Pilot Study of Rapamycin as Treatment for Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Study Details
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 |
|---|---|---|
| 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
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 Names:
|
| 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 Names:
|
| No Intervention: 3 Standard Care |
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
Eligibility Criteria
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
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | 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
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 7736
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Standard Rapamycin Dose (STD) | Low Dose Rapamycin (LD) | Standard Care |
|---|---|---|---|
| Arm/Group Description | 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 | 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 | Standard Care: fluid intake primarily water of 2500-3000ml/24hrs, low sodium diet of 2300mg/24 hrs, caffeine avoidance, control of hypertension |
| Period Title: Overall Study | |||
| STARTED | 10 | 10 | 10 |
| COMPLETED | 8 | 9 | 9 |
| NOT COMPLETED | 2 | 1 | 1 |
Baseline Characteristics
| Arm/Group Title | Standard Rapamycin Dose (STD) | Low Dose Rapamycin (LD) | Standard Care | Total |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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 | Standard Care: fluid intake primarily water of 2500-3000ml/24hrs, low sodium diet of 2300mg/24 hrs, caffeine avoidance, control of hypertension | Total of all reporting groups |
| Overall Participants | 10 | 10 | 10 | 30 |
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
53.2
(15.0)
|
44.9
(8.6)
|
49.4
(11.0)
|
49.3
(12.0)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
5
50%
|
5
50%
|
3
30%
|
13
43.3%
|
| Male |
5
50%
|
5
50%
|
7
70%
|
17
56.7%
|
| Race (NIH/OMB) (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
1
10%
|
1
3.3%
|
| White |
10
100%
|
10
100%
|
9
90%
|
29
96.7%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | ||||
| United States |
10
100%
|
10
100%
|
10
100%
|
30
100%
|
| Baseline characteristics and risk factors (participants) [Number] | ||||
| Hypertension |
3
30%
|
3
30%
|
5
50%
|
11
36.7%
|
| Family history of ESRD |
4
40%
|
8
80%
|
7
70%
|
19
63.3%
|
| Initial iGFR 25-59 ml/min per 1.73 m^2 |
3
30%
|
4
40%
|
2
20%
|
9
30%
|
| Initial TKV>1500ml |
6
60%
|
7
70%
|
6
60%
|
19
63.3%
|
| Initial height-adjusted TKV>=600ml/m |
6
60%
|
8
80%
|
6
60%
|
20
66.7%
|
Outcome Measures
| Title | Change in GFR From Baseline to 12 Months |
|---|---|
| Description | GFR (glomerular filtration rate) was measured by iothalamate. GFR is a key indicator of renal function. |
| Time Frame | From baseline to 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Standard Rapamycin Dose (STD) | Low Dose Rapamycin (LD) | Standard Care |
|---|---|---|---|
| Arm/Group Description | 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 | 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 | Standard Care: fluid intake primarily water of 2500-3000ml/24hrs, low sodium diet of 2300mg/24 hrs, caffeine avoidance, control of hypertension |
| Measure Participants | 8 | 9 | 9 |
| Baseline iGFR |
72.8
(25.7)
|
70.3
(27.0)
|
73.1
(20.3)
|
| 12 month iGFR |
74.4
(34.4)
|
78.0
(35.0)
|
61.9
(15.6)
|
| Change in iGFR |
1.6
(12.1)
|
7.7
(12.5)
|
-11.2
(9.1)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Standard Rapamycin Dose (STD), Low Dose Rapamycin (LD), Standard Care |
|---|---|---|
| Comments | Null hypothesis: no difference between groups in iGFR | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.01 |
| Comments | Pairwise comparisons adjusted for multiple testing (Tukey) | |
| Method | ANOVA | |
| Comments | ||
| Title | Change in Total Kidney Volume as Measured by 3D-CT From Baseline to 12 Months |
|---|---|
| Description | Total kidney volume measured by CT from baseline to 12 months |
| Time Frame | From baseline to 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Standard Rapamycin Dose (STD) | Low Dose Rapamycin (LD) | Standard Care |
|---|---|---|---|
| Arm/Group Description | 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 | 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 | Standard Care: fluid intake primarily water of 2500-3000ml/24hrs, low sodium diet of 2300mg/24 hrs, caffeine avoidance, control of hypertension |
| Measure Participants | 8 | 9 | 9 |
| Baseline TKV |
1454.1
(801.5)
|
1919.1
(903.6)
|
1907.1
(1126.8)
|
| 12 month TKV |
1537
(864.3)
|
2115.8
(1035.0)
|
2059.8
(1236.0)
|
| Change in TKV |
82.9
(111.3)
|
197.7
(201.2)
|
152.7
(129.4)
|
Adverse Events
| Time Frame | ||||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Standard Rapamycin Dose (STD) | Low Dose Rapamycin (LD) | Standard Care | |||
| Arm/Group Description | 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 | 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 | Standard Care: fluid intake primarily water of 2500-3000ml/24hrs, low sodium diet of 2300mg/24 hrs, caffeine avoidance, control of hypertension | |||
All Cause Mortality |
||||||
| Standard Rapamycin Dose (STD) | Low Dose Rapamycin (LD) | Standard Care | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Standard Rapamycin Dose (STD) | Low Dose Rapamycin (LD) | Standard Care | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/10 (20%) | 1/10 (10%) | 1/10 (10%) | |||
| Eye disorders | ||||||
| Decrease visual acuity | 1/10 (10%) | 0/10 (0%) | 0/10 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Hypoglycemia | 0/10 (0%) | 0/10 (0%) | 1/10 (10%) | |||
| Renal and urinary disorders | ||||||
| nephrotic range proteinuria | 1/10 (10%) | 0/10 (0%) | 0/10 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| pulmonary embolus | 0/10 (0%) | 1/10 (10%) | 0/10 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Standard Rapamycin Dose (STD) | Low Dose Rapamycin (LD) | Standard Care | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 10/10 (100%) | 6/10 (60%) | 8/10 (80%) | |||
| Blood and lymphatic system disorders | ||||||
| Edema | 1/10 (10%) | 1 | 0/10 (0%) | 0 | 2/10 (20%) | 2 |
| Gastrointestinal disorders | ||||||
| Gastrointestinal symptoms | 3/10 (30%) | 3 | 1/10 (10%) | 1 | 4/10 (40%) | 5 |
| General disorders | ||||||
| Miscellaneous/other | 4/10 (40%) | 7 | 2/10 (20%) | 2 | 5/10 (50%) | 7 |
| Immune system disorders | ||||||
| Oral ulcerations | 6/10 (60%) | 6 | 2/10 (20%) | 2 | 0/10 (0%) | 0 |
| Infections and infestations | ||||||
| Nonserious infections | 6/10 (60%) | 6 | 2/10 (20%) | 2 | 5/10 (50%) | 5 |
| Skin and subcutaneous tissue disorders | ||||||
| Dermatitis | 0/10 (0%) | 0 | 2/10 (20%) | 2 | 0/10 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr William Braun Consultant Staff Nephrology, Cleveland Clinic |
|---|---|
| Organization | Cleveland Clinic |
| Phone | 216/444/6995 |
| braunw@ccf.org |
- 7736