Clinical trial NCT05574335: Siplizumab in T1DM
Official title: A T Cell Phenotype Signature Driven Dose Finding Study With Siplizumab in Type 1 Diabetes Mellitus (ITN095AI)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Type 1 Diabetes Mellitus
Keywords: diabetic
Type 1 diabetes
T1DM
siplizumab
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2022-10-10
Enrollment: 120
Sex: ALL
Minimum age (years): 8
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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 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.

Primary outcomes:
measure: Acceptable T cell phenotype signature by the change from baseline in the Programmed Cell Death 1 (PD1) during the first 12 weeks.
timeFrame: From week 0 (baseline) to week 12
measure: 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.
timeFrame: From week 0 (baseline) to week 12
measure: 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.
timeFrame: From week 0 (baseline) to week 12
measure: Acceptable T cell phenotype signature by the change from baseline in the CD4 Treg/Tem ratio
timeFrame: From week 0 (baseline) to week 12
Secondary outcomes:
measure: Frequency of Adverse Events (AEs) in all siplizumab dosing arms
timeFrame: From week 0 to week 52
measure: Mixed Meal Tolerance Test (MMTT)-stimulated mean 2-hour C-peptide AUC
timeFrame: At Week 12, 24, 36, 52
measure: Insulin use (U/kg/day)
timeFrame: At Weeks 12, 24, 36 and 52.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham: Division of Endocrinology, Diabetes and Metabolism
state: Alabama
city: San Francisco
country: United States
facility: UCSF School of Medicine: UCSF Diabetes Clinic
state: California
city: Stanford
country: United States
facility: Stanford School of Medicine: Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes
state: California
city: Aurora
country: United States
facility: University of Colorado School of Medicine: Barbara Davis Center for Diabetes
state: Colorado
city: Gainesville
country: United States
facility: University of Florida: Diabetes Center of Excellence
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine: Diabetes Research Institute
state: Florida
city: Tampa
country: United States
facility: University of South Florida: Diabetes Center
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine: Emory & Children's Pediatric Research Center, Division of Endocrinology & Diabetes
state: Georgia
city: Chicago
country: United States
facility: The University of Chicago: Duchossois Center for Academic Medicine-Hyde Park
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Medical Center: Riley Hospital for Children, Department of Pediatric Endocrinology & Diabetology
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Children's Hospital: Department of Pediatrics, Pediatric Endocrinology and Diabetes
state: Iowa
city: Boston
country: United States
facility: Joslin Diabetes Center: Joslin Clinic
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Medical School: Division of Pediatric Endocrinology and Diabetes
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospitals and Clinics: Section of Pediatric Endocrinology and Diabetes
state: Missouri
city: Buffalo
country: United States
facility: University at Buffalo, Department of Pediatrics: Division of Endocrinology and Diabetes
state: New York
city: New York
country: United States
facility: Columbia University Medical Center: Naomi Berrie Diabetes Center
state: New York
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia: Diabetes Center for Children
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center: Department of Internal Medicine, Division of Endocrinology
state: Texas
city: Seattle
country: United States
facility: Benaroya Research Institute at Virginia Mason: Diabetes Research Program
state: Washington
Study officials:
affiliation: University of California San Francisco, School of Medicine: Diabetes Center
name: Stephen Gitelman, M.D.
role: STUDY_CHAIR
References: