Autoimmune DiseasePhase 1NCT00065390
Pyrimethamine to Treat Autoimmune Lymphoproliferative Syndrome
A Phase 1 study testing Pyrimethamine in people with Autoimmune Disease and Lymphatic Disease, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
Trial summary
This study will examine whether the drug pyrimethamine can shrink lymph nodes and spleen in patients with autoimmune lymphoproliferative syndrome (ALPS). In this disease, lymphocytes (white blood cells) do not die as they normally would. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Autoimmune Disease, Lymphatic Disease, Lymphoproliferative Disorder
- What is being tested?
- Pyrimethamine
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2003to Jun 2005
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- All subjects must fulfill the published 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). This must include clinically documented lymphadenopathy involving more than two nodes in more than one regional group of nodes measuring greater than 1 cm in size and/or a palpable spleen.
- Age greater than 2 years and less than 70 years.
- Must have a personal primary care physician.
- Women of reproductive age and potential must have a negative pregnancy test at study entry and commit to using an acceptable method of barrier or hormonal contraception (e.g. condoms, diaphragms, oral contraceptives and long acting progestin agents) if sexually active during the study and for 3 months after the last dose of pyrimethamine.
- Must be willing to sign a consent form.
Who cannot join
- Patient will be excluded if any of the following is present:
- Weight of less than 10 kilograms (22 lbs).
- Patients receiving and requiring anti-folate drugs such as sulfonamides, trimethoprim, pyrimethamine and methotrexate for any other purpose. They should be off these medications, including Bactrim, for at least 7 days prior to enrolling in this protocol.
- Megaloblastic anemia, folate deficiency or a mean corpuscular volume greater than 125 in last three months with evidence of megaloblastic changes in the bone marrow.
- A hemoglobin concentration of less than 8 gm/dl, a platelet count of less than 50 K/mm(3), or an absolute neutrophil count of less than 500/mm(3), at study entry or during the study period.
- Liver disease determined by an ALT, AST or bilirubin 3 times above the upper limit of normal.
Show all 12Show fewer
- Renal dysfunction determined by a calculated urine 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 or using the Schwartz formula or Levy formula based on serum creatinine.
- Patients on immunosuppression (eg: corticosteroid, azathioprine, cyclosphosphamide, etc) are eligible if the dose of the immunosuppressive drug has been stable for at least 3 months prior to enrollment and their hematologic parameters meet the criteria outlined in item 4 (above).
- Pregnancy. Women of reproductive age and potential must have a negative pregnancy test at study entry and commit to using an acceptable method of barrier or hormonal contraception (e.g. condoms, diaphragms, oral contraceptives and long acting progestin agents) if sexually active during the study and for 3 months after the last dose of pyrimethamine.
- Lactating mothers who are breast feeding their babies will not be eligible.
- ALPS patients who have been treated with bone marrow toxic chemotherapy regimens for Hodgkins and Non-Hodgkins lymphoma or other malignancies are not eligible for this pilot study.
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institute of Allergy and Infectious Diseases (NIAID)
Bethesda, Maryland, 20892
About this study
Official title: Pilot (Phase I-II) Study of Pyrimethamine (Daraprim) for the Treatment of the Autoimmune Lymphoproliferative Syndrome (ALPS)
This study will examine whether the drug pyrimethamine can shrink lymph nodes and spleen in patients with autoimmune lymphoproliferative syndrome (ALPS). In this disease, lymphocytes (white blood cells) do not die as they normally would. As a result, patients have enlarged lymph glands, spleen, or liver, and other problems that may involve blood cell counts and autoimmune disease (overactivity of the immune system). Pyrimethamine is an orally administered antibiotic that has been used to treat or prevent malaria and toxoplasma, and may be effective in shrinking lymph nodes and spleen.
Patients with ALPS who are between 2 and 70 years of age and have had lymph gland enlargement for at least 1 year may be eligible for this study. Candidates will be screened with a medical history and physical examination, blood tests, and possibly a bone marrow test. Females of reproductive age will be screened with a urine pregnancy test. Women who are capable of becoming pregnant must use an effective method of birth control during the entire study period, because, taken during early months of pregnancy, pyrimethamine can cause birth defects in the fetus. Women who are pregnant or nursing are excluded from the study.
Read more
Participants will undergo the following tests and procedures:
- CT scan: For this test, the patient lies still in the CT scanner while images are taken of the neck, chest, and stomach area. A contrast dye is injected into a vein to brighten the CT images. Very young children will be evaluated on a case by case basis to determine whether a CT scan will be performed.
- Bone marrow biopsy: Participants undergo this test to rule out underlying bone marrow disease if they have not had a bone marrow test done in the last six months prior to enrolling in pyrimethamine study, as pyrimethamine can affect bone marrow function. Under local anesthesia, a needle is inserted into the back part of the hipbone and a small amount of marrow is removed. (Children are sedated for this test.)
- Leukapheresis: This is a procedure for collecting a small proportion of circulating white blood cells while conserving the majority of blood cells. Specifically, blood is drawn from a needle placed in an arm vein and is directed into a cell separator machine, which separates the blood cells by spinning. A small proportion of circulating white cells are removed, and the red cells, platelets, plasma and majority of white cells are returned to the patient's blood circulation. Only patients who are 7 years of age or older and weigh at least 55 pounds undergo this procedure. Other participants who choose not to have apheresis will have about 3 tablespoons of blood drawn instead.
- Pyrimethamine administration: When the above tests are completed, participants begin taking pyrimethamine. The dose is determined according to the individual's weight and is gradually increased during the study period. Patients take the drug twice a week for a total of 12 weeks.
- Blood tests: Blood samples are collected during weeks 2, 4, 6, 8, and 10 after beginning treatment, and 2 weeks after the last dose of pyrimethamine. The purpose of these blood tests is to check for possible drug-related side effects. Patients who develop a skin rash, mouth sores or other side effects may have one or more doses of the treatment drug withheld. When indicated, the patient will be directed to stop taking the study drug. If needed, drug side effects will be treated with a vitamin supplement, folinic acid, taken by mouth, 3 times weekly.
- Evaluations at the NIH Clinical Center will comprise of a pretreatment visit, one end of treatment visit at the end of 12 weeks and an optional post-treatment visit 3months after stopping pyrimethamine therapy.
Patients who respond well to treatment may be asked to return to NIH for additional visits at 3, 6, and 12 months after the treatment has ended for repeat evaluations. If their lymph glands or spleen become much larger after stopping pyrimethamine, they will be offered treatment for another 12 weeks. If they respond to the second course of treatment, they will return to NIH again after 3, 6, and 12 months. If the symptoms return again, patients will be asked to resume treatment for an additional 6 months or more. They will have blood drawn periodically by their private physician and will return to NIH for evaluation every 12 weeks.
Read the detailed description
The Autoimmune Lymphoproliferative Syndrome (ALPS) is an inherited disease associated with a defect of lymphocyte apoptosis that leads to lymphoproliferation and autoimmunity. Although, there are treatments for many of its complications, there currently is no safe and effective therapy for this syndrome itself. Recently investigators in Europe serendipitously observed that some children with ALPS showed reductions in spleen and lymph node size while in pyrimethamine/sulfadoxine (Fansidar) for Pneumocystis carinii prophylaxis. Our own subsequent pilot clinical trial of Fansidar (Protocol #01-I-0132) was terminated after failure to recruit well-defined ALPS patients who lacked histories suspicious for allergies to sulfa drugs. Our own in vitro studies, however revealed that pyrimethamine and not sulfadoxine induces lymphocyte apoptosis and this observation has suggested to us that pyrimethamine may be beneficial alone, thus avoiding the added risks of allergy and hypersensitivity associated with the sulfa drugs. However, potential bone marrow toxicity that may result from an escalating dose schedule of pyrimethamine should respond to the addition of folinic acid (Leucovorin) to the regimen.
We propose to conduct a pilot study on the safety and efficacy of the drug, pyrimethamine for the treatment of ALPS. Six to 8 individuals, with ALPS will be treated for up to 3 months, initially, with twice-weekly pyrimethamine (Daraprim) at escalating doses adjusted by weight, with the addition of folinic acid when needed to aid management of marrow toxicity. The effects of pyrimethamine treatment on lymph node and/or spleen size will be assessed by CT scan. The effect of treatment on other laboratory features of ALPS will also be assessed. Evaluating the effects of pyrimethamine on these clinical and laboratory parameters will allow us to determine if this drug demonstrates sufficient activity to warrant study in a larger randomized controlled trial.
