Pulsed Oral Sirolimus in Autosomal Dominant Polycystic Kidney Disease

Phase 3UnknownNCT02055079

Medical University of Vienna68 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: Baseline, 24 months

Secondary Outcomes

Change of safety parameters from baseline to month 24

Safety, change in proteinuria, as indicated by albumin/creatinine- and protein/creatinine ratio, respectively.