Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease

Abstract

There are no proven, effective therapies for polycystic kidney disease (PKD) or polycystic liver disease (PLD). We enrolled 42 patients with severe PLD resulting from autosomal dominant PKD (ADPKD) or autosomal dominant PLD (ADPLD) in a randomized, double-blind, placebo-controlled trial of octreotide, a long-acting somatostatin analogue. We randomly assigned 42 patients in a 2:1 ratio to octreotide LAR depot (up to 40 mg every 28+/-5 days) or placebo for 1 year. The primary end point was percent change in liver volume from baseline to 1 year, measured by MRI. Secondary end points were changes in total kidney volume, GFR, quality of life, safety, vital signs, and clinical laboratory tests. Thirty-four patients had ADPKD, and eight had ADPLD. Liver volume decreased by 4.95%+/-6.77% in the octreotide group but remained practically unchanged (+0.92%+/-8.33%) in the placebo group (P=0.048). Among patients with ADPKD, total kidney volume remained practically unchanged (+0.25%+/-7.53%) in the octreotide group but increased by 8.61%+/-10.07% in the placebo group (P=0.045). Changes in GFR were similar in both groups. Octreotide was well tolerated; treated individuals reported an improved perception of bodily pain and physical activity. In summary, octreotide slowed the progressive increase in liver volume and total kidney volume, improved health perception among patients with PLD, and had an acceptable side effect profile.

Figure 1.

Administration of octreotide LAR to a patient with severe PLD resulted in decreased liver and kidney volumes. CT axial sections immediately before (A) and after 8 months of treatment with octreotide (B) are shown. Total liver volume decreased by 18% from baseline, and total kidney volume decreased by 12%.

Figure 2.

Study flow diagram. Protocol violations were as follows: In the octreotide (Oct) arm, five injections of masked study drug and two study visits occurred outside of the protocol window. One 24-hour urine collection was obtained after the study visit. In the placebo arm, two injections of masked study drug and one study visit occurred outside of the protocol window.

Figure 3.

Octreotide therapy (Oct-LAR) decreased total liver volumes. (A) Total liver volumes in each individual patient in placebo (left) and octreotide (right) groups before (0 months) and after (12 months) treatment. (B) Changes in liver volumes in each patient expressed as a percent of change after 12 months of treatment compared with month 0 in placebo and octreotide groups. (C) Averaged changes in total liver volume (mean ± SD) in placebo and octreotide-treated groups; *P = 0.048. (D) Correlation between liver volumes (measured at 0 months) and response to absolute changes in total liver volumes after 12 months of treatment. Individuals with larger liver volumes had greater response to treatment. Colored symbols and lines represent individual patient genotypes (A and B) or by disease group in D. NMD, no mutation detected.

Figure 4.

Octreotide therapy (OctLAR) stalled kidney growth in treated individuals. (A) Total kidney volumes in each individual patient in placebo (left) and octreotide (right) groups at baseline (0 months) and after (12 months) treatment. (B) Changes in kidney volumes in each patient expressed as a percent change after 12 months of treatment compared with month 0 in placebo and octreotide groups. (C) Averaged changes in total kidney volume (mean ± SD) in placebo and octreotide-treated groups; **P = 0.045. (D) Correlation between kidney volumes (measured at 0 months) and response to absolute changes in total kidney volumes after 12 months of treatment. Individuals with larger kidney volumes had greater response to treatment. Colored symbols and lines represent individual patient genotypes (A and B); NMD, no mutation detected.

Figure 5.

Most participants tolerate 40 mg of octreotide monthly. Dosing for all individuals assigned to octreotide treatment by dosing period. Blue, 40 mg; yellow, 30 mg; mauve, 20 mg; and violet, dose withheld.