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

NCT ID: NCT03929601

Last Updated: 2026-02-19

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 74 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-10-30
• Study Completion Date: 2029-03-31

Brief Summary

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

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.

Conditions

Type 1 Diabetes Mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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).

Group Type: ACTIVE_COMPARATOR

Rituximab-pvvr

Intervention Type: DRUG

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.

Abatacept

Intervention Type: DRUG

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).

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.

Group Type: PLACEBO_COMPARATOR

Rituximab-pvvr

Intervention Type: DRUG

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.

Sterile Sodium Chloride

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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).

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Ruxience; Orencia; 0.9% Sodium Chloride Water for Injection

Eligibility Criteria

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 &lt; 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.

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 &lt;3,000/μL

2. Neutrophils &lt;1,500/μL

3. Lymphocytes &lt;800/μL

4. Platelets &lt;100,000/μL

5. Hemoglobin &lt;6.2 mmol/L (10.0 g/dL)

6. Potassium &gt;5.5 mmol/L or &lt;3.0 mmol/L

7. Sodium &gt;150 mmol/L or &lt;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.

• Minimum Eligible Age: 8 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stephen Gitelman, MD

Role: STUDY_CHAIR

Type 1 Diabetes TrialNet

Kevan Herold, MD

Role: STUDY_DIRECTOR

Type 1 Diabetes TrialNet Chairman

Daniel Moore, MD

Role: STUDY_CHAIR

Type 1 Diabetes TrialNet

Locations

Childrens Hospital of Orange County

Orange, California, United States

Stanford University

Palo Alto, California, United States

University of California San Francisco

San Francisco, California, United States

Barbara Davis Center for Childhood Diabetes

Aurora, Colorado, United States

Yale University

New Haven, Connecticut, United States

University of Florida

Gainesville, Florida, United States

University of Miami

Maimi, Florida, United States

Indiana University - Riley Hospital for Children

Indianapolis, Indiana, United States

The Children's Mercy Hospital

Kansas City, Kansas, United States

Joslin Diabetes Center

Boston, Massachusetts, United States

University of Minnesota

Minneapolis, Minnesota, United States

Columbia University

New York, New York, United States

University of Pittsburg

Pittsburgh, Pennsylvania, United States

Sanford Children's Specialty Clinic

Sioux Falls, South Dakota, United States

Vanderbilt Eskind Diabetes Center

Nashville, Tennessee, United States

University of Texas Southwestern

Dallas, Texas, United States

Benaroya Research Institute

Seattle, Washington, United States

Queensland Children's Hospital

South Brisbane, Queensland, Australia

Walter and Eliza Hall Institute of Medical Research

Melbourne, Victoria, Australia

Countries

United States; Australia

References

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.

Reference Type: DERIVED

PMID: 39735417 (View on PubMed)

Related Links

http://www.trialnet.org/

Study Sponsor Website

Other Identifiers

UC4DK117009

Identifier Type: NIH

Identifier Source: secondary_id

View Link

Rituximab-pvvr and Abatacept

Identifier Type: -

Identifier Source: org_study_id