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Valproic Acid (Depakote[Registered Trademark]) to Treat Autoimmune Lymphoproliferative Syndrome (ALPS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00605657
Recruitment Status : Completed
First Posted : January 31, 2008
Results First Posted : March 21, 2013
Last Update Posted : March 21, 2013
Information provided by (Responsible Party):
Koneti Rao, National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:

This study will test whether valproic acid (Depakote[Registered Trademark]) can shrink enlarged lymph glands and spleen in patients with autoimmune lymphoproliferative syndrome (ALPS). Depakote has been used for more than 30 years for treating various medical disorders in adults and children, including migraine headaches, seizures and psychiatric disorders. In animal studies, it was effective in shrinking both lymph nodes and spleen in animals with conditions similar to ALPS.

People with ALPS who are between 2 and 70 years of age and who have had an enlarged spleen or lymph glands for at least 1 year may be eligible for this study.

Participants take Depakote as a tablet or liquid or sprinkled on food twice a day for 16 weeks. The drug dose is increased slowly over the first 3 to 4 weeks until the maximum tolerated dose is reached. Blood tests are done at 2, 4, 6, 8 and 10 weeks after starting the drug and 1 week after the drug is stopped to check for treatment side effects. Valproic acid blood levels will be checked during drug escalation, half way through therapy, and just before the end of treatment. A physical examination and CT scan (or ultrasound of the abdomen for patients who cannot undergo CT) are done before starting treatment and at the end of the 16-week treatment period to evaluate the response to treatment.

Patients who tolerate the treatment well and show shrinkage of the lymph glands or spleen may be offered extended treatment for up to 1 year in consultation with their primary physician. During the extended treatment period, blood tests are done at home every 6 to 8 weeks to monitor for drug side effects. Follow up evaluation visits are scheduled at the NIH Clinical Center every 3 months during the extended treatment period and 3, 6, and 12 months after treatment has ended.

Condition or disease Intervention/treatment Phase
ALPS Hypersplenism Lymphadenopathy Drug: Valproic Acid Procedure: CT Scan Procedure: Blood Sample Phase 1 Phase 2

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 immunosuppressive treatments for many of its complications, there currently is no safe and effective therapy for this syndrome itself.

Valproic acid has been recently used as a histone deacetylase (HDAC) inhibitor for inducing apoptosis in malignancies and is being incorporated as part of hematology/oncology clinical trials. A pilot study will be conducted on the safety and efficacy of the drug valproic acid (Depakote [R]) for the treatment of ALPS. Twelve subjects with ALPS, will be treated initially for 4 months with twice-daily administration of valproic acid at escalating doses adjusted by weight, with close monitoring of toxicity and side effects including laboratory parameters related to the drug. The effects of valproic acid treatment on lymph node and/or spleen size will be assessed by computerized tomography scan, ultrasound and physical examination. If valproic acid is effective in reducing the size of lymph nodes and/or spleen size as defined in the study design, subjects may be offered the option to continue further therapy with valproic acid for up to 1 year. The effect of treatment on other laboratory features specific to ALPS will also be assessed. Evaluating the effects of valproic acid on these clinical and laboratory parameters will help to determine if this drug demonstrates sufficient activity to warrant study in a larger randomized controlled trial.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot (Phase I-II) Study of Valproic Acid (Depakote) for the Treatment of the Autoimmune Lymphoproliferative Syndrome (ALPS)
Study Start Date : January 2008
Actual Primary Completion Date : September 2011
Actual Study Completion Date : September 2011

Arm Intervention/treatment
Experimental: Valproic acid
Single arm study involving oral administration of valproic acid and monitoring of its efficacy by CT scans done before and after the intervention. Blood samples were also obtained to monitor safety labs and biomarkers.
Drug: Valproic Acid
Oral administration of valproic acid
Other Name: Depakote

Procedure: CT Scan
CT scans were done before and after treating the patient with valproic acid
Other Name: Computerized Tomography

Procedure: Blood Sample
Blood samples were collected before and after the intervention to monitor blood counts and biomarkers of ALPS

Primary Outcome Measures :
  1. Number of Participants With Response [ Time Frame: 3 monthly (12 week) intervals ]
    Reduction of lymph node and/or spleen size measured by CT imaging, or physical exam and abdominal ultrasound. A clinical response is defined as a greater than 40% reduction in lymph node size and/or greater than 40% reduction in spleen size. A CT scan with contrast measured lymph node size as well as spleen size.

Secondary Outcome Measures :
  1. To Determine Whether the Treatment Alters, in Favorable Directions, Laboratory Markers of ALPS (e.g., Number of DNT Cells, Immunoglobin Levels, Vitamin B12 Levels, IL-10 Levels, Autoantibody Titers, Fas Mediated Apoptosis) [ Time Frame: 3 monthly (12 week) intervals ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   2 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

    1. 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 than1% TCR alpha/beta+ CD4-CD8- T cells in the peripheral blood). This must include clinically documented lymphadenopathy involving more than 2 nodes in more than 1 regional group of nodes measuring greater than 2cm in size and/or a palpable spleen.
    2. Age greater than or equal to 2 years through less than or equal to 70 years.
    3. Must have a personal primary care physician who is willing to follow the protocol required evaluations during the study period.
    4. Must be willing to sign a consent form.
    5. Patients on immunosuppression (e.g., corticosteroid, mycophenolate mofetil, azathioprine, cyclophosphamide) are eligible if the dose of the immunosuppressive drug has been stable for at least 3 months prior to enrollment and their hematologic parameters do not meet the exclusion criteria (1) as outlined below.


  1. A hemoglobin concentration of less than 8 gm/dL, a platelet count of less than 75 K/mm(3), or an absolute neutrophil count of less than 500/mm(3), at study entry.
  2. Liver disease determined by an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin 2.5 times greater than the upper limit of normal.
  3. History of pancreatitis by clinical features and/or laboratory abnormalities in the last 12 months.
  4. Renal dysfunction determined by a calculated urine creatinine clearance of less than 70 mL/min/1.73 m(2) in children and less than 60 mL/min in adults, or using the Schwartz formula or Levy formula based on serum creatinine.
  5. Patients clinically suspected of suffering from urea cycle disorders will be excluded.
  6. Patients with history of seizure disorders and/or those already receiving valproic acid will be excluded.
  7. Sensitive to or have ever had an allergic reaction to Depakote.
  8. Not able to abstain from alcohol during the length of the study.
  9. Pregnancy. Female adults and adolescents who have attained menarche 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, or long acting progestin agents) if sexually active during the study and for 3 months after the last dose of valproic acid.
  10. Lactating mothers who are breast feeding their babies will not be eligible.
  11. ALPS patients who have been treated with bone marrow toxic chemotherapy regimens for Non-Hodgkin's lymphoma or other malignancies are not eligible for this pilot study.
  12. 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 will be an exclusion criteria.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00605657

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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Koneti Rao
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Principal Investigator: Koneti Rao, MD DIR, NIAID, NIH
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Responsible Party: Koneti Rao, Staff physician, National Institute of Allergy and Infectious Diseases (NIAID) Identifier: NCT00605657    
Other Study ID Numbers: 080053
08-I-0053 ( Other Grant/Funding Number: DIR NIAID )
First Posted: January 31, 2008    Key Record Dates
Results First Posted: March 21, 2013
Last Update Posted: March 21, 2013
Last Verified: February 2013
Keywords provided by Koneti Rao, National Institute of Allergy and Infectious Diseases (NIAID):
Valproic Acid
Histone Deacytelase (HDAC) Inhibitor
Autoimmune Lymphoproliferative Syndrome
Additional relevant MeSH terms:
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Autoimmune Lymphoproliferative Syndrome
Lymphatic Diseases
Lymphoproliferative Disorders
Genetic Diseases, Inborn
Autoimmune Diseases
Immune System Diseases
Immunoproliferative Disorders
Splenic Diseases
Valproic Acid
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs