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

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

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.

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).

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.