Octreotide-LAR in later-stage autosomal dominant polycystic kidney disease (ALADIN 2): A randomized, double-blind, placebo-controlled, multicenter trial

• Published in: PLoS medicine 2019-04, Vol.16 (4), p.e1002777
• Main Authors: Perico, Norberto, Ruggenenti, Piero, Perna, Annalisa, Caroli, Anna, Trillini, Matias, Sironi, Sandro, Pisani, Antonio, Riccio, Eleonora, Imbriaco, Massimo, Dugo, Mauro, Morana, Giovanni, Granata, Antonio, Figuera, Michele, Gaspari, Flavio, Carrara, Fabiola, Rubis, Nadia, Villa, Alessandro, Gamba, Sara, Prandini, Silvia, Cortinovis, Monica, Remuzzi, Andrea, Remuzzi, Giuseppe
• Format: Article
• Language: English
• Subjects: Adult; Analysis; Biology and Life Sciences; CAT scans; Cell growth; Chlorides; Chronic kidney failure; Clinical trials; Complications and side effects; Computed tomography; Contrast media; Creatinine; Cysts; Delayed-Action Preparations; Development and progression; Diabetes mellitus; Disease Progression; Double-Blind Method; Double-blind studies; End-stage renal disease; Female; Glomerular filtration rate; Glomerular Filtration Rate - drug effects; Hemodialysis; Hospitals; Humans; Infections; Injections, Intramuscular; Kidney - drug effects; Kidney - pathology; Kidney diseases; Kidney Failure, Chronic - drug therapy; Kidney Failure, Chronic - etiology; Kidney Failure, Chronic - pathology; Kidneys; Male; Medical research; Medicine and Health Sciences; Middle Aged; Nephrology; Octreotide; Octreotide - administration & dosage; Octreotide - adverse effects; Polycystic kidney; Polycystic kidney disease; Polycystic Kidney, Autosomal Dominant - complications; Polycystic Kidney, Autosomal Dominant - drug therapy; Polycystic Kidney, Autosomal Dominant - pathology; Proteinuria; Public health; Randomization; Renal function; Research and Analysis Methods; Risk factors; Sodium; Sodium chloride; Software; Somatostatin; Tomography; Treatment Outcome; Urinary tract; Urine
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.1002777

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetically determined renal disease. In affected patients, renal function may progressively decline up to end-stage renal disease (ESRD), and approximately 10% of those with ESRD are affected by ADPKD. The somatostatin analog octreotide long-acting release (octreotide-LAR) slows renal function deterioration in patients in early stages of the disease. We evaluated the renoprotective effect of octreotide-LAR in ADPKD patients at high risk of ESRD because of later-stage ADPKD. We did an internally funded, parallel-group, double-blind, placebo-controlled phase III trial to assess octreotide-LAR in adults with ADPKD with glomerular filtration rate (GFR) 15-40 ml/min/1.73 m2. Participants were randomized to receive 2 intramuscular injections of 20 mg octreotide-LAR (n = 51) or 0.9% sodium chloride solution (placebo; n = 49) every 28 days for 3 years. Central randomization was 1:1 using a computerized list stratified by center and presence or absence of diabetes or proteinuria. Co-primary short- and long-term outcomes were 1-year total kidney volume (TKV) (computed tomography scan) growth and 3-year GFR (iohexol plasma clearance) decline. Analyses were by modified intention-to-treat. Patients were recruited from 4 Italian nephrology units between October 11, 2011, and March 20, 2014, and followed up to April 14, 2017. Baseline characteristics were similar between groups. Compared to placebo, octreotide-LAR reduced median (95% CI) TKV growth from baseline by 96.8 (10.8 to 182.7) ml at 1 year (p = 0.027) and 422.6 (150.3 to 695.0) ml at 3 years (p = 0.002). Reduction in the median (95% CI) rate of GFR decline (0.56 [-0.63 to 1.75] ml/min/1.73 m2 per year) was not significant (p = 0.295). TKV analyses were adjusted for age, sex, and baseline TKV. Over a median (IQR) 36 (24 to 37) months of follow-up, 9 patients on octreotide-LAR and 21 patients on placebo progressed to a doubling of serum creatinine or ESRD (composite endpoint) (hazard ratio [HR] [95% CI] adjusted for age, sex, baseline serum creatinine, and baseline TKV: 0.307 [0.127 to 0.742], p = 0.009). One composite endpoint was prevented for every 4 treated patients. Among 63 patients with chronic kidney disease (CKD) stage 4, 3 on octreotide-LAR and 8 on placebo progressed to ESRD (adjusted HR [95% CI]: 0.121 [0.017 to 0.866], p = 0.036). Three patients on placebo had a serious renal cyst rupture/infection and 1 patient had a serious u