Rheumatoid Arthritis Clinical Trial
Official title:
Sirolimus for Patients With Chronic and/or Refractory Autoimmune Cytopenias: A Pilot Series
Verified date | November 2019 |
Source | Children's Hospital of Philadelphia |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
Treatment for patients with autoimmune destruction of blood cells is poor. The part of the body that fights infections is called the immune system and white blood cells (WBCs) are part of the immune system. Normally, a person's body creates WBCs to fight infections and eliminates WBCs which have stopped helping the body function. Patients with autoimmune destruction of blood cells have difficulty eliminating old WBCs. The abnormal WBCs build up and can damage other healthy cells, which can lead to anemia, fatigue, jaundice, internal bleeding, infection, and cancer. Few effective medications exist for treatment for patients with autoimmune cytopenias and those commonly used are fraught with side effects. Nevertheless, as scientific understanding of autoimmune diseases has improved, more directed and less toxic therapies are becoming available. A number of groups have been studying the efficacy of a medication called sirolimus in patients with autoimmune diseases. This medicine has been FDA-approved for over 20 years. Sirolimus is a medicine used in children with other diseases. Sirolimus works, in part, by eliminating old and abnormal WBCs. Our group and others have shown that sirolimus is effective in mice with autoimmunity and in children with a rare condition called Autoimmune Lymphoproliferative Syndrome (ALPS). We believe sirolimus will help children with autoimmune cytopenias. We believe it will improve their symptoms and make them less sick. We propose to study sirolimus in children with chronic and/or refractory autoimmune cytopenias.
Status | Completed |
Enrollment | 30 |
Est. completion date | February 2016 |
Est. primary completion date | February 2016 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 1 Year to 30 Years |
Eligibility |
Inclusion Criteria: - Age > 12 months and < 30 years at the time of study entry - Diagnosis of autoimmune cytopenias requiring treatment with medications - At least one of the following: Autoimmune Neutropenia, Autoimmune Hemolytic Anemia, and/or Autoimmune Thrombocytopenia - Must be proven autoimmune by either a documented autoantibody (positive direct anti globulin test, positive anti-neutrophil, and/or anti-platelet antibody) and/or a documented clinical response to immunosuppression - Autoimmune Cytopenias can be idiopathic (Idiopathic Thrombocytopenic Purpura (ITP), Autoimmune Hemolytic Anemia (AIHA), Autoimmune Neutropenia (AIN), or Evans syndrome) or secondary to one of following conditions: Lupus, Rheumatoid Arthritis (RA), ALPS (Autoimmune Lymphoproliferative Syndrome), or Inflammatory bowel disease (IBD) - Patients must have chronic disease diagnosed by either a documented cytopenia syndrome (Lupus, ALPS, RA, or IBD), or by having Evans syndrome defined as idiopathic destruction of multiple blood cell types, and/or by having disease >6 months - Patients must be refractory to or unable to tolerate standard front-line therapies for autoimmune cytopenias (corticosteroids and/or IVIG) - Patients may be taking second-line agents for autoimmune cytopenias (mycophenolate mofetil, cyclosporine, tacrolimus, mercaptopurine, and/or methotrexate) at time of study entry; however, attempts should be made to wean these agents. Patients may not stay on a combination of sirolimus and a calcineurin inhibitor for greater than 4 weeks - Informed consent/assent must be obtained prior to initiating treatment - Patient must be able to consume oral medication in the form of tablets or solution Exclusion Criteria: - Pregnancy or breast feeding - Uncontrolled infection - Known allergy to Sirolimus or its components - Patients with a documented malignancy on therapy or not in remission - Patients who do not meet organ function requirements listed in protocol - Patients with a documented history of severe combined immunodeficiency or human immunodeficiency virus infection (HIV) |
Country | Name | City | State |
---|---|---|---|
United States | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania |
Lead Sponsor | Collaborator |
---|---|
Children's Hospital of Philadelphia |
United States,
Bride KL, Vincent T, Smith-Whitley K, Lambert MP, Bleesing JJ, Seif AE, Manno CS, Casper J, Grupp SA, Teachey DT. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2016 Jan 7;12 — View Citation
Teachey DT, Greiner R, Seif A, Attiyeh E, Bleesing J, Choi J, Manno C, Rappaport E, Schwabe D, Sheen C, Sullivan KE, Zhuang H, Wechsler DS, Grupp SA. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative sy — View Citation
Teachey DT, Manno CS, Axsom KM, Andrews T, Choi JK, Greenbaum BH, McMann JM, Sullivan KE, Travis SF, Grupp SA. Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). Blood. 2005 Mar 15;105(6):2443-8. Epub 2004 Nov 12. — View Citation
Teachey DT, Obzut DA, Axsom K, Choi JK, Goldsmith KC, Hall J, Hulitt J, Manno CS, Maris JM, Rhodin N, Sullivan KE, Brown VI, Grupp SA. Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS). Blood. 2006 Sep 15;108(6):1965-71. Epub 2006 Jun 6. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Number of Participants With Grade 3 and 4 Toxicities of Administration of Oral Sirolimus | Grade 3 toxicities are those that are considered severe or medically equivalent requiring hospitalization or prolonged hospitalization (according to CTCAE criteria 3.0). Grade 4 toxicities are those that are life-threatening (urgent intervention indicated) (according to CTCAE criteria 3.0). |
6 months | |
Secondary | Number of Participants With Autoimmune Disease Response to Oral Sirolimus | Complete response (CR) is complete resolution in all autoimmune cytopenias (neutropenia, anemia thrombocytopenia) maintained for more than two months, combined with an ability to wean off corticosteroids and/or other immunosuppressive medication. Partial response (PR) is improvement in any cytopenias by at least one grade, lasting more than two months, without worsening any other cytopenias or stable disease with the ability to wean corticosteroids and/or immunosuppressive medications by at least 50%. No response (NR) is no change in cytopenias with treatment, and the inability to wean corticosteroids or other immunosuppressive medications. Progressive disease (PD) refers to obtaining a CR or PR by the 3 month observation and relapsing or progressing by the 6 month observation, leading to cessation of study drug. | 6 months | |
Secondary | Trough Levels Produced by Administration of Oral Sirolimus | Pharmacokinetic levels produced by administration of oral sirolimus | Within first 5 days of starting sirolimus | |
Secondary | Effect of Sirolimus on Intracellular Targets | Needs more specific information | 6 months | |
Secondary | Number of Participants With Lymphoproliferation Response to Oral Sirolimus | Complete response (CR) is complete resolution of any lymphadenopathy and splenomegaly for at least two months. Partial response (PR) is a reduction in size of at least 50% of lymphadenopathy or splenomegaly for at least two months. No response (NR) is no change or < 50% reduction in lymphadenopathy or splenomegaly. Progressive Disease (PD) is obtaining a CR or PR by the 3 month observation and relapsing or progressing by the 6 month observation, leading to cessation of study drug. Not Applicable (N/A) is there is no evidence of disease (No pathologic lymphadenopathy or splenomegaly at time of enrollment). | 6 months |
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