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

National Institutes of Health (NIH)

Status and phase: Active, not recruiting; Phase 2

Conditions: Type 1 Diabetes Mellitus

Treatments: Drug: Abatacept; Drug: Sterile Sodium Chloride; Drug: Rituximab-pvvr

Study type: Interventional

Funder types: NIH

Identifiers

NCT03929601

Rituximab-pvvr and Abatacept

UC4DK117009 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 74 patients

Sex: All

Ages: 8 to 45 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: Triple Blind

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74 participants in 2 patient groups, including a placebo group

Rituximab-pvvr followed by Abatacept

Active Comparator group

Description:

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).

Treatment:

Drug: Rituximab-pvvr

Drug: Abatacept

Rituximab-pvvr followed by Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Rituximab-pvvr

Drug: Sterile Sodium Chloride