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Siplizumab in T1DM (DESIGNATE)

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ClinicalTrials.gov Identifier: NCT05574335
Recruitment Status : Active, not recruiting
First Posted : October 10, 2022
Last Update Posted : January 30, 2024
Sponsor:
Information provided by (Responsible Party):
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. 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.

Condition or disease Intervention/treatment Phase
Type 1 Diabetes Mellitus Drug: Siplizumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated 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)
Actual Study Start Date : April 26, 2023
Estimated Primary Completion Date : December 31, 2026
Estimated Study Completion Date : December 31, 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: TCD 601




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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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



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Ages Eligible for Study:   8 Years to 45 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 pmol/mL following a MMTT conducted ≥ 21 days from diagnosis and within 37 days of enrollment (V0).
  6. Completion of a primary SARS-CoV-2 vaccination series, including any additional vaccine dose(s) for which the participant qualifies, 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. 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®.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 within 37 days of enrollment (V0), confirmed by repeat tests at least 1 week apart:

    1. White blood count (WBC) < 3 x 103/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. Serum creatinine >1.5x ULN in adults or >ULN in pediatrics..
  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 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, 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05574335


Locations
Show Show 20 study locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Study Chair: Stephen Gitelman, M.D. University of California San Francisco, School of Medicine: Diabetes Center
Additional Information:
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT05574335    
Other Study ID Numbers: DAIT ITN095AI
First Posted: October 10, 2022    Key Record Dates
Last Update Posted: January 30, 2024
Last Verified: January 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
Time Frame: On average, within 24 months after database lock for the trial.
Access Criteria: Open access.
URL: https://www.immport.org/home

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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:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases