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| ID | Type | Description | Link |
|---|---|---|---|
| 03-7915-A |
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| Name | Class |
|---|---|
| Hoffmann-La Roche | INDUSTRY |
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This is a 12-month, phase II, prospective, open label study, to evaluate the effect of mycophenolate mofetil (MMF) among patients on the kidney transplant list with high Panel of Reactive Antibody (PRA) levels.
On average, increasing the PRA from 0 to 50% specifically in the Washington Organ Procurement Organization (OPO) increases the waiting time from 3 to 6 years. Spontaneous decreases in the PRA rarely occur and is associated with a decreased chance for transplantation and a decreased rate of survival.
HYPOTHESIS: mycophenolate mofetil given over 8 months to highly sensitized subjects awaiting kidney transplant, will result in a decrement in the PRA by 10% or more in approximately 40% of patients. This decrement should allow an improved rate of transplantation.
BACKGROUND: Patients who have been exposed to human tissue by prior transplants, blood transfusion or pregnancy may develop anti-bodies against the 'cell markers of human white blood cells' called 'Human Leukocyte Antigens' (HLA). Preformed anti-bodies to these foreign human tissues is called SENSITIZATION. Sensitized patients are more likely to reject a kidney from a donor who possesses the antigenic profile to which they are already sensitized. This limits the recipient's possible donor pool out of the general population.
The Panel of Reactive Antibodies (PRA) is a test panel that represents the HLA antigenic profile of the local community. The test panel is used to measure the recipient's reactivity (by percent) to a variety of HLA antigens. A PRA of 75% means the patient reacted to 75% of the antigens on the test panel. A PRA panel greater than 50% indicates that the subject (potential organ recipient) already has a significant number of antibodies pre-formed to other human tissue and is highly sensitized. Spontaneous decreases in PRA titers rarely occur thus the probability of transplantation in sensitized patients is significantly decreased.
STUDY POPULATION: adult University of Washington Medical Center patients, on the kidney transplant waiting list who are currently receiving dialysis with a PRA level over 50% and for a period of 6 months or longer.
TREATMENT PLAN/ INTERVENTION:
CONSENT: Consent will be obtained from all subjects. SCREENING: Prior to starting MMF, a thorough medical history physical exam will be obtained. Patients will be screened clinically for occurrence of infection and for protective antibodies in response to prior vaccinations and assure that they are up to date with their immunizations.
INVESTIGATIONAL PRODUCT: Mycophenolate mofetil (MMF) is used as a routine therapy for the prevention of rejection in transplant recipients and is also used routinely for the treatment of autoimmune disease and primary renal diseases such as IgA nephropathy and lupus nephritis.
HOFFMANN LA ROCHE: Will provide Mycophenolate mofetil, MMF as CellCept well as costs for laboratory testing.
DOSAGE AND ADMINISTRATION: MMF will be dispensed by investigational drug pharmacists in 250mg capsules, taken orally twice daily. Dosing of MMF will begin at 500 mg bid for 30 days then increased to 1 gm bid if subject is not experiencing undo gastrointestinal side effects or a decrease in WBC.
STUDY DESIGN:
The subjects will be continually evaluated for 12 months. Month 4: If the subject's PRA drops by 10% at month 4, subject will remain on MMF without any changes. If subject's PRA does NOT drop by 10% at month four and infections have NOT occurred, subject will remain on MMF and increase dosage if possible.
If at month four, more than 4 serious infections have occurred the MMF dose will be reduced and or stopped for that subject. If stopped they will be followed for 4 months.
Month 8:
If the subject's PRA does NOT drop by 10% at month 8, the MMF will be discontinued and the subject will be followed for the next 4 months to month 12 post enrollment.
If subject's PRA DOES drop by 10% at month 8 and NO infection(s) have occurred, subject will continue on MMF to month 12. Study subjects will be followed for a maximum of 12 months.
