Rituximab and Abatacept for Prevention or Reversal of Type 1 Diabetes (TN25)

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: National Institutes of Health (NIH); Juvenile Diabetes Research Foundation
• Information provided by (Responsible Party): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Description

Brief Summary:

The study is a clinical trial testing sequential therapy with rituximab followed by abatacept in individuals destined to develop clinical type 1 diabetes.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes Mellitus	Drug: Rituximab; Drug: Abatacept	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 36 participants
• Intervention Model: Sequential Assignment
• Intervention Model Description: The arm for this study is experimental. It consists of a rituximab dose followed by an abatacept dose. Rituximab 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 1 of the study. Abatacept will be given by a subcutaneous formulation weekly for 2 years, 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: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Rituximab and Abatacept for Prevention or Reversal of Type 1 Diabetes
• Estimated Study Start Date: July 1, 2019
• Estimated Primary Completion Date: July 2025
• Estimated Study Completion Date: July 2026

Arms and Interventions

Arm

Intervention/treatment

Experimental: Rituximab followed by Abatacept; Rituximab 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 1 of the study. Abatacept will be given by a subcutaneous formulation weekly for 2 years, 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; Participants will receive Rituximab dosing from Week 1 to Week 4 of the trial. Rituximab 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.; Drug: Abatacept; Participants will receive initial Abatacept dosing at Week 16 of trial. Abatacept will be given by a subcutaneous (SC) formulation weekly for two years, 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). Abatacept treatment will continue for full 24-month period regardless of whether participants have progressed to stage 3 type 1 diabetes during treatment.

Outcome Measures

Primary Outcome Measures :

1. Assessment of Insulin Production during course of study [ Time Frame: Collected during initial study visit and during Visit Months 4, 8, 12, 18, 24, 30, and 36. ]
   The insulin data gathered from regular monitoring of glucose tolerance will be used to measure changes in insulin secretion.
2. Assessment of C-peptide during course of study [ Time Frame: Collected during initial study visit and during Visit Months 4, 8, 12, 18, 24, 30, and 36. ]
   The C-peptide data gathered from regular monitoring of glucose tolerance will be used to measure changes in insulin secretion.
3. Assessment of Glucose Tolerance Status to Evaluate Progression to Stage 3 Type 1 Diabetes [ Time Frame: Collected during initial study visit and during Visit Months 4, 8, 12, 18, 24, 30, and 36 ]
   An Oral Glucose Tolerance test (OGTT) will be performed approximately every 4-6 months during this trial, or more frequently if clinically indicated, to determine the glucose levels in the blood. Changes in blood glucose levels will be utilized to measure the progression to Stage 3 type 1 diabetes throughout the study.
4. Assessment of Glucose Tolerance Status to Evaluate Reversal to Normal Glucose Tolerance [ Time Frame: Collected during initial study visit and during Visit Months 4, 8, 12, 18, 24, 30, and 36 ]
   An Oral Glucose Tolerance test (OGTT) will be performed approximately every 4-6 months during this trial, or more frequently if clinically indicated, to determine the glucose levels in the blood. Changes in blood glucose levels will be utilized to measure reversal to normal glucose tolerance throughout the study.
5. Assessment of Insulin Production (post-diagnosis) [ Time Frame: Individuals who develop stage 3 diabetes will undergo MMTT at 6 and 12 months after diagnosis. ]
   For those participants that progress to stage 3 Type 1 Diabetes during the course of this trial, a Mixed Meal Tolerance Test (MMTT) will be performed at six month intervals. C-peptide and Insulin data from the MMTT will be used to measure insulin criteria.

Secondary Outcome Measures :

1. Assessment of the Incidence of Treatment-Emergent Adverse Events of rituximab followed by Abatacept in this Population, as Assessed by CTCAE criteria [ Time Frame: Collected during initial study visit and collection period continues for up to 36 months. ]
   Incidence of Treatment-Emergent Adverse Events will be assessed throughout the course of the study by using the Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0.
2. Assessment of the Proportion of Subjects who End Treatment Due to Adverse Reactions, as Assessed by CTCAE criteria. [ Time Frame: Collected during initial study visit and collection period continues for up to 36 months. ]
   The proportion of subjects who end treatment due to adverse reactions will be assessed throughout the course of the study by using the Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0.
3. Effect of Rituximab followed by Abatacept on the reversal of dysglycemia as defined by reversion to a normal OGTT [ Time Frame: Assessed during initial study visit and assessment period continues for up to 36 months. ]
   An Oral Glucose Tolerance test (OGTT) will be performed approximately every 4-6 months during this trial, or more frequently if clinically indicated, to determine if glucose reverses to normal levels.
4. Effect of Rituximab followed by Abatacept on the reversal of dysglycemia as defined by the duration of normoglycemia [ Time Frame: Assessed during initial study visit and assessment period continues for up to 36 months. ]
   An Oral Glucose Tolerance test (OGTT) will be performed approximately every 4-6 months during this trial, or more frequently if clinically indicated, to determine duration of normoglycemia.
5. Effect of Rituximab followed by Abatacept on changes in C-peptide secretion levels. [ Time Frame: Assessed during initial study visit and assessment period continues for up to 36 months. ]
   An Oral Glucose Tolerance test (OGTT) will be performed approximately every 4-6 months during this trial, or more frequently if clinically indicated, to determine c-peptide secretion levels.
6. Effect of Rituximab followed by Abatacept on changes in insulin secretion levels. [ Time Frame: Assessed during initial study visit and assessment period continues for up to 36 months. ]
   An Oral Glucose Tolerance test (OGTT) will be performed approximately every 4-6 months during this trial, or more frequently if clinically indicated, to determine insulin secretion levels.
7. Effect of Rituximab Followed by Abatacept on Changes in B-Cell Response, as Assessed by Mechanistic Assessments, Characteristic of Disease Activity [ Time Frame: Assessed during initial study visit and assessment period continues for up to 36 months. ]
   Mechanistic assessments, including RNA, plasma, serum, DNA, and measures of B and T cell number and function, will be performed approximately every 2-4 months during this trial up to 36 months, to identify changes in B-Cell response.
8. Effect of Rituximab Followed by Abatacept on Changes in T-Cell Response, as Assessed by Mechanistic Assessments, Characteristic of Disease Activity [ Time Frame: Assessed during initial study visit and assessment period continues for up to 36 months. ]
   Mechanistic assessments, including RNA, plasma, serum, DNA, and measures of B and T cell number and function, will be performed approximately every 2-4 months during this trial up to 36 months, to identify changes in T-Cell response.
9. Effect of Rituximab Followed by Abatacept on Changes in B-Cell Response, as Assessed by Mechanistic Assessments, Characteristic of Identification of Surrogate Immune Markers that Correlate with and May Predict Clinical Response [ Time Frame: Assessed during initial study visit and assessment period continues for up to 36 months. ]
   Mechanistic assessments, including RNA, plasma, serum, DNA, and measures of B and T cell number and function, will be performed approximately every 2-4 months during this trial up to 36 months, to identify changes in B-Cell response.
10. Effect of Rituximab Followed by Abatacept on Changes in T-Cell Response, as Assessed by Mechanistic Assessments, Characteristic of Identification of Surrogate Immune Markers that Correlate with and May Predict Clinical Response [ Time Frame: Assessed during initial study visit and assessment period continues for up to 36 months. ]
    Mechanistic assessments, including RNA, plasma, serum, DNA, and measures of B and T cell number and function, will be performed approximately every 2-4 months during this trial up to 36 months, to identify changes in T-Cell response.
11. Assessment of the Presence of Previous Autoimmune Disease within the Participant's Family, as Assessed by the Past Medical History Questionnaire [ Time Frame: Collected during initial study visit and collection period continues for up to 36 months. ]
    Presence of previous autoimmune disease within the participant's family will be assessed throughout the course of the study by using participant and/or parent/guardian responses to the Past Medical History Questionnaire. The Past Medical History Questionnaire will utilize a set of fourteen dichotomous questions to determine the presence of previous autoimmune disease within the participant's family. The choices will range from "yes" or "no". If they choose "yes" to one of the answers, the participants will also enter a qualitative free-response to specify which relative has been previously diagnosed (i.e. Parent, Child, Sibling, Half-Sibling, Grandparent, Grandchild, Aunt/Uncle, Cousin, Niece/Nephew). This questionnaire is utilized to obtain medical history; thus, questionnaire outcomes will not be defined as better or worse for the purposes of the assessment. Subscales will not be combined to compute a total score.
12. Assessment of the Concentration of Participant's Abnormalities to Body Systems, as Assessed by the Past Medical History Questionnaire [ Time Frame: Collected during initial study visit and collection period continues for up to 36 months. ]
    Body system abnormalities will be assessed throughout the course of the study by using participant and/or parent/guardian responses to the Past Medical History Questionnaire. The Past Medical History Questionnaire will utilize a set of thirteen dichotomous questions to determine the concentration of participant's abnormalities to body systems. The choices will range from "Normal" or "Abnormal". If the questionnaire author chooses "Abnormal" to one of the answers, a qualitative free-response to specify why the body system was deemed abnormal will need to be entered. This questionnaire is utilized to obtain medical history; thus, questionnaire outcomes will not be defined as better or worse for the purposes of the assessment. Subscales will not be combined to compute a total score.
13. Assessment of participant's height to determine safety [ Time Frame: Collected during initial study visit and collection period continues for up to 36 months. ]
    Safety of sequential therapy will be assessed for consideration of outcome measurement for the duration of the study.
14. Assessment of participant's height to determine tolerability [ Time Frame: Collected during initial study visit and collection period continues for up to 36 months. ]
    Tolerability of sequential therapy will be assessed for consideration of outcome measurement for the duration of the study.
15. Assessment of participant's weight to determine safety [ Time Frame: Collected during initial study visit and collection period continues for up to 36 months. ]
    Safety of sequential therapy will be assessed for consideration of outcome measurement for the duration of the study.
16. Assessment of participant's weight to determine tolerability. [ Time Frame: Collected during initial study visit and collection period continues for up to 36 months. ]
    Tolerability of sequential therapy will be assessed for consideration of outcome measurement for the duration of the study.
17. Assessment of the Number of Concomitant Medications, as Assessed by the Past Medical History Questionnaire [ Time Frame: Collected during initial study visit and collection period continues for up to 36 months. ]
    The number of concomitant medications the participant is consuming will be assessed throughout the course of the study by using participant and/or parent/guardian responses to the Past Medical History Questionnaire.

Eligibility Criteria

• Ages Eligible for Study: 8 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Participant in TrialNet Pathway to Prevention Study (TN01).
2. Age ≥ 8 years old at time of enrollment in this trial
3. Participant (or parent or legal guardian if the participant is a minor) is willing to provide Informed Consent.
4. Individuals <18 years of age at time of enrollment must have had a TrialNet-conducted OGTT demonstrating abnormal glucose tolerance within 7 weeks (52 days) of the baseline visit (visit 0).
5. Individuals ≥18 years of age at time of enrollment must have had two consecutive TrialNet conducted OGTTs demonstrating abnormal glucose tolerance, the most recent of which must have been within 7 weeks (52 days) of the baseline visit (visit 0).
6. The participant must be positive for two or more diabetes-related autoantibodies on two occasions. The second occasion must occur within the six months prior to study drug administration, but does not need to involve the same two autoantibodies as were found on the first occasion. The autoantibodies that are to be confirmed are anti-GAD65, anti-ICA512, anti-insulin (MIAA), ZnT8 and/or ICA.
7. Weigh at least 20 kg.
8. If participant is female with reproductive potential, she must have a negative pregnancy test at screening be willing to avoid pregnancy for duration of the treatment period.
9. Willing to forego other forms of experimental treatment during the study.
10. Willing and medically acceptable to postpone live vaccine immunizations for 3 months after treatment.

Exclusion Criteria:

1. Diabetes
2. Immunodeficient or have clinically significant chronic lymphopenia
3. Require use of other immunosuppressive agents
4. Chronic active infection other than localized skin infections.
5. Active infection at the time of infusion.
6. A positive PPD or Quantiferon test, or history of previous treatment for TB.
7. Vaccination with a live virus within 4 weeks prior to enrollment.
8. Vaccination with a killed virus within 4 weeks prior to enrollment.
9. A history of confirmed infectious mononucleosis within the 3 months prior to enrollment, as documented by EBV serology.
10. Not up-to-date on current immunizations
11. Laboratory or clinical evidence of acute infection with EBV or CMV, either via serology or PCR.
12. Serological evidence of current or past HIV, Hepatitis B or Hepatitis C infection.
13. Be currently pregnant or lactating, or anticipate getting pregnant within 2 years and 4 months of enrollment
14. Chronic use of steroids or other immunosuppressive agents.
15. Known and untreated hypothyroidism or active Graves' disease at enrollment.
16. Administration of a monoclonal antibody within the year before enrollment.
17. History of malignancy.
18. Use of exogenous insulin or any other anti-hyperglycemic drugs.
19. Any condition that, in the opinion of the investigator, would interfere with the study conduct or the safety of the participant.
20. Have severe obesity: adults BMI ≥ 40; children BMI-z score ≥ 2.0.

Contacts and Locations

Contacts

Contact: Lisa Rafkin; 305-243-6146; lrafkin@miami.edu

Contact: Ryan O'Donnell; 813-396-9551; Ryan.O'Donnell@epi.usf.edu

Sponsors and Collaborators

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

National Institutes of Health (NIH)

Juvenile Diabetes Research Foundation

Investigators

• Study Chair: Carla Greenbaum; Type 1 Diabetes TrialNet

More Information

Additional Information:

Related Info 

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT03929601 History of Changes
• Other Study ID Numbers: Rituximab and Abatacept
• First Posted: April 29, 2019
• Last Update Posted: May 8, 2019
• Last Verified: April 2019

• 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

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Rituximab; Abatacept; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Immunosuppressive Agents