Clinical trial NCT03751007: 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)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Diabetes type1
Lead sponsor: Precigen Actobio T1D, LLC
Sponsor class: INDUSTRY
Collaborators: name: Intrexon Actobiotics NV, d/b/a Precigen Actobio
First posted: 2018-11-23
Enrollment: 45
Sex: ALL
Minimum age (years): 12
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Incidence of Treatment-emergent Adverse Events (TEAE)
timeFrame: up to 6 months
Secondary outcomes:
measure: AG019 in Systemic Circulation
timeFrame: Up to 3 months after initiation of the treatment
measure: L. Lactis-secreted hPINS or hIL-10 in Systemic Circulation
timeFrame: Up to 3 months after initiation of the treatment
measure: AG019 in Feces
timeFrame: Up to 8 days after completion of the treatment
measure: C-peptide Area Under the Concentration-time Curve (AUC) Calculated From a 2 Hour Mixed Meal Tolerance Test (MMTT) at 12 Months
timeFrame: up to 12 months
Other outcomes:
measure: Incidence of Treatment Emergent Adverse Events up to 12 Months
timeFrame: Up to 12 months from screening
Locations:
city: Birmingham
country: United States
facility: University of Alabama, Birmingham
state: Alabama
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Ventura
country: United States
facility: Coastal Metabolic Research Centre
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale Center for Clinical Investigation
state: Connecticut
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Baltimore
country: United States
facility: Barry J Reiner, MD, LLC
state: Maryland
city: Minneapolis
country: United States
facility: University of Minnesota Health
state: Minnesota
city: Kansas City
country: United States
facility: University of Missouri-Kansas City School of Medicine
state: Missouri
city: Sioux Falls
country: United States
facility: Sanford Children's Specialty Clinic
state: South Dakota
city: Chattanooga
country: United States
facility: University Diabetes and Endocrine Consultants
state: Tennessee
city: Austin
country: United States
facility: Texas Diabetes & Endocrinology, P.A.
state: Texas
city: Dallas
country: United States
facility: Research Institute of Dallas
state: Texas
city: Seattle
country: United States
facility: Benaroya Research Institute
state: Washington
city: Brussels
country: Belgium
facility: UZ Brussel
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Leuven
country: Belgium
facility: UZ Leuven
Study officials:
affiliation: University Hospital of Leuven, Clinical and Experimental Endocrinology
name: Chantal Mathieu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale Center for Clinical Investigation; Yale University
name: Kevan Herold, MD
role: PRINCIPAL_INVESTIGATOR
References: