Sirolimus In Autosomal Dominant Polycystic Kidney Disease And Severe Renal Insufficiency

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Brief Title

Sirolimus In Autosomal Dominant Polycystic Kidney Disease And Severe Renal Insufficiency

Official Title

EFFECTS OF SIROLIMUS ON DISEASE PROGRESSION IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE AND SEVERE RENAL INSUFFICIENCY

Brief Summary

      The general aim of this study in adult patients with Autosomal Dominant Polycystic Kidney
      Disease (ADPKD) and severe renal insufficiency is to assess the safety and the efficacy of
      sirolimus (SRL) in slowing renal function decline as compared to conventional therapy.
    

Detailed Description

      Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal
      disease, responsible for the 8% to 10% of the cases of end-stage renal disease (ESRD) in
      Western Countries.

      ADPKD shows genetic heterogeneity, with at least three different genes implicated: the PKD1
      gene (85% of the cases), the PKD2 (15% of the cases), and probably a PDK3 gene not yet
      identified. Recently, it has been reported that PC1 tail interacts with tuberin, the product
      of the TSC2 gene. The main function of the tuberin is to inactivate the Ser/Thr kinase mTOR,
      whose activity has been linked to increased cell growth, proliferation, apoptosis and
      differentiation. In ADPKD experimental animal models, researchers have shown that cyst lining
      epithelial cells exhibited very high mTOR activity; thus, they hypothesized that PC1 normally
      suppresses mTOR activity, and that defects in PC1 (and other proteins) may lead to aberrant
      mTOR activation. Studies in rat models of ADPKD have shown that short-term treatment with
      sirolimus (SRL) resulted in the dramatic reduction of the kidney size.

      Recently we have documented that in ADPKD patients with normal kidney function or moderate
      renal dysfunction a short-course of SRL halted cyst growth and increased parenchyma volume.
      At this effective SRL dose (target trough blood level 5-10 ng/ml) the only relevant adverse
      effect observed in some patients was the development of aphthous stomatitis, relieved with
      topical treatment alone using a mouthwash.

      Interestingly a retrospective study in a small number of SRL-treated ADPKD transplant
      patients showed that the treatment significantly reduced native kidney volumes over an
      average of 24 month follow-up. This reduction was three times higher than that reported in a
      control group of ADPKD transplant recipients not given SRL over a 40 month period. These
      results suggested that SRL may have a similar beneficial effect in humans as in experimental
      animals.

      Overall, these findings are the basis for designing this study in ADPKD patients with severe
      renal dysfunction (GFR 40-15 ml/min/1.73m2) aimed to assess the safety and the efficacy of
      SRL in slowing renal function decline as compared to conventional therapy.
    

Study Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

Glomerular Filtration Rate (GFR)

Secondary Outcome

 Liver volume parameters.

Condition

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Intervention

Sirolimus

Study Arms / Comparison Groups

 Sirolimus
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

41

Start Date

September 2010

Completion Date

July 2012

Primary Completion Date

July 2012

Eligibility Criteria

        Inclusion Criteria:

          -  Age > 18 years

          -  Clinical and ultrasound diagnosis of ADPKD

          -  GFR 40-15 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)
      

Gender

All

Ages

18 Years - 80 Years

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

Italy

Location Countries

Italy

Administrative Informations


NCT ID

NCT01223755

Organization ID

SIRENA-II

Secondary IDs

2007-005047-21

Responsible Party

Sponsor

Study Sponsor

Mario Negri Institute for Pharmacological Research


Study Sponsor

, , 


Verification Date

February 2013