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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 Recently Diagnosed Type 1 Diabetes Mellitus (T1D)

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ClinicalTrials.gov Identifier: NCT03751007
Recruitment Status : Recruiting
First Posted : November 22, 2018
Last Update Posted : March 5, 2019
Sponsor:
Collaborators:
ActoBio Therapeutics
TFS Trial Form Support
Information provided by (Responsible Party):
Intrexon T1D Partners, LLC

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 who recently developed Type 1 Diabetes Mellitus (T1D).

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 1 Biological: AG019 - Low Dose Drug: Teplizumab Drug: Placebo-AG019 Drug: Placebo-Teplizumab Biological: AG019 - High Dose Biological: AG019 - Low or 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 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).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 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 27, 2018
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

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).




Primary Outcome Measures :
  1. 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 [ Time Frame: up to 6 months from screening ]

Secondary Outcome Measures :
  1. Immune marker cell count in systemic circulation. [ Time Frame: Up to 12 months after initiation of the treatment ]
    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

  2. Cytokines/chemokines in systemic circulation. [ Time Frame: Up to 12 months after initiation of the treatment ]
    Cytokines/chemokines will be measured in pg/mL and may include: interferon(IFN)-gamma, IL-10 and chemokine receptor type 6 (CCR6)

  3. AG019 in systemic circulation [ Time Frame: Up to 12 months after initiation of the treatment ]
    The presence of live L. Lactis bacteria in blood will be assessed by plating

  4. L. Lactis-secreted hPINS or hIL-10 in systemic circulation [ Time Frame: Up to 12 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)

  5. AG019 in feces [ Time Frame: Up to 12 months after initiation 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)


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


Information from the National Library of Medicine

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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)
  • 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

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


Contacts
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Contact: Sven Blomme +32 9 277 11 77 sblomme@actobio.com
Contact: Stefan Herdinius +32 9 277 11 77 sherdinius@actobio.com

Locations
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United States, Alabama
University of Alabama, Birmingham Not yet recruiting
Birmingham, Alabama, United States, 35294
Contact: Tammy Perkins    205-934-4112    tlperkins@uabmc.edu   
Principal Investigator: Fernando Ovalle, MD         
United States, California
University of California, San Francisco Not yet recruiting
San Francisco, California, United States, 94158
Contact: Christine Torok, RN    415-502-9089    christine.torok@ucsf.edu   
Principal Investigator: Steve Gitelman, MD         
Coastal Metabolic Research Centre Not yet recruiting
Ventura, California, United States, 93003
Principal Investigator: Ronald H Chochinov, MD         
United States, Colorado
University of Colorado Not yet recruiting
Aurora, Colorado, United States, 80045
Contact: Hali Broncucia    303-724-7526    hali.broncucia@ucdenver.edu   
Principal Investigator: Peter Gottlieb, MD         
United States, Connecticut
Yale Center for Clinical Investigation Recruiting
New Haven, Connecticut, United States, 06519
Contact: Linda Ryall    203-737-4510    linda.ryall@yale.edu   
Principal Investigator: Kevan Herold, M.D.         
United States, Florida
Avail Clinical Research Not yet recruiting
DeLand, Florida, United States, 32720
Contact: Gail Lavine    386-785-2400 ext 308    glavine@accelclinical.com   
Principal Investigator: Lee Metchick, MD         
University of Miami Not yet recruiting
Miami, Florida, United States, 33136
Contact: Della Matheson, RN, CDE    305-243-3781    dmatheso@med.miami.edu   
Principal Investigator: David Baidal, MD         
University of South Florida Not yet recruiting
Tampa, Florida, United States, 33612
Contact: Emily Eyth    813-974-2793    emilyeyth@health.usf.edu   
Principal Investigator: Henry Rodriguez, MD         
United States, Indiana
Riley Hospital for Childen at IU Health Not yet recruiting
Indianapolis, Indiana, United States, 46202
Contact: Maria Spall    1-317-278-7034    malnicho@iu.edu   
Principal Investigator: Hebatullah Ismail, MB BCh,MSc,PHD         
United States, Maryland
Barry J Reiner, MD, LLC Recruiting
Baltimore, Maryland, United States, 21229
Contact: Ranessa Labovitz    410-646-4009    bjrstudy@gmail.com   
Principal Investigator: Barry J Reiner, MD         
United States, Minnesota
University of Minnesota Health Not yet recruiting
Minneapolis, Minnesota, United States, 55454
Contact: Janice Leschyshyn       lesch004@umn.edu   
Principal Investigator: Antoinette Moran, MD         
United States, Missouri
University of Missouri-Kansas City School of Medicine Not yet recruiting
Kansas City, Missouri, United States, 64108
Contact: Jennifer Bedard    816-960-8940    jabedard@cmh.edu   
Principal Investigator: Wayne Moore, MD, PhD         
United States, Pennsylvania
Children's Hospital of Philadelphia Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Fiona Stuart    215-590-3668    stuartf@email.chop.edu   
Principal Investigator: Steve Willi, MD         
United States, South Dakota
Sanford Children's Specialty Clinic Not yet recruiting
Sioux Falls, South Dakota, United States, 57117
Contact: Christina Huber    605-328-8741    Christina.Huber@sanfordhealth.org   
Principal Investigator: Kurt Griffin, MD         
United States, Tennessee
University Diabetes and Endocrine Consultants Recruiting
Chattanooga, Tennessee, United States, 37411
Contact: Ashley Miller    423-265-3561 ext 112    amiller@drhuffman.com   
Principal Investigator: David M Huffman, MD         
United States, Texas
Research Institute of Dallas Recruiting
Dallas, Texas, United States, 75231
Contact: Stephen Louis Aronoff    214-265-2137    research@researchdallas.com   
Principal Investigator: Stephen Louis Aronoff, MD         
United States, Washington
Benaroya Research Institute Not yet recruiting
Seattle, Washington, United States, 98101
Contact: Marli McCulloch-Olson    206-342-6943    marli@benaroyaresearch.org   
Principal Investigator: Carla Greenbaum, MD         
Belgium
UZ Brussel Not yet recruiting
Brussels, Belgium, 1090
Contact: Valérie Van Damme    +32 2 477 77 60    valerie.vandamme@uzbrussel.be   
Principal Investigator: Bart Keymeulen, MD         
UZ Antwerpen Not yet recruiting
Edegem, Belgium, 2650
Contact: Rie Braspenning    +3238214002    rie.braspenning@uza.be   
Principal Investigator: Christophe de Block, MD         
UZ Leuven Recruiting
Leuven, Belgium, 3000
Contact: Morobe Hilde    +3216340748    hilde.morobe@uzleuven.be   
Principal Investigator: Chantal Mathieu, MD         
Sponsors and Collaborators
Intrexon T1D Partners, LLC
ActoBio Therapeutics
TFS Trial Form Support
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

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Responsible Party: Intrexon T1D Partners, LLC
ClinicalTrials.gov Identifier: NCT03751007     History of Changes
Other Study ID Numbers: AG019-T1D-101
2017-002871-24 ( EudraCT Number )
First Posted: November 22, 2018    Key Record Dates
Last Update Posted: March 5, 2019
Last Verified: March 2019

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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