Siplizumab in T1DM

Study Overview
=================
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: Assess the safety profile of siplizumab in recently diagnosed T1DM. Assess the effects of siplizumab on residual beta cell function in recently diagnosed T1DM participants.

Official Title
-----------------
A T Cell Phenotype Signature Driven Dose Finding Study With Siplizumab in Type 1 Diabetes Mellitus (ITN095AI)

Conditions
-----------------
Type 1 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Siplizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Ability to provide informed consent (parental permission and informed assent of minor, if applicable). Male or female between 8 to 45 years of age. Diagnosis of T1DM within 18 months (550 days) of enrollment (V0). Positive for at least one diabetes-related autoantibody, including: Glutamate decarboxylase (GAD-65), Insulin, if obtained within 10 days of the onset of exogenous insulin therapy, Insulinoma antigen-2 (IA-2), or Zinc transporter-8 (ZnT8). Peak stimulated C-peptide level > 0.15 pmol/mL following a MMTT conducted ≥ 21 days from diagnosis and within 37 days of enrollment (V0). 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. 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. Severe reaction or anaphylaxis to humanized monoclonal antibodies. History of significant allergy (e.g., anaphylaxis) to milk or soy proteins. History of recent (within 180 days of V0) or ongoing uncontrolled bacterial, viral, fungal or other opportunistic infections, including: Human immunodeficiency virus (HIV), Current or prior infection with hepatitis B (HBV), as indicated by positive HBsAg or positive HBcAb, 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), 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, Active infection with EBV as detected by PCR or serology at the screening visit (V-1), Active infection with cytomegalovirus (CMV) as detected by PCR or serology at the screening visit (V-1), Positive molecular testing of SARS-CoV-2 within 30 days of V-1. Any of the following laboratory abnormalities within 37 days of enrollment (V0), confirmed by repeat tests at least 1 week apart: White blood count (WBC) < 3 x 103/μL;, CD4+ count below the lower limit of normal, Platelet count < 150,000 /μL, Hemoglobin < 10 g/dL, ALT ≥ 2x upper limit of normal (ULN) or AST ≥ 2x ULN Serum creatinine >1.5x ULN in adults or >ULN in pediatrics.. 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. 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). 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. Previous or current diagnosis of malignancy. History of bone marrow transplantation, or autoimmune disease associated with lymphopenia. History or diagnoses of other autoimmune diseases with the exception of stable thyroid or celiac disease. History of significant cardiovascular disease. 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. 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. Women who are pregnant, lactating, or planning on pregnancy during the study. 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. 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.

Ages Eligible for Study
-----------------
Minimum Age: 8 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adults with T1D 0.08 mg/kg SQ dose<br>Cohort 1 Group1: 0.08 mg/kg SQ dose for a total of 12 weeks | Drug: Siplizumab<br>* Weekly siplizumab doses for a total of 12 weeks<br>* Other names: TCD 601;|
| Experimental: Adults with T1D 0.12 mg/kg SQ dose<br>Cohort 1 Group 2: 0.12 mg/kg SQ dose for a total of 12 weeks | Drug: Siplizumab<br>* Weekly siplizumab doses for a total of 12 weeks<br>* Other names: TCD 601;|
| Experimental: Adults with T1D 0.18 mg/kg SQ dose<br>Cohort 1 Group 3:0.18 mg/kg SQ dose for a total of 12 weeks | Drug: Siplizumab<br>* Weekly siplizumab doses for a total of 12 weeks<br>* Other names: TCD 601;|
| Experimental: Adults with T1D 0.22 mg/kg SQ dose<br>Cohort 1 Group 4: 0.22 mg/kg SQ dose for a total of 12 weeks | Drug: Siplizumab<br>* Weekly siplizumab doses for a total of 12 weeks<br>* Other names: TCD 601;|
| Experimental: Children with T1D 0.08 mg/kg SQ dose<br>Cohort 2 Group 1:0.08 mg/kg SQ dose for a total of 12 weeks | Drug: Siplizumab<br>* Weekly siplizumab doses for a total of 12 weeks<br>* Other names: TCD 601;|
| Experimental: Children with T1D 0.12 mg/kg SQ dose<br>Cohort 2 Group 2:0.12 mg/kg SQ dose for a total of 12 weeks | Drug: Siplizumab<br>* Weekly siplizumab doses for a total of 12 weeks<br>* Other names: TCD 601;|
| Experimental: Children with T1D 0.18 mg/kg SQ dose<br>Cohort 2 Group 3: 0.18 mg/kg SQ dose for a total of 12 weeks | Drug: Siplizumab<br>* Weekly siplizumab doses for a total of 12 weeks<br>* Other names: TCD 601;|
| Experimental: Children with T1D 0.22 mg/kg SQ dose<br>Cohort 2 Group 4: 0.22 mg/kg SQ dose for a total of 12 weeks | Drug: Siplizumab<br>* Weekly siplizumab doses for a total of 12 weeks<br>* Other names: TCD 601;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acceptable T cell phenotype signature by the change from baseline in the Programmed Cell Death 1 (PD1) during first 12 weeks. | 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. | From week 0 (baseline) to week 12 | 
| 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. | 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. | From week 0 (baseline) to week 12 | 
| 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. | 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. | From week 0 (baseline) to week 12 | 
| Acceptable T cell phenotype signature by the change from baseline in the CD4 Treg/Tem ratio | 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 | From week 0 (baseline) to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Adverse Event (AEs) in all siplizumab dosing arms | AE will include any untoward medical occurrence associated with siplizumab administration or any study-mandated procedure | From week 0 to week 52 | 
| Mixed Meal Tolerance Test (MMTT)-stimulated mean 2-hour C-peptide AUC | The mean 2-hour C-peptide AUC, measured in pmol/ml, is computed by dividing the total AUC by 120 minutes | At Week 12, 24, 36, 52 | 
| Insulin use (U/kg/day) | 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 | At Weeks 6, 12, 24, 36 and 52. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
diabetic, Type 1 diabetes, T1DM, siplizumab