Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin 25 000 Ph. Eur. minimicrospheres (Creon 25000 MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension

Abstract

Background: Pancreatic exocrine insufficiency (PEI) often occurs following pancreatic surgery.

Aim: To demonstrate the superior efficacy of pancreatin 25 000 minimicrospheres (Creon 25000 MMS; 9-15 capsules/day) over placebo in treating PEI after pancreatic resection.

Methods: A 1-week, double-blind, randomised, placebo-controlled, parallel-group, multicentre study with a 1-year, open-label extension (OLE). Subjects ≥18 years old with PEI after pancreatic resection, defined as baseline coefficient of fat absorption (CFA) <80%, were randomised to oral pancreatin or placebo (9-15 capsules/day: 3 with main meals, 2 with snacks). In the OLE, all subjects received pancreatin. The primary efficacy measure was least squares mean CFA change from baseline to end of double-blind treatment (ancova).

Results: All 58 subjects randomised (32 pancreatin, 26 placebo) completed double-blind treatment and entered the OLE; 51 completed the OLE. The least squares mean CFA change in the double-blind phase was significantly greater with pancreatin vs. placebo: 21.4% (95% CI: 13.7, 29.2) vs. -4.2% (-12.8, 4.5); difference 25.6% (13.9, 37.3), P < 0.001. The mean ± s.d. CFA increased from 53.6 ± 20.6% at baseline to 78.4 ± 20.7% at OLE end (P < 0.001). Treatment-emergent adverse events occurred in 37.5% subjects on pancreatin and 26.9% on placebo during double-blind treatment, with flatulence being the most common (pancreatin 12.5%, placebo 7.7%). Only two subjects discontinued due to treatment-emergent adverse events, both during the OLE.

Conclusions: This study demonstrates superior efficacy of pancreatin 25 000 over placebo in patients with PEI after pancreatic surgery, measured by change in CFA. Pancreatin was generally well tolerated at the high dose administered (EudraCT registration number: 2005-004854-29).

© 2013 Blackwell Publishing Ltd.

Figures

Figure 1

Study design. CFA, coefficient of fat absorption; CNA, coefficient of nitrogen absorption; OLE, open-label extension; PERT, pancreatic enzyme replacement therapy.

Figure 2

Patient disposition. OLE, open-label extension. *Majority did not meet the interim inclusion criterion of CFA n = 3); insufficient treatment compliance (n = 1); deviation from inclusion criterion of CFA <80% (n = 3). ‡Insufficient exposure to study medication during double-blind phase (n = 3); insufficient treatment compliance (n = 2); insufficient essential efficacy data (n = 1); use of prohibited/prior concomitant medication (n = 1). §Withdrew consent (n = 3), adverse events (n = 2), lost to follow-up (n = 1), and administrative reasons (n = 1).

Figure 3

Clinical symptoms. BL, baseline; DB, double-blind; OLE, open-label extension.

Figure 4

Clinical global impression of disease symptoms. BL, baseline.

Figure 5

CFA values at the end of double-blind treatment according to type of surgery in patients receiving pancreatin during the double-blind period (n = 31; CFA data missing at end of double-blind phase in one patient). Dashed line indicates desired CFA threshold of 85%. Solid line indicates median value in each category. *Whipple procedure or equivalent, e.g. pylorus-preserving pancreaticoduodenectomy. †Pancreatic resection with splenectomy (n = 1), distal resection (n = 1), partial pancreatectomy due to arterial aneurysm resection (n = 1), longitudinal resection (n = 1), pancreatic head resection with cholecystectomy (n = 1). CFA, coefficient of fat absorption; PHR, pancreatic head resection; PY, pancreatectomy.