Gordon Weir | Harvard Medical School | Cambridge, MA

Terry Strom | Harvard Medical School | Boston, MA

Atlanta Diabetes Associates | Atlanta, GA

Massachusetts General Hospital | Boston, MA

University of Iowa | Iowa City, IA

Joslin Diabetes Center | Boston, MA

Columbia University | New York, NY

Nationwide Children's Hospital | Columbus, OH

Pacific Northwest Research Institute | Seattle, WA

Yale University | New Haven, CT

Children's Hospital of Philadelphia | Philadelphia, PA

University of California, San Diego | San Diego, CA

University of MA Medical School | Worcester, MA

Children's Mercy Hospital | Kansas City, MO

University of Maryland Hospital | Baltimore, MD

Emory University | Atlanta, GA

University of Colorado | Denver, CO

Basis/Rationale

Control of the immune destruction of pancreatic ß cells is a critically important challenge for type 1 diabetes research. Strategies to control autoimmunity have focused on reducing or inhibiting autoreactive T cells, but it seems likely that control of inflammation will also be necessary for an optimal result. Alpha-1 antitrypsin (AAT) is a serine proteinase inhibitor found in high concentrations in serum, which has been found to inhibit a variety of proteolytic enzymes and also has anti-inflammatory properties that result from inhibition of cytokine production, complement activation, and immune cell infiltration. It has been used as a remarkably safe treatment for more than 20 years in patients with deficiency of AAT who have chronic obstructive pulmonary disease. AAT has been found to reverse new-onset diabetes in nonobese diabetes (NOD) mice and to induce a state of self-tolerance. It has also been found to inhibit the rejection of transplanted islets in mice.

Because of its efficacy in preventing immune destruction of islets in rodent models of diabetes and its impressive safety record, we propose that AAT be used in a clinical trial for new-onset T1DM.

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Protocol Summary

• Primary Objective: Determine whether Aralast NP (AAT) will slow the progression of the autoimmune destruction of ß cells and lead to the preservation of C-peptide secretion in T1DM.

• Study Design

Part I. Part 1 is undertaken in two parts, Part 1a and Part 1b:

Part 1a (completed) was an open-label, dose-escalation, pharmacokinetics (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. Part 1a consisted of two cohorts:

Part I consists of two cohorts:

1) Adult cohort (8 participants age 16-35 years with new-onset T1DM).
2) Pediatric Cohort (after 6 patients in the adult cohort had undergone safety review and proceeded to the high dose, the pediatric cohort began enrollment; 8 pediatric patients age 8-15 years with new-onset T1DM were enrolled).

Participants enrolled in Part Ia did not roll over to Part Ib.

Part 1b is an open-label, dose-escalation, pharmacokinetic (PK) and safety study to test two higher doses of Aralast NP. 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.

Similar to Part Ia, Part Ib consists of two cohorts:

1) Adult cohort (8 participants age 18-35 years with new-onset T1DM).
2) Pediatric Cohort (after 6 patients in the adult cohort have undergone safety review and proceeded to the high dose, the pediatric cohort will begin to enroll; 8 pediatric patients age 8-17 years with new-onset T1DM will be enrolled).

Participants enrolled in Part Ib will not roll over to Part II.

Part II. Upon completion of all 12 infusions in both the adult and pediatric cohorts in Part Ia and Part 1b and a satisfactory safety review, general enrollment with random assignment will commence in Part II of the study. The second part of the study is a two-arm, double-blind, placebo-controlled, 2:1 random assignment, parallel-group, phase II study. Adults and children age 8–35 years with new-onset T1DM will be enrolled. Participants randomized to the treatment group will receive Aralast NP 90-180 mg/kg (final dose will be based on results of the PK/PD model derived from Part Ib) via IV infusion once a week for 12 weeks. Participants randomized to the control group will receive placebo.

Total study duration will be approximately 4 years.

• Primary Endpoint: The primary endpoint is an MMTT-stimulated 2-hour C-peptide AUC at week 52.