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The purpose of this study is to determine whether dendritic cells collected via leukapheresis and incubated with antisense DNA oligonucleotides and then injected back into the same subject will serve as modulators of the immune system in a manner that disrupts the autoimmune process responsible for the destruction of pancreatic beta cells in subjects with new onset type 1 diabetes.
Full description
This is a double-blind, placebo-controlled cross study designed to evaluate the safety and efficacy of autologous immunoregulatory dendritic cells (iDC) in patients with type 1 diabetes. To do this, a total of 24 subjects with recent onset (<100 days from diagnosis) type 1 diabetes will have circulating dendritic cells harvested via leukapheresis. The harvested dendritic cells will then be incubated in vitro with antisense DNA oligonucleotides targeting the primary transcripts of cluster of differentiation antigen 40 (CD40), cluster of differentiation antigen 80 (CD80) and cluster of differentiation antigen 86 (CD86). These engineered dendritic cells will then be given as autologous intradermal injections (4 injections administered at 2 week intervals) in the subject' peri-umbilical region. The hypothesis is that the injected cells will generate immunoregulatory cells that suppress the autoimmune process responsible for the development of type 1 diabetes via destruction of the subject's pancreatic beta cells.
Employing a cross-over design, all subjects will undergo leukapheresis at the outset. Twelve subjects will be randomly assigned to receive cell injections at the outset while the other 12 subjects will receive sham injections and serve as controls. At the end of 12 months, all subjects will cross-over to the alternative treatment and continue to be followed for an additional 12 months. (Note: The subjects assigned to receive the cell therapy for this segment will receive injections of their autologous cells harvested and engineered at the time of the leukapheresis performed at study entry. The engineered cells will be stored frozen until needed for administration. This design will test whether treatment later (>1 year after diagnosis) is as effective as immediate treatment (<100 days from the diagnosis of type 1 diabetes).
As an added safety measure, the first 6 subjects randomized will all be over the age of 18. When the last of these 6 subjects complete 3 months of observation following the initiation of therapy, the age for enrollment will be lowered to age 16 for the next 6 subjects unless safety observations dictate otherwise. When all subjects in this cohort have been enrolled, the age for enrollment will be lowered to age 14 unless advised otherwise by the independent Data Safety Monitoring Board. When all subjects in this cohort have completed observation for 3 months, the age for enrollment will be lowered to age 12 following clearance by the Data Safety Monitoring Board.
If this therapy is successful, the subjects' remaining beta cell mass will be preserved and hopefully expanded once the autoimmune process is slowed or stopped. This outcome will be assessed indirectly using plasma c-peptide concentrations following ingestion of a standardized mixed meal at the end of 12 and 24 months of therapy. If the treatment is successful, glucose control should improve and be detectable via measurement of hemoglobin A1c (measure of long-term control), fasting plasma glucose concentrations and the plasma glucose concentrations following ingestion of the standardized mixed meal. In addition, the total daily insulin requirements should decrease. These measures of glucose control will be assessed at baseline and then at 3, 6, 9, 12, 15, 18, 21 and 24 months.
Immune markers will also be profiled at 3 month intervals to assess potential tolerogenic effects of the therapy. To this end, numbers of potentially tolerogenic/regulatory T-cells, B-cells and dendritic cells in the circulating peripheral blood monocyte population will be assessed. In addition, analysis of selected populations of T-cells, B-cells and dendritic cells will be conducted over the entire study period in an attempt to identify molecular signatures correlated with the clinical response.
Finally, in addition to the routine safety laboratory measurements, all reported adverse events will be examined in detail to characterize the safety aspects of the therapy. The review of these safety data will be guided by an independent Data Safety Monitoring Board which will meet at least semi-annually to review the accrued data.
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Inclusion criteria
Exclusion criteria
History of enrollment in a drug, or biologic therapy clinical trial within past 12 months impacting the immune system
Prior or current therapy known to cause a significant, ongoing change in the course of type 1 diabetes or immune status
Evidence of active infection at screening (e.g. "common cold", influenza, hepatitis, tuberculosis, EBV, cytomegalovirus (CMV), herpes simplex virus (HSV), HIV, varicella, chlamydia, evidence of serious fungal infection) or screening laboratory evidence consistent with active microbial, viral, or fungal infection (minor cutaneous fungal infection is not an exclusion)
Leukopenia (<3,000 leukocytes/microliter, neutropenia (<1,500 neutrophils/microliter), lymphopenia (<800 lymphocytes/microliter) or thrombocytopenia (<125,000 platelets/microliter)
Positive screen for HIV, tuberculosis, hepatitis B, hepatitis C, herpes simplex virus 1 (HSV1) or herpes simplex virus 2 (HSV2) infection
Vaccination with any live vaccine product within the 3 months prior to the first cycle of study agent administration
Female subjects pregnant or unwilling to defer pregnancy for the study period
Females lactating at screening
History of significant heart disease (e.g., myocardial infarction, coronary artery disease, angina pectoris, arrhythmia, uncontrolled hypertension, congestive heart failure, structural defects)
Liver disease with alanine transaminase (ALT) or aspartate aminotransferase (AST) >3 times the upper limit of normal
Impaired renal function with a serum creatinine concentration > 1.5.
Any other significant immune disorder including, but not limited to, rheumatoid arthritis, systemic lupus erythematous, multiple sclerosis, vitiligo, ankylosing spondylitis and celiac disease. (Thyroiditis treated with a stable dose of thyroid replacement therapy is allowed.)
Any condition that interferes with accurate measurement of glycated hemoglobin (hemoglobin A1C)
Any condition that, in the investigator's opinion, may compromise continuous study participation or confound study results
Any planned vaccinations scheduled prior to end of study participation
Chronic treatment with systemic corticosteroids (topical or inhaled corticosteroids are allowed)
Current use of diabetes medications other than insulin
Anticipated need for any of the following therapies during the 24-month study period:
Primary purpose
Allocation
Interventional model
Masking
0 participants in 2 patient groups, including a placebo group
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Central trial contact
Orville G Kolterman, MD
Data sourced from clinicaltrials.gov
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