Autosomal Dominant Polycystic Kidney Disease (ADPKD)Phase 2/3SIRENA-IINCT01223755
Sirolimus In Autosomal Dominant Polycystic Kidney Disease And Severe Renal Insufficiency
A Phase 2/3 study testing Sirolimus and conventional therapy in people with Autosomal Dominant Polycystic Kidney Disease (ADPKD), run by Mario Negri Institute for Pharmacological Research at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Autosomal Dominant Polycystic Kidney Disease (ADPKD)
- What is being tested?
- Sirolimus and conventional therapy
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 41 participants
- Where
- 1 siteItaly
- Study dates
- Sep 2010to Jul 2012
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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)
Trial locations and contacts
1 site in 1 country.
Italy1 site
Mario Negri Institute - Clinical Research Center for Rare Diseases
Ranica, Bergamo, 24020
About this study
Official title: EFFECTS OF SIROLIMUS ON DISEASE PROGRESSION IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE AND SEVERE RENAL INSUFFICIENCY
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.
Read the 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.
- Being tested
- Sirolimus, conventional therapy
- Keywords
- Autosomal dominant polycystic kidney disease, Sirolimus, Renal insufficiency
- Medical subject headings
- Polycystic Kidney, Autosomal Dominant, Renal Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SirolimusDrug
Also called Rapamune
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.
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).
| Study group | Role | What they receive |
|---|---|---|
| Sirolimus | Experimental | Not described Receives: Drug: Sirolimus |
| conventional therapy | Active comparator | Not described Receives: Drug: conventional therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: At baseline.
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.
Measured: At 12th month .
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.
Measured: After six months from baseline.
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.
Measured: Every 12 months.
Secondary outcomes (6)
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.
Measured: At baseline.
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.
Measured: At baseline.
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.
Measured: At 12 month.
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.
Measured: At 36 month.
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.
Measured: At 12 month.
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.
Measured: At 36 month.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Oct 2010 (estimated)
- Study startSep 2010
- Primary completionJul 2012
- Study completionJul 2012
Why it stopped: safety and efficacy reason
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Autosomal Dominant Polycystic Kidney Disease (ADPKD)Studies of the same condition, open and under way.
- More trials run by Mario Negri Institute for Pharmacological ResearchThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 41 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01223755
- Sponsor's protocol ID
- SIRENA-II
- Other IDs
- 2007-005047-21
- Acronym
- SIRENA-II
- Status last verified
- Feb 2013
- First submitted
- 12 Oct 2010
- Last updated
- 25 Feb 2013
- Results posted
- No
- Data monitoring committee
- No
Publications
St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3.
PubMed 39356039Ruggenenti 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.
PubMed 26912555
Study at a glance
From the registry record, last updated by the sponsor on 25 Feb 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- EFFECTS OF SIROLIMUS ON DISEASE PROGRESSION IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE AND SEVERE RENAL INSUFFICIENCY
- ClinicalTrials.gov ID
- NCT01223755
- Acronym / sponsor ID
- SIRENA-II / SIRENA-II
- Keywords
- Autosomal dominant polycystic kidney disease, Sirolimus, Renal insufficiency
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: safety and efficacy reason
- Enrolment
- 41 participants (actual)
- Lead sponsor
- Mario Negri Institute for Pharmacological ResearchUniversity, hospital or other
- Study start
- Sep 2010
- Primary completion
- Jul 2012 (actual)
- Study completion
- Jul 2012 (actual)
- First posted
- 19 Oct 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Sirolimus | Experimental | Drug: Sirolimus |
| conventional therapy | Active comparator | Drug: conventional therapy |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SirolimusAlso: RapamunePatients 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. | Drug | Sirolimus |
| conventional therapyConventional 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). | Drug | conventional therapy |
Primary outcome
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.
6 secondary outcomes
Liver volume parameters.
Time frame: At baseline.
Renal volume parameters.
Time frame: At baseline.
Liver volume parameters.
Time frame: At 12 month.
Liver volume parameters.
Time frame: At 36 month.
Renal volume parameters.
Time frame: At 12 month.
Renal volume parameters.
Time frame: At 36 month.
Results and safety
The study was stopped early (reason given: safety and efficacy reason). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Feb 2013.
- Derived from this study: PubMed 39356039St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3.
- Derived from this study: PubMed 26912555Ruggenenti 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Sirolimus and conventional therapy in people with Autosomal Dominant Polycystic Kidney Disease (ADPKD), run by Mario Negri Institute for Pharmacological Research at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 25 Feb 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: safety and efficacy reason). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Glomerular Filtration Rate (GFR) (time frame: At baseline.). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01223755, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Feb 2013.