Tolvaptan-Octreotide LAR Combination in ADPKD

  • End date
    Sep 25, 2021
  • participants needed
  • sponsor
    Mario Negri Institute for Pharmacological Research
Updated on 25 January 2021
glomerular filtration rate
renal disease
vasopressin antagonists


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).

Condition Polycystic Kidney, Autosomal Dominant, autosomal dominant polycystic kidney disease
Treatment Placebo, Tolvaptan, Octreotide LAR
Clinical Study IdentifierNCT03541447
SponsorMario Negri Institute for Pharmacological Research
Last Modified on25 January 2021


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Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have Polycystic Kidney, Autosomal Dominant?
Do you have any of these conditions: autosomal dominant polycystic kidney disease or Polycystic Kidney, Autosomal Dominant?
Adult (>18-yr-old) men and women, with a clinical and ultrasonographic diagnosis of ADPKD
Serum creatinine < 1.0 mg/dl (for man) and < 1.2 mg/dl (for woman) and changes in serum creatinine (and creatinine clearance when available) <30% over the last six months
Creatinine clearance > 80 ml/min/1.73m2 measured one to two weeks apart during the pre-screening period
GFR 80 ml/min/1.73m2 (by iohexol plasma clearance technique) at screening and baseline evaluations
TKV ranging between 1000 and 2000 ml at screening (by ultrasound imaging) and at baseline (by MRI) evaluations
Female participants must be of non-childbearing potential or must agree to abstinence or use a highly effective form of contraception
Written informed consent

Exclusion Criteria

Patients with concomitant systemic, renal parenchymal or urinary tract disease
Overt proteinuria (urinary protein excretion rate >1 g/24 hours)
Abnormal urinalysis suggestive of concomitant, clinically significant glomerular disease, urinary tract lithiasis, infection or obstruction, biliary tract lithiasis or obstruction
Hemorrhagic or complicated cysts which might acutely affect kidney function and volumes
QT-related ECG abnormalities
Cancer and major systemic diseases that could prevent completion of the planned follow-up or interfere with data collection or interpretation
Hypersensitivity to the IMP active substance or to any of the excipients or to benzazepine or benzazepine derivatives
Concomitant treatment with drugs that may affect glomerular hemodynamics during the three months before the beginning of the study (including ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists and non-steroideal anti-inflammatory medications)
Elevated liver enzymes and/or signs or symptoms of liver injury prior to initiation of treatment that meet the requirements for permanent discontinuation of tolvaptan
Patients with anuria, volume depletion and hypernatraemia
Patients who cannot perceive or respond to thirst
Ferro-magnetic prosthesis, aneurysm clips, severe claustrophobia or any other contraindication to MRI evaluation
Psychiatric disorders and any condition that could prevent full comprehension of the purposes and risks of the study
Pregnant or lactating
Participation in another interventional clinical trial within the 4 weeks prior to screening
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