title: Alpha-1 antitrypsin therapy is safe and well tolerated in children and adolescents with recent onset type 1 diabetes mellitus.
abstract: 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).
  
  
  
  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 infusions of 40, 60, or 80 mg/kg/dose high-purity, liquid, ready to use AAT over 28 wk (Glassia(®) ; Kamada Ltd., Ness Ziona, Israel).
  
  
  
  safety and tolerability; secondary outcomes: glycemic control, C-peptide reserve, and autoantibody levels. Possible responders were defined as individuals with peak C-peptide that declined less than 7.5% below baseline.
  
  
  
  No serious adverse events, diabetic ketoacidosis (DKA), or severe hypoglycemic episodes were reported. Adverse events were dose-independent and transient. Glycemic control parameters improved during the study in all groups, independent of dosage. Hemoglobin A1c (HbA1c) decreased from 8.43 to 7.09% (mean, p < 0.001). At the end of the study, 18 subjects (75%) had a peak C-peptide ≥0.2 pmol/mL. Eight subjects (33.3%) were considered possible responders and were characterized by shorter duration of T1DM at screening (54.5 ± 34.3 vs. 95.9 ± 45.7 d, p = 0.036) and greater decrease in their HbA1c during the study period (-2.94 ± 1.55 vs.-0.95 ± 1.83%, p = 0.016).
  
  
  
  AAT treatment was safe and well tolerated in pediatric subjects with recently diagnosed autoimmune diabetes. Placebo-controlled studies with larger cohorts and dose range are warranted in order to assess efficacy in maintaining pancreatic beta cell reserve and glycemic control.
authors.affiliation: Pediatric Diabetes Service, Assaf Harofeh Medical Center, Zerifin, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Marianna
authors.initials: M
authors.lastname: Rachmiel
authors.affiliation: Kamada Ltd, Ness-Ziona, Israel.
authors.forename: Pnina
authors.initials: P
authors.lastname: Strauss
authors.affiliation: The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center, Petah-Tikva, Israel.
authors.forename: Nitzan
authors.initials: N
authors.lastname: Dror
authors.affiliation: The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center, Petah-Tikva, Israel.
authors.forename: Hadassa
authors.initials: H
authors.lastname: Benzaquen
authors.affiliation: The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center, Petah-Tikva, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Horesh
authors.affiliation: Kamada Ltd, Ness-Ziona, Israel.
authors.forename: Nave
authors.initials: N
authors.lastname: Tov
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Pediatric Endocrinology and Diabetes Unit, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Naomi
authors.initials: N
authors.lastname: Weintrob
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Pediatric Endocrine and Diabetes Unit, E. Wolfson Medical Center, Holon, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Landau
authors.affiliation: Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Ben-Ami
authors.affiliation: Pediatric Diabetes Unit, Soroka Medical Center, Beer-Sheva, Israel.|Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Haim
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center, Petah-Tikva, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Phillip
authors.affiliation: Pediatric Diabetes Service, Assaf Harofeh Medical Center, Zerifin, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Tzvi
authors.initials: T
authors.lastname: Bistritzer
authors.affiliation: Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Eli C
authors.initials: EC
authors.lastname: Lewis
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center, Petah-Tikva, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Lebenthal
mesh_terms: D000293:Adolescent; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D011446:Prospective Studies; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D055815:Young Adult; D000515:alpha 1-Antitrypsin / Q000627:therapeutic use*
chemical_list: D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin
keywords: adverse events; alpha-1 antitrypsin; beta cell preservation; children; phase I/II trial; recent onset diabetes