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| Name | Class |
|---|---|
| Wyeth is now a wholly owned subsidiary of Pfizer | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 | Experimental | Arm 1 Rapamune dose 2-6mg aimed at maintaining trough levels 5-8 ng/ml |
|
| 2 | Experimental | Arm 2 Rapamune dose 2-6 mg aimed at maintaining trough levels of 2-5ng/ml |
|
| 3 | No Intervention | Standard Care |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rapamune | Drug | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in GFR From Baseline to 12 Months | GFR (glomerular filtration rate) was measured by iothalamate. GFR is a key indicator of renal function. | From baseline to 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | From baseline to 12 months |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| William E. Braun, MD | The Cleveland Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Cleveland Clinic- main campus | Cleveland | Ohio | 44195 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39356039 | Derived | St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | 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 |
| FG002 | Standard Care | Standard Care: fluid intake primarily water of 2500-3000ml/24hrs, low sodium diet of 2300mg/24 hrs, caffeine avoidance, control of hypertension |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | Low Dose Rapamycin (LD) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Standard Deviation | ml/min/1.73m^2 | From baseline to 12 months |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| pulmonary embolus | Respiratory, thoracic and mediastinal disorders | Patient had massive polycystic kidneys (about 7500ml) and there was compression of the right iliac vein/IVC with clot formation. This has been reported in the literature, so it is not necessarily related to drug. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Oral ulcerations | Immune system disorders |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr William Braun Consultant Staff Nephrology, Cleveland Clinic | Cleveland Clinic | 216/444/6995 | braunw@ccf.org |
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| ID | Term |
|---|---|
| D007690 | Polycystic Kidney Diseases |
| D016891 | Polycystic Kidney, Autosomal Dominant |
| ID | Term |
|---|---|
| D052177 | Kidney Diseases, Cystic |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
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| ID | Term |
|---|---|
| D020123 | Sirolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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|
| AE: nephrotic-range proteinuruia |
|
| AE: pneumonia |
|
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
| BG002 | Standard Care | Standard Care: fluid intake primarily water of 2500-3000ml/24hrs, low sodium diet of 2300mg/24 hrs, caffeine avoidance, control of hypertension |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Baseline characteristics and risk factors | ADPKD, autosomal dominant polycystic kidney disease; iGFR, 125I-iothalamate GFR; TKV, total kidney volume; Hypertension is a BP >= 140/90 mmHg before 35 years old; family history of ESRD occurs from ADPKD before 56 years old | Number | participants |
|
| OG002 |
| Standard Care |
Standard Care: fluid intake primarily water of 2500-3000ml/24hrs, low sodium diet of 2300mg/24 hrs, caffeine avoidance, control of hypertension |
|
|
|
| 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 | Posted | Mean | Standard Deviation | ml | From baseline to 12 months |
|
|
|
| 2 |
| 10 |
| 10 |
| 10 |
| EG001 | 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 | 1 | 10 | 6 | 10 |
| EG002 | Standard Care | Standard Care: fluid intake primarily water of 2500-3000ml/24hrs, low sodium diet of 2300mg/24 hrs, caffeine avoidance, control of hypertension | 1 | 10 | 8 | 10 |
|
| nephrotic range proteinuria | Renal and urinary disorders | Open renal biopsy showed FSGS. Primary glomerulopathies have been reported to be superimposed on underlying ADPKD. |
|
| Decrease visual acuity | Eye disorders | Patient developed transient decrease in visual acuity. Neuro-ophthalmologist did not find any association with drug. Vision improved without specific treatment. |
|
| Hypoglycemia | Metabolism and nutrition disorders | Hypoglycemia associated with excessive beer consumption. |
|
| Nonserious infections | Infections and infestations |
|
| Edema | Blood and lymphatic system disorders |
|
| Gastrointestinal symptoms | Gastrointestinal disorders |
|
| Dermatitis | Skin and subcutaneous tissue disorders |
|
| Miscellaneous/other | General disorders | The problems in this group were minor, extremely varied and transient. |
|
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| D005261 |
| Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D000015 | Abnormalities, Multiple |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D000072661 | Ciliopathies |
| D030342 | Genetic Diseases, Inborn |
|
| Change in TKV |
|