Pulsed Oral Sirolimus in Autosomal Dominant Polycystic Kidney Disease

Study Overview
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Brief Summary
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Sirolimus (SIR) has lead to a reduction of overall kidney size, a decrease in cyst density and general tubular cell proliferation in animal models, and to a reduction of the increase in creatinine and blood urea nitrogen by 34 and 39 percent respectively, as well as a reduction of cyst proliferation, expressed by a 30 percent reduction of overall kidney enlargement, a reduction in general cyst volume, and a reduction of the cyst volume density in the renal cortex in humans. However, despite promising data from animal- and in vivo studies, most mammalian target of rapamycin inhibitor (mTOR-I) studies in patients with autosomal-dominant polycystic kidney disease (ADPKD) produced only subtle if any clinically relevant effects on cyst growth and the preservation of renal function. In this study we will investigate if pulsed administration of SIR in a fixed weekly oral dose of 3 mg over 24 months compared to placebo significantly reduces cyst growth and preserves excretory renal function in patients with ADPKD and an estimated glomerular filtration (eGFR) rate below 60 mL/min per 1.73m2.

Official Title
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Pulsed Oral Sirolimus in Autosomal Dominant Polycystic Kidney Disease - The Vienna RAP Study

Conditions
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Polycystic Kidney, Type 2 Autosomal Dominant Disease, Polycystic Kidney, Type 1 Autosomal Dominant Disease

Intervention / Treatment
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* Drug: Sirolimus
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ADPKD, as confirmed by history, ultrasound, computed- or magnetic resonance tomography Eighteen years of age, or older Baseline eGFR below 60 mL/min per 1.73m2 Negative serum pregnancy test prior to administration of sirolimus and agreement to use contraception throughout the study and three months after Written informed consent Exclusion Criteria: Need for renal replacement therapy Pregnancy/lactation Plans to become pregnant in the near future Refusal to use sufficient contraception Proteinuria as defined as protein:creatinine ratio >1000 or >1g/d, respectively History of life threatening complications of ADPKD Evidence of active systemic- or localized major infection Evidence of infiltrate or consolidation on chest X-ray Use of any investigational drug or -treatment up to 4 weeks prior to enrolment and during the study Known allergy/hypersensitivity to sirolimus and its derivatives Medication that will interfere with the cytochrome P450 (CYP3A4/CYP3A5) system Total white blood cell count below or equal to 3000/mm3 Platelet count below or equal to 100.000/mm3 Fasting triglycerides above or equal to 400 mg/dL Fasting total cholesterol above or equal to 300 mg/dL Concomitant glomerular diseases Psychiatric disorders and any condition that might prevent full comprehension of the purposes and risks of the study History of malignancy, with the exception of adequately treated basal cell- and squamous cell carcinoma of the skin HIV positivity

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus<br>Fixed oral dose of 3 mg Sirolimus (blinded) once weekly for 24 months. | Drug: Sirolimus<br>* Fixed oral dose of 3 mg sirolimus (blinded) once weekly for 24 months.<br>* Other names: Rapamune;|
| Placebo Comparator: Placebo<br>Fixed oral dose of placebo (blinded) once weekly for 24 months. | Drug: Placebo<br>* Fixed oral dose of 3 mg placebo (blinded) once weekly for 24 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in kidney function from baseline to month 24 | Fifty percent reduction in doubling of serum creatinine, or initiation of dialysis over a period of two years. Less or equal than 1.5 fold increase in serum creatinine without initiation of dialysis over two years is considered a beneficial outcome, increases in serum creatinine greater than 1.5 over two years or initiation of dialysis are considered a non-beneficial outcome. | Baseline, 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of safety parameters from baseline to month 24 | Safety, change in proteinuria, as indicated by albumin/creatinine- and protein/creatinine ratio, respectively. | Baseline, 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADPKD, Polycystic kidney disease, Mammalian target of rapamycin, mTOR-I, Sirolimus, PKD