PLoS medicine · 2019
Octreotide-LAR in later-stage autosomal dominant polycystic kidney disease (ALADIN 2): A randomized, double-blind, placebo-controlled, multicenter trial.
Клиническое исследование III фазыСтатьяМногоцентровое исследованиеРандомизированное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
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, ALADIN 2 Study Group
Аннотация
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.
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.