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

This study has suspended participant recruitment.
(Pending an efficacy review)
Sponsor:
Collaborators:
Immune Tolerance Network (ITN)
Juvenile Diabetes Research Foundation
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01183468
First received: August 16, 2010
Last updated: February 25, 2014
Last verified: February 2014
  Purpose

The drug Alpha-1 Antitrypsin (AAT) which is being tested in this research study is 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 that are thought to be involved in the development of type 1 diabetes. Researchers are doing this study to see whether AAT will help slow the progression of type 1 diabetes.

Currently, Part I.b. is open and enrolling. Please see the detailed description for more information on this portion of the study.


Condition Intervention Phase
Diabetes Mellitus, Type 1
Biological: Alpha 1-Antitrypsin
Biological: Alpha-1 Antitrypsin
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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 - Part I (ITN041AI)

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Mixed-Meal Tolerance Test (MMTT)-stimulated 2-hour C-peptide Area under the curve (AUC) [ Time Frame: Week 52 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • MMTT-stimulated peak and 4-hour C-peptide AUC [ Time Frame: Weeks 52 and 104 ] [ Designated as safety issue: No ]
  • MMTT-stimulated 2-hour C-peptide AUC assessed longitudinally [ Time Frame: Weeks 0, 14, 26, 52, and 104 ] [ Designated as safety issue: No ]
  • Insulin use in units per kilogram body weight per day [ Time Frame: Weeks 52 and 104 ] [ Designated as safety issue: No ]
    Insulin use in units per kilogram body weight per day

  • Hypoglycemic Events [ Time Frame: Enrollment to Week 104 ] [ Designated as safety issue: Yes ]
  • Glycosylated Hemoglobin (HbA1C) Levels [ Time Frame: Weeks 52 and 104 ] [ Designated as safety issue: Yes ]
  • Emergence of anti-AAT antibodies [ Time Frame: Enrollment to Week 104 ] [ Designated as safety issue: Yes ]
  • Frequency and severity of all AEs (including infusion reactions, hypersensitivity reactions, and viral infections) [ Time Frame: Enrollment to Week 104 ] [ Designated as safety issue: Yes ]
  • Changes in D-dimer levels indicating alteration in coagulant/anticoagulant balance [ Time Frame: Enrollment to Week 104 ] [ Designated as safety issue: Yes ]
  • Pharmacokinetic parameters of Aralast NP [ Time Frame: Enrollment to Week 104 ] [ Designated as safety issue: No ]

Estimated Enrollment: 32
Study Start Date: October 2010
Estimated Study Completion Date: November 2017
Estimated Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1.a. - Adult Biological: Alpha 1-Antitrypsin
- 45 mg/kg/week
Other Names:
  • AAT
  • Aralast NP
Biological: Alpha-1 Antitrypsin
- 90 mg/kg/week
Experimental: Part 1.a. - Pediatric Biological: Alpha 1-Antitrypsin
- 45 mg/kg/week
Other Names:
  • AAT
  • Aralast NP
Biological: Alpha-1 Antitrypsin
- 90 mg/kg/week
Experimental: Part 1.b. - Adult Biological: Alpha-1 Antitrypsin
- 90 mg/kg/week
Biological: Alpha-1 Antitrypsin
- 180 mg/kg/week
Experimental: Part 1.b. - Pediatric Biological: Alpha-1 Antitrypsin
- 90 mg/kg/week
Biological: Alpha-1 Antitrypsin
- 180 mg/kg/week

Detailed Description:

This study has two parts, Part I.a. and Part I.b.:

  • Part I.a. (Complete): The first portion of Part I was an open-label, dose-escalation, pharmacokinetic (PK) and safety study in which participants received 12 infusions of Aralast NP. Infusions 1 through 6 were administered at 45 mg/kg/wk and infusions 7 through 12 were administered at 90 mg/kg/wk. Participants enrolled in Part Ia will not roll over to Part Ib. Part Ia consisted of two cohorts:

    • Adult cohort: The first cohort had 8 participants, age 16-35 years, with new-onset T1DM. These participants received Aralast NP 45 mg/kg via IV infusion once a week for 6 weeks. One participant discontinued before the low dose infusion was complete. After completing the week-6 infusion, the remaining 7 participants underwent a 3-week washout period during which his or her safety data was reviewed by the protocol chair, the NIAID medical monitor, and the ITN clinical trial physician. No individual stopping rule had been met as defined in Section 5.2. Subsequently, each participant proceeded to the higher dose of 90 mg/kg/wk for the next 6 weeks, for a total of 12 infusions. When all participants completed 12 weeks of infusions, a second safety review was performed.
    • Pediatric cohort: After 6 participants in the adult cohort underwent the safety review and proceeded to the high dose, the pediatric cohort began to enroll. This cohort was comprised of 8 pediatric participants, age 8-15 years, with new-onset T1DM. These participants received Aralast NP 45 mg/kg via IV infusion once a week for 6 weeks. One participant did not receive the 4th low-dose infusion (elevated D-dimer level) but completed all other infusions. After completing the week-6 infusion, each participant underwent a minimum 3-week washout period during which his or her safety data were reviewed by the protocol chair, the NIAID medical monitor, and the ITN clinical trial physician. No individual stopping rule had been met as defined in Section 5.2. When at least 6 participants from the pediatric cohort safely completed the low dose and at least 6 participants from the adult cohort safely completed the high dose, dose escalation to 90 mg/kg/wk in the pediatric cohort proceeded for the next 6 weeks. A total of 12 infusions were given as outlined for the adult cohort. When all participants completed 12 weeks of infusions, a second safety review was performed.
  • Part I.b.: This part of the trial is an open-label, dose-escalation, pharmacokinetic (PK) and safety study in which participants will receive 12 infusions of Aralast NP. Infusions 1 through 6 will be administered at 90 mg/kg/wk and, infusions 7 through 12 will be administered at 180 mg/kg/wk. Participants in Part Ib will not roll over into Part II. Part Ib consists of two cohorts:

    • Adult cohort: The first cohort will be comprised of 8 participants, age 18-35 years, with new-onset T1DM. Part Ib participants will receive Aralast NP 90 mg/kg via IV infusion once a week for 6 weeks. After completing the week-6 infusion, each participant will undergo a 3-week washout period. Subsequently, each participant will proceed to the higher dose of 180 mg/kg/wk for the next 6 weeks, for a total of 12 infusions. When all participants have completed 12 weeks of infusions, a safety review will be performed.
    • Pediatric cohort: After 6 participants in the adult cohort have proceeded to the high dose, the pediatric cohort may begin to enroll. This cohort will be comprised of 8 pediatric participants, age 8-17 years, with new-onset T1DM. These participants will receive Aralast NP 90 mg/kg via IV infusion once a week for 6 weeks. After completing the week-6 infusion, each participant will undergo a minimum 3-week washout period. When at least 6 participants from the pediatric cohort have safely completed the low dose and at least 6 participants from the adult cohort have safely completed the high dose, dose escalation to 180 mg/kg/wk in the pediatric cohort may proceed for the next 6 weeks. A total of 12 infusions will be given as outlined for the adult cohort. When all participants have completed 12 weeks of infusions, a second safety review will be performed.
  Eligibility

Ages Eligible for Study:   8 Years to 35 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosed with type 1 diabetes 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 > 0.2 pmol/mL following a mixed meal tolerance test (MMTT)

Exclusion Criteria:

  • Serve 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 HBV, HCV, HIV or toxoplasmosis
  • Clinically active infection with EBV, CMV, or tuberculosis
  • 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 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.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01183468

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
Joslin Diabetes Center
Boston, Massachusetts, United States, 02215
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
University of Massachusetts Memorial Medical Center
Worchester, 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
Immune Tolerance Network (ITN)
Juvenile Diabetes Research Foundation
Investigators
Study Chair: Gordon Weir, MD Joslin Diabetes Center
  More Information

Additional Information:
No publications provided by National Institute of Allergy and Infectious Diseases (NIAID)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01183468     History of Changes
Other Study ID Numbers: DAIT ITN041AI
Study First Received: August 16, 2010
Last Updated: February 25, 2014
Health Authority: United States: Data and Safety Monitoring Board
United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Diabetes Mellitus, Type 1
Diabetes Mellitus, Insulin-Dependent
Diabetes Mellitus, Juvenile-Onset
Diabetes, Autoimmune
Aralast NP
Alpha-1 Antitrypsin

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
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 28, 2014