Clinical trial NCT01223755: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Keywords: Autosomal dominant polycystic kidney disease
Sirolimus
Renal insufficiency
Lead sponsor: Mario Negri Institute for Pharmacological Research
Sponsor class: OTHER
First posted: 2010-10-19
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Glomerular Filtration Rate (GFR)
timeFrame: At baseline.
measure: Glomerular Filtration Rate (GFR)
timeFrame: At 12th month .
measure: Glomerular Filtration Rate (GFR)
timeFrame: After six months from baseline.
measure: Glomerular Filtration Rate (GFR)
timeFrame: Every 12 months.
Secondary outcomes:
measure: Liver volume parameters.
timeFrame: At baseline.
measure: Renal volume parameters.
timeFrame: At baseline.
measure: Liver volume parameters.
timeFrame: At 12 month.
measure: Liver volume parameters.
timeFrame: At 36 month.
measure: Renal volume parameters.
timeFrame: At 12 month.
measure: Renal volume parameters.
timeFrame: At 36 month.
Other outcomes:
Locations:
city: Ranica
country: Italy
facility: Mario Negri Institute - Clinical Research Center for Rare Diseases
state: Bergamo
Study officials:
References:
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.