Everolimus and long acting octreotide as a volume reducing treatment of polycystic livers (ELATE): study protocol for a randomized controlled trial

Melissa Chrispijn, Joost P H Drenth, Melissa Chrispijn, Joost P H Drenth

Abstract

Background: Polycystic liver disease (PLD) is defined as having more than 20 liver cysts and can present as a severe and disabling condition. Most symptoms are caused by the mass effect of the liver size and include abdominal pain and distension. The somatostatin analogues octreotide and lanreotide have proven to reduce polycystic liver volume. mTOR inhibitors such as everolimus inhibit cell proliferation and might thereby reduce growth of liver cysts. This trial aims to assess the benefit of combination therapy of everolimus and octreotide compared to octreotide monotherapy. In this study we present the structure of the trial and the characteristics of the included patients.

Methods/design: This is a randomized open-label clinical trial comparing the effect of 12 months of everolimus and octreotide to octreotide monotherapy in PLD patients. Primary outcome is change in liver volume determined by CT-volumetry. Secondary outcomes are changes in abdominal symptoms and quality of life. Moreover, safety and tolerability of the drugs will be assessed.

Discussion: This trial will compare the relative efficacy of combination therapy with octreotide and everolimus to octreotide monotherapy. Since they apply to different pathways of cystogenesis we expect that combining octreotide and everolimus will result in a cumulative reduction of polycystic liver volume.

Trial registration number: ClinicalTrials.gov: NCT01157858.

Figures

Figure 1
Figure 1
Trial design of the ELATE trial. All patients are screened for eligibility and the patients who suit the criteria are randomized in an equal ratio to either the octreotide monotherapy arm or the octreotide and everolimus arm. All patients receive a CT scan at baseline and after 12 months of treatment. Control visits are performed at 2, 6, 12, 24, 36 and 48 after baseline.
Figure 2
Figure 2
Intraobserver and interobserver variability. The figure on the left panel shows the intraobserver variability, which is the accuracy of a single researcher that has measured the same CT scan at two different times. The correlation between the consequent measurements is 1.00 (p < 0.01). The figure on the right panel shows the interobserver variability, which is the accuracy between two researchers who measured the same CT scan. The correlation between the measurements is 1.00 (p < 0.01).
Figure 3
Figure 3
Course of inclusion. This figure shows at which frequency the patients entered the trial. In the first 5 months of inclusion was very rapid, but then went flat for a few months. At month 11 the protocol was changed to such an extent that ADPKD patients were also allowed to participate in the trial. This reignited inclusion and the intended sample size was reached within 3 months.

References

    1. Drenth JP, Chrispijn M, Nagorney DM, Kamath PS, Torres VE. Medical and surgical treatment options for polycystic liver disease. Hepatology. 2010;52:2223–2230. doi: 10.1002/hep.24036.
    1. Bae KT, Zhu F, Chapman AB, Torres VE, Grantham JJ, Guay-Woodford LM. et al.Magnetic resonance imaging evaluation of hepatic cysts in early autosomal-dominant polycystic kidney disease: the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort. Clin J Am Soc Nephrol. 2006;1:64–69.
    1. van Keimpema L, de Koning DB, van Hoek B, van den Berg AP, van Oijen MG, de Man RA. et al.Patients with isolated polycystic liver disease referred to liver centres: clinical characterization of 137 cases. Liver Int. 2011;31:92–98. doi: 10.1111/j.1478-3231.2010.02247.x.
    1. Masyuk TV, Masyuk AI, Torres VE, Harris PC, Larusso NF. Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3',5'-cyclic monophosphate. Gastroenterology. 2007;132:1104–1116. doi: 10.1053/j.gastro.2006.12.039.
    1. van Keimpema L, de Man RA, Drenth JP. Somatostatin analogues reduce liver volume in polycystic liver disease. Gut. 2008;57:1338–1339. doi: 10.1136/gut.2008.155721.
    1. van Keimpema L, Drenth JP. Effect of octreotide on polycystic liver volume. Liver Int. 2010;30:633–634. doi: 10.1111/j.1478-3231.2009.02123.x.
    1. van Keimpema L, Nevens F, Vanslembrouck R, van Oijen MG, Hoffmann AL, Dekker HM. et al.Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2009;137:1661–1668. doi: 10.1053/j.gastro.2009.07.052.
    1. Hogan MC, Masyuk TV, Page LJ, Kubly VJ, Bergstralh EJ, Li X. et al.Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J Am Soc Nephrol. 2010;21:1052–1061. doi: 10.1681/ASN.2009121291.
    1. Caroli A, Antiga L, Cafaro M, Fasolini G, Remuzzi A, Remuzzi G. et al.Reducing polycystic liver volume in ADPKD: effects of somatostatin analogue octreotide. Clin J Am Soc Nephrol. 2010;5:783–789. doi: 10.2215/CJN.05380709.
    1. Qian Q, Du H, King BF, Kumar S, Dean PG, Cosio FG. et al.Sirolimus reduces polycystic liver volume in ADPKD patients. J Am Soc Nephrol. 2008;19:631–638. doi: 10.1681/ASN.2007050626.
    1. Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N. et al.The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci USA. 2006;103:5466–5471. doi: 10.1073/pnas.0509694103.
    1. Wahl PR, Serra AL, Le HM, Molle KD, Hall MN, Wuthrich RP. Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD) Nephrol Dial Transplant. 2006;21:598–604. doi: 10.1093/ndt/gfi181.
    1. Tao Y, Kim J, Schrier RW, Edelstein CL. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J Am Soc Nephrol. 2005;16:46–51.
    1. Wu M, Wahl PR, Le HM, Wackerle-Men Y, Wuthrich RP, Serra AL. Everolimus retards cyst growth and preserves kidney function in a rodent model for polycystic kidney disease. Kidney Blood Press Res. 2007;30:253–259. doi: 10.1159/000104818.
    1. Wu M, Arcaro A, Varga Z, Vogetseder A, Le HM, Wuthrich RP. et al.Pulse mTOR inhibitor treatment effectively controls cyst growth but leads to severe parenchymal and glomerular hypertrophy in rat polycystic kidney disease. Am J Physiol Renal Physiol. 2009;297:F1597–F1605. doi: 10.1152/ajprenal.00430.2009.
    1. Bovenschen HJ, Janssen MJ, van Oijen MG, Laheij RJ, van Rossum LG, Jansen JB. Evaluation of a gastrointestinal symptoms questionnaire. Dig Dis Sci. 2006;51:1509–1515. doi: 10.1007/s10620-006-9120-6.
    1. 2011. Ref Type: Internet Communication.
    1. Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 2009;76:149–168. doi: 10.1038/ki.2009.128.
    1. Temmerman F, Missiaen L, Bammens B, Laleman W, Cassiman D, Verslype C. et al.Systematic review: the pathophysiology and management of polycystic liver disease. Aliment Pharmacol Ther. 2011;34:702–713. doi: 10.1111/j.1365-2036.2011.04783.x.
    1. Serra AL, Poster D, Kistler AD, Krauer F, Raina S, Young J. et al.Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363:820–829. doi: 10.1056/NEJMoa0907419.
    1. Walz G, Budde K, Mannaa M, Nurnberger J, Wanner C, Sommerer C. et al.Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363:830–840. doi: 10.1056/NEJMoa1003491.

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