A Research Trial of Aralast in New Onset Diabetes (RETAIN) (RETAIN)

Effect of Intravenous Alpha-1 Antitrypsin on Preserving Beta-cell Function in New-onset Type 1 Diabetes Mellitus (ITN041AI)

The drug Alpha-1 Antitrypsin (AAT, Aralast NP) is being tested in this study as an anti-inflammatory drug (a medication that decreases inflammation, which is part of the body's normal ability to fight infection and respond to injuries) that affects the cells thought to be involved in the development of type 1 diabetes mellitus (T1DM, T1D).

All subjects enrolled in this study have new-onset T1DM (diagnosis of T1DM within 100 days of Visit 0; T1DM diagnosis fulfilling American Diabetes Association standard T1DM criteria). The focus of Part I of this trial (NCT01183468) is pharmacokinetics (PK), pharmacodynamics (PD) and safety. Upon completion of Part I, including a satisfactory safety review, enrollment in Part II (NCT01183455, Phase II Clinical Trial) will begin.

Study Overview

• Status: Terminated
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Biological: Aralast NP 45 mg dose; Biological: Aralast NP 90 mg dose; Biological: Aralast NP 180 mg dose

Detailed Description

Researchers are interested in conducting this study to assess whether Aralast NP (AAT, Alpha-1 Antitrypsin ) will help slow the progression of T1DM.

Part I of this study has two parts:-1a and -1b:

Part 1a (Complete): An open-label, dose-escalation, PK, PD and safety study. Participants receive 12 intravenous (IV) infusions of Aralast NP. Infusions 1 through 6 are administered at 45 mg/kg/wk and infusions 7 through 12 are administered at 90 mg/kg/wk.

Part Ia consists of two groups:

• Subjects aged 16 - 35 years at enrollment with new-onset T1DM
• Subjects aged 8 -15 years at enrollment with new-onset T1DM.

Part 1b (study terminated prior to subject enrollment): An open-label, dose-escalation PK, PD and safety study in which participants receive 12 infusions of Aralast NP. Infusions 1 through 6 are administered at 90 mg/kg/wk and infusions 7 through 12 are administered at 180 mg/kg/wk. Part Ib consists of two groups:

• Subjects aged 16 - 35 years at enrollment with new-onset T1DM
• Subjects 8 - 15 years at enrollment with new-onset T1DM.

Participants in Part Ib do not roll over into Part II (Refer to NCT01183455).

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92093
      • RADY Children's Hospital (University of California, San Diego)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Barbara Davis Center (University of Colorado)
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Atlanta Diabetes Associates
    • Atlanta, Georgia, United States, 30322
      • Children's Hospital of Atlanta (Emory University)
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Children's Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • New York
    • New York, New York, United States, 10032
      • Naomi Berrie Diabetes Center (Columbia University)
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Washington
    • Seattle, Washington, United States, 98122
      • Pacific Northwest Research Institute-University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 35 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosed with T1DM within the past 100 days (of enrollment)
• Positive for at least one diabetes-related autoantibody (Anti-GAD; Anti-insulin, if obtained within 10 days of the onset of insulin therapy; IA-2 antibody and/or ICA, or ZnT8.)
• Peak stimulated C-peptide level > 0.2 pmol/mL following a mixed meal tolerance test (MMTT)

Exclusion Criteria:

