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

Norberto Perico, Piero Ruggenenti, Annalisa Perna, Anna Caroli, Matias Trillini, Sandro Sironi, Antonio Pisani, Eleonora Riccio, Massimo Imbriaco, Mauro Dugo, Giovanni Morana, Antonio Granata, Michele Figuera, Flavio Gaspari, Fabiola Carrara, Nadia Rubis, Alessandro Villa, Sara Gamba, Silvia Prandini, Monica Cortinovis, Andrea Remuzzi, Giuseppe Remuzzi, ALADIN 2 Study Group, Norberto Perico, Piero Ruggenenti, Annalisa Perna, Anna Caroli, Matias Trillini, Sandro Sironi, Antonio Pisani, Eleonora Riccio, Massimo Imbriaco, Mauro Dugo, Giovanni Morana, Antonio Granata, Michele Figuera, Flavio Gaspari, Fabiola Carrara, Nadia Rubis, Alessandro Villa, Sara Gamba, Silvia Prandini, Monica Cortinovis, Andrea Remuzzi, Giuseppe Remuzzi, ALADIN 2 Study Group

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 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 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 later-stage ADPKD, octreotide-LAR slowed kidney growth and delayed progression to ESRD, in particular in CKD stage 4.

Trial registration: ClinicalTrials.gov NCT01377246; EudraCT: 2011-000138-12.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Trial profile.
Fig 1. Trial profile.
CT, computed tomography; ESRD, end-stage renal disease; GFR, glomerular filtration rate; octreotide-LAR, octreotide long-acting release; TKV, total kidney volume.
Fig 2. Absolute changes in total kidney…
Fig 2. Absolute changes in total kidney volume from baseline to 1-year and 3-year follow-up.
Absolute changes in total kidney volume from baseline to 1-year (primary short-term outcome) and 3-year follow-up in patients randomized to either placebo or octreotide-LAR. Data are reported as median and interquartile range. P values from non-parametric ANCOVA adjusted for age, sex and baseline total kidney volume. Analysis performed including all non-missing data. octreotide-LAR, octreotide long-acting release.
Fig 3. Kaplan–Meier curves for the secondary…
Fig 3. Kaplan–Meier curves for the secondary composite endpoint of doubling of serum creatinine or ESRD.
Kaplan–Meier curves show the proportion of patients who reached the composite endpoint of doubling of serum creatinine or ESRD in the placebo and octreotide-LAR groups during the 3-year study period. *Adjusted by age, sex, and baseline serum creatinine.°Adjusted by age, sex, and baseline serum creatinine and total kidney volume. ESRD, end-stage renal disease; HR, hazard ratio; octreotide-LAR, octreotide long-acting release.
Fig 4. Kaplan–Meier curves for the secondary…
Fig 4. Kaplan–Meier curves for the secondary composite endpoint of doubling of serum creatinine or ESRD and for the single endpoint of ESRD in patients with CKD stage 4.
Kaplan–Meier curves show the proportion of patients with CKD stage 4 who reached (A) the composite endpoint of doubling of serum creatinine or ESRD or (B) ESRD considered as a single endpoint (secondary outcomes) in the placebo and octreotide-LAR groups during the 3-year study period. *Adjusted by age, sex, and baseline serum creatinine.°Adjusted by age, sex, and baseline serum creatinine and total kidney volume. CKD, chronic kidney disease; ESRD, end-stage renal disease; HR, hazard ratio; octreotide LAR, octreotide long-acting release.

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