Ignite Creation Date:
2024-05-05 @ 10:59 PM
Last Modification Date:
2024-10-26 @ 10:26 AM
Study NCT ID:
NCT01223755
Status:
TERMINATED
Last Update Posted:
2013-02-25
First Post:
2010-10-12
Brief Title:
Sirolimus In Autosomal Dominant Polycystic Kidney Disease And Severe Renal Insufficiency
Sponsor:
Mario Negri Institute for Pharmacological Research
Organization:
Mario Negri Institute for Pharmacological Research
Study Overview
Official Title:
EFFECTS OF SIROLIMUS ON DISEASE PROGRESSION IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE AND SEVERE RENAL INSUFFICIENCY
Status:
TERMINATED
Status Verified Date:
2013-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
safety and efficacy reason
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
SIRENA-II
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 SerThr 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 ngml 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 mlmin173m2 aimed to assess the safety and the efficacy of SRL in slowing renal function decline as compared to conventional therapy
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 SerThr 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 ngml 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 mlmin173m2 aimed to assess the safety and the efficacy of SRL in slowing renal function decline as compared to conventional therapy
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2007-005047-21 | EUDRACT_NUMBER | None | None |