ALPSPhase 1/2NCT00605657
Valproic Acid (Depakote[Registered Trademark]) to Treat Autoimmune Lymphoproliferative Syndrome (ALPS)
A Phase 1/2 study testing Valproic Acid, CT Scan and Blood Sample in people with ALPS and Hypersplenism, run by Koneti Rao at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 2 to 70 years
- Conditions the study is for
- ALPS, Hypersplenism, Lymphadenopathy
- What is being tested?
- Valproic Acid, CT Scan and Blood Sample
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2008to Sep 2011
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 2 to 70 years
- 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 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.
- 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.
Who cannot join
- 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.
Show all 12Show fewer
- 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.
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Pilot (Phase I-II) Study of Valproic Acid (Depakote) for the Treatment of the Autoimmune Lymphoproliferative Syndrome (ALPS)
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.
Read more
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.
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 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.
- Conditions
- ALPS, Hypersplenism, Lymphadenopathy
- Being tested
- Valproic Acid, CT Scan, Blood Sample
- Keywords
- ALPS, Valproic Acid, Lymphadenopathy, Splenomegaly, Histone Deacytelase (HDAC) Inhibitor, Autoimmune Lymphoproliferative Syndrome
- Medical subject headings
- Hypersplenism, Lymphadenopathy, Splenomegaly, Autoimmune Lymphoproliferative Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Valproic AcidDrug
Also called Depakote
Oral administration of valproic acid
CT ScanProcedure or surgery
Also called Computerized Tomography
CT scans were done before and after treating the patient with valproic acid
Blood SampleProcedure or surgery
Blood samples were collected before and after the intervention to monitor blood counts and biomarkers of ALPS
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Valproic Acid; Procedure: CT Scan; Procedure: Blood Sample |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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)
Measured: 3 monthly (12 week) intervals
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Jan 2008 (estimated)
- Study startJan 2008
- Primary completionSep 2011
- Study completionSep 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for ALPSStudies of the same condition, open and under way.
- 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 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Koneti Rao
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor-investigator, Koneti Rao, National Institute of Allergy and Infectious Diseases (NIAID)
- Investigators
- Koneti Rao, MD, Principal investigator, DIR, NIAID, NIH
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00605657
- Sponsor's protocol ID
- 080053
- Other IDs
- 08-I-0053
- Status last verified
- Feb 2013
- First submitted
- 15 Jan 2008
- Last updated
- 21 Mar 2013
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
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.
PubMed 1386609Rao VK, Straus SE. Causes and consequences of the autoimmune lymphoproliferative syndrome. Hematology. 2006 Feb;11(1):15-23. doi: 10.1080/10245330500329094.
PubMed 16522544Rao 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.
PubMed 16432855
Study at a glance
From the registry record, last updated by the sponsor on 21 Mar 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot (Phase I-II) Study of Valproic Acid (Depakote) for the Treatment of the Autoimmune Lymphoproliferative Syndrome (ALPS)
- ClinicalTrials.gov ID
- NCT00605657
- Acronym / sponsor ID
- 080053
- Conditions
- ALPS, Hypersplenism, Lymphadenopathy
- Keywords
- ALPS, Valproic Acid, Lymphadenopathy, Splenomegaly, Histone Deacytelase (HDAC) Inhibitor, Autoimmune Lymphoproliferative Syndrome
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Koneti RaoUS National Institutes of Health
- Study start
- Jan 2008
- Primary completion
- Sep 2011 (actual)
- Study completion
- Sep 2011 (actual)
- First posted
- 31 Jan 2008 (estimated)
- Results
- Posted 21 Mar 2013
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 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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Valproic acid | Experimental | Drug: Valproic Acid, Procedure: CT Scan, Procedure: Blood SampleSingle 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. |
Who may qualify
- Ages
- 2 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
Key exclusion criteria (12 listed)
- 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.
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 |
|---|---|---|
| Valproic AcidAlso: DepakoteOral administration of valproic acid | Drug | Valproic acid |
| CT ScanAlso: Computerized TomographyCT scans were done before and after treating the patient with valproic acid | Procedure or surgery | Valproic acid |
| Blood SampleBlood samples were collected before and after the intervention to monitor blood counts and biomarkers of ALPS | Procedure or surgery | Valproic acid |
Primary outcome
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.
1 secondary outcome
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Mar 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 1386609Sneller 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.
- Background: PubMed 16522544Rao VK, Straus SE. Causes and consequences of the autoimmune lymphoproliferative syndrome. Hematology. 2006 Feb;11(1):15-23. doi: 10.1080/10245330500329094.
- Background: PubMed 16432855Rao 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.
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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.
Koneti Rao, MD principal investigator
DIR, NIAID, NIH
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Valproic Acid, CT Scan and Blood Sample in people with ALPS and Hypersplenism, run by Koneti Rao 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 21 Mar 2013. 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 combined 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.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 21 Mar 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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.
What does the primary outcome measure?
Number of Participants With Response (time frame: 3 monthly (12 week) intervals). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00605657, 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 21 Mar 2013.