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Pyrimethamine and Sulfadoxine for Treatment of Autoimmune Lymphoproliferative Syndrome

Primary Purpose

Autoimmune Disease, Lymphoproliferative Disorder

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Fansidar (pyrimethamine and sulfadoxine)
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Autoimmune Disease focused on measuring Lymphadenopathy, Splenomegaly, Children, Tomography, Autoimmune Lymphoproliferative Syndrome (ALPS)

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA All subjects must fulfill the current criteria for the diagnosis of ALPS (documented nonmalignant lymphadenopathy and/or splenomegaly of at least 1 year duration; greater than or equal to 1% TCR alpha/beta(+) CD4 (-) CD8(-) T cells in the peripheral blood and defective apoptosis by in vitro assay). Subjects must be between 4 to 70 years of age. Subjects must have a primary care physician. EXCLUSION CRITERIA Weigh less than 18 kgs (40 lbs.) will be excluded. Have a known hypersensitivity reaction to pyrimethamine, sulfonamides, sulfonylureas, furosemide or other sulfa-like drugs will be excluded. If you are receiving and requiring anti-folate drugs such as sulfonamides, trimethoprim, pyrimethamine and methotrexate will be excluded. Patients who are G-6-PD deficient will be excluded. Have a history of megaloblastic anemia, folate deficiency or a mean corpuscular volume greater than 101 CU MICR will be excluded. Have a usual Hb concentration of less than 9 gm/dl, a platelet count of less than 75 K/mm(3), or an absolute neutrophil count of less than 1000/mm(3) will be excluded. Liver disease determined by an ALT, AST or bilirubin 3 times above the upper limit of normal, and/or a serum albumin of less than 3 gm/dL will be excluded. Renal dysfunction determined by a calculated creatinine clearance of less than or equal to 70 ml/min/1.73 m(2) in children and less than or equal to 60 ml/min in adults will be excluded. Patients on immunosuppression (eg: corticosteroid, azathioprine, cyclophosphamide, etc.) are not eligible if the dose of the immunosuppressive drug has not been stable for at least 6 months prior to enrollment will be excluded. Pregnant women will be excluded. Women of reproductive age must have a negative pregnancy test and commit to use an acceptable method of contraception. Unwilling or unable to comply with the need to have periodic blood tests to monitor possible side effects of treatment, or other major requirements of this study.

Sites / Locations

  • National Institute of Allergy and Infectious Diseases (NIAID)

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

First Posted
March 28, 2001
Last Updated
March 3, 2008
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00013689
Brief Title
Pyrimethamine and Sulfadoxine for Treatment of Autoimmune Lymphoproliferative Syndrome
Official Title
Pilot Study of Pyrimethamine and Sulfadoxine (Fansidar) for the Treatment of Individuals With the Autoimmune Lymphoproliferative Syndrome (ALPS)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2003
Overall Recruitment Status
Completed
Study Start Date
March 2001 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
March 2003 (undefined)

3. Sponsor/Collaborators

Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

Brief Summary
This study will evaluate the safety and effectiveness of an antibiotic called Fansidar on autoimmune lymphoproliferative syndrome (ALPS). Patients with ALPS have enlarged lymph glands, spleen and/or liver, abnormal blood cell counts and overactive immune function. Current treatments are aimed at suppressing the immune system and improving symptoms, such as anemia (low red blood cell count) and low white blood cell and platelet counts. These treatments, however, are only partially effective and may have complications. Fansidar is a combination of two drugs, sulfadoxine and pyrimethamine, that is used to treat or prevent parasitic infections such as malaria. Recently a child with ALPS who was treated with Fansidar for a different illness had a marked shrinkage of the lymph organs. This study will examine whether Fansidar can shrink the lymph glands or spleen in patients with ALPS. Patients with ALPS between the ages of 4 and 70 years who have had lymph gland enlargement for at least 1 year and are not allergic to sulfa drugs may be eligible for this study. Candidates will be screened with a medical history and physical examination and blood tests. Females of reproductive age will have a urine pregnancy test. Participants will be evaluated at the NIH Clinical Center in Bethesda, MD, with blood tests and a computed tomography (CT) scan of the lymph nodes. For the CT scan, the patient lies on a table during an X-ray scan of the neck, part of the chest, and, if the spleen has not been removed, the stomach area. When these baseline tests are completed, patients will be given Fansidar pills to take once a week for 12 weeks. The dosage will be increased after 2 weeks and again after 4 weeks. At 2, 4, 6, 8 and 10 weeks after starting the treatment and 2 weeks after the last dose, patients will have blood drawn to check for possible side effects of therapy. Women will have a repeat urine pregnancy test at week 6 of treatment. Within a week before completing treatment or after completing treatment, patients will return to NIH for a history, physical examination, blood tests and CT scan. Patients who responded well to treatment will be offered to return to NIH again 3, 6 and 12 months later to repeat the evaluations. If ALPS symptoms recur during this time, patients will be offered another 12-week course of Fansidar and the procedure, including the 3, 6 and 12-month evaluations will be repeated again. If symptoms recur again, patients will be asked to resume Fansidar for 6 months or longer, with doses adjusted as needed. During this time, patients will be seen at NIH every 12 weeks for evaluation and blood will be drawn by the patient's private physician every 6 weeks or 2 and 4 weeks after the dose is increased to check for side effects.
Detailed Description
The Autoimmune Lymphoproliferative Syndrome is an inherited disease associated with a defect of lymphocyte apoptosis, lymphoproliferation and autoimmunity. Although, there are treatments for many of its autoimmune complications, there currently is no safe and effective therapy for this syndrome itself. Recently investigators in Europe serendipitously found that a child with ALPS type I had significant clinical improvement while on pyrimethamine/sulfadoxine (Fansidar) for Pneumocystis carinii prophylaxis. Based on this finding, we propose to conduct a pilot study to obtain information on safety and initial data on efficacy of the drug combination Fansidar for the treatment of ALPS. Six to 8 individuals, with ALPS who report no allergy to sulfa drugs will be treated for up to 3 months with weekly Fansidar at escalating doses adjusted by weight. The effect of Fansidar treatment on lymph node and/or spleen size will be assessed by CT scanning. The effect of treatment on other laboratory features of ALPS will also be assessed. Evaluating the effects of Fansidar on these clinical and laboratory parameters will allow us to determine if this drug demonstrates sufficient activity to warrant further study in a larger randomized controlled trial.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autoimmune Disease, Lymphoproliferative Disorder
Keywords
Lymphadenopathy, Splenomegaly, Children, Tomography, Autoimmune Lymphoproliferative Syndrome (ALPS)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Enrollment
8 (false)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
Fansidar (pyrimethamine and sulfadoxine)

