Pilot Study of Rapamycin as Treatment for Autosomal Dominant Polycystic Kidney Disease (ADPKD)

• ClinicalTrials.gov Identifier: NCT00286156
• Recruitment Status: Completed
• First Posted: February 3, 2006
• Results First Posted: April 6, 2015
• Last Update Posted: April 6, 2015
• Sponsor: The Cleveland Clinic
• Collaborator: Wyeth is now a wholly owned subsidiary of Pfizer
• Information provided by (Responsible Party): The Cleveland Clinic

Study Description

Brief Summary:

This study is a prospective, randomized, open-label, pilot clinical trial designed to compare the effects of an agent that has antiproliferative (1,2), antiangiogenesis (3),and tumor-progression blocking capabilities (4), namely, rapamycin (Rapamune®), in the treatment of autosomal-dominant polycystic kidney disease (ADPKD).

Up to this time, only generic renal disease treatments for ADPKD have been in use, such as the treatment of hypertension, urinary tract infections, renal stones, renal call carcinomas, and replacement therapy with dialysis and/or renal transplantation. The fundamental aberrations in ADPKD are proliferation of cyst-forming tubuloepithelial cells, secretion of cytokine-rich fluid into those cysts, and progressive cyst expansion and release of inflammatory mediators that injure surrounding normal renal tissue. Consequently, therapy directed specifically at blocking the proliferation of tubuloepithelial cells and their tendency to malignant transformation, as well as impeding their blood supply, should have obvious merit.

General Procedures:

In Group I participants will have an iothalamate glomerular filtration rate (GFR) equal to or greater than 60 ml/min/1.73 m2, and in Group II participants will have a GFR less than 25-59 ml/min/1.73 m2. Both males and females with ADPKD who volunteer and qualify, will be randomly and prospectively assigned to treatment with rapamycin at either a high or low trough blood level or to standard care (each 1/3 of enrolled patients) for one year. The two treatment groups will receive rapamycin doses aimed at maintaining the 20- to 24-hour trough blood levels at either 2 to 5 ng/mL (low-dose), or greater than 5 to 8 ng/mL (high-dose). These trough levels are in the lower range of levels used when treating renal transplant recipients in whom trough levels are typically maintained between 5 and 15 ng/mL.

Condition or disease	Intervention/treatment	Phase
Polycystic Kidney Diseases	Drug: Rapamune	Phase 1; Phase 2

Detailed Description:

This study is a prospective, randomized,open label, pilot clinical trial designed to compare the effects of an agent that has antiproliferative (1,2), antiangiogenesis (3),and tumor-progression blocking capabilities (4), namely, rapamycin (Rapamune®), in the treatment of autosomal-dominant polycystic kidney disease (ADPKD).

Up to this time, only generic renal disease treatments for ADPKD have been in use, such as the treatment of hypertension, urinary tract infections, renal stones, renal call carcinomas, and replacement therapy with dialysis and/or renal transplantation. The fundamental aberrations in ADPKD are proliferation of cyst-forming tubuloepithelial cells, secretion of cytokine-rich fluid into those cysts, and progressive cyst expansion and release of inflammatory mediators that injure surrounding normal renal tissue. Consequently, therapy directed specifically at blocking the proliferation of tubuloepithelial cells and their tendency to malignant transformation, as well as impeding their blood supply, should have obvious merit.

General Procedures:

In Group I participants will have an iothalamate glomerular filtration rate (GFR) equal to or greater than 60 ml/min/1.73 m2, and in Group II participants will have a GFR less than 25-59 ml/min/1.73 m2. Both males and females with ADPKD who volunteer and qualify, will be randomly and prospectively assigned to treatment with rapamycin at either a high or low trough blood level or to standard care (each 1/3 of enrolled patients) for one year. The two treatment groups will receive rapamycin doses aimed at maintaining the 20- to 24-hour trough blood levels at either 2 to 5 ng/mL (low-dose), or greater than 5 to 8 ng/mL (high-dose). These trough levels are in the lower range of levels used when treating renal transplant recipients in whom trough levels are typically maintained between 5 and 15 ng/mL.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Study of Rapamycin as Treatment for Autosomal Dominant Polycystic Kidney Disease
• Study Start Date: October 2006
• Actual Primary Completion Date: March 2012
• Actual Study Completion Date: December 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1; Arm 1 Rapamune dose 2-6mg aimed at maintaining trough levels 5-8 ng/ml	Drug: Rapamune; Group 1- doses of Rapamune aimed at maintaining trough levels 5-8ng/ml Group 2 - doses of Rapamune aimed at maintaining trough levels 2-5ng/ml Group 3- Standard Care; Other Name: Rapamycin
Experimental: 2; Arm 2 Rapamune dose 2-6 mg aimed at maintaining trough levels of 2-5ng/ml	Drug: Rapamune; Group 1- doses of Rapamune aimed at maintaining trough levels 5-8ng/ml Group 2 - doses of Rapamune aimed at maintaining trough levels 2-5ng/ml Group 3- Standard Care; Other Name: Rapamycin
No Intervention: 3; Standard Care

Outcome Measures

Primary Outcome Measures :

1. Change in GFR From Baseline to 12 Months [ Time Frame: From baseline to 12 months ]
   GFR (glomerular filtration rate) was measured by iothalamate. GFR is a key indicator of renal function.

Secondary Outcome Measures :

1. Change in Total Kidney Volume as Measured by 3D-CT From Baseline to 12 Months [ Time Frame: From baseline to 12 months ]
   Total kidney volume measured by CT from baseline to 12 months

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• ADPKD
• > 18 y.o. GFR greater than or equal to 25. Willingness to be randomized to any treatment group Willingness to follow protocol requirements-frequent testing and follow-up required at Cleveland Clinic(Cleveland, OH) signed informed consent Willingness to use birth control(male and female)

Exclusion Criteria:

• Pregnancy
• post partum
• lactating
• system illness with renal involvement

Contacts and Locations

Locations

United States, Ohio

The Cleveland Clinic- main campus

Cleveland, Ohio, United States, 44195

Sponsors and Collaborators

The Cleveland Clinic

Wyeth is now a wholly owned subsidiary of Pfizer

Investigators

• Principal Investigator: William E. Braun, MD; The Cleveland Clinic

More Information

• Responsible Party: The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT00286156
• Other Study ID Numbers: 7736
• First Posted: February 3, 2006
• Results First Posted: April 6, 2015
• Last Update Posted: April 6, 2015
• Last Verified: March 2014

Keywords provided by The Cleveland Clinic:

ADPKD

Additional relevant MeSH terms:

Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Urologic Diseases; Kidney Diseases, Cystic; Abnormalities, Multiple; Congenital Abnormalities; Ciliopathies; Genetic Diseases, Inborn; Sirolimus; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs