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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03751007
Recruitment Status : Completed
First Posted : November 23, 2018
Results First Posted : February 1, 2023
Last Update Posted : February 1, 2023
Sponsor:
Collaborator:
Intrexon Actobiotics NV, d/b/a Precigen Actobio
Information provided by (Responsible Party):
Precigen Actobio T1D, LLC

Study Description
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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).

Condition or disease Intervention/treatment Phase
Diabetes type1 Biological: AG019 - Low Dose Drug: Teplizumab Drug: Placebo-AG019 Drug: Placebo-Teplizumab Biological: AG019 - High Dose Phase 1 Phase 2

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).

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: For the randomized participants in the combination cohorts, blinding will be accomplished by arranging for AG019 and placebo components as well as teplizumab and placebo components to have identical packaging.
Primary Purpose: Treatment
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)
Actual Study Start Date : October 24, 2018
Actual Primary Completion Date : October 13, 2021
Actual Study Completion Date : October 13, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

Arms and Interventions
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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
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
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 - High Dose
Solid, orally administered capsule - 6 capsules per day for 8 weeks.
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 - High Dose
Solid, orally administered capsule - 6 capsules per day for 8 weeks.


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of Treatment-emergent Adverse Events (TEAE) [ Time Frame: up to 6 months ]
    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


Secondary Outcome Measures :
  1. AG019 in Systemic Circulation [ Time Frame: Up to 3 months after initiation of the treatment ]
    The presence of live L. lactis bacteria in blood will be assessed by plating

  2. L. Lactis-secreted hPINS or hIL-10 in Systemic Circulation [ Time Frame: Up to 3 months after initiation of the treatment ]
    The presence of L. lactis-secreted hPINS or hIL-10 in the blood will be assessed by ELISA (enzyme-linked immunosorbent assay)

  3. AG019 in Feces [ Time Frame: Up to 8 days after completion of the treatment ]
    The presence of L. lactis (live or dead) in feces will be assessed by Q-PCR (quantitative real-time polymerase chain reaction)

  4. C-peptide Area Under the Concentration-time Curve (AUC) Calculated From a 2 Hour Mixed Meal Tolerance Test (MMTT) at 12 Months [ Time Frame: up to 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.


Other Outcome Measures:
  1. Incidence of Treatment Emergent Adverse Events up to 12 Months [ Time Frame: Up to 12 months from screening ]
    Incidence of all reported TEAE up to the 12-month follow-up visit. The TEAE are counted once within each patient on the preferred term level.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years to 40 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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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): NCT03751007


Locations
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Sponsors and Collaborators
Precigen Actobio T1D, LLC
Intrexon Actobiotics NV, d/b/a Precigen Actobio
Investigators
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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 Documents (Full-Text)

Documents provided by Precigen Actobio T1D, LLC:
Study Protocol  [PDF] June 11, 2020
Statistical Analysis Plan  [PDF] May 28, 2021

More Information
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Responsible Party: Precigen Actobio T1D, LLC
ClinicalTrials.gov Identifier: NCT03751007    
Other Study ID Numbers: AG019-T1D-101
2017-002871-24 ( EudraCT Number )
First Posted: November 23, 2018    Key Record Dates
Results First Posted: February 1, 2023
Last Update Posted: February 1, 2023
Last Verified: January 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
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