OBJECTIVES:
The primary endpoint:
1) The number of subjects who achieve a PRA reduction of 10% or greater within 8 months of initiating mycophenolate mofetil (MMF)therapy.
The secondary outcome measures will include:
CLINICAL AND LABORATORY EVALUATIONS:
LAB ASSESSMENT:
Immunology: PRA (panel of reactive antibodies) will be taken monthly and the levels of individual HLA anti-bodies will be evaluated every other month.
Safety:
Total levels of Immunoglobulin G (IgG) and Immunoglobulin M (IgM), as measures of the indigenous anti-body population levels. As well as HepB surface Antibody and CMV are tests done to monitor to screen for changes in the health of the subject's immune system ie. loss of memory for immunization.
A complete blood count (CBC) is taken at each visit to screen for anemia. Differential analysis on CBD for screening against platelet reduction and possible bone marrow suppression. The subject's CBC will be checked more frequently if his/her WBC, hematocrit or platelets are low. Subjects will be followed closely through 12 months.
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| mycophenolate mofetil (CellCept) | Drug | 500mg - 1,000mg, taken PO, twice daily. |
| Measure | Description | Time Frame |
|---|---|---|
| The Number of Subjects With a 10% Decrease in PRA Level at Month 8. | Enrollment to month 8 |
| Measure | Description | Time Frame |
|---|---|---|
| The Number of Subjects With Significant Infections up to Month 12. | The number of infections while on-study up to month 12. Subjects who's PRA decreased by 10% at month 8 and who went on to the Mycophenolate mofetil + Rituximab study were followed to month 8. Those subjects who stayed on the Mycophenolate mon-therapy study were observed for infection over 12 months or until they seperated from the study. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Connie L Davis, MD | University of Washington | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Universtiy of Washington Medical Center | Seattle | Washington | 98195 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 11267267 | Background | Miura S, Okazaki H, Satoh T, Amada N, Ohashi Y. Long-term follow-up of living donor renal transplant recipients sensitized after donor specific blood transfusion. Transplant Proc. 2001 Feb-Mar;33(1-2):1221-3. doi: 10.1016/s0041-1345(00)02395-2. No abstract available. | |
| 11092347 | Background | Takeda A, Uchida K, Haba T, Tominaga Y, Katayama A, Kobayashi T, Oikawa T, Morozumi K. Acute humoral rejection of kidney allografts in patients with a positive flow cytometry crossmatch (FCXM). Clin Transplant. 2000;14 Suppl 3:15-20. doi: 10.1034/j.1399-0012.2000.0140s3015.x. |
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Subjects were consented, given a physical exan and laboratory tests including serum virologies current Hepatitis B immunization and Tuberculosis (TB) testing initially. Abnormalities in white or red blood cells, platelets, TB test or signs of infection or evidence of cancer were grounds for exclusion.
All study subjects were recruited from University of Washington Medical Center's kidney transplant wait list. Patients with a Panel of Reactive Antibodies (PRA)over 50% for 6 months or longer between 18 and 75 year of age were contacted by letter and then by phone to schedule screening visit. Enrollment occured from 4/24/06 to 9/06/07.
