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

PHASE2RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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.
  • 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. 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

  • 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 T1D clinical trial.
  • Have had previous clinical use of Tzield (Teplizumab) not part of a T1D treatment study.
  • Any laboratory abnormality or condition that, in the opinion of the investigator, would interfere with the study conduct or the safety of the participant.
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    Eligibility

    Age eligible for study : 8 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2023-10-30

    Primary completion: 2027-10-01

    Study completion finish: 2029-10-01

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE2

    trial

    Trial ID

    NCT03929601

    Intervention or treatment

    DRUG: Rituximab-pvvr

    DRUG: Abatacept

    DRUG: Sterile Sodium Chloride

    Conditions

    • • Type 1 Diabetes Mellitus
    Image related to Type 1 Diabetes Mellitus

    • Condition: Type 1 Diabetes Mellitus

    • DRUG: Rituximab-pvvr and other drugs

    • South Brisbane, Queensland, Australia and more

    • Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

    You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.

    Are you running this trial? If you're a clinic or sponsor, you can claim this study. Claim or learn more.

    Find a site

    Closest Location:

    Queensland Children's Hospital

    Research sites nearby

    Select from list below to view details:

    • Queensland Children's Hospital

      South Brisbane, Queensland, Australia

    • Walter and Eliza Hall Institute of Medical Research

      Melbourne, Victoria, Australia

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    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/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: 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.
    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: 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.

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    C-Peptide Response to 2-hr MMTT at 24 months post-randomizationThe 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

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    C-peptide AUC MeansC-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 groupAnalysis 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

    Frequently Asked Questions

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    References

    Clinical Trials Gov: Rituximab-pvvr and Abatacept Vs Rituximab-pvvr Alone in New Onset Type 1 Diabetes

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