A Research Trial of Aralast NP in New Onset Diabetes (RETAIN) - Part II (RETAIN)

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

Aralast NP (alpha-1 antitrypsin, AAT), an alpha-1 proteinase inhibitor (human), was the drug to be tested in this clinical trial. Aralast NP is an anti-inflammatory drug that affects the cells that are thought to be involved in the development of type 1 diabetes mellitus (T1DM, T1D). This study, known as RETAIN, was planned as a two-part trial to investigate the effect of Aralast NP on preserving beta cell function and to determine if the intervention would slow the progression of type 1 diabetes.

Part I of this trial (NCT 01183468) was an open-label, safety and dose level study consisting of two groups. After completion of Part I, including a satisfactory safety review, enrollment in Part II was to begin. Part II was designed as a two-arm, double-blind, placebo-controlled clinical trial, and participants were to be randomly assigned to either the Aralast NP treatment or placebo group.

Study Overview

• Status: Withdrawn
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Drug: Aralast NP; Drug: Placebo

Detailed Description

T1D is an autoimmune disease. This means that your immune system (the part of your body that helps fight infections) mistakenly attacks the cells that produce insulin (beta cells in the pancreas). As beta cells are destroyed by your immune cells, your ability to produce insulin is decreased. Insulin helps keep blood glucose levels normal.

Individuals with T1D who have the ability to produce some of their own insulin (even though they still need to take insulin) may be able to achieve better glucose control than people who produce no insulin at all. Better glucose control has been shown to reduce the long-term complications of diabetes. Previous research has shown that giving medicines to affect the immune system soon after type 1 diabetes is diagnosed may stop, delay or decrease the destruction of beta cells, resulting in better glucose control.

In mouse models of disease, alpha-1 proteinase inhibitors have been shown to reverse new-onset diabetes and induce a state of self-tolerance. The RETAIN clinical trial was intended to investigate the effect of Aralast NP on preserving beta cell function and slowing the progression of T1D.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093
      • University of California San Diego
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Barbara Davis Center
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Yale University
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Atlanta, Georgia, United States, 30309
      • Atlanta Diabetes Associates
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
    • Prince Frederick, Maryland, United States, 20678
      • Calvert Memorial Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
    • Worchester, Massachusetts, United States, 01655
      • University of Massachusetts Medical School
  • New York
    • New York, New York, United States, 10027
      • Columbia University
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Pennsylvania
    • Philadephia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
  • Texas
    • San Antonio, Texas, United States, 78229
      • Cetero Research San Antonio

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 type 1 diabetes (T1D) within the past 100 days
• 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 greater than (>) 0.2 pmol/mL following a mixed meal tolerance test (MMTT)

Exclusion Criteria:

• Severe active disease (hepatitis, cardiac or pulmonary disease, hypertension, immunodeficiency)
• History of any bleeding or clotting factor deficiencies, or stroke
• History of vascular disease or significant vascular abnormalities
• Positive serology exposure to hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or toxoplasmosis
• Clinically active infection with Epstein-Barr virus (EBV), cytomegalovirus (CMV), 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 T1D or immunologic status
• Prior treatment with alpha1-antitrypsin (AAT) or hypersensitivity to AAT 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
• Immunoglobulin A (IgA) 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: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aralast NP; Participants will receive Aralast NP (90mg/kg) intravenously once a week for 12 weeks.	Drug: Aralast NP; Participants will receive IV infusions of Aralast NP (90mg/kg) once a week for 12 weeks.; Other Names: AAT; Alpha 1-Proteinase Inhibitor Human; Alpha,-antitrypsin
Placebo Comparator: Placebo; Participants will receive placebo intravenously once a week for 12 weeks.	Drug: Placebo; Participants will receive IV infusions of placebo once a week for 12 weeks.; Other Names: Placebo for Aralast NP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mixed-Meal Tolerance Test (MMTT)-Stimulated 2-hour C-peptide Area Under the Curve (AUC)	Week 52

Secondary Outcome Measures

Outcome Measure	Time Frame
MMTT-Stimulated Peak and 4-hour C-peptide AUC	Weeks 52 and 104
MMTT-Stimulated 2-hour C-Peptide AUC Assessed Over Time	Weeks 0, 14, 26, 52, and 104
Insulin Use in Units Per Kilogram Body Weight Per Day	Weeks 52 and 104
Hypoglycemic Events Occurring from Randomization to End of Trial	Throughout the Study
Glycosylated Hemoglobin (HbA1c) Levels	Weeks 52 and 104
Emergence of Anti-Alpha 1-Antitrypsin (AAT) Antibodies	Throughout the Study
Frequency and Severity of All Adverse Events (AEs)	Throughout the study
Changes in D-dimer Levels Indicating Alteration in Coagulant/Anticoagulant Balance	Throughout the study
Pharmacokinetic Parameters of Aralast NP	Throughout the study

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

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

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 (Estimate): December 31, 2014
• Last Update Submitted That Met QC Criteria: December 30, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: AAT; Diabetes, Autoimmune; Alpha-1 Antitrypsin; Diabetes Mellitus, Type 1 (new-onset); T1DM (new-onset); T1D (new-onset); Alpha1-Proteinase Inhibitor
• 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; Serine Proteinase Inhibitors; Trypsin Inhibitors; Protease Inhibitors; Alpha 1-Antitrypsin
• Other Study ID Numbers: DAIT ITN041AI Part II