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| ID | Title | Description |
|---|---|---|
| FG000 | Mycophenolate Mofetil (MMF) Single Arm Study | MMF mono-therapy, oral dosing of 500 - 1,000 mg twice daily as tolerated. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| 8 Months |
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| From enrollment to month 12. |
| The Number of Kidney Transplant up to 12 Months. | The number of kidney transplants up to month 12. Subjects who's PRA decreased by 10% at month 8 and who went on to the Mycophenolate mofetil + Rituximab study were followed to month 8. Those subjects who stayed on the Mycophenolate mon-therapy study were observed for infection over 12 months or until they seperated from the study. | Enrollment to month 8 or month 12 post enrollment. |
| The Number of Pariticpants With a White Blood Cell Count Below 2.0 Thousand (Low) or Total IgG/IgM Titers Below Range (620-1490 mg/dL). | The number of subjects with adverse hematologic effects with MMF while on-study. Subjects who's PRA decreased by 10% at month 8 and who went on to the Mycophenolate mofetil + Rituximab study were followed to month 8. Those subjects who stayed on the Mycophenolate mon-therapy study were observed for hematologic effects up to 12 months. | Enrollment to month 12. |
| The Number of Transplants With a Negative Crossmatch at Transplant. | The number negative crossmatch transplants up to month 12. Positivie crossmatch transplant carries a higher risk for rejection. Subjects who's PRA decreased by 10% at month 8 and who went on to the Mycophenolate mofetil + Rituximab study were followed to month 8. Those subjects who stayed on the Mycophenolate mon-therapy study were observed for negative crossmatch transplants to 12 months. | Number of Transplants with a Negative Crossmatch. |
| 11118102 | Background | Schweitzer EJ, Wilson JS, Fernandez-Vina M, Fox M, Gutierrez M, Wiland A, Hunter J, Farney A, Philosophe B, Colonna J, Jarrell BE, Bartlett ST. A high panel-reactive antibody rescue protocol for cross-match-positive live donor kidney transplants. Transplantation. 2000 Nov 27;70(10):1531-6. doi: 10.1097/00007890-200011270-00023. |
| 2014527 | Background | Dafoe DC, Bromberg JS, Grossman RA, Tomaszewski JE, Zmijewski CM, Perloff LJ, Naji A, Asplund MW, Alfrey EJ, Sack M, et al. Renal transplantation despite a positive antiglobulin crossmatch with and without prophylactic OKT3. Transplantation. 1991 Apr;51(4):762-8. doi: 10.1097/00007890-199104000-00005. |
| 8959852 | Background | Zanker B, Schleibner S, Schneeberger H, Krauss M, Land W. Mycophenolate mofetil in patients with acute renal failure: evidence of metabolite (MPAG) accumulation and removal by dialysis. Transpl Int. 1996;9 Suppl 1:S308-10. doi: 10.1007/978-3-662-00818-8_76. |
| 10392326 | Background | Kaplan B, Meier-Kriesche HU, Friedman G, Mulgaonkar S, Gruber S, Korecka M, Brayman KL, Shaw LM. The effect of renal insufficiency on mycophenolic acid protein binding. J Clin Pharmacol. 1999 Jul;39(7):715-20. doi: 10.1177/00912709922008353. |
| 12078944 | Background | Haubitz M, de Groot K. Tolerance of mycophenolate mofetil in end-stage renal disease patients with ANCA-associated vasculitis. Clin Nephrol. 2002 Jun;57(6):421-4. doi: 10.5414/cnp57421. |
| 12698082 | Background | Gloor JM, Lager DJ, Moore SB, Pineda AA, Fidler ME, Larson TS, Grande JP, Schwab TR, Griffin MD, Prieto M, Nyberg SL, Velosa JA, Textor SC, Platt JL, Stegall MD. ABO-incompatible kidney transplantation using both A2 and non-A2 living donors. Transplantation. 2003 Apr 15;75(7):971-7. doi: 10.1097/01.TP.0000058226.39732.32. |
| 12736998 | Background | Holechek MJ, Hiller JM, Paredes M, Rickard JC, Montgomery RA. Expanding the living organ donor pool: positive crossmatch and ABO incompatible renal transplantation. Nephrol Nurs J. 2003 Apr;30(2):195-204. |
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| 12 Months |
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| ID | Title | Description |
|---|---|---|
| BG000 | Mycophenolate Mofetil (MMF) Single Arm Study | MMF mono-therapy, oral dosing of 500 - 1,000 mg twice daily as tolerated. |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||||
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| Age, Categorical | Count of Participants | Participants |
