to evaluate their disease response. The purpose of this study is to observe data trends.

Our specific aim is to determine whether the use of sirolimus will allow for a decrease in the dosage of the corticosteroid prednisone, which so far is the only type of drugs that can control these diseases, without making the pemphigus worse.

• Study Type: Interventional
• Study Phase: Early Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Pemphigus

Intervention

Drug: Sirolimus (formerly known as Rapamycin)

For low to moderate immunologic risk, the loading dose is 6mg immediately after transplantation, followed by 2mg PO Qday in conjunction with cyclosporine and corticosteroids. After 2-4 months, cyclosporine should be discontinued over 4-8 weeks while titrating sirolimus drug concentrations within the target-range with whole blood trough concentrations every 1-2 weeks. Monitoring is needed because cyclosporine inhibits the metabolism of sirolimus, and discontinuation of cyclosporine can lead to lower levels of sirolimus. In high immunologic risk patients, the loading dose is 15mg after transplantation, followed by 5mg PO Qday in conjunction with cyclosporine and corticosteroids for 12 months. A whole blood trough level is recommended between days 5 and 7 with adjustment to the daily dose.

Other Names:

• Sirolimus
• Rapamycin

Study Arms

Experimental: Sirolimus (formerly known as Rapamycin)

Subjects with stable pemphigus vulgaris already on treatment with prednisone will be enrolled. Subjects will start taking oral sirolimus and have it up-titrated while decreasing the prednisone dosage. Their disease state will be monitored during this time.

Intervention: Drug: Sirolimus (formerly known as Rapamycin)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: February 24, 2016): 3
• Original Estimated Enrollment (submitted: March 10, 2011): 15
• Actual Study Completion Date: October 2014
• Actual Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Subject must be 18 years of age or older.
2. Subject must have an established diagnosis of pemphigus disorder via biopsy and/or serologic titer, as determined appropriate by the lead researcher.
3. Subject must have active disease at the time of enrollment, as defined by a positive Nikolsky sign.
4. Subject must not be taking any immunosuppressive medication or therapy other than corticosteroids.
5. Subject must be able to understand and follow directions.
6. If female, subject is not currently breast feeding and/or pregnant as confirmed via negative pregnancy test, no potential for pregnancy, or if of child-bearing age, agrees to using birth control for entire duration of study and 12 weeks after end of study.

Exclusion Criteria:

1. Subject may not be under 18 years old.
2. Subject cannot understand or follow directions.
3. Subject may not have any condition that could, in the opinion of the investigator, compromise the subject's ability to give written consent and/or comply with the study procedures, such as a history of substance abuse or a psychiatric condition.
4. If female and of child bearing age, is pregnant or unwilling to use birth control during the study period.

5. Subject may not have any of the following laboratory abnormalities at baseline:

   • total white blood cell count < 2,000/mm3 or platelet count < 100,000/mm3
   • creatinine >1.5mg/dL
   • urine analysis protein of 2+ or greater
   • fasting triglycerides > 400 mg/dL, fasting total cholesterol > 300 mg/dL, or fasting LDLcholesterol > 160 mg/dL
   • transaminases > 2 times the upper limit of normal
6. Subjects may not be using any of the following medications: systemic antifungals, antiepileptics, HIV protease inhibitors, cimetidine, cisapride, clarithromycin, danazol, diltiazem, erythromycin, metoclopramide, rifabutin, rifampin, rifapentine, troleandomycin, or verapamil
7. Subject may not consume grapefruit juice and/or St. John's Wort (hypericum perforatum) throughout the duration of the study.

8. Subject may not have other significant concurrent medical conditions, including

   • Active malignancy, including evidence of cutaneous basal or squamous cell carcinoma or melanoma, or history of cancer (other than fully resected and surgically cured cutaneous basal cell and squamous cell carcinoma) within 5 years before the first 13 of 25 sirolimus dose. If malignancy occurred more than 5 years ago, documentation of disease-free state since treatment is required.
   • Known immunodeficiency syndromes, including HIV
   • Renal failure or insufficiency, as defined by laboratory parameters above
   • Significant proteinuria, as defined by laboratory parameters above
   • History of high cholesterol, lipids, or liver disease, as defined by laboratory parameters above
   • Uncontrolled hypertension, as defined by a blood pressure > 140/90 despite optimal medical therapy, as prescribed by primary care doctor
   • Any condition that, in the opinion of the investigator, might cause this study to be detrimental to the subject
   • Any active Common Terminology Criteria (CTC) grade 2 (localized infection; requiring local intervention) or higher infection (including chronic or localized infections) within 30 days prior to screening, at screening, or during screening period prior to first dose of sirolimus

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01313923
• Other Study ID Numbers: 2010-7844
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Sergei Grando, University of California, Irvine
• Original Responsible Party: Sergei Grando, MD, PhD, DSci, University of California, Irvine
• Current Study Sponsor: University of California, Irvine
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Sergei Grando, MD, PhD; University of California, Irvine

• PRS Account: University of California, Irvine
• Verification Date: May 2017