- Being tested
- Pyrimethamine
- Keywords
- ALPS, Pyrimethamine, Folinic Acid, Lymphadenopathy, Splenomegaly, Autoimmune Lymphoproliferative Syndrome
- Medical subject headings
- Autoimmune Diseases, Lymphatic Diseases, Lymphoproliferative Disorders, Lymphadenopathy, Splenomegaly, Autoimmune Lymphoproliferative Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PyrimethamineDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jul 2003 (estimated)
- Study startJul 2003
- Study completionJun 2005
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Autoimmune DiseaseStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Enrolment
- 8 participants
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00065390
- Sponsor's protocol ID
- 030248
- Other IDs
- 03-I-0248
- Status last verified
- Jun 2005
- First submitted
- 21 Jul 2003
- Last updated
- 4 Mar 2008
- Results posted
- No
Publications
Sneller MC, Wang J, Dale JK, Strober W, Middelton LA, Choi Y, Fleisher TA, Lim MS, Jaffe ES, Puck JM, Lenardo MJ, Straus SE. Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood. 1997 Feb 15;89(4):1341-8.
PubMed 9028957Straus 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.
PubMed 10189330Avila 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.
PubMed 10405750
Study at a glance
From the registry record, last updated by the sponsor on 4 Mar 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot (Phase I-II) Study of Pyrimethamine (Daraprim) for the Treatment of the Autoimmune Lymphoproliferative Syndrome (ALPS)
- ClinicalTrials.gov ID
- NCT00065390
- Acronym / sponsor ID
- 030248
- Keywords
- ALPS, Pyrimethamine, Folinic Acid, Lymphadenopathy, Splenomegaly, Autoimmune Lymphoproliferative Syndrome
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- Jul 2003
- Study completion
- Jun 2005
- First posted
- 22 Jul 2003 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will examine whether the drug pyrimethamine can shrink lymph nodes and spleen in patients with autoimmune lymphoproliferative syndrome (ALPS). In this disease, lymphocytes (white blood cells) do not die as they normally would. As a result, patients have enlarged lymph glands, spleen, or liver, and other problems that may involve blood cell counts and autoimmune disease (overactivity of the immune system). Pyrimethamine is an orally administered antibiotic that has been used to treat or prevent malaria and toxoplasma, and may be effective in shrinking lymph nodes and spleen.
Patients with ALPS who are between 2 and 70 years of age and have had lymph gland enlargement for at least 1 year may be eligible for this study. Candidates will be screened with a medical history and physical examination, blood tests, and possibly a bone marrow test. Females of reproductive age will be screened with a urine pregnancy test. Women who are capable of becoming pregnant must use an effective method of birth control during the entire study period, because, taken during early months of pregnancy, pyrimethamine can cause birth defects in the fetus. Women who are pregnant or nursing are excluded from the study.
Participants will undergo the following tests and procedures:
- CT scan: For this test, the patient lies still in the CT scanner while images are taken of the neck, chest, and stomach area. A contrast dye is injected into a vein to brighten the CT images. Very young children will be evaluated on a case by case basis to determine whether a CT scan will be performed.
- Bone marrow biopsy: Participants undergo this test to rule out underlying bone marrow disease if they have not had a bone marrow test done in the last six months prior to enrolling in pyrimethamine study, as pyrimethamine can affect bone marrow function. Under local anesthesia, a needle is inserted into the back part of the hipbone and a small amount of marrow is removed. (Children are sedated for this test.)
- Leukapheresis: This is a procedure for collecting a small proportion of circulating white blood cells while conserving the majority of blood cells. Specifically, blood is drawn from a needle placed in an arm vein and is directed into a cell separator machine, which separates the blood cells by spinning. A small proportion of circulating white cells are removed, and the red cells, platelets, plasma and majority of white cells are returned to the patient's blood circulation. Only patients who are 7 years of age or older and weigh at least 55 pounds undergo this procedure. Other participants who choose not to have apheresis will have about 3 tablespoons of blood drawn instead.
- Pyrimethamine administration: When the above tests are completed, participants begin taking pyrimethamine. The dose is determined according to the individual's weight and is gradually increased during the study period. Patients take the drug twice a week for a total of 12 weeks.
- Blood tests: Blood samples are collected during weeks 2, 4, 6, 8, and 10 after beginning treatment, and 2 weeks after the last dose of pyrimethamine. The purpose of these blood tests is to check for possible drug-related side effects. Patients who develop a skin rash, mouth sores or other side effects may have one or more doses of the treatment drug withheld. When indicated, the patient will be directed to stop taking the study drug. If needed, drug side effects will be treated with a vitamin supplement, folinic acid, taken by mouth, 3 times weekly.
- Evaluations at the NIH Clinical Center will comprise of a pretreatment visit, one end of treatment visit at the end of 12 weeks and an optional post-treatment visit 3months after stopping pyrimethamine therapy.
Patients who respond well to treatment may be asked to return to NIH for additional visits at 3, 6, and 12 months after the treatment has ended for repeat evaluations. If their lymph glands or spleen become much larger after stopping pyrimethamine, they will be offered treatment for another 12 weeks. If they respond to the second course of treatment, they will return to NIH again after 3, 6, and 12 months. If the symptoms return again, patients will be asked to resume treatment for an additional 6 months or more. They will have blood drawn periodically by their private physician and will return to NIH for evaluation every 12 weeks.
Detailed description
The Autoimmune Lymphoproliferative Syndrome (ALPS) is an inherited disease associated with a defect of lymphocyte apoptosis that leads to lymphoproliferation and autoimmunity. Although, there are treatments for many of its complications, there currently is no safe and effective therapy for this syndrome itself. Recently investigators in Europe serendipitously observed that some children with ALPS showed reductions in spleen and lymph node size while in pyrimethamine/sulfadoxine (Fansidar) for Pneumocystis carinii prophylaxis. Our own subsequent pilot clinical trial of Fansidar (Protocol #01-I-0132) was terminated after failure to recruit well-defined ALPS patients who lacked histories suspicious for allergies to sulfa drugs. Our own in vitro studies, however revealed that pyrimethamine and not sulfadoxine induces lymphocyte apoptosis and this observation has suggested to us that pyrimethamine may be beneficial alone, thus avoiding the added risks of allergy and hypersensitivity associated with the sulfa drugs. However, potential bone marrow toxicity that may result from an escalating dose schedule of pyrimethamine should respond to the addition of folinic acid (Leucovorin) to the regimen.
We propose to conduct a pilot study on the safety and efficacy of the drug, pyrimethamine for the treatment of ALPS. Six to 8 individuals, with ALPS will be treated for up to 3 months, initially, with twice-weekly pyrimethamine (Daraprim) at escalating doses adjusted by weight, with the addition of folinic acid when needed to aid management of marrow toxicity. The effects of pyrimethamine treatment on lymph node and/or spleen size will be assessed by CT scan. The effect of treatment on other laboratory features of ALPS will also be assessed. Evaluating the effects of pyrimethamine on these clinical and laboratory parameters will allow us to determine if this drug demonstrates sufficient activity to warrant study in a larger randomized controlled trial.
Study design
- Primary purpose
- Treatment
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
- All subjects must fulfill the published 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). This must include clinically documented lymphadenopathy involving more than two nodes in more than one regional group of nodes measuring greater than 1 cm in size and/or a palpable spleen.
- Age greater than 2 years and less than 70 years.
- Must have a personal primary care physician.
- Women of reproductive age and potential must have a negative pregnancy test at study entry and commit to using an acceptable method of barrier or hormonal contraception (e.g. condoms, diaphragms, oral contraceptives and long acting progestin agents) if sexually active during the study and for 3 months after the last dose of pyrimethamine.
- Must be willing to sign a consent form.
Key exclusion criteria (12 listed)
- Weight of less than 10 kilograms (22 lbs).
- Patients receiving and requiring anti-folate drugs such as sulfonamides, trimethoprim, pyrimethamine and methotrexate for any other purpose. They should be off these medications, including Bactrim, for at least 7 days prior to enrolling in this protocol.
- Megaloblastic anemia, folate deficiency or a mean corpuscular volume greater than 125 in last three months with evidence of megaloblastic changes in the bone marrow.
- A hemoglobin concentration of less than 8 gm/dl, a platelet count of less than 50 K/mm(3), or an absolute neutrophil count of less than 500/mm(3), at study entry or during the study period.
- Liver disease determined by an ALT, AST or bilirubin 3 times above the upper limit of normal.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Pyrimethamine | Drug | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Mar 2008.
- Background: PubMed 9028957Sneller MC, Wang J, Dale JK, Strober W, Middelton LA, Choi Y, Fleisher TA, Lim MS, Jaffe ES, Puck JM, Lenardo MJ, Straus SE. Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood. 1997 Feb 15;89(4):1341-8.
- Background: PubMed 10189330Straus 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.
- Background: PubMed 10405750Avila 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Pyrimethamine in people with Autoimmune Disease and Lymphatic Disease, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Mar 2008. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00065390, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Mar 2008.