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A Phase II, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Alpha-1 Antitrypsin (AAT) (Glassia®) in the Treatment of Recent-Onset Type 1 Diabetes.

Published on Nov 29, 2019in International Journal of Molecular Sciences4.183
· DOI :10.3390/IJMS20236032
Yael Lebenthal12
Estimated H-index: 12
(TAU: Tel Aviv University),
Yael Lebenthal14
Estimated H-index: 14
+ 11 AuthorsRachmielMarianna14
Estimated H-index: 14
Abstract
Our aim was to assess the efficacy, safety, and tolerability of alpha-1 antitrypsin (AAT) as a therapeutic modality for β-cell preservation in patients with recent-onset type 1 diabetes. Seventy type 1 diabetes patients (37 males; mean age 13.1 ± 4.1years) were randomized to treatment with 22 infusions of AAT (Glassia®) (60 or 120 mg/kg) or placebo. The primary outcome was the area under the curve (AUC) of C-peptide from a 2-h mixed-meal tolerance test after 52 weeks. At week 52, C-peptide was 0.9, 0.45, and 0.48 pmol/mL in the AAT-120, AAT-60, and placebo groups (p = 0.170 and p = 0.866 vs. placebo, respectively). The declines in C-peptide glycated hemoglobin (HbA1c) and the total insulin dose (U/kg) were similar across groups. Within the predefined 12–18-years subgroup, the C-peptide AUC decreased significantly in the placebo and AAT-60 groups (−0.34 and −0.54 pmol/mL, respectively, p < 0.01), with a borderline decrease in the AAT-120 group (−0.29 pmol/mL, p = 0.047). The mean HbA1c level was significantly lower in the AAT-120 group compared to the placebo (6.7% ± 0.9% vs. 8.2 ± 1.4%, p = 0.05), and a higher percentage of patients attained HbA1c ≤ 7% (75% vs. 25%, p = 0.05). AAT was tolerated well, with a similar safety profile between groups. The AAT intervention showed promise in the subgroup of adolescents with recent-onset type 1 diabetes. Further studies are warranted to determine the impact and proposed mechanism of action of AAT in β-cell preservation.
  • References (25)
  • Citations (1)
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References25
Newest
#1Avivit Brener (TAU: Tel Aviv University)H-Index: 1
#2Yael Lebenthal (TAU: Tel Aviv University)H-Index: 14
Last. RachmielMarianna (TAU: Tel Aviv University)H-Index: 14
view all 9 authors...
1 CitationsSource
Abstract Background Death due to cerebral stroke afflicts a large number of neuronal populations, including glial cells depending on the brain region affected. Drugs with a wide cellular range of protection are needed to develop effective therapies for stroke. Human alpha 1-antitrypsin (hAAT) is a serine proteinase inhibitor with potent anti-inflammatory, anti-apoptotic and immunoregulatory activities. This study aimed to test whether hAAT can protect different kind of neurons and glial cells af...
Source
#1Gordon C. Weir (Harvard University)H-Index: 85
#2Mario R. EhlersH-Index: 12
Last. Terry B. Strom (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 46
view all 11 authors...
4 CitationsSource
#1Rémi J. Creusot (CUMC: Columbia University Medical Center)H-Index: 13
#2Jorge Postigo-Fernandez (CUMC: Columbia University Medical Center)H-Index: 3
Last. Nato Teteloshvili (CUMC: Columbia University Medical Center)H-Index: 2
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Type 1 diabetes (T1D) arises from a failure to maintain tolerance to specific β-cell antigens. Antigen-specific immunotherapy (ASIT) aims to reestablish immune tolerance through the supply of pertinent antigens to specific cell types or environments that are suitable for eliciting tolerogenic responses. However, antigen-presenting cells (APCs) in T1D patients and in animal models of T1D are affected by a number of alterations, some due to genetic polymorphism. Combination of these alterations, i...
4 CitationsSource
#1Ofer Guttman (BGU: Ben-Gurion University of the Negev)H-Index: 5
#2Gabriella S. Freixo-Lima (BGU: Ben-Gurion University of the Negev)H-Index: 3
Last. Eli C. Lewis (BGU: Ben-Gurion University of the Negev)H-Index: 28
view all 6 authors...
α1-antitrypsin (AAT), a circulating glycoprotein that rises during acute phase responses and healthy pregnancies, exhibits immunomodulatory properties in several T-cell–dependent immune pathologies. However, AAT does not interfere with isolated T-cell responses; instead, it facilitates polarization of macrophages and dendritic cells towards M2-like and tolerogenic cells, respectively. AAT also allows NK cell responses against tumor cells, while attenuating DC-dependent NK cell activities. Since ...
1 CitationsSource
#1Boris M. Baranovski (BGU: Ben-Gurion University of the Negev)H-Index: 6
#2Eyal Ozeri (BGU: Ben-Gurion University of the Negev)H-Index: 6
Last. Eli C. Lewis (BGU: Ben-Gurion University of the Negev)H-Index: 28
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Lifelong weekly infusions of human α 1-antitrypsin (hAAT) are currently administered as augmentation therapy for patients with genetic AAT deficiency (AATD). Several recent clinical trials attempt to extend hAAT therapy to conditions outside AATD, including type 1 diabetes. Because the endpoint for AATD is primarily the reduction of risk for pulmonary emphysema, the present study explores hAAT dose protocols and routes of administration in attempt to optimize hAAT therapy for islet-related injur...
3 CitationsSource
#1A. Mario Marcondes (UW: University of Washington)H-Index: 8
#2David M. Hockenbery (UW: University of Washington)H-Index: 42
Last. H. Joachim Deeg (UW: University of Washington)H-Index: 80
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Abstract α 1 -Antitrypsin (AAT) is a serine protease inhibitor with anti-inflammatory, antiapoptotic, and immunomodulatory properties. It has therapeutic efficacy in animal models of autoimmune diseases, inflammatory disorders, and transplantation. In a phase I/II open-label single-center study, we administered AAT (Glassia; Baxalta/Kamada, New Ziona, Israel) as salvage therapy to 12 patients with steroid-refractory acute graft-versus-host disease (GVHD). AAT was given i.v. at 2 dose levels over...
15 CitationsSource
#1RachmielMarianna (TAU: Tel Aviv University)H-Index: 14
#2Pnina StraussH-Index: 3
Last. Yael Lebenthal (TAU: Tel Aviv University)H-Index: 14
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Background and objectives Alpha-1 antitrypsin (AAT) has been shown to reduce pro-inflammatory markers and protect pancreatic islets from autoimmune responses in recent studies. Our aim was to evaluate its safety and tolerability in three different doses, in a pediatric population with recent onset type 1 diabetes mellitus (T1DM). Methods A 37-wk prospective, open-label, phase I/II interventional trial, comprised of 24 recently diagnosed subjects (12 males; age 12.9 ± 2.4 yr), who received 18 inf...
14 CitationsSource
Context: Recent studies have implicated proinflammatory responses in the mechanism of type 1 diabetes (T1D). Objective: Our objective was to evaluate the safety and effects of therapy with the anti-inflammatory serum protein α1-antitrypsin (AAT) on islet function and innate immunity in recent-onset patients. Design and Setting: This was an open-label phase I trial at the Barbara Davis Center for Childhood Diabetes, University of Colorado Denver. Patients: Twelve recently diagnosed subjects with ...
36 CitationsSource
#1Avishag Abecassis (BGU: Ben-Gurion University of the Negev)H-Index: 3
#2Ronen Schuster (BGU: Ben-Gurion University of the Negev)H-Index: 3
Last. Eli C. Lewis (BGU: Ben-Gurion University of the Negev)H-Index: 28
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Although islet transplantation for individuals with type 1 diabetes has been shown to yield superior blood glucose control, it remains inadequate for long-term control. This is partly due to islet injuries and stresses that can lead to beta cell loss. Inhibition of excess IL-1β activity might minimize islet injuries, thus preserving function. The IL-1 receptor antagonist (IL-1Ra), an endogenous inhibitor of IL-1β, protects islets from cytokine-induced necrosis and apoptosis. Therefore, an imbala...
20 CitationsSource
Cited By1
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#1Sabri El-Saied (BGU: Ben-Gurion University of the Negev)H-Index: 4
#2Heike SchmittH-Index: 4
Last. Athanasia WarneckeH-Index: 14
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OBJECTIVES: To determine the levels of endogenous alpha1-antitrypsin in the perilymph of patients undergoing cochlear implant (CI), and its reverse association with the severity of hearing loss. STUDY DESIGN: Retrospective study SETTING: Tertiary care university hospital PARTICIPANTS: The study includes 38 patients undergoing CI surgery, 11 patients diagnosed with congenital deafness and 27 non-congenital deafness, 8 patients diagnosed with moderate hearing loss (N=8; PTA=70 dB), severe hearing ...
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