Clinical trial NCT01183455: A Research Trial of Aralast NP in New Onset Diabetes (RETAIN) - Part II
Official title: Effect of Intravenous Alpha-1 Antitrypsin on Preserving Beta-cell Function in New-onset Type 1 Diabetes Mellitus (ITN041AI)- Part II
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 1
Keywords: Diabetes Mellitus, Type 1 (new-onset)
T1DM (new-onset)
T1D (new-onset)
Diabetes, Autoimmune
Alpha1-Proteinase Inhibitor
Alpha-1 Antitrypsin
AAT
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
name: Juvenile Diabetes Research Foundation
First posted: 2010-08-17
Enrollment: 0
Sex: ALL
Minimum age (years): 8
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Mixed-Meal Tolerance Test (MMTT)-Stimulated 2-hour C-peptide Area Under the Curve (AUC)
timeFrame: Week 52
Secondary outcomes:
measure: MMTT-Stimulated Peak and 4-hour C-peptide AUC
timeFrame: Weeks 52 and 104
measure: MMTT-Stimulated 2-hour C-Peptide AUC Assessed Over Time
timeFrame: Weeks 0, 14, 26, 52, and 104
measure: Insulin Use in Units Per Kilogram Body Weight Per Day
timeFrame: Weeks 52 and 104
measure: Hypoglycemic Events Occurring from Randomization to End of Trial
timeFrame: Throughout the Study
measure: Glycosylated Hemoglobin (HbA1c) Levels
timeFrame: Weeks 52 and 104
measure: Emergence of Anti-Alpha 1-Antitrypsin (AAT) Antibodies
timeFrame: Throughout the Study
measure: Frequency and Severity of All Adverse Events (AEs)
timeFrame: Throughout the study
measure: Changes in D-dimer Levels Indicating Alteration in Coagulant/Anticoagulant Balance
timeFrame: Throughout the study
measure: Pharmacokinetic Parameters of Aralast NP
timeFrame: Throughout the study
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Aurora
country: United States
facility: Barbara Davis Center
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Atlanta
country: United States
facility: Atlanta Diabetes Associates
state: Georgia
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Prince Frederick
country: United States
facility: Calvert Memorial Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
city: Worchester
country: United States
facility: University of Massachusetts Medical School
state: Massachusetts
city: New York
country: United States
facility: Columbia University
state: New York
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Philadephia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: San Antonio
country: United States
facility: Cetero Research San Antonio
state: Texas
Study officials:
affiliation: Joslin Diabetes Center
name: Gordon Weir, MD
role: STUDY_CHAIR
References: