Rituximab-pvvr and Abatacept vs Rituximab-pvvr Alone in New Onset Type 1 Diabetes

Study Overview
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Brief Summary
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The study is a two-arm, multicenter, double-blinded clinical trial testing sequential therapy with rituximab-pvvr followed by abatacept versus rituximab-pvvr alone in new onset T1D. The primary objective is to test whether the C-peptide response to a 2-hour mixed meal tolerance test, 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.

Detailed Description
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This 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 T1D to determine whether rituximab-pvvr followed by abatacept results in an improvement in the AUC C-Peptide during a MMTT compared to Rituximab-pvvr alone at 24 months. Additional aims will compare the safety, tolerability in the two treatment arms as well as other clinical metabolic measures: exogenous insulin use, hemoglobin A1c, time in range from continuous glucose monitors, and severe hypoglycemia. Exploratory studies will assess changes in immune markers.

Official Title
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Rituximab-pvvr and Abatacept vs Rituximab-pvvr Alone in New Onset Type 1 Diabetes

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Rituximab-pvvr
* Drug: Abatacept
* Drug: Sterile Sodium Chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Must be willing to provide informed consent or assent with a parent or legal guardian providing informed consent if < 18 years of age. 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 mixed-meal tolerance test (MMTT) conducted at least 21 days after the diagnosis of diabetes. Enrollees must be willing to comply with intensive diabetes management. Body weight must be ≥ 20.0 kg for study agent administration. Subjects 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. Female participants with reproductive potential who are sexually active will be instructed to use a highly effective contraceptive method until one year after the last dose of rituximab-pvvr. 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. The following additional inclusion criteria regarding vaccines must be met: More than 4 weeks from immunization with a live viral vaccine Be up to date on all recommended vaccinations based on age of subject* Receive non-live influenza vaccination at least 2 weeks prior to randomization when vaccine for the current or upcoming flu season is available Up to date, including eligible boosters as indicated for COVID-19 with an authorized non-live COVID-19 vaccination at least two weeks prior to randomization. Willingness to forgo vaccines (other than killed influenza) during the 6 months after the rituximab-pvvr treatment period Participants must be willing to practice public health prevention measures such as social distancing, masking, and good hand hygiene, and/or receive therapeutics such as monoclonal antibodies and antivirals as directed by the study and recommended by local health authorities to prevent SARS-Cov-2 infection. Willing to wear a continuous glucose monitoring device for a minimum of 10 days every 6 months * Adult subjects must be fully immunized. Pediatric subjects who have not completed their primary vaccination schedule must receive all vaccinations allowable per local public health immunization guidelines for their current age prior to study drug delivery. Any remaining vaccinations should be given and continue per the schedule at least 6 months after rituximab-pvvr is administered. Exclusion Criteria: One or more screening laboratory values as stated: 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 Bilirubin ≥ 1.5 times upper limit of normal 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 active signs or symptoms of acute infection at the time of randomization. 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 or Hepatitis B or active Hepatitis C infection. Be currently pregnant, lactating or anticipate pregnancy within 14 weeks of the last study drug administration (Visit 15). Chronic use of oral or inhaled steroids or other immunosuppressive agents. Known and untreated hypothyroidism or active Graves' disease at randomization. History of malignancy. Prior treatment with active study agent from a previous clinical trial. Any laboratory abnormality or condition that, in the opinion of the investigator, would interfere with the study conduct or the safety of the participant.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This protocol will enroll 74 participants who will be 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. Rituximab-pvvr will be given by IV infusion over a 3-8 hour period, at a dose of 375mg/m2 on four visits each one week apart, starting at Week 0 of the study. Abatacept/placebo will be given by a subcutaneous formulation weekly for 20 months, beginning at Week 16 (Month 4) of the study. Dosing will be determined by weight: Up to 25 kg: 50 mg (0.4 mL); 25 to <50 kg receive 87.5 mg (0.7 mL), and > 50 kg receive 125 mg (1.0 mL).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab-pvvr followed by Abatacept<br>Rituximab-pvvr will be given by IV infusion over a 3-8 hour period, at a dose of 375mg/m2 on four visits each one week apart, starting at Week 0 of the study. Abatacept will be given by a subcutaneous formulation weekly for 20 months, beginning at Week 16 (Month 4) of the study. Dosing will be determined by weight: Up to 25 kg: 50 mg (0.4 mL); 25 to <50 kg receive 87.5 mg (0.7 mL), and > 50 kg receive 125 mg (1.0 mL). | Drug: Rituximab-pvvr<br>* All participants will receive Rituximab-pvvr dosing from Week 1 to Week 4 of the trial. Rituximab-pvvr will be given by IV infusion over a 3-8 hour period, at a dose of 375mg/m2 on four visits each one week apart.<br>* Other names: Ruxience;Drug: Abatacept<br>* Participants in the active drug arm will receive initial Abatacept dosing at Week 16 of trial. Abatacept will be given by a subcutaneous (SC) formulation weekly for 20 months, and dosing be will determined according to weight: Up to 25 kg: 50 mg (0.4 mL); 25 to <50 kg receive 87.5 mg (0.7 mL), and > 50 kg receive 125 mg (1.0 mL).<br>* Other names: Orencia;|
| Placebo Comparator: Rituximab-pvvr followed by Placebo<br>Rituximab-pvvr will be given by IV infusion over a 3-8 hour period, at a dose of 375mg/m2 on four visits each one week apart, starting at Week 0 of the study. Placebo will be given by a subcutaneous isotonic saline formulation weekly for 20 months, beginning at Week 16 (Month 4) of the study. Dosing will be match to active comparator, determined by weight: Up to 25 kg: 0.4 mL; 25 to <50 kg rec 0.7 mL, and > 50 kg receive 1.0 mL. | Drug: Rituximab-pvvr<br>* All participants will receive Rituximab-pvvr dosing from Week 1 to Week 4 of the trial. Rituximab-pvvr will be given by IV infusion over a 3-8 hour period, at a dose of 375mg/m2 on four visits each one week apart.<br>* Other names: Ruxience;Drug: Sterile Sodium Chloride<br>* Participants in the placebo arm will receive initial placebo injection at Week 16 of trial. Saline Placebo will be given by a subcutaneous (SC) formulation weekly for 20 months, and dosing volume be will determined according to weight to match active comparator: Up to 25 kg: 0.4 mL; 25 to <50 kg receive 0.7 mL and > 50 kg receive 1.0 mL.<br>* Other names: 0.9% Sodium Chloride Water for Injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C-Peptide Response to 2-hr MMTT at 24 months post-randomization | The primary objective is to test whether the C-peptide response to a 2-hour mixed meal tolerance test, will be improved in participants with new onset T1D who are treated with Abatacept after Rituximab compared to those participants treated with Rituximab and placebo 24 months after enrollment. | 48-months from Day 0 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C-peptide AUC Means | C-peptide AUC Mean at 0, 6, 12, 18, 24, 30, 36, 42 and 48 months using the ANCOVA model. | Day 0 and every 6 months to trial end (up to 4 years) | 
| Analysis of changes in immune responses to known diabetes antigens and a neoantigen over time by treatment group | Analysis of changes in immune responses to known diabetes antigens and a neoantigen. The investigators will compare the effects of drug treatments on the titers of autoantibodies: anti-insulin, anti-GAD65, anti-IA-2, anti-ZnT8. The investigators will also compare the effects of drug treatments on the response to Keyhole Limpet Hemocyanin (KLH) for which standardized immunological responses have been characterized. | Day 0, month 2, 4, 5, 6, 12, 13, 18, 24, 25, 30, and 36 |