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)

Sponsor

Precigen Actobio T1D, LLC (Industry)

Overall Status

Completed

CT.gov ID

NCT03751007

Collaborator

Intrexon Actobiotics NV, d/b/a Precigen Actobio (Other), TFS Trial Form Support (Industry)

Enrollment

Locations

Arms

35.5

Actual Duration (Months)

2.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

Study Design

Study Type:

Interventional

Actual Enrollment :

42 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.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 :

Oct 27, 2018

Actual Primary Completion Date :

Oct 13, 2021

Actual Study Completion Date :

Oct 13, 2021

Arms and Interventions

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).

Outcome Measures

Primary Outcome Measures

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

Immune marker cell count in systemic circulation. [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
Cytokines/chemokines in systemic circulation. [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)
AG019 in systemic circulation [Up to 12 months after initiation of the treatment]
The presence of live L. Lactis bacteria in blood will be assessed by plating
L. Lactis-secreted hPINS or hIL-10 in systemic circulation [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)
AG019 in feces [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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama, Birmingham	Birmingham	Alabama	United States	35294
2	University of California, San Francisco	San Francisco	California	United States	94158
3	Coastal Metabolic Research Centre	Ventura	California	United States	93003
4	University of Colorado	Aurora	Colorado	United States	80045
5	Yale Center for Clinical Investigation	New Haven	Connecticut	United States	06519
6	University of Miami	Miami	Florida	United States	33136
7	University of South Florida	Tampa	Florida	United States	33612
8	Barry J Reiner, MD, LLC	Baltimore	Maryland	United States	21229
9	University of Minnesota Health	Minneapolis	Minnesota	United States	55454
10	University of Missouri-Kansas City School of Medicine	Kansas City	Missouri	United States	64108
11	Sanford Children's Specialty Clinic	Sioux Falls	South Dakota	United States	57117
12	University Diabetes and Endocrine Consultants	Chattanooga	Tennessee	United States	37411
13	Texas Diabetes & Endocrinology, P.A.	Austin	Texas	United States	78749
14	Research Institute of Dallas	Dallas	Texas	United States	75231
15	Benaroya Research Institute	Seattle	Washington	United States	98101
16	UZ Brussel	Brussels		Belgium	1090
17	UZ Antwerpen	Edegem		Belgium	2650
18	UZ Leuven	Leuven		Belgium	3000

Sponsors and Collaborators

Precigen Actobio T1D, LLC
Intrexon Actobiotics NV, d/b/a Precigen Actobio
TFS Trial Form Support

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 Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Precigen Actobio T1D, LLC

ClinicalTrials.gov Identifier:

NCT03751007

Other Study ID Numbers:

AG019-T1D-101
2017-002871-24

First Posted:

Nov 23, 2018

Last Update Posted:

Nov 10, 2021

Last Verified:

Nov 1, 2021

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Diabetes Mellitus

Diabetes Mellitus, Type 1

Study Results

No Results Posted as of Nov 10, 2021