Pulsed Oral Sirolimus in Autosomal Dominant Polycystic Kidney Disease (RAP)

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

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 Overview

• Status: Unknown
• Conditions: Polycystic Kidney, Type 1 Autosomal Dominant Disease; Polycystic Kidney, Type 2 Autosomal Dominant Disease
• Intervention / Treatment: Drug: Sirolimus; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 68
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Recruiting
    • Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna
    • Contact: Markus Riegersperger, MD; Phone Number: 4391 0043140400; Email: markus.riegersperger@gmail.com
    • Contact: Gere Sunder-Plassmann, MD; Phone Number: 4391 0043140400; Email: gere.sunder-plassmann@meduniwien.ac.at
    • Principal Investigator: Markus Riegersperger, MD
    • Sub-Investigator: Gere Sunder-Plassmann, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Principal Investigator: Markus Riegersperger, MD, Medical University of Vienna

Publications and helpful links

General Publications

• Riegersperger M, Herkner H, Sunder-Plassmann G. Pulsed oral sirolimus in advanced autosomal-dominant polycystic kidney disease (Vienna RAP Study): study protocol for a randomized controlled trial. Trials. 2015 Apr 23;16:182. doi: 10.1186/s13063-015-0692-3.

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Anticipated): April 1, 2019
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: January 31, 2014
• First Submitted That Met QC Criteria: February 3, 2014
• First Posted (Estimate): February 4, 2014

Study Record Updates

• Last Update Posted (Actual): October 31, 2018
• Last Update Submitted That Met QC Criteria: October 30, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: ADPKD; Sirolimus; PKD; Polycystic kidney disease; Mammalian target of rapamycin; mTOR-I
• Additional Relevant MeSH Terms: Urologic Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Musculoskeletal Abnormalities; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Arthrogryposis; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: V5.1/20.1.2013; 2012-000550-60 (EudraCT Number); 15170 (Oesterreichische Nationalbank); 1060/2012 (Other Identifier: Ethics committee Medical University of Vienna)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No