Rituximab-pvvr and Abatacept vs Rituximab-pvvr Alone in New Onset Type 1 Diabetes (TN25)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Abatacept; Drug: Sterile Sodium Chloride; Drug: Rituximab-pvvr

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Queensland Children's Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • Walter and Eliza Hall Institute of Medical Research
• United States
  • California
    • Orange, California, United States, 92868
      • Childrens Hospital of Orange County
    • Palo Alto, California, United States, 94304
      • Stanford University
    • San Francisco, California, United States, 94158
      • University of California San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Barbara Davis Center for Childhood Diabetes
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Maimi, Florida, United States, 33136
      • University of Miami
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University - Riley Hospital for Children
  • Kansas
    • Kansas City, Kansas, United States, 64114
      • The Children's Mercy Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • University of Pittsburg
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Sanford Children's Specialty Clinic
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Eskind Diabetes Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern
  • Washington
    • Seattle, Washington, United States, 98101
      • Benaroya Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years and older (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 8 and ≤ 45 years old at time of signing informed consent.
2. Fulfill the ADA criteria for diagnosis of T1D within 100 days of randomization.
3. Must be willing to provide informed consent or assent with a parent or legal guardian providing informed consent if < 18 years of age.
4. 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
5. 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.
6. Enrollees must be willing to comply with intensive diabetes management.
7. Body weight must be ≥ 20.0 kg for study agent administration.
8. 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.
9. 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.
10. 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.

11. The following additional inclusion criteria regarding vaccines must be met:

    1. More than 4 weeks from immunization with a live viral vaccine
    2. Be up to date on all recommended vaccinations based on age of subject*
    3. Receive non-live influenza vaccination at least 2 weeks prior to randomization when vaccine for the current or upcoming flu season is available
    4. Willingness to forgo vaccines (other than killed influenza) during the 6 months after the rituximab-pvvr treatment period
12. 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.

13. Willing to wear a continuous glucose monitoring device for a minimum of 10 days every 6 months

    • Adult participants 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. HPV vaccine may be initiated and/or series completion delayed until after completion of study drug in both adult and pediatric participants. Any remaining vaccinations should be given and continue per the schedule at least 6 months after rituximab-pvvr is administered. For COVID-19 vaccination, all participants will be strongly encouraged to be up-to-date with COVID-19 vaccine(s) as indicated by country-specific guidelines at least 2 weeks prior to randomization.

Exclusion Criteria:

1. One or more screening laboratory values as stated:

   1. Leukocytes <3,000/μL
   2. Neutrophils <1,500/μL
   3. Lymphocytes <800/μL
   4. Platelets <100,000/μL
   5. Hemoglobin <6.2 mmol/L (10.0 g/dL)
   6. Potassium >5.5 mmol/L or <3.0 mmol/L
   7. Sodium >150 mmol/L or <130 mmol/L
   8. AST or ALT ≥ 2.5 times the upper limits of normal
   9. Total bilirubin ≥ 1.5 times upper limit of normal, except in the case of Gilbert's disease
2. History of immune deficiency
3. Current or ongoing use of non-insulin pharmaceuticals that affect glycemic control within 7 days of screening visit.
4. Chronic active infection other than localized skin infections.
5. Have active signs or symptoms of acute infection at the time of randomization.
6. Have IgG and/or IgM levels below the normal reference ranges.
7. Positive PPD, interferon gamma release assay (IGRA) or history of previous treatment for TB.
8. Vaccination with a live virus within 4 weeks prior to initiating study treatment.
9. 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).
10. Laboratory evidence of current or past HIV or Hepatitis B or active Hepatitis C infection.
11. Be currently pregnant, lactating or anticipate pregnancy within 14 weeks of the last study drug administration (Visit 15).
12. Chronic use of oral or inhaled steroids or other immunosuppressive agents.
13. Known and untreated hypothyroidism or active Graves' disease at randomization.
14. History of malignancy.
15. Prior treatment with active study agent from a previous T1D clinical trial.*
16. Have had previous clinical use of Tzield (Teplizumab) not part of a T1D treatment study.

17. Any laboratory abnormality or condition that, in the opinion of the investigator, would interfere with the study conduct or the safety of the participant.

    • Study drug exposure may be reviewed by the TrialNet Eligibility and Events Committee and determination will be made as to whether subjects can be considered eligible for this study based on agent, length of time since exposure, duration of treatment, durability of effect, and potential for lingering immunomodulation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Rituximab-pvvr followed by Abatacept; Rituximab-pvvr will be given by IV infusion over at least 3 hours, 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: Abatacept; 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).; Other Names: Orencia; Drug: Rituximab-pvvr; 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 at least 3 hours, at a dose of 375mg/m2 on four visits each one week apart.; Other Names: Ruxience
Placebo Comparator: Rituximab-pvvr followed by Placebo; Rituximab-pvvr will be given by IV infusion over at least 3 hours, 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: Sterile Sodium Chloride; 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.; Other Names: 0.9% Sodium Chloride Water for Injection; Drug: Rituximab-pvvr; 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 at least 3 hours, at a dose of 375mg/m2 on four visits each one week apart.; Other Names: Ruxience

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: National Institutes of Health (NIH)
• Investigators: Study Chair: Stephen Gitelman, MD, Type 1 Diabetes TrialNet; Study Director: Kevan Herold, MD, Type 1 Diabetes TrialNet Chairman; Study Chair: Daniel Moore, MD, Type 1 Diabetes TrialNet

Publications and helpful links

General Publications

• Ajmal N, Bogart MC, Khan P, Max-Harry IM, Healy AM, Nunemaker CS. Identifying Promising Immunomodulators for Type 1 Diabetes (T1D) and Islet Transplantation. J Diabetes Res. 2024 Dec 20;2024:5151171. doi: 10.1155/jdr/5151171. eCollection 2024.

Helpful Links

• Study Sponsor Website

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2023
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): March 31, 2029

Study Registration Dates

• First Submitted: May 16, 2018
• First Submitted That Met QC Criteria: April 23, 2019
• First Posted (Actual): April 29, 2019

Study Record Updates

• Last Update Posted (Actual): February 19, 2026
• Last Update Submitted That Met QC Criteria: February 17, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 1; Immunoconjugates; Amino Acids, Peptides, and Proteins; Proteins; Therapeutics; Drug Administration Routes; Drug Therapy; Antibodies; Immunoglobulins; Blood Proteins; Serum Globulins; Globulins; Abatacept; Injections
• Other Study ID Numbers: Rituximab-pvvr and Abatacept; UC4DK117009 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes