IgA DeficiencyPhase 1NCT00024934
B-Lymphocyte Stimulator (BLyS) To Treat Selective IgA Deficiency
A Phase 1 study testing B-Lymphocyte Stimulator (BLyS) in people with IgA Deficiency, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
This study will examine the safety of BlyS, an experimental drug being developed to treat immune deficiency. As of July 17, 2001, 7 persons with common variable immune deficiency (CVID) have received BlyS, with no problems reported. This study will test the safety of the drug in people with IgA deficiency. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- IgA Deficiency
- What is being tested?
- B-Lymphocyte Stimulator (BLyS)
- How many people
- 20 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2001to Aug 2004
- 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
- Eligible subjects must meet the diagnostic criteria for IgA deficiency as defined by WHO or PAGID/ESID (Conley, 1999).
- Diagnosis of IgA-D with recurrent or chronic sinopulmonary infection or chronic diarrhea/malabsorption.
- Serum IgA at least 2 standard deviations below the mean at screening.
- Eligible patients will be at least 18 years of age.
- Liver function tests (SGOT, SGPT, alkaline phosphatase, total bilirubin) within 1.25 x upper limit of normal.
- Serum creatinine within normal limits.
- Patients must be able to understand and sign an informed consent form.
Who cannot join
- A history of malignancy (other than adequately treated in situ carcinoma or non-melanotic skin cancer).
- Active clinically-significant autoimmune manifestations within 2 years of study entry; any history of IgA nephropathy or Henoch-Schonlein purpura.
- Pre-existing renal disease; proteinuria greater than trace at screening.
- Symptomatic cardiac disease (greater than grade 1 NCI CTC) at screening. Patients with adequately treated well-controlled hypertension or minor arrythmias are eligible.
- Pulmonary disease requiring treatment, bronchiectasis on baseline chest x-ray or FEV1 less than 75% normal limits at baseline evaluation. Patients with adequately treated well-controlled asthma are eligible.
- Splenomegaly associated with cytopenias.
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- Significant cytopenias: Anemia (Hct less than 30%); Neutropenia (ANC less than 1500/microL); Thrombocytopenia (Platelets less than 75,000/mm(3)).
- Biopsy-proven granulomatous disease.
- B-lymphocyte count at screening less than 50/microL.
- Use immune-based therapies (other than IVIG) such as chronic corticosteroid use, growth factors or other immune-modulating drugs within 4 weeks of screening (inhaled corticosteroids are permitted).
- Pregnant female or nursing mother. (All females of childbearing potential must have had a negative blood or urine pregnancy test at screening. Over the course of the study, all female subjects must have practiced a method of contraception with greater than 90% reliability, or be sterile or postmenopausal.)
- Participation in any clinical trial involving investigational or conventional drugs within 30 days of screening.
- Known active hepatitis (testing not required for study entry).
Trial locations and contacts
1 site in 1 country.
United States1 site
National Cancer Institute (NCI)
Bethesda, Maryland, 20892
About this study
Official title: A Phase I Dose Escalation Study of B-Lymphocyte Stimulator (BLyS) Administered Subcutaneously in Patients With Selective IgA Deficiency
This study will examine the safety of BlyS, an experimental drug being developed to treat immune deficiency. As of July 17, 2001, 7 persons with common variable immune deficiency (CVID) have received BlyS, with no problems reported. This study will test the safety of the drug in people with IgA deficiency.
Patients 18 years of age and older with IgA deficiency who have recurrent or chronic sinus or lung infections or chronic diarrhea or malabsorption may be eligible for this study. Candidates will be screened with a physical examination, blood and urine tests, electrocardiogram (EKG), chest X-ray and a breathing test (spirometry).
Read more
Participants will be divided into five groups of three persons each to receive different doses (0.1, 1, 5, 15 or 45 micrograms/kilogram of body weight) of BlyS. The first group will receive a single dose at the lowest dose level (0.l mg). Each succeeding group will receive a single higher dose following a 2-week observation period of the preceding group. The drug will be injected under the skin, with vital signs (temperature, pulse, blood pressure and breathing rate) monitored for one hour after dosing. Blood samples will be collected several times on the day of dosing (before the dose and at 1.5, 3, 5, 8 and 12 hours after the dose) and again at 1,2, 4, 8 and 12 weeks after the dose to measure BlyS levels and evaluate safety. Participants receiving one of the three higher doses will have additional blood samples collected 36, 48 and 60 hours after the dose. Blood will also be collected from all participants 6 and 12 months after dosing to look for any unexpected long-term effects. A total of 289 ml (1.2 cups) of blood will be collected.
Blood will be checked for changes in blood count, kidney and liver function, antibody levels and autoimmune problems. Saliva will be collected four times by placing a cotton ball in the mouth-once before the dose and three times after the dose-to measure antibody levels.
