Study of Human Plasma-Derived Alpha1-Proteinase Inhibitor in Subjects With New-Onset Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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This is a multicenter, randomized, partial-blinded, five-arm, placebo-controlled study of human plasma-derived alpha1-proteinase inhibitor (alpha1-PI) in children (ages 6-11 years old) and teens/adults (ages 12-35 years old) with new onset Type 1 Diabetes Mellitus (T1DM). Currently enrolling ages 12-35 only. Once 25 patients are randomized and data is reviewed enrollment will be opened to the child cohort. The purpose of this study is to evaluate the safety and efficacy of four dosing regimens of human plasma-derived alpha1-PI in T1DM.

Official Title
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A Multicenter, Randomized, Partial-Blinded, Placebo-Controlled Study to Evaluate the Safety and Efficacy of a Human Plasma-Derived Alpha1-Proteinase Inhibitor in Subjects With New-Onset Type 1 Diabetes Mellitus

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Biological: 180 mg/kg Alpha1-PI
* Biological: 90 mg/kg Alpha1-PI
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of T1DM according to the ADA criteria. Current use of injected insulin therapy and one positive result on testing for any of the following antibodies (If not currently on insulin therapy, must have positive result for at least two of the below antibodies): Anti-islet-cell antibodies (islet cell antigen 512, insulinoma associated protein 2), Anti-glutamic acid decarboxylase antibodies, or Anti-insulin antibodies (unless received insulin therapy for > 7 days). Body Mass Index (BMI) ≤ 28 kg/m2 for adults (≥ 20 years of age) OR ≤ 90th percentile in accordance with the Centers for Disease Control BMI assessment for children and teens (2 through 19 years old). Exclusion Criteria: History of or current diabetic retinopathy, neuropathy, or nephropathy. Known thrombophilia or history of thrombosis. Malignant disease (including malignant melanoma; however, other forms of skin cancer are allowed) within five years of randomization. Active Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, or Human Immunodeficiency Virus infection. History of anaphylaxis or severe systemic response to any plasma-derived alpha1-PI preparation or other blood product(s). Known selective or severe Immunoglobulin A deficiency. Elevated liver enzymes (aspartate transaminase, alanine aminotransferase, and alkaline phosphatase) equal to or greater than 2.5 times the upper limit of normal. Therapy with exenatide or any other agents that stimulate pancreatic β cell regeneration or insulin secretion, or any antidiabetic agents (oral or parenteral) other than insulin within one month prior to screening. Use of omega-3 fatty acid supplements, including fish oil, within seven days prior to screening. Current or planned therapy with inhaled insulin, if it becomes available. Chronic use of systemic steroids, with the exception of inhaled steroids, above a stable dose equivalent to 5 mg/day prednisone (e.g., 10 mg every 2 days) within 4 weeks prior to randomization. It is recommended to maintain the same dose throughout the study. (Note: Subjects with autoimmune conditions (i.e., asthma) necessitating treatment with systemic short-term corticosteroids and administered a rapid taper are eligible per protocol with the caveat that the tapering is complete or decreased to the minimum requirement (i.e., 5 mg/day) at least 1 week prior to the Baseline visit (when randomization occurs) to ensure the subject is stable. For longer term steroid usage, please consult the Grifols Medical Monitor before considering the subject for study participation.) Treatment with immunosuppressants or cytostatic agents within 6 months of randomization.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alpha1-PI 180 mg/kg/wk, 26 weeks<br>180 mg/kg weekly infusions of Alpha1-PI for 26 weeks. | Biological: 180 mg/kg Alpha1-PI<br> <br> * Other names: Alpha-1 MP;|
| Experimental: 90 mg/kg/wk Alpha1-PI, 26 weeks<br>90 mg/kg weekly infusions of Alpha1-PI for 26 weeks. | Biological: 90 mg/kg Alpha1-PI<br> <br> * Other names: Alpha-1 MP;|
| Placebo Comparator: Placebo, 26 weeks<br>Weekly infusions of placebo for 26 weeks. | Biological: Placebo<br> <br> |
| Experimental: 180 mg/kg/wk Alpha1-PI, 13 weeks<br>180 mg/kg weekly infusions of Alpha1-PI for 13 weeks. | Biological: 180 mg/kg Alpha1-PI<br> <br> * Other names: Alpha-1 MP;|
| Experimental: 90 mg/kg/wk Alpha1-PI, 13 weeks<br>90 mg/kg weekly infusions of Alpha1-PI for 13 weeks | Biological: 90 mg/kg Alpha1-PI<br> <br> * Other names: Alpha-1 MP;|
| Placebo Comparator: Placebo, 13 weeks<br>Weekly infusions of placebo for 13 weeks. | Biological: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mixed Meal Tolerance Test (MMTMT) Stimulated C-peptide 2 Hour Area Under the Concentration-time Curve (AUC) | C-peptide concentration during MMTT with high protein energy drink. Dose for time frame refers to intake of high protein energy drink. | Baseline, Week 52 (pre-high protein drink and 15, 30, 60, 90, 120 minutes post-drink) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline for MMTT Stimulated C-peptide 2h AUC |  | Baseline, Weeks 14, 27, 39, 69, 87, and 104 (pre-high protein drink and 15, 30, 60, 90, 120 minutes post-drink) | 
| Change From Baseline for HbA1c Levels |  | Baseline, Weeks 14, 27, 39, 52, 69, 87, and 104 | 
| Number of Subjects With Overall Severe Hypoglycemic Episodes | Severe hypoglycemia defined according the ADA Workgroup on Hypoglycemia definition, as follows: An event requiring assistance of another person to actively administer carbohydrate, glucagons, or other resuscitative actions. | 104 weeks | 
| Change From Baseline for Mean Daily Insulin Dose Requirements |  | Baseline, Weeks 2, 4, 14, 27, 39, 52, 69, 87, and 104 | 
| Change From Baseline for Mean Daily Glucose Levels Prior to Meals and Bedtime | For each visit, the mean daily glucose levels were calculated over the previous 3-7 days prior to the study visit from blood glucose levels recorded daily prior to meals and bedtime. | Baseline, Weeks 2, 4, 14, 27, 39, 52, 69, 87, and 104 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 Diabetes Mellitus, Alpha1-Proteinase Inhibitor, Beta Cell, Alpha1-Antitrypsin