Polycystic Kidney Diseases
Conditions
Keywords
ADPKD
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.
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.
Interventions
DRUGRapamune
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
Sponsors
Wyeth is now a wholly owned subsidiary of Pfizer
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in GFR From Baseline to 12 Months | From baseline to 12 months | GFR (glomerular filtration rate) was measured by iothalamate. GFR is a key indicator of renal function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Kidney Volume as Measured by 3D-CT From Baseline to 12 Months | From baseline to 12 months | Total kidney volume measured by CT from baseline to 12 months |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard Rapamycin Dose (STD) Arm 1 Rapamune dose 2-6mg aimed at maintaining trough levels 5-8 ng/ml
Rapamycin: Group 1- doses of Rapamune aimed at maintaining trough levels 5-8ng/ml | 10 |
| Low Dose Rapamycin (LD) Arm 2 Rapamune dose 2-6 mg aimed at maintaining trough levels of 2-5ng/ml
Rapamycin: Group 2 - doses of Rapamune aimed at maintaining trough levels 2-5ng/ml | 10 |
| Standard Care Standard Care: fluid intake primarily water of 2500-3000ml/24hrs, low sodium diet of 2300mg/24 hrs, caffeine avoidance, control of hypertension | 10 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | AE: nephrotic-range proteinuruia | 1 | 0 | 0 |
| Overall Study | AE: pneumonia | 1 | 0 | 0 |
| Overall Study | AE: pulmonary embolus | 0 | 1 | 0 |
| Overall Study | Missed 12 month visit | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Low Dose Rapamycin (LD) | Standard Care | Total | Standard Rapamycin Dose (STD) |
|---|---|---|---|---|
| Age, Continuous | 44.9 years STANDARD_DEVIATION 8.6 | 49.4 years STANDARD_DEVIATION 11 | 49.3 years STANDARD_DEVIATION 12 | 53.2 years STANDARD_DEVIATION 15 |
| Baseline characteristics and risk factors Family history of ESRD | 8 participants | 7 participants | 19 participants | 4 participants |
| Baseline characteristics and risk factors Hypertension | 3 participants | 5 participants | 11 participants | 3 participants |
| Baseline characteristics and risk factors Initial height-adjusted TKV>=600ml/m | 8 participants | 6 participants | 20 participants | 6 participants |
| Baseline characteristics and risk factors Initial iGFR 25-59 ml/min per 1.73 m^2 | 4 participants | 2 participants | 9 participants | 3 participants |
| Baseline characteristics and risk factors Initial TKV>1500ml | 7 participants | 6 participants | 19 participants | 6 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 9 Participants | 29 Participants | 10 Participants |
| Region of Enrollment United States | 10 participants | 10 participants | 30 participants | 10 participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 13 Participants | 5 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 17 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 6 / 10 | 8 / 10 |
| serious Total, serious adverse events | 2 / 10 | 1 / 10 | 1 / 10 |
Outcome results
Primary
Change in GFR From Baseline to 12 Months
GFR (glomerular filtration rate) was measured by iothalamate. GFR is a key indicator of renal function.
Time frame: From baseline to 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard Rapamycin Dose (STD) | Change in GFR From Baseline to 12 Months | 12 month iGFR | 74.4 ml/min/1.73m^2 | Standard Deviation 34.4 |
| Standard Rapamycin Dose (STD) | Change in GFR From Baseline to 12 Months | Baseline iGFR | 72.8 ml/min/1.73m^2 | Standard Deviation 25.7 |
| Standard Rapamycin Dose (STD) | Change in GFR From Baseline to 12 Months | Change in iGFR | 1.6 ml/min/1.73m^2 | Standard Deviation 12.1 |
| Low Dose Rapamycin (LD) | Change in GFR From Baseline to 12 Months | 12 month iGFR | 78.0 ml/min/1.73m^2 | Standard Deviation 35 |
| Low Dose Rapamycin (LD) | Change in GFR From Baseline to 12 Months | Baseline iGFR | 70.3 ml/min/1.73m^2 | Standard Deviation 27 |
| Low Dose Rapamycin (LD) | Change in GFR From Baseline to 12 Months | Change in iGFR | 7.7 ml/min/1.73m^2 | Standard Deviation 12.5 |
| Standard Care | Change in GFR From Baseline to 12 Months | Baseline iGFR | 73.1 ml/min/1.73m^2 | Standard Deviation 20.3 |
| Standard Care | Change in GFR From Baseline to 12 Months | Change in iGFR | -11.2 ml/min/1.73m^2 | Standard Deviation 9.1 |
| Standard Care | Change in GFR From Baseline to 12 Months | 12 month iGFR | 61.9 ml/min/1.73m^2 | Standard Deviation 15.6 |
Comparison: Null hypothesis: no difference between groups in iGFRp-value: <0.01ANOVA
Secondary
Change in Total Kidney Volume as Measured by 3D-CT From Baseline to 12 Months
Total kidney volume measured by CT from baseline to 12 months
Time frame: From baseline to 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard Rapamycin Dose (STD) | Change in Total Kidney Volume as Measured by 3D-CT From Baseline to 12 Months | 12 month TKV | 1537 ml | Standard Deviation 864.3 |
| Standard Rapamycin Dose (STD) | Change in Total Kidney Volume as Measured by 3D-CT From Baseline to 12 Months | Baseline TKV | 1454.1 ml | Standard Deviation 801.5 |
| Standard Rapamycin Dose (STD) | Change in Total Kidney Volume as Measured by 3D-CT From Baseline to 12 Months | Change in TKV | 82.9 ml | Standard Deviation 111.3 |
| Low Dose Rapamycin (LD) | Change in Total Kidney Volume as Measured by 3D-CT From Baseline to 12 Months | 12 month TKV | 2115.8 ml | Standard Deviation 1035 |
| Low Dose Rapamycin (LD) | Change in Total Kidney Volume as Measured by 3D-CT From Baseline to 12 Months | Baseline TKV | 1919.1 ml | Standard Deviation 903.6 |
| Low Dose Rapamycin (LD) | Change in Total Kidney Volume as Measured by 3D-CT From Baseline to 12 Months | Change in TKV | 197.7 ml | Standard Deviation 201.2 |
| Standard Care | Change in Total Kidney Volume as Measured by 3D-CT From Baseline to 12 Months | Baseline TKV | 1907.1 ml | Standard Deviation 1126.8 |
| Standard Care | Change in Total Kidney Volume as Measured by 3D-CT From Baseline to 12 Months | Change in TKV | 152.7 ml | Standard Deviation 129.4 |
| Standard Care | Change in Total Kidney Volume as Measured by 3D-CT From Baseline to 12 Months | 12 month TKV | 2059.8 ml | Standard Deviation 1236 |