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

NCT00605657 | Completed Phase 1 Results

• 2 other identifiers: 08005308-I-0053
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

ALPS; Hypersplenism; Lymphadenopathy

Keywords

ALPS; Valproic Acid; Lymphadenopathy; Splenomegaly; Histone Deacytelase (HDAC) Inhibitor; Autoimmune Lymphoproliferative Syndrome

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Response

  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.

  3 monthly (12 week) intervals

Secondary Outcomes (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)

  3 monthly (12 week) intervals

Study Arms (1)

Valproic acid

EXPERIMENTAL

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; Procedure: CT Scan; Procedure: Blood Sample

Interventions

Valproic Acid DRUG

Oral administration of valproic acid

Also known as: Depakote

Valproic acid

CT Scan PROCEDURE

CT scans were done before and after treating the patient with valproic acid

Also known as: Computerized Tomography

Valproic acid

Blood Sample PROCEDURE

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

Valproic acid

Eligibility Criteria

• Age: 2 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Age greater than or equal to 2 years through less than or equal to 70 years.
• Must have a personal primary care physician who is willing to follow the protocol required evaluations during the study period.
• Must be willing to sign a consent form.

You may not qualify if:

• 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.
• Liver disease determined by an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin 2.5 times greater than the upper limit of normal.
• History of pancreatitis by clinical features and/or laboratory abnormalities in the last 12 months.
• 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.
• Patients clinically suspected of suffering from urea cycle disorders will be excluded.
• Patients with history of seizure disorders and/or those already receiving valproic acid will be excluded.
• Sensitive to or have ever had an allergic reaction to Depakote.
• Not able to abstain from alcohol during the length of the study.
• 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.
• 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 Non-Hodgkin's lymphoma or other malignancies are not eligible for this pilot study.

Sponsors & Collaborators

• Koneti Rao: lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Sneller MC, Straus SE, Jaffe ES, Jaffe JS, Fleisher TA, Stetler-Stevenson M, Strober W. A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Invest. 1992 Aug;90(2):334-41. doi: 10.1172/JCI115867.

  PMID: 1386609 BACKGROUND

• Rao VK, Straus SE. Causes and consequences of the autoimmune lymphoproliferative syndrome. Hematology. 2006 Feb;11(1):15-23. doi: 10.1080/10245330500329094.

  PMID: 16522544 BACKGROUND

• Rao VK, Carrasquillo JA, Dale JK, Bacharach SL, Whatley M, Dugan F, Tretler J, Fleisher T, Puck JM, Wilson W, Jaffe ES, Avila N, Chen CC, Straus SE. Fluorodeoxyglucose positron emission tomography (FDG-PET) for monitoring lymphadenopathy in the autoimmune lymphoproliferative syndrome (ALPS). Am J Hematol. 2006 Feb;81(2):81-5. doi: 10.1002/ajh.20523.

  PMID: 16432855 BACKGROUND

MeSH Terms

Conditions

Hypersplenism; Lymphadenopathy; Splenomegaly; Autoimmune Lymphoproliferative Syndrome

Interventions

Valproic Acid; Blood Specimen Collection

Condition Hierarchy (Ancestors)

Splenic Diseases; Lymphatic Diseases; Hemic and Lymphatic Diseases; Hypertrophy; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Lymphoproliferative Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Autoimmune Diseases; Immune System Diseases; Immunoproliferative Disorders

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Results Point of Contact

• Title: V. Koneti Rao, MD
• Organization: NIAID

korao@niaid.nih.gov

301-496-6502

Study Officials

• Koneti Rao, MD

  DIR, NIAID, NIH

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Staff physician

Study Record Dates

• First Submitted: January 15, 2008
• First Posted: January 31, 2008
• Study Start: January 1, 2008
• Primary Completion: September 1, 2011
• Study Completion: September 1, 2011
• Last Updated: March 21, 2013
• Results First Posted: March 21, 2013

Record last verified: 2013-02

Locations

US (1)