Alpha-1 Antitrypsin Therapy Does Not Improve C-Peptide in Chronic Pancreatitis

Hongjun Wang, PhD

Credit: Medical University of South Carolina

A study found alpha-1 antitrypsin therapy (AAT) does not improve C-peptide AUC in patients with chronic pancreatitis undergoing total pancreatectomy and islet autotransplantation (TP-IAT).¹

Stress-induced islet graft loss before undergoing total pancreatectomy and islet autotransplantation (TP-IAT) can reduce the efficacy of the surgical procedure—and leave ≥ 60% of patients needing insulin.²

Investigators, led by Hongjun Wang, PhD, from the Medical University of South Carolina, aimed to see if 60 mg/kg human alpha-1 antitrypsin (AAT) infusion for 4 consecutive weeks starting the morning before the surgery reduced the islet graft loss and improved surgical outcomes.¹ Since low or a decline in C-peptide levels may indicate an islet graft loss or dysfunction, investigators evaluated the C-peptide area under the curve (AUC) following a 4-hour mixed meal tolerance test at around 365 days post-transplantation as their primary endpoint. They also assessed safety throughout the study.

The team conducted a single-center, randomized, double-blind, placebo-controlled study on 43 patients with chronic pancreatitis (aged ≥ 18 years) undergoing TP-IAT at the Medical University of South Carolina between January 2017 and November 2021.

Participants were randomized 2:1 to receive 60 mg/kg intravenous ATT (Prolastin-C) (n = 29) or intravenous 0.9% saline placebo (n = 14). The first ATT infusion began the morning before the total pancreatectomy and the following infusions were administered at 7 ± 2, 14 ± 2, and 21 ± 2 days post-surgery. Participants had to complete a mixed meal tolerance test at days 75 and 365 post-surgery on top of their routine post-operation visits at months 1, 3, 6, and 9 and then annually.

Investigators observed no significant differences in baseline characteristics for AAT versus healthy controls: age (mean: 39.31 vs 38.39 years), body weight (78.07kg vs 73.79kg), body mass index (27.96 vs 24.31 kg/m2), HbA1 levels (5.42% vs 5.43%). The control participants did have a longer chronic pancreatitis duration than AAT participants (10.3 ± 5.2 vs 6.4 ± 5.5 years, P = .03). The groups had no significant differences in the total volume of islet product and islet equivalent infused.

Adverse events, such as abdominal pain, fatigue, nausea, vomiting, hypotension, and cellulitis occurred in 15 participants (51.7%) and 6 placebo participants (42.9%). Serious adverse events occurred in 69.8% of participants: 22 on AAT therapy (75.9%) and 8 on placebo (57.1%). Most of the serious adverse events fell under gastrointestinal manifestations, such as worsened abdominal pain, nausea, vomiting, gastric ulcer, colitis, and abdominal fluid collections. Two patients—one in each arm—had portal vein thrombosis.

Investigators saw islet graft function was not significantly different between arms. At 3 months, the C-peptide AUC was 543.8 ± 93.0 ng/ml × min in placebo compared to 422.6 ± 54.0 ng/ml × min in the AAT arm (P = .33). At month 3, the C-peptide AUC was 354.1 ± 78.0 ng/ml × min in placebo compared to 232.5 ± 42.2 ng/ml × min in the AAT arm (P = .43)

Furthermore, the AUC/IEQ/kg at 3 months for the placebo arm versus the AAT arm was 0.11 ± 0.02 ng/ml × min and 0.13 ± 0.01 ng/ml × min, respectively (P = .32). At 12 months it was 0.09 ± 0.01 ng/ml × min/IEQ/kg in placebo compared to 0.10 ± 0.05 ng/ml × min/IEQ/kg in AAT (P = .1).

The team observed the SF-12 physiological quality of life score improved in both arms, rising in the placebo arm to 27.6 ± 9.0 before the surgery to 30.5 ± 12.4 at 6 months and to 33.6 ± 11.4 at 12 months. The physiological quality of life score in the AAT arm improved from 23.3 ± 7.1 before the surgery to 31.8 ± 11.2 at 6 months and to 32.2 ± 12.6 at 12 months.

Despite AAT therapy showing minimal improvement of islet function after the operation, investigators looked at the bright side of this unpromising data: they were able to enroll patients with chronic pancreatitis for a complex trial, suggesting this patient population is willing to participate in the trials.

“Although the current dose of AAT was safe and well-tolerated in this patient population, this treatment regimen is not recommended, and a different treatment strategy is needed to improve the outcomes of TP-IAT,” investigators concluded.

References

1. ^{Wang H, Gou W, Nietert PJ, et al. Alpha-1 Antitrypsin Augmentation Therapy in Chronic Pancreatitis Patients Undergoing Total Pancreatectomy and Islet Autotransplantation: A Randomized, Controlled Study. Cell Transplant. 2024;33:9636897241243014. doi:10.1177/09636897241243014}
2. ^{Kesseli SJ, Smith KA, Gardner TB. Total pancreatectomy with islet autologous transplantation: the cure for chronic pancreatitis?. Clin Transl Gastroenterol. 2015;6(1):e73. Published 2015 Jan 29. doi:10.1038/ctg.2015.2}