Antibody Treatment for Advanced Celiac Disease
- - Celiac disease is a condition where the immune system attacks the cells of the small intestine.
- - To see if antibody therapy is a safe and effective treatment for celiac disease that has not responded to standard treatments.
- - Individuals at least 18 years of age who have been on a gluten-free diet for 6 to 12 months but still have symptoms of celiac disease.
- - Participants will be screened with a physical exam and medical history.
- - Before the start of the study, participants will have a biopsy of the small intestine.
- - Participants will receive three doses of the study antibody as injections.
- - Treatment will be monitored with blood tests and heart function tests.
Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms
An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.
An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.
Searching Both is inclusive of interventional and observational studies.
|Eligible Ages||18 Years and Over|
- - INCLUSION CRITERIA 2.1.
- - Total white blood cell count (WBC) <300/mm(3) - Platelet count <85,000/mm(3) - INR greater than or equal to 1.5 - Serum creatinine level > 1.5 mg/dL - Serum alanine transaminase, aspartate transaminase or creatinine kinase > 2 x the upper limits of normal 2.1.
This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.
Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.
Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.
Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.
Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.
|National Cancer Institute (NCI)|
The person who is responsible for the scientific and technical direction of the entire clinical study.
|Thomas A Waldmann, M.D.|
|Principal Investigator Affiliation||National Cancer Institute (NCI)|
Category of organization(s) involved as sponsor (and collaborator) supporting the trial.
The disease, disorder, syndrome, illness, or injury that is being studied.
|Celiac Disease, Celiac Sprue, Gluten Enteropathy, Gluten-Sensitive Enteropathy|
- - Celiac disease is a complex inflammatory disorder with an autoimmune component characterized by a dramatic expansion of intraepithelial cytotoxic T lymphocytes that usually regress on a gluten-free diet.
- - It is estimated that approximately 10% of patients become refractory on a gluten-free diet.
- - A subgroup of refractory celiac disease is characterized by expansion of a highly oligoclonal intraepithelial T-lymphocyte population that exhibits a high risk of developing enteropathy associated T-cell lymphoma (EATL).
- - There is presently no effective therapy for refractory celiac disease.
- - A number of studies indicate that intestinal epithelial derived IL-15 plays a critical role in the disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis that characterizes refractory celiac disease.
- - A pivotal role for IL-15 in refractory celiac disease and EATL is further supported by the finding that in two murine models of celiac disease the pathognomonic features were reversed completely by administration of an antibody to CD122 (IL-2/IL-15R beta) that blocks IL-15 transpresentation and action.
- - A Phase I clinical trial in patients with T-cell LGL and hematocytopenia using the monoclonal antibody, Hu-Mik-Beta-1 that blocks IL-15 action produced under cGMP conditions by the BDP NCI has been completed in the Metabolism Branch, NCI at the Clinical Center NIH.
- - Phase I trial to define the safety of Hu-Mik-Beta-1 infusions to 2 groups of patients each with refractory celiac disease at escalating 0.5 (7 patients) and 1.0 (2 patients) mg/kg doses.
- - To define the clinical efficacy of Hu-Mik-Beta-1 infusions in 9 patients with refractory celiac disease and to correlate these findings with celiac disease specific tests.
- - Definition of the receptor saturation capacity on CD122 (IL-2/IL-15R beta) of intravenously administered Hu-Mik-Beta-1 administered at 0.5 and 1.0 mg/kg body weight to 2 groups of patients on three occasions separated by 3 weeks in patients with refractory celiac disease.
- - Determine the immunogenicity of intravenously administered Hu-Mik-Beta-1.
- - Determine the effects of Hu-Mik-Beta-1 on the phenotype and the state of activation of the elements of the cellular immune system in the circulation and in intestinal biopsies with special focus on the cells implicated in the pathogenesis of celiac disease.
- - Patients with refractory celiac disease (RCD) defined by the following internationally accepted criteria: persistent or recurrent symptoms (diarrhea, weight loss, and abdominal pain) associated with intestinal damage characterized by partial to total villous atrophy with intraepithelial lymphocytes (defined by >25 intraepithelial lymphocytes per 100 epithelial cells) despite strict adherence to a gluten-free diet for 6-12 months.
- - Lack of antibodies to Hu-Mik-Beta-1.
- - Patients are not to have circulating antibodies to tissue transglutaminase that are greater than 10 assay units using recombinant human transglutaminase antibodies.
- - Patients will be enrolled and treated at the Mayo Clinic with the University of Chicago and the Clinical Center at the NIH involved as laboratory sites.
- - In this phase I trial initial patients are enrolled to receive 0.5 mg/kg of Hu-Mik-Beta-1 (3 patients).
- - At the completion of Week 9, the safety data are reviewed by the Principal Investigator and DSMB.
- - Modification: Three subjects completed study dosing with 0.5mg/kg without serious adverse events.
- - At specific points in time the following cardiac tests/studies are obtained, the results reviewed prior to subsequent doses (at week 3 and week 6): i.
- - FACS of peripheral blood mononuclear cells and peroral intestinal biopsies for expression of NKG2D, CD94, NKG2C, NKG2A, NKb44, NKb30, CD158 and granzyme.
- - Immune profiling on intestinal biopsies performed on the first infusion and one week + or -3 days following the third infusion to analyze for CD8 T-cells, TCR gamma rearrangements by multiplex PCR and fluorescence analysis of CD8 and CD3 expression, high-resolution PCR expression for immunoglobulin gene rearrangement and for IEL, ERK and JNK phosphorylation reflecting abnormal IEL activation.
- - Furthermore, IL-15, IL-15R alpha and interferon alpha expression will be assayed in the cells of the intestinal biopsy and in the serum.
- - FACS of PBMCs with Hu-Mik-Beta-1 and Hu-Mik-Beta-3 to define saturation of CD122 (IL2/IL-15R beta).
- - Complete clinical response and by clinical biochemical results at the 20-week time point.
- - Secondary partial response, duration of response, toxicities, immunogenicity of Hu-Mik-Beta- 1.
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