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

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

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.

Study Overview

• Status: Terminated
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Biological: Placebo; Biological: 180 mg/kg Alpha1-PI; Biological: 90 mg/kg Alpha1-PI

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Los Angeles, California, United States, 90015
      • Clinica Medica San Miguel
    • Orange, California, United States, 92868
      • Diabetes Associates Medical Group
    • San Diego, California, United States, 92123
      • Rady Children's Hospital San Diego
    • Tarzana, California, United States, 91356
      • Metabolic Institute of America
    • Ventura, California, United States, 93003
      • Ronald H Chochinov MD
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Yale New Haven Hospital
  • Delaware
    • Newark, Delaware, United States, 19713
      • Christiana Care Health Services
  • Florida
    • Jacksonville, Florida, United States, 32258
      • Solutions Through Advanced Research Inc.
    • Miami, Florida, United States, 33133
      • CCM Clinical Research
    • Miami, Florida, United States, 33136
      • Advanced Pharma CR LLC
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Atlanta Diabetes Associates
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Rocky Mountain Diabetes and Osteoporosis Center
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Cook County Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Methodist Research Institute
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • Barry J. Reiner MD, LLC.
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • UMass Memorial Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • Children's Hospitals and Clinics of Minnesota
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Morristown Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131-0001
      • University of New Mexico, Health Sciences Center
  • New York
    • Buffalo, New York, United States, 14222
      • Women and Children's Hospital
  • North Carolina
    • Raleigh, North Carolina, United States, 27610
      • WakeMed Children's Hospital
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
    • Columbus, Ohio, United States, 43201
      • Endocrinology Associates Inc
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Pediatric Endocrinology, Genetics & Metabolism
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19106
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Rapid City Regional Hospital/Health Clinical Research
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75231
      • Research Institute of Dallas
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center
    • San Antonio, Texas, United States, 78154
      • Northeast Clinical Research of San Antonio LLC
    • San Antonio, Texas, United States, 78232
      • Consano Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 35 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alpha1-PI 180 mg/kg/wk, 26 weeks; 180 mg/kg weekly infusions of Alpha1-PI for 26 weeks.	Biological: 180 mg/kg Alpha1-PI; Other Names: Prolastin-C; Alpha-1 MP; Alpha1-antitrypsin; Alpha1-Proteinase Inhibitor (human), Modified Process
Experimental: 90 mg/kg/wk Alpha1-PI, 26 weeks; 90 mg/kg weekly infusions of Alpha1-PI for 26 weeks.	Biological: 90 mg/kg Alpha1-PI; Other Names: Prolastin-C; Alpha-1 MP; Alpha1-antitrypsin; Alpha1-Proteinase Inhibitor (human), Modified Process
Placebo Comparator: Placebo, 26 weeks; Weekly infusions of placebo for 26 weeks.	Biological: Placebo
Experimental: 180 mg/kg/wk Alpha1-PI, 13 weeks; 180 mg/kg weekly infusions of Alpha1-PI for 13 weeks.	Biological: 180 mg/kg Alpha1-PI; Other Names: Prolastin-C; Alpha-1 MP; Alpha1-antitrypsin; Alpha1-Proteinase Inhibitor (human), Modified Process
Experimental: 90 mg/kg/wk Alpha1-PI, 13 weeks; 90 mg/kg weekly infusions of Alpha1-PI for 13 weeks	Biological: 90 mg/kg Alpha1-PI; Other Names: Prolastin-C; Alpha-1 MP; Alpha1-antitrypsin; Alpha1-Proteinase Inhibitor (human), Modified Process
Placebo Comparator: Placebo, 13 weeks; Weekly infusions of placebo for 13 weeks.	Biological: Placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Grifols Therapeutics LLC

Publications and helpful links

General Publications

• Lagarde WH, Courtney KL, Reiner B, Steinmann K, Tsalikian E, Willi SM. Human plasma-derived alpha1 -proteinase inhibitor in patients with new-onset type 1 diabetes mellitus: A randomized, placebo-controlled proof-of-concept study. Pediatr Diabetes. 2021 Mar;22(2):192-201. doi: 10.1111/pedi.13162. Epub 2020 Dec 13.

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): January 1, 2017
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: March 11, 2014
• First Submitted That Met QC Criteria: March 18, 2014
• First Posted (Estimate): March 20, 2014

Study Record Updates

• Last Update Posted (Actual): September 5, 2018
• Last Update Submitted That Met QC Criteria: August 6, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Type 1 Diabetes Mellitus; Beta Cell; Alpha1-Antitrypsin; Alpha1-Proteinase Inhibitor
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Respiratory Tract Diseases; Immune System Diseases; Autoimmune Diseases; Lung Diseases; Endocrine System Diseases; Liver Diseases; Genetic Diseases, Inborn; Subcutaneous Emphysema; Emphysema; Diabetes Mellitus; Diabetes Mellitus, Type 1; Alpha 1-Antitrypsin Deficiency; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Serine Proteinase Inhibitors; Trypsin Inhibitors; Protease Inhibitors; Alpha 1-Antitrypsin; Protein C Inhibitor
• Other Study ID Numbers: GTI1302