Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a leading cause of End Stage Kidney
Disease (ESKD) worldwide. Elevated levels of 3', 5' - cyclic AMP (cAMP) play a central role
in the pathogenesis and progression of the disease. Vasopressin antagonists and somatostatin
analogues, which indirectly reduce adenyl cyclase 6 activity, have been found to markedly
reduce renal tubular cell proliferation and cyst growth in experimental models of ADPKD. In
combination, the two treatments show a clear additive effect and may significantly reduce
renal cystic and fibrotic volume as well as cAMP levels to wild type levels.
The vasopressin antagonist Tolvaptan and the somatostatin analogue Octreotide share a similar
renoprotective effect also in human disease.
Both medications effectively slow total kidney and cystic volume (TKV and TCV, respectively)
growth and glomerular filtration rate (GFR) decline in patients with ADPKD. The short-term
effect of both medications appear to be larger when the GFR is normal or even higher than
normal and kidney volumes are still relatively stable. On the basis of experimental data, it
is conceivable that Tolvaptan and Octreotide LAR should have an additive effect also in human
disease, during initial treatment as well as in the long-term. To address the working
hypothesis of an additional short-term effect of Tolvaptan and Octreotide, we propose to run
a pilot, explorative, randomized, placebo-controlled, clinical trial with a Cross-Over Design
to compare the short-term effects of Tolvaptan monotherapy and Tolvaptan plus Octreotide LAR
combination therapy on TKV as assessed by MRI, and on GFR as directly measured by the iohexol
plasma clearance technique in ADPKD patients with normal (80 to 120 ml/min/1.73m2) kidney
function or even kidney hyperfiltration (GFR ≥120 ml/min/1.73m2).
Phase:
Phase 2
Details
Lead Sponsor:
Mario Negri Institute for Pharmacological Research