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Efficacy of 4 Years of Octreotide Long-Acting Release Therapy in Patients With Severe Polycystic Liver Disease.

ABSTRACT: To observe the effect on total liver volume (TLV) on and off therapy in selected symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD) or autosomal dominant polycystic liver disease (PLD) who received octreotide long-acting release (OctLAR) for up to 4 years.Twenty-eight of 42 participants in a prospective 2-year clinical trial of OctLAR (40 mg monthly) consisting of double-blind, randomized (year 1) and open-label treatment (year 2) phases reenrolled in a 2-year open-label extension (OLE) study after being off OctLAR a mean of 8.3 months (original study: July 1, 2007, through June 30, 2013). Participants underwent magnetic resonance imaging at baseline, years 1 and 2, reenrollment, and study completion. Primary end point: change in TLV; secondary end points: changes in total kidney volume, glomerular filtration rate, quality of life (QoL), safety, vital signs, and laboratory parameters.Twenty-five participants (59.5%) completed the OLE. Off therapy, TLVs increased a mean ± SD of 3.4%±8.2% per year; after resuming therapy, TLVs decreased a mean ± SD of -4.7%±6.1% per year. Despite regrowth off treatment, overall reductions were observed, with a median (interquartile range) TLV of 4047 mL (3107-7402 mL) at baseline and 3477 (2653-7131 mL) at study completion (-13.2%; P<.001) and with improved health-related QoL. Total kidney volumes increased, and glomerular filtration rates declined from 58.2 mL/min to 54.5 mL/min (n=16) in patients with ADPKD on therapy from baseline to study completion.Therapy with OctLAR over 4 years in selected patients with symptomatic PLD arrested PLD progression, alleviating symptoms and improving health-related QoL. Discontinuation led to organ regrowth.clinicaltrials.gov Identifier: NCT00426153.

SUBMITTER: Hogan MC

PROVIDER: S-EPMC4928579 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Efficacy of 4 Years of Octreotide Long-Acting Release Therapy in Patients With Severe Polycystic Liver Disease.

Hogan Marie C MC Masyuk Tetyana T Bergstralh Eric E Li Bill B Kremers Walter K WK Vaughan Lisa E LE Ihrke Angela A Severson Amanda L AL Irazabal Maria V MV Glockner James J LaRusso Nicholas F NF Torres Vicente E VE

Mayo Clinic proceedings 20150709 8

<h4>Objective</h4>To observe the effect on total liver volume (TLV) on and off therapy in selected symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD) or autosomal dominant polycystic liver disease (PLD) who received octreotide long-acting release (OctLAR) for up to 4 years.<h4>Patients and methods</h4>Twenty-eight of 42 participants in a prospective 2-year clinical trial of OctLAR (40 mg monthly) consisting of double-blind, randomized (year 1) and open-label treatment ...[more]

PMID: 26166166

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Project description:Background and objectivesWe assessed safety and efficacy of another somatostatin receptor analog, pasireotide long-acting release, in severe polycystic liver disease and autosomal dominant polycystic kidney disease. Pasireotide long-acting release, with its broader binding profile and higher affinity to known somatostatin receptors, has potential for greater efficacy.Design, setting, participants, & measurementsIndividuals with severe polycystic liver disease were assigned in a 2:1 ratio in a 1-year, double-blind, randomized trial to receive pasireotide long-acting release or placebo. Primary outcome was change in total liver volume; secondary outcomes were change in total kidney volume, eGFR, and quality of life.ResultsOf 48 subjects randomized, 41 completed total liver volume measurements (n=29 pasireotide long-acting release and n=12 placebo). From baseline, there were -99±189 ml/m absolute and -3%±7% change in annualized change in height-adjusted total liver volume (from 2582±1381 to 2479±1317 ml/m) in the pasireotide long-acting release group compared with 136±117 ml/m absolute and 6%±7% increase (from 2387±759 to 2533±770 ml/m) in placebo (P<0.001 for both). Total kidney volumes decreased by -12±34 ml/m and -1%±4% in pasireotide long-acting release compared with 21±21 ml/m and 4%±5% increase in the placebo group (P=0.05 for both). Changes in eGFR were similar between groups. Among the n=48 randomized, adverse events included hyperglycemia (26 of 33 [79%] in pasireotide long-acting release versus four of 15 [27%] in the placebo group; P<0.001), and among the 47 without diabetes at baseline, 19 of 32 (59%) in the pasireotide long-acting release group versus one of 15 (7%) in the placebo group developed diabetes (P=0.001).ConclusionsAnother somatostatin analog, pasireotide long-acting release, slowed progressive increase in both total liver volume/total kidney volume growth rates without affecting GFR decline. Participants experienced higher frequency of adverse events (hyperglycemia and diabetes).Clinical trial registry name and registration numberPasireotide LAR in Severe Polycystic Liver Disease, NCT01670110 PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_08_28_CJN13661119.mp3.

Project description:BackgroundWe showed in a randomized double-blinded placebo-controlled clinical trial that octreotide long-acting repeatable depot.® (OctLAR(®)) for 12 months reduces kidney and liver growth in autosomal dominant polycystic kidney patients with severe polycystic liver disease (PLD) and liver growth in patients with severe isolated PLD. We have now completed an open-label extension for one additional year to assess safety and clinical benefits of continued use of OctLAR for 2 years (O → O) and examined drug effect in the placebo group who crossed over to OctLAR in Year 2 (P → O).MethodsThe primary end point was change in total liver volume (TLV) measured by magnetic resonance imaging (MRI); secondary end points were changes in total kidney volume (TKV) measured by MRI, glomerular filtration rate (GFR), quality of life (QOL), safety, vital signs and laboratory parameters.ResultsForty-one of 42 patients received OctLAR (n = 28) or placebo (n = 14) in Year 1 and received OctLAR in Year 2 (maximum dose 40 mg). Patients originally randomized to placebo (P → O) showed substantial reduction in TLV after treatment with OctLAR in Year 2 (Δ% -7.66 ± 9.69%, P = 0.011). The initial reduction of TLV in the OctLAR group (O → O) was maintained for 2 years (Δ% -5.96 ± 8.90%), although did not change significantly during Year 2 (Δ% -0.77 ± 6.82%). OctLAR inhibited renal enlargement during Year 1 (Δ% +0.42 ± 7.61%) in the (O → O) group and during Year 2 (Δ% -0.41 ± 9.45%) in the (P → O) group, but not throughout Year 2 (Δ% +6.49 ± 7.08%) in the (O → O) group. Using pooled analyses of all individuals who received OctLAR for 12 months, i.e. in Year 1 for O → O patients and Year 2 for P → O patients, average reduction in TLV was -6.08 ± 7.58% (P = 0.001) compared to net growth of 0.9 ± 8.35% in the original placebo group. OctLAR-treated individuals continued to experience improvements in QOL in Year 2, although overall physical and mental improvements were not significant during Year 2 compared to Year 1. Changes in GFR were similar in both groups.ConclusionOver 2 years, OctLAR significantly reduced the rate of increase in TLV and possibly the rate of increase in TKV.

Project description:BackgroundTolvaptan and octreotide-long-acting release (LAR) have renoprotective effects in autosomal dominant polycystic kidney disease (ADPKD) that are partially mediated by amelioration of compensatory glomerular hyperfiltration. We compared the effects of tolvaptan and octreotide-LAR combination therapy versus those of tolvaptan monotherapy in patients with ADPKD.MethodsThis pilot, randomized, placebo-controlled, cross-over trial primarily compared the effects of 1- and 4-week treatments with octreotide-LAR (two 20-mg i.m. injections) or placebo (two i.m. 0.9% saline solution injections) added-on tolvaptan (up to 90 and 30 mg/d) on GFR (iohexol plasma clearance) in 19 consenting patients with ADPKD referred to a clinical research center in Italy. Analyses were intention-to-treat. The local ethical committee approved the study.ResultsAt 4 weeks, GFR significantly decreased by a median (interquartile range) of 3 (-1 to 5) ml/min per 1.73 m2 with tolvaptan and placebo (P=0.01) and by 7 (3-14) ml/min per 1.73 m2 with tolvaptan and octreotide-LAR (P=0.03). GFR changes during the two treatment periods differed by 2 (-5 to 14) ml/min per 1.73 m2 (P=0.28). At 1 week, GFR significantly decreased by 3 (0-7) ml/min per 1.73 m2 with tolvaptan and placebo (P=0.006) and by 10 (-6 to 16) ml/min per 1.73 m2 with tolvaptan and octreotide-LAR add-on therapy (P<0.001). GFR changes during the two treatment periods significantly differed by 3 (0-12) ml/min per 1.73 m2 (P=0.012). Total kidney volume nonsignificantly changed by 4 (-48 to 23) ml with tolvaptan and placebo (P=0.74), whereas it decreased significantly by 41 (25-77) ml with tolvaptan and octreotide-LAR (P=0.001). Changes during the two treatment periods differed by 36 (0-65) ml (P=0.01). Octreotide-LAR also attenuated (P=0.02) the aquaretic effect of tolvaptan. Treatments were well tolerated.ConclusionsIn patients with ADPKD, octreotide-LAR added-on tolvaptan reduced GFR more effectively than octreotide-LAR and placebo. Octreotide-LAR also reduced total and cystic kidney volumes and attenuated the acquaretic effect of tolvaptan.Clinical trial registry name and registration numberTolvaptan-Octreotide LAR Combination in ADPKD (TOOL), NCT03541447.

Dataset Information

Efficacy of 4 Years of Octreotide Long-Acting Release Therapy in Patients With Severe Polycystic Liver Disease.

Publications

Efficacy of 4 Years of Octreotide Long-Acting Release Therapy in Patients With Severe Polycystic Liver Disease.

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