Hepatic Cyst Infection During Use of the Somatostatin Analog Lanreotide in Autosomal Dominant Polycystic Kidney Disease: An Interim Analysis of the Randomized Open-Label Multicenter DIPAK-1 Study

Abstract

Introduction and aims: The DIPAK-1 Study investigates the reno- and hepatoprotective efficacy of the somatostatin analog lanreotide compared with standard care in patients with later stage autosomal dominant polycystic kidney disease (ADPKD). During this trial, we witnessed several episodes of hepatic cyst infection, all during lanreotide treatment. We describe these events and provide a review of the literature.

Methods: The DIPAK-1 Study is an ongoing investigator-driven, randomized, controlled, open-label multicenter trial. Patients (ADPKD, ages 18-60 years, estimated glomerular filtration rate 30-60 mL/min/1.73 m2) were randomized 1:1 to receive lanreotide 120 mg subcutaneously every 28 days or standard care during 120 weeks. Hepatic cyst infection was diagnosed by local physicians.

Results: We included 309 ADPKD patients of which seven (median age 53 years [interquartile range: 48-55], 71% female, median estimated glomerular filtration rate 42 mL/min/1.73 m2 [interquartile range: 41-58]) developed eight episodes of hepatic cyst infection during 342 patient-years of lanreotide use (0.23 cases per 10 patient-years). These events were limited to patients receiving lanreotide (p < 0.001 vs. standard care). Baseline characteristics were similar between subjects who did or did not develop a hepatic cyst infection during lanreotide use, except for a history of hepatic cyst infection (29 vs. 0.7%, p < 0.001). Previous studies with somatostatin analogs reported cyst infections, but did not identify a causal relationship.

Conclusions: These data suggest an increased risk for hepatic cyst infection during use of somatostatin analogs, especially in ADPKD patients with a history of hepatic cyst infection. The main results are still awaited to fully appreciate the risk-benefit ratio. CLINICALTRIALS.

Gov identifier: NCT 01616927.

Conflict of interest statement

Compliance with Ethical Standards Funding The DIPAK-1 study is made possible by a grant from the Dutch Kidney Foundation (CP10.12), with Ipsen Farmaceutica B.V., the Netherlands acting as a minor co-sponsor. The Dutch Kidney Foundation and Ipsen had no role in the design or conduct of the study, or in the writing and submission of the manuscript. Conflict of interest Marten A. Lantinga, Hedwig M.A. D’Agnolo, Niek F. Casteleijn, Johan W. de Fijter, Esther Meijer, Annemarie L. Messchendorp, Dorien J.M. Peters, Mahdi Salih, Darius Soonawala, Folkert W. Visser, and Jack F.M. Wetzels have no conflicts of interest that are directly relevant to the content of this study. Edwin M. Spithoven has received payment for an Otsuka presentation about the epidemiology of ADPKD and future perspectives. Robert Zietse has received previous grant support from Ipsen. Joost P.H. Drenth has received previous grant support from Ipsen and Novartis. Ron T. Gansevoort holds the rights on the Orphan Designation status of lanreotide for the indication ADPKD, which was granted by the European Medicines Agency (EU/3/15/1514). Ethics approval and consent to participate All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Consent for publication Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1

Baseline T2-weighted magnetic resonance imaging of patients developing hepatic cyst infection during the DIPAK-1 Study. Height-adjusted liver volume (hTLV) were 2670, 1579, 823, 2723, 8635, 1901, and 997 mL/m in respectively, cases 1–7 (a–f). In five of seven patients, the phenotype consists of multiple small- and medium-sized cysts spread throughout the liver, with remaining large areas of non-cystic liver parenchyma [cases 1–4 (a–d) and 6 (f)]. One patient [case 5 (e)] showed a phenotype with massive diffuse involvement of liver parenchyma by small- and medium-sized liver cysts, with only a few areas of remaining normal liver parenchyma between cysts. Remarkably, the liver phenotype of the last patient who developed a hepatic cyst infection was limited to a single hepatic cyst [case 7 (g)]

Fig. 2

Reverse Kaplan–Meier curve showing time to development of a first hepatic cyst infection in autosomal dominant polycystic kidney disease patients participating in the lanreotide and control groups of the ongoing DIPAK-1 Study (interim analysis). The median time patients had received lanreotide until onset of hepatic cyst infection was 4 months (interquartile range 2–5 months)