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Sirolimus In Autosomal Dominant Polycystic Kidney Disease And Severe Renal Insufficiency (SIRENA-II)

This study has been terminated.
(safety and efficacy reason)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01223755
First Posted: October 19, 2010
Last Update Posted: February 25, 2013
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Mario Negri Institute for Pharmacological Research
  Purpose
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.

Condition Intervention Phase
Autosomal Dominant Polycystic Kidney Disease (ADPKD) Drug: Sirolimus Drug: conventional therapy Phase 2 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: EFFECTS OF SIROLIMUS ON DISEASE PROGRESSION IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE AND SEVERE RENAL INSUFFICIENCY

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Glomerular Filtration Rate (GFR) [ Time Frame: At baseline. ]
    To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.

  • Glomerular Filtration Rate (GFR) [ Time Frame: At 12th month . ]
    To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.

  • Glomerular Filtration Rate (GFR) [ Time Frame: After six months from baseline. ]
    To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.

  • Glomerular Filtration Rate (GFR) [ Time Frame: Every 12 months. ]
    To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.


Secondary Outcome Measures:
  • Liver volume parameters. [ Time Frame: At baseline. ]
    To compare absolute and relative changes over baseline of liver volume parameters, assessed by contrast-enhanced spiral computed tomography, in SRL and conventional treatment ADPKD patients.

  • Renal volume parameters. [ Time Frame: At baseline. ]
    To compare absolute and relative changes over baseline of renal volume parameters, assessed by contrast-enhanced spiral computed tomography, in SRL and conventional treatment ADPKD patients.

  • Liver volume parameters. [ Time Frame: At 12 month. ]
    To compare absolute and relative changes over baseline of liver volume parameters, assessed by contrast-enhanced spiral computed tomography, in SRL and conventional treatment ADPKD patients.

  • Liver volume parameters. [ Time Frame: At 36 month. ]
    To compare absolute and relative changes over baseline of liver volume parameters, assessed by contrast-enhanced spiral computed tomography, in SRL and conventional treatment ADPKD patients.

  • Renal volume parameters. [ Time Frame: At 12 month. ]
    To compare absolute and relative changes over baseline of renal volume parameters, assessed by contrast-enhanced spiral computed tomography, in SRL and conventional treatment ADPKD patients.

  • Renal volume parameters. [ Time Frame: At 36 month. ]
    To compare absolute and relative changes over baseline of renal volume parameters, assessed by contrast-enhanced spiral computed tomography, in SRL and conventional treatment ADPKD patients.


Enrollment: 41
Study Start Date: September 2010
Study Completion Date: July 2012
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sirolimus Drug: Sirolimus
Patients will be given SRL for one year starting at the oral daily dose of 3 mg, with periodical whole blood level measurements. The daily dose will be adjusted to keep SRL concentration within 5-10 ng/ml. Drug levels will be assessed at day 7 after starting treatment and every two weeks for the first month. Subsequently SRL concentrations will be monitored at monthly intervals (or at least 5 days after drug dose adjustments) until the end of the treatment period.
Other Name: Rapamune
Active Comparator: conventional therapy Drug: conventional therapy
Conventional treatment relates usually to the administration of antihypertensive drugs for patients with high blood pressure. Thus, for the present study, no major change in antihypertensive treatment should be introduced throughout the whole study period unless deemed clinically necessary (the reasons of the changes should be, however, clearly explained in the CRF). Only small changes in the doses of the ongoing treatments are recommended in order to maintain the same level of blood pressure control (target systolic/diastolic blood pressure <130/80 mmHg). This approach is aimed to minimize the confounding effect of any change in concomitant treatments on some efficacy variables (such as urinary protein excretion rate).

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01223755


Locations
Italy
Mario Negri Institute - Clinical Research Center for Rare Diseases
Ranica, Bergamo, Italy, 24020
Sponsors and Collaborators
Mario Negri Institute for Pharmacological Research
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier: NCT01223755     History of Changes
Other Study ID Numbers: SIRENA-II
2007-005047-21 ( EudraCT Number )
First Submitted: October 12, 2010
First Posted: October 19, 2010
Last Update Posted: February 25, 2013
Last Verified: February 2013

Keywords provided by Mario Negri Institute for Pharmacological Research:
Autosomal dominant polycystic kidney disease
Sirolimus
Renal insufficiency

Additional relevant MeSH terms:
Polycystic Kidney Diseases
Polycystic Kidney, Autosomal Dominant
Kidney Diseases
Renal Insufficiency
Urologic Diseases
Kidney Diseases, Cystic
Abnormalities, Multiple
Congenital Abnormalities
Genetic Diseases, Inborn
Sirolimus
Everolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs