Siplizumab in T1DM

Phase 1

Active, not recruiting

• Conditions: Type 1 Diabetes Mellitus
• Interventions: Drug: Siplizumab

• Registration Number: NCT05574335
• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief 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. If indicated, participants will enter into long-term safety monitoring for up to an additional 48 weeks. Blood samples for mechanistic analyses will be obtained during the treatment phase and thereafter. Adults aged 18- 45 will be enrolled initially at the study sites.

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-09-19
• Study First Submitted QC: 2022-10-06
• Study First Posted: 2022-10-10
• Study Start: 2023-04-26
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-31
• Last Update Posted: 2024-08-02
• Primary Completion: 2026-12-31
• Study Completion: 2027-12-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 120

Inclusion Criteria

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

2. Male or female between 8 to 45 years of age.

3. Diagnosis of T1DM within 18 months (550 days) of enrollment (V0).

4. 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), or
   4. Zinc transporter-8 (ZnT8).

5. Peak stimulated C-peptide level > 0.15 nmol/L following a MMTT conducted ≥ 21 days from diagnosis and within 37 days of enrollment (V0).

6. Completion of a SARS-CoV-2 vaccination, according to current 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. 1. Use of investigational drugs within 24 weeks of participation with the exception of any vaccine for the prevention of SARS-CoV-2 infection and emergency use authorization medications for treating SARS-CoV-2.

2. Severe reaction or anaphylaxis to humanized monoclonal antibodies.

3. Inability to complete a mixed meal tolerance test:

   1. History of significant allergy (e.g., anaphylaxis) to milk or soy proteins.
   2. Inability to disable hybrid closed loop system.

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®.TB may be substituted for the QuantiFERON-TB Gold or QuantiFERON-TB Gold Plus tests,
   5. Active infection with EBV as detected by 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 30 days of V-1.

6. Any of the following laboratory abnormalities confirmed by repeat tests at least 1 week apart:

   1. White blood count (WBC) < 3 x 103/μL;,
   2. CD 3+ CD4+, T cell 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. Serum creatinine >1.5x ULN in adults or >ULN in pediatrics.
   8. Absolute lymphocyte count (ALC) below the LLN.

7. Prior or current treatment that is known to alter the natural history of 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 MMTT) use of any medication known to influence glucose tolerance (e.g., atypical antipsychotics, diphenylhydantoin, thiazide, or other potassium-depleting diuretics, β-adrenergic blockers, niacin).

9. Current or prior (within the last 30 days of the V-1 MMTT) use of non-insulin medications to treat insulin resistance or elevated glucose levels.

10. Previous or current diagnosis of malignancy.

11. History of bone marrow transplantation, solid organ transplantation, or primary immunodeficiencies.

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, cold-attenuated 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 that are not listed above, 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 impact the quality or interpretation of the data obtained from the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Adults with T1D 0.08 mg/kg SQ dose	Siplizumab	Cohort 1 Group1: 0.08 mg/kg SQ dose for a total of 12 weeks
Adults with T1D 0.12 mg/kg SQ dose	Siplizumab	Cohort 1 Group 2: 0.12 mg/kg SQ dose for a total of 12 weeks
Adults with T1D 0.18 mg/kg SQ dose	Siplizumab	Cohort 1 Group 3:0.18 mg/kg SQ dose for a total of 12 weeks
Adults with T1D 0.22 mg/kg SQ dose	Siplizumab	Cohort 1 Group 4: 0.22 mg/kg SQ dose for a total of 12 weeks
Children with T1D 0.08 mg/kg SQ dose	Siplizumab	Cohort 2 Group 1:0.08 mg/kg SQ dose for a total of 12 weeks
Children with T1D 0.12 mg/kg SQ dose	Siplizumab	Cohort 2 Group 2:0.12 mg/kg SQ dose for a total of 12 weeks
Children with T1D 0.18 mg/kg SQ dose	Siplizumab	Cohort 2 Group 3: 0.18 mg/kg SQ dose for a total of 12 weeks
Children with T1D 0.22 mg/kg SQ dose	Siplizumab	Cohort 2 Group 4: 0.22 mg/kg SQ dose for a total of 12 weeks

