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

Phase 1

Terminated

Conditions: Diabetes Mellitus, Type 1

Interventions: Biological: Aralast NP 45 mg dose
Biological: Aralast NP 90 mg dose
Biological: Aralast NP 180 mg dose

Registration Number: NCT01183468

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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.

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).

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 17

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1a(Aralast NP)-Subjects Aged 16-35 Yrs	Aralast NP 45 mg dose	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.
Part 1a(Aralast NP)-Subjects Aged 16-35 Yrs	Aralast NP 90 mg dose	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.
Part 1b (Aralast NP)--Subjects Aged 18-35 Yrs	Aralast NP 180 mg dose	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.
Part 1a (Aralast NP)-Subjects 8-15 Yrs	Aralast NP 90 mg dose	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.
Part 1b (Aralast NP)-Subjects 8-17 Yrs	Aralast NP 90 mg dose	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.
Part 1b (Aralast NP)--Subjects Aged 18-35 Yrs	Aralast NP 90 mg dose	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.
Part 1b (Aralast NP)-Subjects 8-17 Yrs	Aralast NP 180 mg dose	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.
Part 1a (Aralast NP)-Subjects 8-15 Yrs	Aralast NP 45 mg dose	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.

Primary Outcome Measures

Name	Time	Method
C-peptide 2-hour AUC in Response to a Mixed-meal Tolerance Test at Week 52	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.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (15): Atlanta Diabetes Associates
🇺🇸
Atlanta, Georgia, United States
Nationwide Children's Hospital
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Columbus, Ohio, United States
Yale University
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New Haven, Connecticut, United States
RADY Children's Hospital (University of California, San Diego)
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San Diego, California, United States
Children's Hospital of Atlanta (Emory University)
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Atlanta, Georgia, United States
Barbara Davis Center (University of Colorado)
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Aurora, Colorado, United States
University of Iowa Children's Hospital
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Iowa City, Iowa, United States
University of Maryland Medical Center
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Baltimore, Maryland, United States
Massachusetts General Hospital
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Boston, Massachusetts, United States
University of Massachusetts Memorial Medical Center
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Worcester, Massachusetts, United States
Children's Mercy Hospital
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Kansas City, Missouri, United States
Naomi Berrie Diabetes Center (Columbia University)
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New York, New York, United States
Pacific Northwest Research Institute-University of Washington
🇺🇸
Seattle, Washington, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Joslin Diabetes Center
🇺🇸
Boston, Massachusetts, United States