A Study to Assess the Safety and Tolerability of Different Doses of AG019 Administered Alone or in Combination With Teplizumab in Participants With Recent-onset Diagnosed Type 1 Diabetes (T1D)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the safety and tolerability of different doses of AG019 administered alone or in combination with teplizumab in participants with recent-onset type 1 diabetes (T1D).

Detailed Description
-----------------
This Phase 1b/2a, multi-center study will be conducted in participants with clinical recent-onset type 1 diabetes (T1D). The primary objective of this study is to assess the safety and tolerability of different doses of AG019 alone as well as AG019 in combination with teplizumab. The secondary objectives of this study are: to obtain pharmacodynamic (PD) data of AG019 alone as well as AG019 in combination with teplizumab; and to determine the potential presence of AG019 in systemic circulation (safety - systemic exposure) and the presence of L. lactis bacteria in fecal excretion (local exposure): Pharmacokinetic (PK) profile. This study consists of 2 phases: Phase 1b: this open-label part of the study will investigate the safety and tolerability of 2 different doses of AG019 in 2 age groups (18-40 years of age and 12-17 years of age). Phase 2a: this randomized, double-blind part of the study will investigate the safety and tolerability of AG019, in combination with teplizumab, in 2 age groups (18-40 years of age and 12-17 years of age).

Official Title
-----------------
A Prospective, Multi-center, Phase 1b/2a Study to Assess the Safety and Tolerability of Different Doses of AG019 Administered Alone or in Association With Teplizumab in Patients With Clinical Recent-onset Type 1 Diabetes Mellitus (T1D)

Conditions
-----------------
Diabetes type1

Intervention / Treatment
-----------------
* Biological: AG019 - Low Dose
* Drug: Teplizumab
* Drug: Placebo-AG019
* Drug: Placebo-Teplizumab
* Biological: AG019 - High Dose
* Biological: AG019 - High Dose


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or non-pregnant, non-lactating females, 18 - 40 years of age (both inclusive) or 12-17 years of age (both inclusive) Diagnosis of diabetes according to the American Diabetes Association (ADA) recommended criteria Evidence of auto-antibodies to at least 1 β-cell autoantigen Stimulated C-peptide measured during 4h Mixed Meal tolerance Test (MMTT) > 0.2 nmol/L The first administration of AG019 should occur no later than 150 days post diagnosis of diabetes Body weight ≥ 33kg Written informed consent obtained and documented (participant, parent, guardian as applicable) Exclusion Criteria: Previous history of serious cytokine release syndrome to teplizumab or other humanized anti-CD3 monoclonal antibodies with no or minimal capacity to bind Fc receptors. (Participants enrolled in the second phase of the trial in either Combination Cohort 1 or Combination Cohort 2, only) Use of immunosuppressive or immunomodulatory therapies, including systemic steroids within 1 month prior to randomization Participation in another investigational drug trial within 12 weeks prior to the first study drug intake and during participation in this study History of recurrent infections, other autoimmune diseases, cardiac disease, malignancy, or any other (chronic) medical condition which, in the investigator's opinion, could compromise participant safety Documented history of human immunodeficiency virus (HIV), Hepatitis Virus Type C (HCV), Hepatitis Virus Type B (HBV) infection Evidence of active infection with Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) Evidence of active or latent tuberculosis (TB) Administration of anti-CD3 antibody in past year Current therapy with any other anti-diabetic agents other than insulin (MDI, CSII or analogue). Current or planned therapy with experimental (i.e., unapproved) insulin. Patients on therapy for type 2 diabetes (e.g. metformin) should stop their therapy in order to be eligible for study participation. Use of medications known to influence glucose tolerance Daily use of non-steroidal anti-inflammatory agents Compromised GI mucosal integrity or motility, not attributable to T1D (i.e., recent diarrhea, gluten sensitive enteropathy, inflammatory bowel disease, irritable bowel syndrome), or current use of medications known to influence GI motility Positive result of SARS-Cov2 PCR test at screening or within 3 days before randomization

