Sirolimus Treatment in Patients With Autosomal Dominant Polycystic Kidney Disease: Renal Efficacy and Safety (SIRENA)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier:
NCT00491517
First received: June 25, 2007
Last updated: April 23, 2013
Last verified: April 2013
  Purpose

Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal disease, characterized by the progressive development of fluid-filled cysts in the kidney leading to progressive loss of renal function and eventually to renal failure. It is responsible for 8% to 10% of the cases of end stage renal disease (ESRD) in Western countries. ADPKD progression is largely dependent on the development and growth of the cysts and secondary disruption of the normal tissue. Renoprotective interventions in ADPKD - in addition to achieve maximal reduction of arterial blood pressure and proteinuria and to limit the effects of additional potential promoters of disease progression such as dyslipidemia, chronic hyperglycemia or smoking - should also be specifically aimed to correct the dysregulation of epithelial cell growth, secretion, and matrix interactions characteristic of the disease. Genetically in the ADPKD three different genes are implicated (PKD1 85% of the cases, PKD2 15% and probably PDK3 not yet identified). PKD1 gene encodes a protein named polycystin-1 (PC1). Defect in PC1 lead to aberrant activation of the enzyme mTOR in the epithelial cells of the renal tubules which eventually leads to abnormal proliferation of these cells and cysts generation.

Sirolimus (Rapamycin) is an immunosuppressant mostly used for the management of kidney transplant recipients. This drug by very specifically and effectively inhibiting mTOR, exerts antiproliferative and growth inhibiting effects and could be extremely important for the inhibition of cyst progression in ADPKD. Animal models of ADPKD have shown that short-term treatment with sirolimus resulted in dramatic reduction of kidney size, prevented the loss of kidney function, and lowered cyst volume density. Similarly, retrospective observations from kidney transplant recipients have documented that sirolimus treatment reduced kidney volumes by 25%, whereas there was no effect in patients not given the drug.

Overall, these findings provide the basis for designing a prospective study in ADPKD patients aimed to document the efficacy of sirolimus treatment in preventing further increase or even reducing the total kidney volume and the renal volume taken up by small cysts, eventually halting kidney disease progression. It is a 6 month treatment with sirolimus compared to conventional therapy in adult patients with ADPKD and normal renal function or mild to moderate renal insufficiency.


Condition Intervention Phase
Polycystic Kidney
Drug: Sirolimus
Drug: conventional therapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Sirolimus Treatment in Patients With ADPKD

Resource links provided by NLM:


Further study details as provided by Mario Negri Institute for Pharmacological Research:

Primary Outcome Measures:
  • Total kidney volume (estimated by computed tomography, CT) in sirolimus and conventional treatment ADPKD groups during 6 month follow-up. [ Time Frame: At 0,6 and 12 months. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Renal cyst volume, renal parenchymal volume and renal intermediate volume. [ Time Frame: At 0,6 and 12 months. ] [ Designated as safety issue: Yes ]

Enrollment: 22
Study Start Date: March 2007
Study Completion Date: August 2009
Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sirolimus Drug: Sirolimus
Patients will be given Sirolimus starting at the oral daily dose of 3 mg with periodically whole blood level measurements. The daily dose will be adjusted to keep sirolimus concentration within 10-15 ng/ml.
Active Comparator: conventional therapy Drug: conventional therapy
Antihypertensive drugs for patients with high blood pressure.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age >18 years
  • Clinical and ultrasound diagnosis of ADPKD
  • GFR >40 ml/min/1.73 m2 (estimated by the 4 variable MDRD equation)
  • Urinary protein excretion rate ≤ 0.5 g/ 24 hrs
  • Written informed consent

Exclusion Criteria:

  • Diabetes
  • Urinary protein excretion rate >0.5 g/ 24 hrs or abnormal urinalysis suggestive of concomitant, clinically significant glomerular disease
  • Urinary tract lithiasis, infection or obstruction
  • Cancer
  • Psychiatric disorders and any condition that might prevent full comprehension of the purposes and risks of the study
  • Pregnancy, lactation or child bearing potential and ineffective contraception (estrogen therapy in post menopausal women should not be stopped)
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00491517

Locations
Italy
Hospital "Azienda Ospedaliera Ospedali Riuniti di Bergamo" Unit of Neprology and Dialysis
Bergamo, Italy
Sponsors and Collaborators
Mario Negri Institute for Pharmacological Research
Investigators
Study Director: Norberto Perico, MD Mario Negri Institute for Pharmacological Research
  More Information

No publications provided

Responsible Party: Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier: NCT00491517     History of Changes
Other Study ID Numbers: SIRENA, 2006-003427-37
Study First Received: June 25, 2007
Last Updated: April 23, 2013
Health Authority: Italy: Ministry of Health

Additional relevant MeSH terms:
Polycystic Kidney Diseases
Multicystic Dysplastic Kidney
Polycystic Kidney, Autosomal Dominant
Kidney Diseases, Cystic
Kidney Diseases
Urologic Diseases
Urogenital Abnormalities
Congenital Abnormalities
Sirolimus
Everolimus
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 19, 2014