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DESIGNATE: Siplizumab in T1DM

Sponsor
National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
Overall Status
Not yet recruiting
CT.gov ID
NCT05574335
Collaborator
(none)
120
Enrollment
20
Locations
8
Arms
57.6
Anticipated Duration (Months)
6
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

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. 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.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Study Design

Study Type:
Interventional
Anticipated Enrollment :
120 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A T Cell Phenotype Signature Driven Dose Finding Study With Siplizumab in Type 1 Diabetes Mellitus (ITN095AI)
Anticipated Study Start Date :
Mar 15, 2023
Anticipated Primary Completion Date :
Dec 31, 2026
Anticipated Study Completion Date :
Dec 31, 2027

Arms and Interventions

Arm Intervention/Treatment
Experimental: Adults with T1D 0.08 mg/kg SQ dose

Cohort 1 Group1: 0.08 mg/kg SQ dose for a total of 12 weeks

Drug: Siplizumab
Weekly siplizumab doses for a total of 12 weeks
Other Names:
  • TCD 601

    		•
    Experimental: Adults with T1D 0.12 mg/kg SQ dose

    Cohort 1 Group 2: 0.12 mg/kg SQ dose for a total of 12 weeks

    Drug: Siplizumab
    Weekly siplizumab doses for a total of 12 weeks
    Other Names:
  • TCD 601

    		•
    Experimental: Adults with T1D 0.18 mg/kg SQ dose

    Cohort 1 Group 3:0.18 mg/kg SQ dose for a total of 12 weeks

    Drug: Siplizumab
    Weekly siplizumab doses for a total of 12 weeks
    Other Names:
  • TCD 601

    		•
    Experimental: Adults with T1D 0.22 mg/kg SQ dose

    Cohort 1 Group 4: 0.22 mg/kg SQ dose for a total of 12 weeks

    Drug: Siplizumab
    Weekly siplizumab doses for a total of 12 weeks
    Other Names:
  • TCD 601

    		•
    Experimental: Children with T1D 0.08 mg/kg SQ dose

    Cohort 2 Group 1:0.08 mg/kg SQ dose for a total of 12 weeks

    Drug: Siplizumab
    Weekly siplizumab doses for a total of 12 weeks
    Other Names:
  • TCD 601

    		•
    Experimental: Children with T1D 0.12 mg/kg SQ dose

    Cohort 2 Group 2:0.12 mg/kg SQ dose for a total of 12 weeks

    Drug: Siplizumab
    Weekly siplizumab doses for a total of 12 weeks
    Other Names:
  • TCD 601

    		•
    Experimental: Children with T1D 0.18 mg/kg SQ dose

    Cohort 2 Group 3: 0.18 mg/kg SQ dose for a total of 12 weeks

    Drug: Siplizumab
    Weekly siplizumab doses for a total of 12 weeks
    Other Names:
  • TCD 601

    		•
    Experimental: Children with T1D 0.22 mg/kg SQ dose

    Cohort 2 Group 4: 0.22 mg/kg SQ dose for a total of 12 weeks

    Drug: Siplizumab
    Weekly siplizumab doses for a total of 12 weeks
    Other Names:
  • TCD 601

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Acceptable T cell phenotype signature by the change from baseline in the Programmed Cell Death 1 (PD1) during 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 5th per protocol participant (PP) per dosing arm reaches Week 12 in each age cohort.

    2. Acceptable T cell phenotype signature by the change from baseline in the T cell immunoreceptor with Ig and ITIM domains (TIGIT) during 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.

    3. Acceptable T cell phenotype signature by the change from Baseline in the frequency within circulating cluster of differentiation 4 (CD4) Tem cells during 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 reach Week 12 in each age cohort.

    4. 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

    1. Frequency of Adverse Event (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

    2. 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 pmol/ml, is computed by dividing the total AUC by 120 minutes

    3. Insulin use (U/kg/day) [At Weeks 6, 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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    8 Years to 45 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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:

    4. Glutamate decarboxylase (GAD-65)

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

    6. Insulinoma antigen-2 (IA-2)

    7. Zinc transporter-8 (ZnT8)

    8. 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)

    9. 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:

    5. Human immunodeficiency virus (HIV)

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

    7. 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)

    8. 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

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

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

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

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

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

    14. CD4+ count below the lower limit of normal

    15. Platelet count <150,000 /µL

    16. Hemoglobin < 10 g/dL

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

    18. AST >= 2x ULN

    19. 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

    20. 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)

    21. 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

    22. Previous or current diagnosis of malignancy

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

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

    25. History of significant cardiovascular disease

    26. 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

    27. 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

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

    29. 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

    30. 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Alabama at Birmingham: Division of Endocrinology, Diabetes and Metabolism Birmingham Alabama United States 35294
    2 UCSF School of Medicine: UCSF Diabetes Clinic San Francisco California United States 94143
    3 Stanford School of Medicine: Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes Stanford California United States 94305
    4 University of Colorado School of Medicine: Barbara Davis Center for Diabetes Aurora Colorado United States 80045
    5 University of Florida: Diabetes Center of Excellence Gainesville Florida United States 32608
    6 University of Miami Miller School of Medicine: Diabetes Research Institute Miami Florida United States 33136
    7 University of South Florida: Diabetes Center Tampa Florida United States 33612
    8 Emory University School of Medicine: Emory & Children's Pediatric Research Center, Division of Endocrinology & Diabetes Atlanta Georgia United States 30307
    9 The University of Chicago: Kovler Diabetes Center Chicago Illinois United States 60637
    10 Indiana University Medical Center: Riley Hospital for Children, Department of Pediatric Endocrinology & Diabetology Indianapolis Indiana United States 46202
    11 University of Iowa Children's Hospital: Department of Pediatrics, Pediatric Endocrinology and Diabetes Iowa City Iowa United States 52242
    12 Joslin Diabetes Center: Joslin Clinic Boston Massachusetts United States 02215
    13 University of Minnesota Medical School: Division of Pediatric Endocrinology and Diabetes Minneapolis Minnesota United States 55454
    14 Children's Mercy Hospitals and Clinics: Section of Pediatric Endocrinology and Diabetes Kansas City Missouri United States 64108
    15 University at Buffalo, Department of Pediatrics: Division of Endocrinology and Diabetes Buffalo New York United States 14203
    16 Columbia University Medical Center: Naomi Berrie Diabetes Center New York New York United States 10032
    17 Children's Hospital of Philadelphia: Diabetes Center for Children Philadelphia Pennsylvania United States 19104
    18 Sanford Health, Sanford Research Center Sioux Falls South Dakota United States 57117
    19 University of Texas Southwestern Medical Center: Department of Internal Medicine, Division of Endocrinology Dallas Texas United States 75390
    20 Benaroya Research Institute at Virginia Mason: Diabetes Research Program Seattle Washington United States 98101

    Sponsors and Collaborators

    • National Institute of Allergy and Infectious Diseases (NIAID)

    Investigators

    • Study Chair: Stephen Gitelman, M.D., University of California San Francisco, School of Medicine: Diabetes Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    National Institute of Allergy and Infectious Diseases (NIAID)
    ClinicalTrials.gov Identifier:
    NCT05574335
    Other Study ID Numbers:
    • DAIT ITN095AI
    First Posted:
    Oct 10, 2022
    Last Update Posted:
    Jan 26, 2023
    Last Verified:
    Jan 1, 2023
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID)
    diabetic
    Type 1 diabetes
    T1DM
    siplizumab
    Additional relevant MeSH terms:
    Diabetes Mellitus
    Diabetes Mellitus, Type 1

    Study Results

    No Results Posted as of Jan 26, 2023