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 40 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: Sequential Assignment
Interventional Model Description: The phase 1b part of the study will enroll 4 sequential AG019 cohorts of up to 6 participants, in ascending dose cohorts and descending age cohorts. All participants in these cohorts will be treated with AG019 in an open label fashion. The phase 2a part of the study will evaluate 2 cohorts of participants administered AG019 and teplizumab. The first 2 participants will be treated with active treatment in an open label fashion. Participants 3-12 will be randomized (4:1) to receive active treatment or placebo in a double-blind fashion.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AG019 Cohort 1 - Low Dose/Adults<br> | Biological: AG019 - Low Dose<br>* Solid, orally administered capsule - 2 capsules per day for 1 day (single dose) or 8 weeks (repeat dose)<br>|
| Experimental: AG019 Cohort 2 - High Dose/Adults<br> | Biological: AG019 - High Dose<br>* Solid, orally administered capsule - 6 capsules per day for 1 day (single dose) or 8 weeks<br>|
| Experimental: AG019 Cohort 3 - Low Dose/Adolescents<br> | Biological: AG019 - Low Dose<br>* Solid, orally administered capsule - 2 capsules per day for 1 day (single dose) or 8 weeks (repeat dose)<br>|
| Experimental: AG019 Cohort 4 - High Dose/Adolescents<br> | Biological: AG019 - High Dose<br>* Solid, orally administered capsule - 6 capsules per day for 1 day (single dose) or 8 weeks<br>|
| Experimental: Combination Cohort 1 - Adults<br> | Drug: Teplizumab<br>* Daily IV infusions of Teplizumab during the first 12 days of AG019 treatment. Total cumulative dose is approximately 17mg (dose calculation based on body surface area).<br>Drug: Placebo-AG019<br>* Formulated identically to AG019 with the active ingredient removed.<br>Drug: Placebo-Teplizumab<br>* Formulated identically to teplizumab with the active ingredient removed.<br>Biological: AG019 - High Dose<br>* Solid, orally administered capsule - 6 capsules per day for 8 weeks.<br>|
| Experimental: Combination Cohort 2 - Adolescents<br> | Drug: Teplizumab<br>* Daily IV infusions of Teplizumab during the first 12 days of AG019 treatment. Total cumulative dose is approximately 17mg (dose calculation based on body surface area).<br>Drug: Placebo-AG019<br>* Formulated identically to AG019 with the active ingredient removed.<br>Drug: Placebo-Teplizumab<br>* Formulated identically to teplizumab with the active ingredient removed.<br>Biological: AG019 - High Dose<br>* Solid, orally administered capsule - 6 capsules per day for 8 weeks.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-emergent Adverse Events (TEAE) | Treatment-emergent adverse events assessed by the investigator, review of lab reports and information provided by the participant during site visits and/or participant diary with AG019 alone or with teplizumab | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AG019 in Systemic Circulation | The presence of live L. lactis bacteria in blood will be assessed by plating | Up to 3 months after initiation of the treatment | 
| L. Lactis-secreted hPINS or hIL-10 in Systemic Circulation | The presence of L. lactis-secreted hPINS or hIL-10 in the blood will be assessed by ELISA (enzyme-linked immunosorbent assay) | Up to 3 months after initiation of the treatment | 
| AG019 in Feces | The presence of L. lactis (live or dead) in feces will be assessed by Q-PCR (quantitative real-time polymerase chain reaction) | Up to 8 days after completion of the treatment | 
| C-peptide Area Under the Concentration-time Curve (AUC) Calculated From a 2 Hour Mixed Meal Tolerance Test (MMTT) at 12 Months | MMTT-stimulated 2-hour C-peptide AUC was defined as the mean area under the C-peptide level time curve over the 2-hour period divided by the duration after a mixed-meal tolerance test. | up to 12 months |