Articles www.thelancet.com Published online August 21, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61407-5 1 Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial Anna Caroli*, Norberto Perico*, Annalisa Perna*, Luca Antiga, Paolo Brambilla, Antonio Pisani, Bianca Visciano, Massimo Imbriaco, Piergiorgio Messa, Roberta Cerutti, Mauro Dugo, Luca Cancian, Erasmo Buongiorno, Antonio De Pascalis, Flavio Gaspari, Fabiola Carrara, Nadia Rubis, Silvia Prandini, Andrea Remuzzi, Giuseppe Remuzzi*, Piero Ruggenenti*, for the ALADIN study group† Summary Background Autosomal dominant polycystic kidney disease slowly progresses to end-stage renal disease and has no effective therapy. A pilot study suggested that the somatostatin analogue octreotide longacting release (LAR) could be nephroprotective in this context. We aimed to assess the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with this disorder. Methods We did an academic, multicentre, randomised, single-blind, placebo-controlled, parallel-group trial in five hospitals in Italy. Adult (>18 years) patients with estimated glomerular filtration rate (GFR) of 40 mL/min per 1·73 m² or higher were randomly assigned (central allocation by phone with a computerised list, 1:1 ratio, stratified by centre, block size four and eight) to 3 year treatment with two 20 mg intramuscular injections of octreotide-LAR (n=40) or 0·9% sodium chloride solution (n=39) every 28 days. Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation. The primary endpoint was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, NCT00309283. Findings Recruitment was between April 27, 2006, and May 12, 2008. 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this timepoint, mean TKV increased significantly less in the octreotide-LAR group (46·2 mL, SE 18·2) compared with the placebo group (143·7 mL, 26·0; p=0·032). 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this timepoint, mean TKV increase in the octreotide-LAR group (220·1 mL, 49·1) was numerically smaller than in the placebo group (454·3 mL, 80·8), but the difference was not significant (p=0·25). 37 (92·5%) participants in the octreotide-LAR group and 32 (82·1%) in the placebo group had at least one adverse event (p=0·16). Participants with serious adverse events were similarly distributed in the two treatment groups. However, four cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related. Interpretation These findings provide the background for large randomised controlled trials to test the protective effect of somatostatin analogues against renal function loss and progression to end-stage kidney disease. Funding Polycystic Kidney Disease Foundation. Introduction Autosomal dominant polycystic kidney disease is the most common monogenic renal disorder, accounting for 8–10% of patients receiving renal replacement therapy for end- stage renal disease worldwide. 1 Its clinical phenotype is progressive and substantial enlargement of the kidneys, caused by sustained expansion of many fluid-filled cysts that originate from the tubule wall, leading to crowding of adjacent nephrons, injury to normal parenchyma, 2,3 and eventually kidney failure. No proven treatments exist and an effective disease-modifying drug would have important implications for patients. The progressive enlargement of cysts derived from renal tubules is believed to be largely attributable to proliferation of mural epithelial cells and transport of fluid into cavities generated by accelerated epithelial cell growth. 4 In-vitro evidence suggests that this cell growth and transepithelial secretion of fluid is controlled by cyclic AMP (cAMP). 4 Somatostatin—a cyclic 14 aminoacid peptide secreted by pancreatic islets, the gastrointestinal tract, nervous system, and thyroid gland—is thought to inhibit adenyl cyclase and post-cAMP events in addi- tion to fluid secretion stimulated by agents that do not generate cAMP. 5 These findings and the presence of specific receptors for somatostatin in human kidneys 6 led us to do a pilot feasibility study 7 with the somato- statin analogue octreotide longacting release (LAR) in 12 participants with autosomal dominant polycystic kidney disease with different degrees of renal insuf- ficiency. The intention was to inhibit cAMP production in renal cells, thereby reducing rates of cell proliferation and fluid secretion. 7 6 month octreotide-LAR treatment retarded by more than 60% the time-dependent increase in total kidney volume (TKV), compared with placebo in Published Online August 21, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)61407-5 See Online/Comment http://dx.doi.org/10.1016/ S0140-6736(13)61541-X *Contributed equally †Members listed in appendix IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases, Aldo e Cele DaccÒ, Bergamo, Italy (A Caroli PhD, N Perico MD, A Perna MSc, L Antiga PhD, F Gaspari ChemD, F Carrara Chemist, N Rubis Res Nurse, S Prandini Res Nurse, A Remuzzi EngD, G Remuzzi FRCP, P Ruggenenti MD); Unit of Radiology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy (P Brambilla MD); Università Federico II, Cattedra di Nefrologia, Napoli, Italy (A Pisani MD, B Visciano MD); Università Federico II, Unità di Radiologia, Napoli, Italy (M Imbriaco MD); Ospedale Maggiore Policlinico IRCCS Milano, Unità di Nefrologia e Dialisi, Milan, Italy (P Messa MD, R Cerutti MD); Ospedale Cà Foncello, Unità di Nefrologia e Dialisi, Treviso, Italy (M Dugo MD); Ospedale Cà Foncello, Unità di Radiologia, Treviso, Italy (L Cancian MD); Ospedale V Fazzi, Unità di Nefrologia e Dialisi, Lecce, Italy (E Buongiorno MD, A De Pascalis MD); Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy (G Remuzzi, P Ruggenenti); Department of Industrial Engineering, University of Bergamo, Italy (A Remuzzi); and Orobix Srl, Bergamo, Italy (L Antiga)