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

• ClinicalTrials.gov Identifier: NCT01183468
• Recruitment Status: Terminated
• First Posted: August 17, 2010
• Results First Posted: January 16, 2015
• Last Update Posted: June 13, 2018
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Immune Tolerance Network (ITN); Juvenile Diabetes Research Foundation
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 1	Biological: Aralast NP 45 mg dose; Biological: Aralast NP 90 mg dose; Biological: Aralast NP 180 mg dose	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 17 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effect of Intravenous Alpha-1 Antitrypsin on Preserving Beta-cell Function in New-onset Type 1 Diabetes Mellitus (ITN041AI)
• Study Start Date: October 2010
• Actual Primary Completion Date: July 2013
• Actual Study Completion Date: July 2013

Arms and Interventions

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: Alpha 1-Antitrypsin; AAT; Biological: Aralast NP 90 mg dose; - 90 mg/kg/week; Other Names: Alpha 1-Antitrypsin; AAT
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: Alpha 1-Antitrypsin; AAT; Biological: Aralast NP 90 mg dose; - 90 mg/kg/week; Other Names: Alpha 1-Antitrypsin; AAT
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: Alpha 1-Antitrypsin; AAT; Biological: Aralast NP 180 mg dose; - 180 mg/kg/week; Other Names: Alpha-1 Antitrypsin; AAT
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: Alpha 1-Antitrypsin; AAT; Biological: Aralast NP 180 mg dose; - 180 mg/kg/week; Other Names: Alpha-1 Antitrypsin; AAT

Outcome Measures

Primary Outcome Measures :

1. C-peptide 2-hour AUC in Response to a Mixed-meal Tolerance Test at Week 52 [ Time Frame: 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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, California

RADY Children's Hospital (University of California, San Diego)

San Diego, California, United States, 92093

United States, Colorado

Barbara Davis Center (University of Colorado)

Aurora, Colorado, United States, 80045

United States, Connecticut

Yale University

New Haven, Connecticut, United States, 06520

United States, Georgia

Atlanta Diabetes Associates

Atlanta, Georgia, United States, 30309

Children's Hospital of Atlanta (Emory University)

Atlanta, Georgia, United States, 30322

United States, Iowa

University of Iowa Children's Hospital

Iowa City, Iowa, United States, 52242

United States, Maryland

University of Maryland Medical Center

Baltimore, Maryland, United States, 21201

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Joslin Diabetes Center

Boston, Massachusetts, United States, 02215

University of Massachusetts Memorial Medical Center

Worcester, Massachusetts, United States, 01655

United States, Missouri

Children's Mercy Hospital

Kansas City, Missouri, United States, 64108

United States, New York

Naomi Berrie Diabetes Center (Columbia University)

New York, New York, United States, 10032

United States, Ohio

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

United States, Washington

Pacific Northwest Research Institute-University of Washington

Seattle, Washington, United States, 98122

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Immune Tolerance Network (ITN)

Juvenile Diabetes Research Foundation

Investigators

• Study Chair: Gordon Weir, MD; Joslin Diabetes Center

More Information

Additional Information:

National Institute of Allergy and Infectious Diseases (NIAID) website 

Immune Tolerance Network (ITN) website 

Juvenile Diabetes Research Foundation (JDRF) 

Study Data/Documents: Individual Participant Data Set 

Identifier: RETAIN ITN041AI
RETAIN ITN041AI is the Study Identifier in the Immune Tolerance Network (ITN) TrialShare Clinical Trials Research Portal

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT01183468
• Other Study ID Numbers: DAIT ITN041AI Part 1
• First Posted: August 17, 2010
• Results First Posted: January 16, 2015
• Last Update Posted: June 13, 2018
• Last Verified: May 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Time Frame: IPD is now available in TrialShare.
• Access Criteria: Open to the public.
• URL: https://www.itntrialshare.org/project/Studies/ITN041AIPUBLIC/Study%20Data/begin.view?pageId=study.DATA_ANALYSIS

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Diabetes Mellitus, Type 1 (new-onset); Diabetes Mellitus, Insulin-Dependent (new-onset); new-onset T1DM; new-onset T1D; Diabetes Mellitus, Juvenile-Onset; Diabetes, Autoimmune; Aralast NP; Alpha-1 Antitrypsin; AAT

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Alpha 1-Antitrypsin; Protein C Inhibitor; Trypsin Inhibitors; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action