Primary Outcome Measures

Name	Time	Method
Acceptable T cell phenotype signature by the change from baseline in the Programmed Cell Death 1 (PD1) during the first 12 weeks.	From week 0 (baseline) to week 12	Evaluating four siplizumab dosing regimens for induction of a T cell phenotype signature based on the 20% increase or greater from baseline in PD1.; The primary analysis will identify siplizumab doses with acceptable safety profiles and favorable changes in the T cell phenotype in each age cohort. The primary assessments will be made during the first 12 weeks with an interim analysis for futility after the 5th per protocol participant (PP) per dosing arm reaches Week 12 in each age cohort.
Acceptable T cell phenotype signature by the change from baseline in the T cell immunoreceptor with Ig and ITIM domains (TIGIT) during the first 12 weeks.	From week 0 (baseline) to week 12	Evaluating four siplizumab dosing regimens for induction of a T cell phenotype signature based on the 20% increase or greater from baseline in TIGIT.; The primary analysis will identify siplizumab doses with acceptable safety profiles and favorable changes in the T cell phenotype in each age cohort. The primary assessments will be made during the first 12 weeks with an interim analysis for futility after 5 PP per dosing arm reach Week 12 in each age cohort.
Acceptable T cell phenotype signature by the change from Baseline in the frequency within circulating cluster of differentiation 4 (CD4) Tem cells during the first 12 weeks.	From week 0 (baseline) to week 12	Evaluating four siplizumab dosing regimens for induction of a T cell phenotype signature based on the 20% increase or greater from baseline in frequency on CD4 Tem.; The primary analysis will identify siplizumab doses with acceptable safety profiles and favorable changes in the T cell phenotype in each age cohort. The primary assessments will be made during the first 12 weeks with an interim analysis for futility after 5 PP per dosing arm reaches Week 12 in each age cohort.
Acceptable T cell phenotype signature by the change from baseline in the CD4 Treg/Tem ratio	From week 0 (baseline) to week 12	Evaluating four siplizumab dosing regimens for induction of a T cell phenotype signature based on the 75% increase or greater from baseline in the Treg/Tem ratio

Secondary Outcome Measures

Name	Time	Method
Frequency of Adverse Events (AEs) in all siplizumab dosing arms	From week 0 to week 52	AE will include any untoward medical occurrence associated with siplizumab administration or any study-mandated procedure
Mixed Meal Tolerance Test (MMTT)-stimulated mean 2-hour C-peptide AUC	At Week 12, 24, 36, 52	The mean 2-hour C-peptide AUC, measured in nmol/L, is computed by dividing the total AUC by 120 minutes
Insulin use (U/kg/day)	At Weeks 12, 24, 36 and 52.	Measured as U/kg body weight/day; participants should record the type and amount of insulin they have used during the 5-day period immediately preceding the beginning of treatment, middle of treatment, end of treatment, and at all follow-up visits

Trial Locations

Locations (19)

Stanford School of Medicine: Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes; 🇺🇸 Stanford, California, United States

Emory University School of Medicine: Emory & Children's Pediatric Research Center, Division of Endocrinology & Diabetes; 🇺🇸 Atlanta, Georgia, United States

The University of Chicago: Duchossois Center for Academic Medicine-Hyde Park; 🇺🇸 Chicago, Illinois, United States

Indiana University Medical Center: Riley Hospital for Children, Department of Pediatric Endocrinology & Diabetology; 🇺🇸 Indianapolis, Indiana, United States

University of Colorado School of Medicine: Barbara Davis Center for Diabetes; 🇺🇸 Aurora, Colorado, United States

University of Alabama at Birmingham: Division of Endocrinology, Diabetes and Metabolism; 🇺🇸 Birmingham, Alabama, United States

UCSF School of Medicine: UCSF Diabetes Clinic; 🇺🇸 San Francisco, California, United States

University of South Florida: Diabetes Center; 🇺🇸 Tampa, Florida, United States

University of Minnesota Medical School: Division of Pediatric Endocrinology and Diabetes; 🇺🇸 Minneapolis, Minnesota, United States

Joslin Diabetes Center: Joslin Clinic; 🇺🇸 Boston, Massachusetts, United States

University of Iowa Children's Hospital: Department of Pediatrics, Pediatric Endocrinology and Diabetes; 🇺🇸 Iowa City, Iowa, United States

University of Miami Miller School of Medicine: Diabetes Research Institute; 🇺🇸 Miami, Florida, United States

University at Buffalo, Department of Pediatrics: Division of Endocrinology and Diabetes; 🇺🇸 Buffalo, New York, United States

Children's Hospital of Philadelphia: Diabetes Center for Children; 🇺🇸 Philadelphia, Pennsylvania, United States

Columbia University Medical Center: Naomi Berrie Diabetes Center; 🇺🇸 New York, New York, United States

University of Texas Southwestern Medical Center: Department of Internal Medicine, Division of Endocrinology; 🇺🇸 Dallas, Texas, United States

Benaroya Research Institute at Virginia Mason: Diabetes Research Program; 🇺🇸 Seattle, Washington, United States

University of Florida: Diabetes Center of Excellence; 🇺🇸 Gainesville, Florida, United States

Children's Mercy Hospitals and Clinics: Section of Pediatric Endocrinology and Diabetes; 🇺🇸 Kansas City, Missouri, United States