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA All subjects must fulfill the current criteria for the diagnosis of ALPS (documented nonmalignant lymphadenopathy and/or splenomegaly of at least 1 year duration; greater than or equal to 1% TCR alpha/beta(+) CD4 (-) CD8(-) T cells in the peripheral blood and defective apoptosis by in vitro assay). Subjects must be between 4 to 70 years of age. Subjects must have a primary care physician. EXCLUSION CRITERIA Weigh less than 18 kgs (40 lbs.) will be excluded. Have a known hypersensitivity reaction to pyrimethamine, sulfonamides, sulfonylureas, furosemide or other sulfa-like drugs will be excluded. If you are receiving and requiring anti-folate drugs such as sulfonamides, trimethoprim, pyrimethamine and methotrexate will be excluded. Patients who are G-6-PD deficient will be excluded. Have a history of megaloblastic anemia, folate deficiency or a mean corpuscular volume greater than 101 CU MICR will be excluded. Have a usual Hb concentration of less than 9 gm/dl, a platelet count of less than 75 K/mm(3), or an absolute neutrophil count of less than 1000/mm(3) will be excluded. Liver disease determined by an ALT, AST or bilirubin 3 times above the upper limit of normal, and/or a serum albumin of less than 3 gm/dL will be excluded. Renal dysfunction determined by a calculated creatinine clearance of less than or equal to 70 ml/min/1.73 m(2) in children and less than or equal to 60 ml/min in adults will be excluded. Patients on immunosuppression (eg: corticosteroid, azathioprine, cyclophosphamide, etc.) are not eligible if the dose of the immunosuppressive drug has not been stable for at least 6 months prior to enrollment will be excluded. Pregnant women will be excluded. Women of reproductive age must have a negative pregnancy test and commit to use an acceptable method of contraception. Unwilling or unable to comply with the need to have periodic blood tests to monitor possible side effects of treatment, or other major requirements of this study.
Facility Information:
Facility Name
National Institute of Allergy and Infectious Diseases (NIAID)
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
9695976
Citation
van der Werff ten Bosch JE, Demanet C, Balduck N, Bakkus MH, De Raeve H, Desprechins B, Otten J, Thielemans K. The use of the anti-malaria drug Fansidar (pyrimethamine and sulphadoxine) in the treatment of a patient with autoimmune lymphoproliferative syndrome and Fas deficiency. Br J Haematol. 1998 Jul;102(2):578-81. doi: 10.1046/j.1365-2141.1998.00791.x.
Results Reference
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PubMed Identifier
10189330
Citation
Straus SE, Sneller M, Lenardo MJ, Puck JM, Strober W. An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med. 1999 Apr 6;130(7):591-601. doi: 10.7326/0003-4819-130-7-199904060-00020.
Results Reference
background
PubMed Identifier
10405750
Citation
Avila NA, Dwyer AJ, Dale JK, Lopatin UA, Sneller MC, Jaffe ES, Puck JM, Straus SE. Autoimmune lymphoproliferative syndrome: a syndrome associated with inherited genetic defects that impair lymphocytic apoptosis--CT and US features. Radiology. 1999 Jul;212(1):257-63. doi: 10.1148/radiology.212.1.r99jl40257.
Results Reference
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Pyrimethamine and Sulfadoxine for Treatment of Autoimmune Lymphoproliferative Syndrome

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