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

Primary Purpose

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Status
Terminated
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Sirolimus
conventional therapy
Sponsored by
Mario Negri Institute for Pharmacological Research
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Autosomal Dominant Polycystic Kidney Disease (ADPKD) focused on measuring Autosomal dominant polycystic kidney disease, Sirolimus, Renal insufficiency

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Mario Negri Institute - Clinical Research Center for Rare Diseases

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Sirolimus

conventional therapy

Arm Description

Outcomes

Primary Outcome Measures

Glomerular Filtration Rate (GFR)
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)
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)
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)
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
October 12, 2010
Last Updated
February 22, 2013
Sponsor
Mario Negri Institute for Pharmacological Research
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1. Study Identification

Unique Protocol Identification Number
NCT01223755
Brief Title
Sirolimus In Autosomal Dominant Polycystic Kidney Disease And Severe Renal Insufficiency
Acronym
SIRENA-II
Official Title
EFFECTS OF SIROLIMUS ON DISEASE PROGRESSION IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE AND SEVERE RENAL INSUFFICIENCY
Study Type
Interventional

2. Study Status

Record Verification Date
February 2013
Overall Recruitment Status
Terminated
Why Stopped
safety and efficacy reason
Study Start Date
September 2010 (undefined)
Primary Completion Date
July 2012 (Actual)
Study Completion Date
July 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mario Negri Institute for Pharmacological Research

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Keywords
Autosomal dominant polycystic kidney disease, Sirolimus, Renal insufficiency

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
41 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sirolimus
Arm Type
Experimental
Arm Title
conventional therapy
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamune
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
conventional therapy
Intervention Description
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).
Primary Outcome Measure Information:
Title
Glomerular Filtration Rate (GFR)
Description
To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.
Time Frame
At baseline.
Title
Glomerular Filtration Rate (GFR)
Description
To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.
Time Frame
At 12th month .
Title
Glomerular Filtration Rate (GFR)
Description
To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.
Time Frame
After six months from baseline.
Title
Glomerular Filtration Rate (GFR)
Description
To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.
Time Frame
Every 12 months.
Secondary Outcome Measure Information:
Title
Liver volume parameters.
Description
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.
Time Frame
At baseline.
Title
Renal volume parameters.
Description
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.
Time Frame
At baseline.
Title
Liver volume parameters.
Description
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.
Time Frame
At 12 month.
Title
Liver volume parameters.
Description
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.
Time Frame
At 36 month.
Title
Renal volume parameters.
Description
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.
Time Frame
At 12 month.
Title
Renal volume parameters.
Description
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.
Time Frame
At 36 month.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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)
Facility Information:
Facility Name
Mario Negri Institute - Clinical Research Center for Rare Diseases
City
Ranica
State/Province
Bergamo
ZIP/Postal Code
24020
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
26912555
Citation
Ruggenenti P, Gentile G, Perico N, Perna A, Barcella L, Trillini M, Cortinovis M, Ferrer Siles CP, Reyes Loaeza JA, Aparicio MC, Fasolini G, Gaspari F, Martinetti D, Carrara F, Rubis N, Prandini S, Caroli A, Sharma K, Antiga L, Remuzzi A, Remuzzi G; SIRENA 2 Study Group. Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4. Clin J Am Soc Nephrol. 2016 May 6;11(5):785-794. doi: 10.2215/CJN.09900915. Epub 2016 Feb 22.
Results Reference
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Sirolimus In Autosomal Dominant Polycystic Kidney Disease And Severe Renal Insufficiency

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