Effect of Lanreotide on Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease: The DIPAK 1 Randomized Clinical Trial

Abstract

Importance: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation in both kidneys and loss of renal function, eventually leading to a need for kidney replacement therapy. There are limited therapeutic management options.

Objective: To examine the effect of the somatostatin analogue lanreotide on the rate of kidney function loss in patients with later-stage ADPKD.

Design, setting, and participants: An open-label randomized clinical trial with blinded end point assessment that included 309 patients with ADPKD from July 2012 to March 2015 at 4 nephrology outpatient clinics in the Netherlands. Eligible patients were 18 to 60 years of age and had an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2. Follow-up of the 2.5-year trial ended in August 2017.

Interventions: Patients were randomized to receive either lanreotide (120 mg subcutaneously once every 4 weeks) in addition to standard care (n = 153) or standard care only (target blood pressure <140/90 mm Hg; n = 152).

Main outcomes and measures: Primary outcome was annual change in eGFR assessed as slope through eGFR values during the 2.5-year treatment phase. Secondary outcomes included change in eGFR before vs after treatment, incidence of worsening kidney function (start of dialysis or 30% decrease in eGFR), change in total kidney volume and change in quality of life (range: 1 [not bothered] to 5 [extremely bothered]).

Results: Among the 309 patients who were randomized (mean [SD] age, 48.4 [7.3] years; 53.4% women), 261 (85.6%) completed the trial. Annual rate of eGFR decline for the lanreotide vs the control group was -3.53 vs -3.46 mL/min/1.73 m2 per year (difference, -0.08 [95% CI, -0.71 to 0.56]; P = .81). There were no significant differences for incidence of worsening kidney function (hazard ratio, 0.87 [95% CI, 0.49 to 1.52]; P = .87), change in eGFR (-3.58 vs -3.45; difference, -0.13 mL/min/1.73 m2 per year [95% CI, -1.76 to 1.50]; P = .88), and change in quality of life (0.05 vs 0.07; difference, -0.03 units per year [95% CI, -0.13 to 0.08]; P = .67). The rate of growth in total kidney volume was lower in the lanreotide group than the control group (4.15% vs 5.56%; difference, -1.33% per year [95% CI, -2.41% to -0.24%]; P = .02). Adverse events in the lanreotide vs control group included injection site discomfort (32% vs 0.7%), injection site papule (5.9% vs 0%), loose stools (91% vs 6.6%), abdominal discomfort (79% vs 20%), and hepatic cyst infections (5.2% vs 0%).

Conclusions and relevance: Among patients with later-stage autosomal dominant polycystic kidney disease, treatment with lanreotide compared with standard care did not slow the decline in kidney function over 2.5 years of follow-up. These findings do not support the use of lanreotide for treatment of later-stage autosomal dominant polycystic kidney disease.

Trial registration: ClinicalTrials.gov Identifier: NCT01616927.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Gansevoort received grant support and fees for serving on advisory boards and steering committees from IPSEN, Otsuka Pharmaceuticals and Sanofi-Genzyme. In addition, Dr Gansevoort holds the Orphan Medicinal Product Designation status at the European Medicines Agency for lanreotide as treatment for ADPKD (EMA/OD/027/15). Dr Drenth has received grant support and fees for serving on advisory boards and consultancy from IPSEN and Novartis. All money is paid to their employers. No other potential conflict of interest relevant to this article was reported.

Figures

Figure 1.. Patient Enrollment and Flow Through the Study of Lanreotide for Polycystic Kidney Disease

Enrollment occurred from July 2012 to February 2014, and follow-up of the 2.5-year trial was completed in August 2017. Supplement 3 contains additional information regarding specific reasons for exclusion and withdrawal. aIf patients did not complete the study, eGFR data for the primary efficacy analysis (slope of eGFR decline on treatment) was based on all available data points as long as medication was given. bFor the safety analysis, all information was used until patients withdrew consent or were lost to follow-up.

Figure 2.. Effect of Lanreotide and Standard Care Compared With Standard Care Only on Change in Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease

Kidney function over time, depicting mean and 95% CIs for estimated glomerular filtration rate (eGFR).

Figure 3.. Effect of Lanreotide and Standard Care Compared With Standard Care Only on Estimated Glomerular Filtration Rate (eGFR) in Patients With Autosomal Dominant Polycystic Kidney Disease

The effect of lanreotide on slope of eGFR decline during the treatment phase according to prespecified baseline subgroups. htTKV indicates height-adjusted total kidney volume.

Figure 4.. Effect of Lanreotide and Standard Care Compared With Standard Care Only on Secondary Outcomes

A, Change in kidney function, calculated as change in estimated glomerular filtration rate (eGFR) measured 12 weeks after the end of treatment visit (ie, at the posttreatment visit) compared with the pretreatment value (difference, −0.13 mL/min/1.73 m2 per year [95% CI, −1.76 to 1.50]; P = .88). B, Change in height-adjusted total kidney volume (htTKV; difference, −1.33% per year [95% CI, −2.41 to −0.24]; P = .02). C, Change in health-related quality of life (QOL; difference −0.03 units per year [95% CI, −0.13 to 0.08]; P = .67). QOL is measured on a scale ranging from 1 (not bothered) to 5 (extremely bothered). For all panels, boxplots show predicted mean and 25th and 75th percentile, and lower and upper ends of the error bars show predicted 2.5th and 97.5th percentile, respectively, as derived from the mixed model analyses.

Figure 5.. Effect of Lanreotide and Standard Care Compared With Standard Care Only on the Secondary Outcome of Worsening Kidney Function

The cumulative incidence of worsening kidney function (30% decrease in estimated glomerular filtration rate or start of dialysis). Mean duration of the treatment phase was 104 and 117 weeks for the lanreotide and control group, respectively.