This study is a two-arm, double-blind, multicenter clinical trial testing sequential therapy with rituximab-pvvr followed by abatacept versus rituximab-pvvr alone in individuals with new onset type 1 diabetes (T1D) to determine whether rituximab-pvvr followed by abatacept results in an improvement in the area under the curve (AUC) C-peptide during a mixed meal tolerance test (MMTT) compared to rituximab-pvvr alone at 24 months.

Additional aims compare the safety and tolerability in the two treatment arms as well as other clinical metabolic measures such as exogenous insulin use, hemoglobin A1c, time in range from continuous glucose monitors, and severe hypoglycemia. Participants are treated with a course of rituximab-pvvr (weekly infusion for 4 weeks), followed by treatment with abatacept or placebo starting at 4 months after initial rituximab-pvvr treatment and continuing to month 24. The abatacept/placebo treatment will be self-administered by participants (or their families/guardians, where most appropriate, particularly with pediatric participants) weekly for 20 months.

The primary objective is to test whether the C-peptide response to a 2-hour MMTT will be improved in participants with new onset T1D who are treated with abatacept after rituximab-pvvr compared to those treated with rituximab-pvvr and placebo 24 months after enrollment.

Secondary objectives include the safety and tolerability of the regimens, and the impact on additional metabolic measures, including changes of either study arm relative to historical controls, insulin use and hemoglobin A1c levels, and effects of drug therapy on responses to a neoantigen (keyhole limpet hemocyanin (KLH) immunization). In addition, other metabolic and immunologic measures will be performed as exploratory studies.

The primary outcome measure for each participant is the area under the stimulated C-peptide curve (AUC) over the first 2 hours of a MMTT conducted at the 2-year visit. Additional analyses of the primary outcome include C-peptide AUC means and longitudinal analysis at 0, 6, 12, 18, 24, 30, 36, 42, and 48 months, total daily insulin use, and treatment interactions with covariates such as baseline C-peptide, sex, and age at randomization. Other variables to be tested for treatment interactions are baseline HbA1c levels, HLA, other genotype and immune phenotypes, and race/ethnicity, as appropriate.

Secondary outcome measures include assessment of HbA1c over time by treatment group, insulin dose over time by treatment group, adverse events, hypoglycemia, continuous glucose monitoring data, and changes in immune responses to known diabetes antigens and the KLH neoantigen.

• Age ≥ 8 and ≤ 45 years old at time of signing informed consent
• Fulfill the ADA criteria for diagnosis of T1D within 100 days of randomization
• Positive for at least one islet cell autoantibody: GAD65A, mIAA (if obtained within 10 days of the onset of insulin therapy), IA-2A, ICA, or ZnT8A
• Must have stimulated C-peptide of ≥ 0.2 pmol/mL measured during MMTT conducted at least 21 days after diabetes diagnosis
• Enrollees must be willing to comply with intensive diabetes management
• Body weight must be ≥ 20.0 kg for study agent administration
• Participants who are CMV and/or EBV seronegative at screening must be CMV and/or EBV PCR negative and may not have had signs or symptoms of a CMV and/or EBV compatible illness prior to randomization
• Female participants with reproductive potential must have a negative pregnancy test at screening and be willing to avoid pregnancy for the duration of treatment and until 3 months after the last dose of abatacept
• Male participants of reproductive age must use an adequate contraceptive method for the duration of rituximab-pvvr treatment and 12 months following the last dose of rituximab-pvvr
• More than 4 weeks from immunization with a live viral vaccine
• Receive non-live influenza vaccination at least 2 weeks prior to randomization when vaccine for the current or upcoming flu season is available
• Willingness to forgo vaccines (other than killed influenza or COVID-19) during the 6 months after the rituximab-pvvr treatment period
• Willing to wear a continuous glucose monitoring device for a minimum of 10 days every 6 months

• One or more screening laboratory values: leukocytes < 3,000/μL, neutrophils < 1,500/μL, lymphocytes < 800/μL, platelets < 100,000/μL, hemoglobin < 6.2 mmol/L (10.0 g/dL), potassium > 5.5 mmol/L or < 3.0 mmol/L, sodium > 150 mmol/L or < 130 mmol/L, AST or ALT ≥ 2.5 times the upper limits of normal, or total bilirubin ≥ 1.5 times upper limit of normal (except in the case of Gilbert’s disease)
• History of immune deficiency
• Current or ongoing use of non-insulin pharmaceuticals that affect glycemic control within 7 days of screening visit
• Chronic active infection other than localized skin infections
• Have IgG and/or IgM levels below the normal reference ranges
• Positive PPD, interferon gamma release assay (IGRA), or history of previous treatment for TB
• Vaccination with a live virus within 4 weeks prior to initiating study treatment
• A history of confirmed infectious mononucleosis within the 3 months prior to initiating study treatment, as documented by EBV serology (EBV VCA-IgM and VCA-IgG; PCR would be confirmatory)
• Laboratory evidence of current or past HIV, Hepatitis B, or active Hepatitis C infection
• Currently pregnant, lactating, or anticipating pregnancy within 14 weeks of the last study drug administration
• Chronic use of oral or inhaled steroids or other immunosuppressive agents
• Known and untreated hypothyroidism or active Graves’ disease at randomization
• Prior treatment with active study agent from a previous T1D clinical trial
• Have had previous clinical use of Tzield (Teplizumab) not part of a T1D treatment study

This study is ongoing.