Human plasma-derived alpha1 -proteinase inhibitor in patients with new-onset type 1 diabetes mellitus: A randomized, placebo-controlled proof-of-concept study

William H Lagarde, Kecia L Courtney, Barry Reiner, Kimberly Steinmann, Eva Tsalikian, Steven M Willi, William H Lagarde, Kecia L Courtney, Barry Reiner, Kimberly Steinmann, Eva Tsalikian, Steven M Willi

Abstract

Background: While circulating levels of alpha1 -proteinase inhibitor (alpha1 -PI) are typically normal, antiprotease activity appears to be compromised in patients with Type 1 diabetes mellitus (T1DM). Because alpha1 -PI [human] (alpha1 -PI[h]) therapy can inhibit pro-inflammatory mediators associated with β-cell destruction and reduced insulin production, it has been proposed for T1DM disease prevention. The aim of this study was to evaluate safety, tolerability, and efficacy of intravenous (IV) alpha1 -PI[h] in preserving C-peptide production in newly diagnosed T1DM patients.

Participants: Seventy-six participants (aged 6-35 years) were randomized at 25 centers within 3 months of T1DM diagnosis.

Methods: A Phase II, multicenter, partially blinded, placebo-controlled, proof-of-concept study evaluating four dosing regimens of alpha1 -PI[h] (NCT02093221, GTI1302): weekly IV infusions of either 90 or 180 mg/kg, each for either 13 or 26 weeks. Safety and efficacy were monitored over 52 weeks with an efficacy evaluation planned at 104 weeks. The primary efficacy endpoint was change from baseline in the 2-h area-under-the-curve C-peptide level from a mixed-meal tolerance test at 52 weeks. A battery of laboratory tests, including inflammatory biomarkers, constituted exploratory efficacy variables.

Results: Infusions were well tolerated with no new safety signals. All groups exhibited highly variable declines in the primary outcome measure at 52 weeks with no statistically significant difference from placebo. Interleukin-6 (IL-6) was reduced from baseline in all alpha1 -PI treatment groups but not the placebo group.

Conclusion: Pharmacologic therapy with alpha1 -PI[h] is safe, well tolerated, and able to reduce IL-6 levels; however, due to variability in the efficacy endpoint, its effects on preservation of C-peptide production were inconclusive.

Keywords: C-peptide; Interleukin-6; Type 1 diabetes; alpha 1-proteinase inhibitor; prolastin.

© 2020 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Study design. aBlood samples for total serum alpha1‐PI concentration were collected from approximately 30 patients, consisting of at least three teens/adults (ages 12–35 years old) and at least three children (ages 6–11 years old) from each treatment arm, to evaluate the steady state PK of IV‐administered alpha1‐PI. Alpha1‐PI, alpha1‐proteinase inhibitor (Prolastin‐C); PK, pharmacokinetics
FIGURE 2
FIGURE 2
Patient disposition. aOther = study terminated by sponsor because planned follow‐up to determine the duration of drug response was unnecessary owing to no apparent response at Week 52. Alpha1‐PI, alpha1‐proteinase inhibitor (Prolastin‐C)
FIGURE 3
FIGURE 3
Change from baseline in MMTT‐stimulated C‐peptide 2‐hour AUC at Week 52: Analysis using ANCOVA with baseline AUC and age as covariates using LOCF method (ITT population). ANCOVA, analysis of covariance; AUC, area under the curve; CI, confidence interval; ITT, intent‐to‐treat; LOCF, last observation carried forward; LS, least square; MMTT, mixed‐meal tolerance test
FIGURE 4
FIGURE 4
Change from baseline in interleukin (IL)‐6: intent‐to‐treat (ITT) population. A. 13‐week groups. B. 26‐week groups. Placebo group is common to both groups
FIGURE 5
FIGURE 5
Alpha1‐PI concentrations over 52 weeks. Alpha1‐PI, alpha1‐proteinase inhibitor (Prolastin‐C)

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