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

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)

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 who recently developed Type 1 Diabetes Mellitus (T1D).

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Biological: AG019 - Low Dose; Biological: AG019 - High Dose; Drug: Teplizumab; Drug: Placebo-AG019; Drug: Placebo-Teplizumab; Biological: AG019 - Low or High Dose

Detailed Description

This Phase 1b/2a, multi-center study will be conducted in participants with clinical recent-onset Type 1 Diabetes Mellitus (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 association with teplizumab. The secondary objectives of this study are: to obtain pharmacodynamic (PD) data of AG019 alone as well as AG019 in association 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 association with teplizumab, in 2 age groups (18-40 years of age and 12-17 years of age).

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1090
    • UZ Brussel
  • Edegem, Belgium, 2650
    • UZ Antwerpen
  • Leuven, Belgium, 3000
    • UZ Leuven
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama, Birmingham
  • California
    • San Francisco, California, United States, 94158
      • University of California, San Francisco
    • Ventura, California, United States, 93003
      • Coastal Metabolic Research Centre
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale Center for Clinical Investigation
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • Barry J Reiner, MD, LLC
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • University of Minnesota Health
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • University of Missouri-Kansas City School of Medicine
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117
      • Sanford Children's Specialty Clinic
  • Tennessee
    • Chattanooga, Tennessee, United States, 37411
      • University Diabetes and Endocrine Consultants
  • Texas
    • Austin, Texas, United States, 78749
      • Texas Diabetes & Endocrinology, P.A.
    • Dallas, Texas, United States, 75231
      • Research Institute Of Dallas
  • Washington
    • Seattle, Washington, United States, 98101
      • Benaroya Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 40 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AG019 Cohort 1 - Low Dose/Adults	Biological: AG019 - Low Dose; Solid, orally administered capsule - 2 capsules per day for 1 day (single dose) or 8 weeks (repeat dose)
Experimental: AG019 Cohort 2 - High Dose/Adults	Biological: AG019 - High Dose; Solid, orally administered capsule - 6 capsules per day for 1 day (single dose) or 8 weeks (repeat dose)
Experimental: AG019 Cohort 3 - Low Dose/Adolescents	Biological: AG019 - Low Dose; Solid, orally administered capsule - 2 capsules per day for 1 day (single dose) or 8 weeks (repeat dose)
Experimental: AG019 Cohort 4 - High Dose/Adolescents	Biological: AG019 - High Dose; Solid, orally administered capsule - 6 capsules per day for 1 day (single dose) or 8 weeks (repeat dose)
Experimental: Combination Cohort 1 - Adults	Drug: Teplizumab; 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).; Drug: Placebo-AG019; Formulated identically to AG019 with the active ingredient removed.; Drug: Placebo-Teplizumab; Formulated identically to teplizumab with the active ingredient removed.; Biological: AG019 - Low or High Dose; Solid, orally administered capsule - 2 or 6 capsules per day for 8 weeks (repeat dose).
Experimental: Combination Cohort 2 - Adolescents	Drug: Teplizumab; 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).; Drug: Placebo-AG019; Formulated identically to AG019 with the active ingredient removed.; Drug: Placebo-Teplizumab; Formulated identically to teplizumab with the active ingredient removed.; Biological: AG019 - Low or High Dose; Solid, orally administered capsule - 2 or 6 capsules per day for 8 weeks (repeat dose).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of participants with treatment-related adverse events assessed by the investigator, review of lab reports and information provided by the participant during site visits and/or participant diary during treatment with AG019 alone or with teplizumab	up to 6 months from screening

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune marker cell count in systemic circulation.	Immune markers will be measured in cells/mm^3 and may include: human proinsulin (hPINS), specific cluster of differentiation(CD)4+ T cells and circulating interleukin-10 (IL-10) producing CD4+ T cells	Up to 12 months after initiation of the treatment
Cytokines/chemokines in systemic circulation.	Cytokines/chemokines will be measured in pg/mL and may include: interferon(IFN)-gamma, IL-10 and chemokine receptor type 6 (CCR6)	Up to 12 months after initiation of the treatment
AG019 in systemic circulation	The presence of live L. Lactis bacteria in blood will be assessed by plating	Up to 12 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 12 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 12 months after initiation of the treatment

Other Outcome Measures

Outcome Measure	Time Frame
Number of participants with treatment-emergent adverse events as assessed by the investigator observed at timepoints other than those specified in the Primary Outcome.	Up to 12 months from screening

Collaborators and Investigators

• Sponsor: Precigen Actobio T1D, LLC
• Collaborators: TFS Trial Form Support; Intrexon Actobiotics NV, d/b/a Precigen Actobio
• Investigators: Principal Investigator: Chantal Mathieu, MD, University Hospital of Leuven, Clinical and Experimental Endocrinology; Principal Investigator: Kevan Herold, MD, Yale Center for Clinical Investigation; Yale University

Study record dates

Study Major Dates

• Study Start (Actual): October 27, 2018
• Primary Completion (Actual): October 13, 2021
• Study Completion (Actual): October 13, 2021

Study Registration Dates

• First Submitted: November 8, 2018
• First Submitted That Met QC Criteria: November 20, 2018
• First Posted (Actual): November 23, 2018

Study Record Updates

• Last Update Posted (Actual): November 10, 2021
• Last Update Submitted That Met QC Criteria: November 9, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: AG019-T1D-101; 2017-002871-24 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No