Urine samples will also be collected during the study.
Read the detailed description
B Lymphocyte Stimulator (BLyS (Trademark)) is a member of the tumor necrosis factor (TNF) superfamily of cytokines that is expressed on peripheral blood monocytes and dendritic cells. Cellular receptors for BLyS are detected on mature immunoglobulin (Ig) expressing B-lymphocytes. In vitro studies show that BLyS increases B cell number, Ig production, antigen-specific immunoglobulin response, and induces production of secretory IgA.
B-cells collected from patients with Common Variable Immune Deficiency show evidence for BLyS binding to B cells and enhanced immunoglobulin secretion.
In 28-day toxicology studies in mice, pharmacological effects were restricted to B lymphoid tissues including B lymphocyte hyperplasia, increased splenic weight without significant increase in spleen size, and increased immunoglobulin production. Murine models suggest that all of the pharmacological effects are fully and rapidly reversible.
The biological profile of BLyS suggests that it may have therapeutic utility in the treatment of immunodeficiency disorders characterized by low or absent immunoglobulin such as selective IgA deficiency (IGA-D).
Risk that BLyS might contribute to IGA-D complications has been assessed. A series of special in vitro and short-term in vivo studies have shown BLyS does not enhance tumorigenicity or allergy/hypersensitivity. Enhanced autoimmunity with immune complex formation could not be ruled out in two mouse studies in which BLyS was administered at higher doses on multiple dosing schedules. Renal changes with glomerular protein deposits were noted in a subset of mice treated at 0.1 and 1.0 mg/kg in the first study and 0.3 and 3.0 mg/kg in the second study. Renal changes have not been reproducible in either of 2 repeat mouse studies designed to replicate conditions on the first study. Renal changes were not observed in the GLP toxicity study in which mice were treated for 4 weeks with BLyS followed by a 2-week recovery period, or in an exploratory monkey study.
This study is a phase I; single-dose, open-label, non-randomized, dose escalation study of BLyS administered subcutaneously to a total of 20 evaluable subjects with IgA-D. Each subject will receive a single dose of BLyS.
The proposed study consists of a screening phase, a 1-day treatment phase with pharmacokinetic sampling, day 2 and day 3 follow-up, and 1, 2, 4, 8, and 12-week acute safety evaluations. Dose escalation to the next cohort is dependent on results of the 2-week acute safety evaluation. Autoimmunity and interim infection history will be evaluated 4-6 weeks and 6 and 12 months. Long-term data will be collected on incidence of malignancy for a minimum of one year.
- Conditions
- IgA Deficiency
- Being tested
- B-Lymphocyte Stimulator (BLyS)
- Keywords
- Immunodeficiency, Primary, Cancer, Genetics, IGA Deficiency, Immune Deficiency
- Medical subject headings
- IgA Deficiency, Immunologic Deficiency Syndromes, Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
B-Lymphocyte Stimulator (BLyS)Drug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Oct 2001 (estimated)
- Study startOct 2001
- Study completionAug 2004
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for IgA DeficiencyStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)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
- 20 participants
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00024934
- Sponsor's protocol ID
- 020009
- Other IDs
- 02-C-0009
- Status last verified
- Sep 2016
- First submitted
- 9 Oct 2001
- Last updated
- 22 Sep 2016
- Results posted
- No
Study at a glance
From the registry record, last updated by the sponsor on 22 Sep 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Dose Escalation Study of B-Lymphocyte Stimulator (BLyS) Administered Subcutaneously in Patients With Selective IgA Deficiency
- ClinicalTrials.gov ID
- NCT00024934
- Acronym / sponsor ID
- 020009
- Conditions
- IgA Deficiency
- Keywords
- Immunodeficiency, Primary, Cancer, Genetics, IGA Deficiency, Immune Deficiency
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- Oct 2001
- Study completion
- Aug 2004
- First posted
- 10 Oct 2001 (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 the safety of BlyS, an experimental drug being developed to treat immune deficiency. As of July 17, 2001, 7 persons with common variable immune deficiency (CVID) have received BlyS, with no problems reported. This study will test the safety of the drug in people with IgA deficiency.
Patients 18 years of age and older with IgA deficiency who have recurrent or chronic sinus or lung infections or chronic diarrhea or malabsorption may be eligible for this study. Candidates will be screened with a physical examination, blood and urine tests, electrocardiogram (EKG), chest X-ray and a breathing test (spirometry).
Participants will be divided into five groups of three persons each to receive different doses (0.1, 1, 5, 15 or 45 micrograms/kilogram of body weight) of BlyS. The first group will receive a single dose at the lowest dose level (0.l mg). Each succeeding group will receive a single higher dose following a 2-week observation period of the preceding group. The drug will be injected under the skin, with vital signs (temperature, pulse, blood pressure and breathing rate) monitored for one hour after dosing. Blood samples will be collected several times on the day of dosing (before the dose and at 1.5, 3, 5, 8 and 12 hours after the dose) and again at 1,2, 4, 8 and 12 weeks after the dose to measure BlyS levels and evaluate safety. Participants receiving one of the three higher doses will have additional blood samples collected 36, 48 and 60 hours after the dose. Blood will also be collected from all participants 6 and 12 months after dosing to look for any unexpected long-term effects. A total of 289 ml (1.2 cups) of blood will be collected.
Blood will be checked for changes in blood count, kidney and liver function, antibody levels and autoimmune problems. Saliva will be collected four times by placing a cotton ball in the mouth-once before the dose and three times after the dose-to measure antibody levels.
Urine samples will also be collected during the study.
Detailed description
B Lymphocyte Stimulator (BLyS (Trademark)) is a member of the tumor necrosis factor (TNF) superfamily of cytokines that is expressed on peripheral blood monocytes and dendritic cells. Cellular receptors for BLyS are detected on mature immunoglobulin (Ig) expressing B-lymphocytes. In vitro studies show that BLyS increases B cell number, Ig production, antigen-specific immunoglobulin response, and induces production of secretory IgA.
B-cells collected from patients with Common Variable Immune Deficiency show evidence for BLyS binding to B cells and enhanced immunoglobulin secretion.
In 28-day toxicology studies in mice, pharmacological effects were restricted to B lymphoid tissues including B lymphocyte hyperplasia, increased splenic weight without significant increase in spleen size, and increased immunoglobulin production. Murine models suggest that all of the pharmacological effects are fully and rapidly reversible.
The biological profile of BLyS suggests that it may have therapeutic utility in the treatment of immunodeficiency disorders characterized by low or absent immunoglobulin such as selective IgA deficiency (IGA-D).
Risk that BLyS might contribute to IGA-D complications has been assessed. A series of special in vitro and short-term in vivo studies have shown BLyS does not enhance tumorigenicity or allergy/hypersensitivity. Enhanced autoimmunity with immune complex formation could not be ruled out in two mouse studies in which BLyS was administered at higher doses on multiple dosing schedules. Renal changes with glomerular protein deposits were noted in a subset of mice treated at 0.1 and 1.0 mg/kg in the first study and 0.3 and 3.0 mg/kg in the second study. Renal changes have not been reproducible in either of 2 repeat mouse studies designed to replicate conditions on the first study. Renal changes were not observed in the GLP toxicity study in which mice were treated for 4 weeks with BLyS followed by a 2-week recovery period, or in an exploratory monkey study.
This study is a phase I; single-dose, open-label, non-randomized, dose escalation study of BLyS administered subcutaneously to a total of 20 evaluable subjects with IgA-D. Each subject will receive a single dose of BLyS.
The proposed study consists of a screening phase, a 1-day treatment phase with pharmacokinetic sampling, day 2 and day 3 follow-up, and 1, 2, 4, 8, and 12-week acute safety evaluations. Dose escalation to the next cohort is dependent on results of the 2-week acute safety evaluation. Autoimmunity and interim infection history will be evaluated 4-6 weeks and 6 and 12 months. Long-term data will be collected on incidence of malignancy for a minimum of one year.
Study design
- Primary purpose
- Treatment
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (7 listed)
- Eligible subjects must meet the diagnostic criteria for IgA deficiency as defined by WHO or PAGID/ESID (Conley, 1999).
- Diagnosis of IgA-D with recurrent or chronic sinopulmonary infection or chronic diarrhea/malabsorption.
- Serum IgA at least 2 standard deviations below the mean at screening.
- Eligible patients will be at least 18 years of age.
- Liver function tests (SGOT, SGPT, alkaline phosphatase, total bilirubin) within 1.25 x upper limit of normal.
Key exclusion criteria (13 listed)
- A history of malignancy (other than adequately treated in situ carcinoma or non-melanotic skin cancer).
- Active clinically-significant autoimmune manifestations within 2 years of study entry; any history of IgA nephropathy or Henoch-Schonlein purpura.
- Pre-existing renal disease; proteinuria greater than trace at screening.
- Symptomatic cardiac disease (greater than grade 1 NCI CTC) at screening. Patients with adequately treated well-controlled hypertension or minor arrythmias are eligible.
- Pulmonary disease requiring treatment, bronchiectasis on baseline chest x-ray or FEV1 less than 75% normal limits at baseline evaluation. Patients with adequately treated well-controlled asthma are eligible.
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 |
|---|---|---|
| B-Lymphocyte Stimulator (BLyS) | 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 22 Sep 2016.
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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 B-Lymphocyte Stimulator (BLyS) in people with IgA Deficiency, run by National Cancer Institute (NCI) 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 7 inclusion and 13 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 22 Sep 2016. 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?
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 22 Sep 2016.