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

NCT00491517 | Completed Phase 2 DMC

• 2 other identifiers: SIRENA2006-003427-37
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Polycystic Kidney

Outcome Measures

Primary Outcomes (1)

• Total kidney volume (estimated by computed tomography, CT) in sirolimus and conventional treatment ADPKD groups during 6 month follow-up.

  At 0,6 and 12 months.

Secondary Outcomes (1)

• Renal cyst volume, renal parenchymal volume and renal intermediate volume.

  At 0,6 and 12 months.

Study Arms (2)

Sirolimus

EXPERIMENTAL

Drug: Sirolimus

conventional therapy

ACTIVE COMPARATOR

Drug: conventional therapy

Interventions

Sirolimus DRUG

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.

Sirolimus

conventional therapy DRUG

Antihypertensive drugs for patients with high blood pressure.

conventional therapy

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Mario Negri Institute for Pharmacological Research: lead

Study Sites (1)

Hospital "Azienda Ospedaliera Ospedali Riuniti di Bergamo" Unit of Neprology and Dialysis

Bergamo, Italy

Location

Related Publications (1)

• St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3.

  PMID: 39356039 DERIVED

MeSH Terms

Conditions

Polycystic Kidney Diseases

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Kidney Diseases, Cystic; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Ciliopathies; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Norberto Perico, MD

  Mario Negri Institute for Pharmacological Research

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 25, 2007
• First Posted: June 26, 2007
• Study Start: March 1, 2007
• Primary Completion: July 1, 2009
• Study Completion: August 1, 2009
• Last Updated: April 24, 2013

Record last verified: 2013-04

Locations

IT (1)