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| Age Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| 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 | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Secondary | The Number of Subjects With Significant Infections up to Month 12. | The number of infections while on-study up to month 12. Subjects who's PRA decreased by 10% at month 8 and who went on to the Mycophenolate mofetil + Rituximab study were followed to month 8. Those subjects who stayed on the Mycophenolate mon-therapy study were observed for infection over 12 months or until they seperated from the study. | Forty five subjects were screened, of these 37 received MMF. | Posted | Nov 2009 | Number | Participants | From enrollment to month 12. |
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| Primary | The Number of Subjects With a 10% Decrease in PRA Level at Month 8. | Posted | Dec 2009 | Number | Participant | Enrollment to month 8 |
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| Secondary | The Number of Kidney Transplant up to 12 Months. | The number of kidney transplants up to month 12. Subjects who's PRA decreased by 10% at month 8 and who went on to the Mycophenolate mofetil + Rituximab study were followed to month 8. Those subjects who stayed on the Mycophenolate mon-therapy study were observed for infection over 12 months or until they seperated from the study. | Posted | Dec 2009 | Number | Participants | Enrollment to month 8 or month 12 post enrollment. |
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| Secondary | The Number of Pariticpants With a White Blood Cell Count Below 2.0 Thousand (Low) or Total IgG/IgM Titers Below Range (620-1490 mg/dL). | The number of subjects with adverse hematologic effects with MMF while on-study. Subjects who's PRA decreased by 10% at month 8 and who went on to the Mycophenolate mofetil + Rituximab study were followed to month 8. Those subjects who stayed on the Mycophenolate mon-therapy study were observed for hematologic effects up to 12 months. | Posted | Dec 2009 | Number | Participant | Enrollment to month 12. |
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| Secondary | The Number of Transplants With a Negative Crossmatch at Transplant. | The number negative crossmatch transplants up to month 12. Positivie crossmatch transplant carries a higher risk for rejection. Subjects who's PRA decreased by 10% at month 8 and who went on to the Mycophenolate mofetil + Rituximab study were followed to month 8. Those subjects who stayed on the Mycophenolate mon-therapy study were observed for negative crossmatch transplants to 12 months. | Posted | Dec 2009 | Number | Participant | Number of Transplants with a Negative Crossmatch. |
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From enrollment to month 12.
Definition of SAE: hospitalization or significant treatment or interference with ADLs.
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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 | Mycophenolate Mofetil (MMF) Single Arm Study | MMF mono-therapy, oral dosing of 500 - 1,000 mg twice daily as tolerated. | 2 | 37 | 6 | 37 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Myocardial infarction | Cardiac disorders | Non-systematic Assessment | Potasium level increase in this subject caused M.I. |
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| Retinal stroke | Cardiac disorders | Non-systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Peritonitis | Infections and infestations | Non-systematic Assessment |
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| Anemia | Blood and lymphatic system disorders | Non-systematic Assessment |
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| Abscess | Infections and infestations | Non-systematic Assessment | Abscess-folliculitis and peri-renal abscess |
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The treatment of highly sensitized patients on dialysis with single agent therapy of mycophenolate was hampered by gastrointestinal side effects that reduced anticipated maximum tolerated doses and duration of treatment.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Connie L. Davis | University of Washington | 206-598-7162 | cdavis@u.washington.edu |
| ID | Term |
|---|---|
| D007676 | Kidney Failure, Chronic |
| D003928 | Diabetic Nephropathies |
| D005922 | Glomerulonephritis, IGA |
| D006977 | Hypertension, Renal |
| D007674 | Kidney Diseases |
| D003920 | Diabetes Mellitus |
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D051436 | Renal Insufficiency, Chronic |
| D051437 | Renal Insufficiency |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D048909 | Diabetes Complications |
| D004700 | Endocrine System Diseases |
| D005921 | Glomerulonephritis |
| D009393 | Nephritis |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D009173 | Mycophenolic Acid |
| ID | Term |
|---|---|
| D002208 | Caproates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
| D005227 | Fatty Acids |
| D008055 | Lipids |
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