• Severe active disease (chronic active hepatitis; cardiac, pulmonary disease, hepatic, renal or immunodeficiency)
• History of any bleeding or clotting factor deficiencies, or stroke
• History of vascular disease or significant vascular abnormalities
• Positive serology of exposure to (hepatitis B virus) HBV, HCV (hepatitis C virus), HIV (human immunodeficiency virus) or toxoplasmosis
• Clinically active infection with EBV (Epstein-Barr virus), CMV (cytomegalovirus), or tuberculosis(TB)
• Prior or current use of oral, inhaled or intranasal glucocorticoids, or any medication known to cause a significant, ongoing change in the course of T1DM or immunologic status
• Prior treatment with Alpha 1-Antitrypsin (Aralast NP, AAT) or hypersensitivity to alpha 1-antitrypsin or human plasma-derived products
• Current or prior (within the last 30 days) use of metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors or amylin
• Current use of any medication known to influence glucose tolerance (e.g., beta-blockers, angiotensin-converting enzyme inhibitors, interferons, quinidine anti-malarial drugs, lithium, niacin)
• Females who are pregnant or lactating, or are unwilling to defer pregnancy during study participation
• IgA (immunoglobulin A) deficiency
• Uncontrolled hypertension
• Current life-threatening malignancy
• Any condition that in the investigator's opinion may compromise study participation or may confound the interpretation of the study results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1a(Aralast NP)-Subjects Aged 16-35 Yrs; Subjects aged 16-35 years at enrollment with new-onset type 1 diabetes mellitus (T1DM) received Aralast NP 45 mg/kg by intravenous (IV) infusion once a week for 6 weeks. Following the Week 6 infusion, participants underwent a minimum 3-week washout period. After the washout period, each participant proceeded to a high dose of Aralast NP 90 mg/kg by IV infusion for the next 6 weeks, for a total of 12 infusions.	Biological: Aralast NP 45 mg dose; - 45 mg/kg/week; Other Names: AAT; Alpha 1-Antitrypsin; Biological: Aralast NP 90 mg dose; - 90 mg/kg/week; Other Names: AAT; Alpha 1-Antitrypsin
Experimental: Part 1a (Aralast NP)-Subjects 8-15 Yrs; Subjects aged 8-15 years at enrollment with new-onset type 1 diabetes mellitus (T1DM) received Aralast NP 45 mg/kg by IV infusion once a week for 6 weeks. Following the Week 6 infusion, participants underwent a minimum 3-week washout period. After the washout period, each participant proceeded to a high dose of Aralast NP 90 mg/kg by IV infusion for the next 6 weeks, for a total of 12 infusions.	Biological: Aralast NP 45 mg dose; - 45 mg/kg/week; Other Names: AAT; Alpha 1-Antitrypsin; Biological: Aralast NP 90 mg dose; - 90 mg/kg/week; Other Names: AAT; Alpha 1-Antitrypsin
Experimental: Part 1b (Aralast NP)--Subjects Aged 18-35 Yrs; Aralast NP 90 mg/kg/wk by IV infusion once a week for 6 weeks. Following the Week 6 infusion, participants undergo a minimum 3-wk washout period than then, each participant proceeds to high dose Aralast NP 180 mg/kg/wk by IV infusion for the next 6 weeks, for a total of 12 infusions.	Biological: Aralast NP 90 mg dose; - 90 mg/kg/week; Other Names: AAT; Alpha 1-Antitrypsin; Biological: Aralast NP 180 mg dose; - 180 mg/kg/week; Other Names: AAT; Alpha-1 Antitrypsin
Experimental: Part 1b (Aralast NP)-Subjects 8-17 Yrs; Aralast NP 90 mg/kg/wk by IV infusion once a week for 6 weeks. Following the Week 6 infusion, participants undergo a minimum 3-wk washout period than then, each participant proceeds to high dose Aralast NP 180 mg/kg/wk by IV infusion for the next 6 weeks, for a total of 12 infusions.	Biological: Aralast NP 90 mg dose; - 90 mg/kg/week; Other Names: AAT; Alpha 1-Antitrypsin; Biological: Aralast NP 180 mg dose; - 180 mg/kg/week; Other Names: AAT; Alpha-1 Antitrypsin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
C-peptide 2-hour AUC in Response to a Mixed-meal Tolerance Test at Week 52	No results for the primary outcome measure are available since the study was terminated prior to reaching the outcome measure time frame of 52 weeks.	Week 52

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Juvenile Diabetes Research Foundation; Immune Tolerance Network (ITN)
• Investigators: Study Chair: Gordon Weir, MD, Joslin Diabetes Center

Publications and helpful links

General Publications

• Ozeri E, Mizrahi M, Shahaf G, Lewis EC. alpha-1 antitrypsin promotes semimature, IL-10-producing and readily migrating tolerogenic dendritic cells. J Immunol. 2012 Jul 1;189(1):146-53. doi: 10.4049/jimmunol.1101340. Epub 2012 May 25.

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID) website
• Immune Tolerance Network (ITN) website
• Juvenile Diabetes Research Foundation (JDRF)

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: August 16, 2010
• First Submitted That Met QC Criteria: August 16, 2010
• First Posted (Estimate): August 17, 2010

Study Record Updates

• Last Update Posted (Actual): June 13, 2018
• Last Update Submitted That Met QC Criteria: May 14, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: AAT; Diabetes, Autoimmune; Alpha-1 Antitrypsin; Diabetes Mellitus, Type 1 (new-onset); Diabetes Mellitus, Insulin-Dependent (new-onset); new-onset T1DM; new-onset T1D; Diabetes Mellitus, Juvenile-Onset; Aralast NP
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Trypsin Inhibitors; Alpha 1-Antitrypsin; Protein C Inhibitor
• Other Study ID Numbers: DAIT ITN041AI Part 1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Participant level data and additional relevant materials are available to the public in TrialShare, the Immune Tolerance Network (ITN) Clinical Trials Research Portal.
• IPD Sharing Time Frame: IPD is now available in TrialShare.
• IPD Sharing Access Criteria: Open to the public.

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: RETAIN ITN041AI
   Information comments: RETAIN ITN041AI is the Study Identifier in the Immune Tolerance Network (ITN) TrialShare Clinical Trials Research Portal