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Randomized Controlled Trial
. 2023 Feb 1;18(2):223-233.
doi: 10.2215/CJN.0000000000000049.

Effects of Octreotide-Long-Acting Release Added-on Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease: Pilot, Randomized, Placebo-Controlled, Cross-Over Trial

Matias Trillini  1 , Anna Caroli  1 , Norberto Perico  1 , Andrea Remuzzi  2 , Paolo Brambilla  3 , Giulia Villa  1 , Annalisa Perna  1 , Tobia Peracchi  1 , Nadia Rubis  1 , Davide Martinetti  1 , Mariarosa Caruso  4 , Valentina Fanny Leone  4 , Daniela Cugini  1 , Fabiola Carrara  1 , Giuseppe Remuzzi  1 , Piero Ruggenenti  1   4 ; TOOL Study Group
Affiliations
Randomized Controlled Trial

Effects of Octreotide-Long-Acting Release Added-on Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease: Pilot, Randomized, Placebo-Controlled, Cross-Over Trial

Matias Trillini et al. Clin J Am Soc Nephrol. .

Abstract

Background: Tolvaptan 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.

Methods: This 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.

Results: At 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.

Conclusions: In 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 number: Tolvaptan-Octreotide LAR Combination in ADPKD (TOOL), NCT03541447.

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Conflict of interest statement

A. Caroli reports research funding from Alexion Pharmaceuticals, Brembo, and Laminate Medical Technologies and speakers bureau for Fresenius Medical Care. F. Carrara, D. Cugini, D. Martinetti, T. Peracchi, A. Perna, N. Rubis, M. Trillini, and G. Villa report employment with Istituto di Ricerche Farmacologiche Mario Negri IRCCS. P. Ruggenenti and M. Caruso report employment with ASST Papa Giovanni XXIII. V.F. Leone reports employment with ASST Papa Giovanni XXIII; research funding from Achillion Pharmaceuticals, Alexion Pharmaceuticals, and Novartis Pharmaceutical company; and other interests or relationships with ERK Net. N. Perico reports research funding from Bayer AG and honoraria from Bayer S.p.A. G. Remuzzi reports consulting fees from Akebia Pharmaceuticals, Alexion Pharmaceutical, AstraZeneca, BioCryst Pharmaceuticals, Janssen Research & Development, Menarini Ricerche Spa, Otsuka, and Silence Therapeutics and serving as a member of numerous editorial boards of scientific medical journals. All remaining authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
GFR changes during the different study periods. (A) GFR changes during the two 1-month treatment periods with tolvaptan and placebo or with tolvaptan and octreotide-LAR add-on therapy as compared with GFR changes during the run-in period and during the two corresponding washout periods from tolvaptan and placebo and from tolvaptan and octreotide-LAR. The black points indicate values of each single individual during each study period and the horizontal bars show the mean of corresponding individual points. (B) GFR changes during the two 1-week treatment periods with tolvaptan and placebo or with tolvaptan and octreotide-LAR add-on therapy as compared with GFR changes during the 1-month run-in period and during the two corresponding 1-month washout periods from tolvaptan and placebo and from tolvaptan and octreotide-LAR. The black points indicate values of each single individual during each study period and the horizontal bars show the mean of corresponding individual points. The P values without brackets indicate that changes observed in the considered variables in the considered period were significant. The P values with brackets show that the changes in the two considered treatment periods were significantly different. LAR, long-acting release; octr. and octreo, octreotide-LAR; plac., placebo; tolv., tolvaptan.
Figure 2
Figure 2
Changes in kidney volumes during the different study periods. Changes in total kidney volumes (A) and cystic kidney volume (B) during the two 1-month treatment periods with tolvaptan and placebo or with tolvaptan and octreotide-LAR add-on therapy as compared with changes during the two corresponding washout periods from tolvaptan and placebo and from tolvaptan and octreotide-LAR. The black points indicate values of each single individual during each study period and the horizontal bars show the mean of corresponding individual points. The P values without brackets indicate that changes observed in the considered variables in the considered period were significant. The P values with brackets show that the changes in the two considered treatment periods were significantly different.
Figure 3
Figure 3
Changes in BP, heart rate, and albumin fractional clearance during the study periods. Changes in systolic (A) and diastolic (B) BP, heart rate (C), and albumin fractional clearance (D) during the two 1-month treatment periods with tolvaptan and placebo or with tolvaptan and octreotide-LAR add-on therapy as compared with changes during the two corresponding washout periods from tolvaptan and placebo and from tolvaptan and octreotide-LAR. The black points indicate values of each single individual during each study period and the horizontal bars show the mean of corresponding individual points. The P values without brackets indicate that changes observed in the considered variables in the considered period were significant. The P values with brackets show that the changes in the two considered treatment periods were significantly different.
Figure 4
Figure 4
Changes in kidney excretory function during the different study periods. (A) Urinary output changes during the two 1-month treatment periods with tolvaptan and placebo or with tolvaptan and octreotide-LAR add-on therapy as compared with urinary output changes during the run-in period and during the two corresponding washout periods from tolvaptan and placebo and from tolvaptan and octreotide-LAR. The black points indicate values of each single individual during each study period and the horizontal bars show the mean of corresponding individual points. (B) Free-water fractional clearance changes during the two 1-week treatment periods with tolvaptan and placebo or with tolvaptan and octreotide-LAR add-on therapy as compared with free-water fractional clearance changes during the 1-month run-in period and during the two corresponding 1-month washout periods from tolvaptan and placebo and from tolvaptan and octreotide-LAR. The black points indicate values of each single individual during each study period and the horizontal bars show the mean of corresponding individual points. The P values without brackets indicate that changes observed in the considered variables in the considered period were significant. The P values with brackets show that the changes in the two considered treatment periods were significantly different.
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References

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