Alpha-1 antitrypsin therapy is safe and well tolerated in children and adolescents with recent onset type 1 diabetes mellitus

• Published in: Pediatric diabetes Vol. 17; no. 5; pp. 351 - 359
• Main Authors: Rachmiel, Marianna, Strauss, Pnina, Dror, Nitzan, Benzaquen, Hadassa, Horesh, Orit, Tov, Nave, Weintrob, Naomi, Landau, Zohar, Ben-Ami, Michal, Haim, Alon, Phillip, Moshe, Bistritzer, Tzvi, Lewis, Eli C, Lebenthal, Yael
• Format: Journal Article
• Language: English
• Published: Former Munksgaard John Wiley & Sons A/S 01.08.2016
• Subjects: Adolescent; adverse events; alpha 1-Antitrypsin - therapeutic use; alpha-1 antitrypsin; beta cell preservation; Child; children; Diabetes Mellitus, Type 1 - drug therapy; Female; Humans; Male; phase I/II trial; Prospective Studies; recent onset diabetes; Serine Proteinase Inhibitors - therapeutic use; Young Adult; alpha-1 antitrypsin; beta cell preservation; adverse events; recent onset diabetes; children; phase I/II trial
• ISSN: 1399-543X; 1399-5448
• DOI: 10.1111/pedi.12283

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 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). Primary outcomes: 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. Results 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). Conclusions 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.