Prospective Study of Rapamycin for the Treatment of SLE

Study Overview
=================
Brief Summary
-----------------
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin. It involves multiple organs including the joints, skin, kidneys and central nervous system. The disease process is caused by a dysfunction of the immune system. The drugs currently used for the treatment of SLE are only partially effective and carry significant risks for side-effects. Patients that were resistant or intolerant to conventional medication have been effectively treated with Rapamycin and were able to decrease the amount of prednisone they needed. The purpose of this study is to prospectively determine the therapeutic efficacy and mechanism of action of Rapamune in patients with SLE. Healthy subjects not receiving Rapamune will be asked to donate blood to serve as controls. As part of the research effort to understand the reason for the variations in the effects of treatment drugs by different individuals, a sub-study of the DNA makeup of subjects enrolled in the trial will also be done. The purpose of the sub-study is to possibly determine whether different responses to the drugs used to treat SLE have a correlation with the differences in the genetic makeup of the subjects.

Detailed Description
-----------------
40 SLE subjects and 40 healthy controls are being recruited. The study will last 1 year with 9 study visits from day 0 to day 360. The healthy controls only need to donate blood once. The study drug, sirolimus, is taken by mouth at a starting dose of 2mg/day. The dose is adjusted to achieve blood levels in the range of 6-15 ng/ml (the levels found to be effective for preventing organ rejections). Blood samples are obtained before taking sirolimus, every two weeks for the first month, then every three months until 1 year, and then three months later to check the effect of discontinuing rapamycin. Each SLE subject will be asked to provide up to 100 ml (20 teaspoons) of blood at each visit. The first 6 visits will take place within 3 months and the remaining 3 visits every 3 months. Routine laboratory work will be performed. Part of the blood drawn will be used for research and part will be used for routine lab work as part of standard of care. The non-routine laboratory studies include: Assessment of mitochondrial function in intact T cells Analysis of mTOR activity, FKBP12 expression, and global gene expression in lupus T cells. Predictors of therapeutic efficacy of sirolimus in SLE. The study drug levels will be checked at every visit. The non-routine laboratory studies will be performed at Visits 0 and 8 for SLE subjects and at Visit 0 for the healthy control subjects. Healthy control subjects will be matched by age (a decade or less), gender, and ethnic origin. They will be recruited and analyzed on the same day as lupus subjects. All subjects will sign an informed consent at visit 0. There is a separate informed consent for the main study, one for the SLE subjects and one for the Healthy Controls. The same subjects can participate in the genetic sub-study. They must sign another informed consent for the genetic sub-study, one for the SLE subjects and one for the Healthy Controls. There is no need for additional blood drawing since part of the blood drawn for the main study can be used for the genetic sub-study.

Official Title
-----------------
Prospective Study of Rapamycin for the Treatment of SLE

Conditions
-----------------
Systemic Lupus Erythematosus (SLE)

Intervention / Treatment
-----------------
* Drug: Rapamycin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: For SLE Subjects: SLE patients who exhibit ongoing disease activity by SLEDAI greater or equal to 4. SLE patients whose disease activity is controlled by administration of corticosteroids, most commonly, at least 10 mg/day of prednisone. 18 years of age or older. Updated vaccinations prior to study entry. Use of effective contraception for male patients before, during and up to 12 weeks after sirolimus therapy. For Healthy Control Subjects: 18 years of age or older Must be matched with one of the SLE patients enrolled in the study by age, gender and ethnic origin Must not have any acute or chronic illness. Exclusion Criteria: For SLE Subjects: Patients who are pregnant. Patients with allergy or intolerance to sirolimus. Patients with life-threatening manifestations of SLE. Patients with proteinuria exceeding 500 mg/24 h or urine protein/creatine ratio >0.5. Patients with total cholesterol > 300 mg/dl or triglyceride > 400 mg.dl will be excluded. Patients with acute infection requiring antibiotics. Patients on sirolimus who develop infections and require intravenous antibiotics and fail to show clinical improvement in 5 days. Patients concurrently undergoing B cell-depleting therapy, cyclophosphamide, cyclosporine, and tacrolimus. Patients who have received investigational biologic B-cell depleting products within one year of study initiation. Patients with a history of chronic viral infections (e.g., HIV, hepatitis B, hepatitis C) or with a history of a malignancy (except non-melanoma skin cancer). Due to interference with sirolimus metabolism, subjects will not be allowed to receive concomitant rifampin, ketoconazole,voriconazole, itraconazole, erythromycin, or clarithromycin during the study. Patients with any type of interstitial lung disease. For Healthy control Subjects: Subjects who are pregnant. Subjects with any acute or chronic illness.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>SLE subjects receiving the study drug, Rapamune. | Drug: Rapamycin<br>* Rapamycin, is given to this group at a starting dose of 2 mg/day.<br>* Other names: Sirolimus;|
| No Intervention: 2<br>Healthy control group donating blood for the main study. | |
| No Intervention: 3<br>SLE subjects donating blood for Genetic sub-study | |
| No Intervention: 4<br>Healthy control subjects donating blood for the Genetic sub-study | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of the disease activity |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| decrease of the amount of prednisone needed to treat SLE. |  | 1 year |