Immune Effects of Vedolizumab With or Without Anti-TNF Pre-treatment in T1D
Immune Effects of Vedolizumab With or Without Anti-TNF Pre-treatment in T1D
The underlying hypothesis is that vedolizumab will modify immune cell trafficking in type 1 diabetes, and that this will be enhanced by pre-treatment with etanercept. This study will determine whether there is mechanistic evidence in support of this hypothesis and provide preliminary information about safety, efficacy, and tolerability of vedolizumab with and without pretreatment with etanercept in adults with type 1 diabetes (T1D)
Vedolizumab directly blocks integrin α4ß7 on circulating immune cells preventing their egress from the blood, while etanercept blocks the TNFα signaling necessary for the α4ß7 cognate addressin MAdCAM-1 to be expressed in pancreatic endothelial cells. For these reasons, the investigators hypothesize that the two agents may synergistically prevent diabetogenic immune cells from trafficking from the periphery to their target tissue to cause islet cell destruction. Cells from both the myeloid (e.g., myeloid DC1 cells and non-classical monocytes) and lymphoid compartments (e.g., diabetes antigen-specific T cells) would be impacted by this therapeutic combination.
Inclusion Criteria:
Males and females 18-45 years of age, inclusive
Diagnosis of T1D between 21 days and 3 years from screening
Positive for at least one diabetes-related autoantibody any time since diagnosis, including but not limited to:
Random (non-fasting) C-peptide or peak MMTT stimulated C-peptide ≥ 0.2 pmol/mL.
Females of child-bearing potential must be willing to use effective birth control from the screening visit through 12 weeks post last dose of study medication.
Up to date for clinically recommended immunizations including COVID-19 and seasonal influenza vaccine at least 3 weeks prior to baseline treatment.
Willing to forgo live vaccines 6 weeks prior to baseline treatment visit until 6 weeks following last treatment visit.
HbA1c ≤ 8.5% at screening
Willing and able to give informed consent for participation
Exclusion Criteria:
History of severe reaction or anaphylaxis to human, humanized or murine monoclonal antibodies
History of malignancy or serious uncontrolled cardiovascular, nervous system, pulmonary, renal, or gastrointestinal disease
History of immunodeficiency
Recent (within 3 months) serious bacterial, viral, fungal, or other infections
Pending or positive SARS-CoV-2 test or symptoms of possible COVID-19 illness at baseline treatment visit.
Serologic evidence of current or past HIV, Hepatitis B, or Hepatitis C.
Positive QuantiFERON or PPD TB test, history of tuberculosis, or active TB infection.
Active infection with EBV as defined by real-time polymerase chain reaction (PCR).
Active infection with CMV as defined by real-time PCR.
Clinically significant liver function abnormalities as defined by ALT or AST> 1.5 x the upper limit of age-determined normal (ULN).
Any of the following hematologic abnormalities:
Females who are pregnant or lactating.
Receipt of live vaccine (e.g., varicella, MMR (measles, mumps and rubella), intranasal influenza vaccine) within 6 weeks of randomization.
Receipt of other vaccines within 3 weeks of baseline treatment.
Receipt of an immune modulating biologic or investigational drug within 3 months or 5 half-lives before screening visit.
Use of non-insulin therapies aimed to control hyperglycemia within 30 days of screening visit.
History of other clinically significant autoimmune disease needing chronic therapy with biologics or steroids with the exception of celiac disease and stable thyroid disease.
Use of medications known to influence glucose tolerance. Topical, nasal, inhaled corticosteroids acceptable per investigator discretion.
Any medical or psychological condition that in the opinion of the principal investigator would interfere with the safe completion of the trial.