Siplizumab in T1DM

• Status: Not yet recruiting
• Trial end date: 2027-12-31
• Target enrollment: 0
• Participant gender: All

Summary

This is a multicenter, Phase Ib, open-label, siplizumab dose-finding study in individuals aged 8-45 years with a Type 1 diabetes mellitus (T1DM) diagnosis. within 18 months of V0. Participants will be randomized 1:1:1:1 to one of four possible siplizumab dosing arms. All dosing arms will receive weekly siplizumab doses for a total of 12 weeks. After the completion of treatment, participants will undergo follow-up visits at weeks 12, 24, 36 and 52 which include longitudinal MMTTs. Blood samples for mechanistic analyses will be obtained during the treatment phase and thereafter.

The primary objective is to identify a safe, metabolically favorable, dosing regimen for siplizumab in patients with type 1 diabetes that induces changes in T cell phenotypes observed with alefacept therapy in new-onset T1DM.

The secondary objectives are to:

1. Assess the safety profile of siplizumab in recently diagnosed T1DM.

2. Assess the effects of siplizumab on residual beta cell function in recently diagnosed T1DM participants.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Criteria

Inclusion Criteria:

1. Ability to provide informed consent (parental permission and informed assent of minor, if applicable)

2. Diagnosis of Type 1 Diabetes Mellitus (T1DM) within 18 months (550 days) of enrollment (V0)

3. Positive for at least one diabetes-related autoantibody including:

1. Glutamate decarboxylase (GAD-65)

2. Insulin, if obtained within 10 days of the onset of exogenous insulin therapy

3. Insulinoma antigen-2 (IA-2)

4. Zinc transporter-8 (ZnT8)

4. Peak stimulated C-peptide level > 0.15 pmol/mL following a mixed- meal tolerance test (MMTT) conducted >= 21 days from diagnosis and within 37 days of enrollment (V0)

5. Completion of a primary SARS-CoV-2 vaccination series, including any additional vaccine dose(s) for which the participant qualifies for, according to current The Centers for Disease Control and Prevention (CDC) recommendations and FDA approval(s) or emergency use authorization(s). If the participant requires administration of vaccine(s) to meet eligibility requirements, they must complete the vaccination series at least 2 weeks prior to enrollment (V0)

Exclusion Criteria:

1. Use of investigational drugs within 24 weeks of participation with the exception of any vaccine for the prevention of SARS-CoV2 infection and emergency use authorization medications for treating SARS- CoV2

2. Severe reaction or anaphylaxis to humanized monoclonal antibodies

3. History of significant allergy (e.g. anaphylaxis) to milk or soy proteins

4. History of recent (within 180 days of V0) or ongoing uncontrolled bacterial, viral, fungal or other opportunistic infections, including:

1. Human immunodeficiency virus (HIV)

2. Current or prior infection with hepatitis B (HBV), as indicated by positive HBsAg or positive HBcAb

3. Current or prior hepatitis C (HCV), unless treated with anti-viral therapy with achievement of a sustained virologic response (undetectable viral load 12 weeks after cessation of therapy)

4. Positive Quantiferon-TB Gold or Quantiferon-TB Gold Plus tests. PPD or T-SPOT (R). TB may be substituted for the Quantiferon-TB Gold or Quantiferon-TB Gold Plus tests

5. Active infection with Epstein-Barr virus (EBV) as detected by Polymerase Chain Reaction (PCR) or serology at the screening visit (V-1)

6. Active infection with cytomegalovirus (CMV) as detected by PCR or serology at the screening visit (V-1)

5. Positive molecular testing of SARS-CoV-2 within 21 days of V-1

6. Any of the following laboratory abnormalities within 37 days of enrollment (V0), confirmed by repeat tests at least 1 week apart:

1. White blood count (WBC) < 3 x 10^3/µL

2. CD4+ count below the lower limit of normal

3. Platelet count <150,000 /µL

4. Hemoglobin < 10 g/dL

5. ALT >= 2x upper limit of normal (ULN) or

6. AST >= 2x ULN

7. Prior or current treatment that is known to alter the natural history of Type 1 Diabetes Mellitus (T1DM) or immunologic status, including high dose inhaled, extensive topical or systemic glucocorticoids

8. Current or prior (within last 14 days of the V-1 mixed meal tolerance test (MMTT)) use of any medication known to influence glucose tolerance (e.g., atypical antipsychotics, diphenylhydantoin, thiazide, or other potassium- depleting diuretics, ß-adrenergic blockers, niacin)

9. Current or prior (within the last 30 days of the V-1 MMTT) use of metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors or amylin

10. Previous or current diagnosis of malignancy

11. History of bone marrow transplantation, or autoimmune disease associated with lymphopenia

12. History or diagnoses of other autoimmune diseases with the exception of stable thyroid or celiac disease

13. History of significant cardiovascular disease

14. Vaccination with a live attenuated vaccine (e.g., varicella, measles, mumps, rubella, coldattenuated intranasal influenza vaccine, bacillus Calmette- Guérin, and smallpox) within 30 days of V0

15. Women of child-bearing potential who are unwilling to use a medically acceptable form of contraception from 14 days prior to V0 until study Week 52

16. Women who are pregnant, lactating, or planning on pregnancy during the study

17. Current, diagnosed mental illness (e.g. severe depression), current diagnosed or self-reported drug, or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements

18. Past or current medical problems or findings from physical examination or laboratory testing, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may affect the quality or interpretation of the data obtained from the study