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

Abstract

Background 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. Methods and findings 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 m 2 . 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 m 2 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 urinary tract infection/obstruction, versus 1 patient on octreotide-LAR with a serious renal cyst infection. The main study limitation was the small sample size. Conclusions In this study we observed that in la...

Long-acting somatostatin analogue treatments in autosomal dominant polycystic kidney disease and polycystic liver disease: a systematic review and meta-analysis

“…A total of six studies were included consisting of five RCTs23–27 and one randomised crossover trial 28. Of these, four included ADPKD patients alone25–28 and the remaining two included patients with PLD and ADPKD, but provided a subset of data for ADPKD patients when measuring renal function and TKV 23 24. A further three publications were included as they were secondary analyses of previous studies,29–31 all of which were investigating the change in TLV for a subset of patients with PLD in a post-hoc analysis.…”

Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease

“…Apart from tolvaptan, several candidate treatments have been suggested for the management of ADPKD patients. The ALADIN trials 47 , 48 have proposed that the administration of octreotide long-acting release may delay the progression of renal failure, while its use was linked with non-serious adverse effects, especially diarrhea and cholelithiasis. In contrast, the mTOR inhibitor everolimus with or without octreotide did not lead to beneficial clinical outcomes, but was linked to higher risk of toxicity, such as bone marrow suppression and dyslipidemia.…”

New insights into targeting hepatic cystogenesis in autosomal dominant polycystic liver and kidney disease

“…octreotide with a high affinity for SSTR2 and SSTR5 and lanreotide with a high affinity for SSTR2 and minor affinity for SSTR5). Octreotide longacting release (LAR) showed a reduction of both hepatic and renal cystic growth at 1 year and 3 years of administration in several studies with ADPKD patients [3,26,27]. These studies did not observe any beneficial effect on the estimated glomerular filtration rate (eGFR) decline, but one trial documented that fewer patients progressed from chronic kidney disease stage 4 to stage 5 [27].…”

“…Octreotide longacting release (LAR) showed a reduction of both hepatic and renal cystic growth at 1 year and 3 years of administration in several studies with ADPKD patients [3,26,27]. These studies did not observe any beneficial effect on the estimated glomerular filtration rate (eGFR) decline, but one trial documented that fewer patients progressed from chronic kidney disease stage 4 to stage 5 [27]. Similarly, lanreotide reduced both hepatic and renal cyst growth in ADPLD and ADPKD patients in several large studies [3,[28][29][30].…”