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The aim of this study is to evaluate whether peri-transplant administration of a drug named aminophylline to children undergoing a kidney transplant from deceased donors improves early graft function and also projects on long term graft function.
This is a Double-blinded, placebo-controlled, randomized, clinical trial to evaluate whether administration of aminophylline starting pretransplant until post-transplant day 5 improves early kidney function and projects also on long term graft function.
Study Arms and intervention: On admit to the hospital prior to transplant, patients will be randomized into treatment or control arms. The randomization will be based on age groups 1-5y, 5-12y and 12-18y Treatment arm: Patients will receive aminophylline loading dose 5mg/kg prior to transplant and will continue to receive aminophylline 1.8mg/kg Q6h for a total of 20 doses.
Control arm: Patients will receive placebo infusion of normal saline, pre-transplant, followed by normal saline infusions matched by volume and frequency to treatment arm for a total of 20doses.
The only difference between the two arms will be the study intervention. Other than that all patients will receive the same standard of care for patients undergoing a kidney transplant.
Theophylline drug levels will be monitored every morning from all patients for the first 4 days post- transplant. Theophylline levels will be reported independently by the laboratory in a faxed research report directly to the pharmacist who will perform dose adjustments, according to the following table.
Theophylline Level (mcg/ml) Dose Adjustment <2 Increase subsequent doses by 50% 2-2.9 Increase subsequent doses by 33% 3-3.9 Increase subsequent doses by 25% 4-4.9 Increase subsequent doses by 15% 5-7 (goal) Target Level; No dose adjustment 7.1-8.4 Decrease subsequent doses by 10% 8.5-9.9 Decrease subsequent doses by 15% 10-12.4 Decrease subsequent doses by 25% 12.5-14.9 Decrease subsequent doses by 50% 15-19.9 Decrease subsequent doses by 67% >19.9 Discontinue all aminophylline doses. Contact Medical Monitor
All involved personnel will be blinded to the patient's allocation and to the drug level results.
The investigators will also collect a urine sample for NGAL (Neutrophil gelatinase-associated lipocalin)levels from all patients at 12 hours post-transplant.
Primary outcome will be calculated Glomerular Filtration Rate(GFR) on postoperative day 5. The investigators will determine whether patients in the aminophylline group had improved GFR compared to control group.
The investigators will also determine whether patients who received aminophylline had lower urinary NGAL levels compared to control group indicating a lesser degree of kidney injury. Urinary NGAL (Neutrophil gelatinase-associated lipocalin) is a biomarker of kidney injury. Elevated urinary NGAL levels post-transplant were found to be predictive of delayed graft function and the need for dialysis post-transplant.
At the investigators' center all patients undergo routine kidney protocol biopsies at 6 months post- transplant. After the slides are read by the pathologist the investigators will use the same tissue blocks to quantify the amount of fibrosis using computerized image analysis of Sirius Red-stained biopsies. The amount of fibrosis seen on 6 months protocol biopsies was proven to be correlated with expected graft survival.
An independent medical monitor will be assigned to manage toxic theophylline levels >20mcg/mL. The laboratory will report directly to the medical monitor, who will discontinue aminophylline and remove the patient from the study.
The trial will be also be monitored with a Data Safety Monitoring Board (DSMB) unrelated to the study. The DSMB will meet after enrollment of 20 patients to assess for drug safety and monitor for adverse events of the drug.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Aminophylline | Experimental | Patients will receive aminophylline loading dose 5mg/kg prior to transplant and will continue to receive aminophylline 1.8mg/kg Q6h for a total of 20 doses. Theophylline drug levels will be monitored daily for 4 days. |
|
| Control | Placebo Comparator | Patients will receive placebo infusion of normal saline, pre-transplant, followed by normal saline infusions matched by volume and frequency to treatment arm for a total of 20 doses. Drug levels will be monitored daily for 4 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Aminophylline | Drug | Aminophylline loading dose 5mg/kg prior to transplant and will continue to receive aminophylline 1.8mg/kg Q6h for a total of 20 doses. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Calculated Estimated Glomerular Filtration Rate (eGFR) | The investigators will measure blood creatinine on post-operative day 5 and using the Schwartz equation will calculate estimated glomerular filtration rate (GFR) to determine kidney function. | 5 days |
| Measure | Description | Time Frame |
|---|---|---|
| Urinary NGAL (Neutrophil Gelatinase-associated Lipocalin)/ Creatinine Ratio | urinary NGAL(Neutrophil gelatinase-associated lipocalin) is a biomarker for kidney injury. NGAL levels 12h post-transplant were found to be a marker for development of delayed graft function and need for dialysis post-transplant. NGAL levels are corrected for urine creatinine. | 12 hours post transplant |
| Measure | Description | Time Frame |
|---|---|---|
| Presence of Fibrosis Measured on Protocol Biopsy | The investigators will use the same cores that are obtained during routine 6 months protocol biopsies to quantify the amount of fibrosis | 6 months |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Paul C Grimm, MD | Medical director, Pediatric Kidney Transplant Program Department of Pediatric Nephrology , Lucile Packard Children's hospital | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Lucile Packard Children's Hospital at Stanford | Stanford | California | 94305-5208 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16410406 | Background | Grenz A, Baier D, Petroktistis F, Wehrmann M, Kohle C, Schenk M, Sessler M, Gleiter CH, Fandrich F, Osswald H. Theophylline improves early allograft function in rat kidney transplantation. J Pharmacol Exp Ther. 2006 May;317(2):473-9. doi: 10.1124/jpet.105.096917. Epub 2006 Jan 12. | |
| 16887430 | Background | Bhat MA, Shah ZA, Makhdoomi MS, Mufti MH. Theophylline for renal function in term neonates with perinatal asphyxia: a randomized, placebo-controlled trial. J Pediatr. 2006 Aug;149(2):180-4. doi: 10.1016/j.jpeds.2006.03.053. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Aminophylline | Patients will receive aminophylline loading dose 5mg/kg prior to transplant and will continue to receive aminophylline 1.8mg/kg Q6h for a total of 20 doses. Theophylline drug levels will be monitored daily for 4 days. Target theophylline level is 5-7mcg/ml. Aminophylline dosing will be adjusted in order to achieve desired levels as stated in the study protocol. |
| FG001 | Control | Patients will receive placebo infusion of normal saline, pre-transplant, followed by normal saline infusions matched by volume and frequency to treatment arm for a total of 20 doses. Drug levels will be monitored daily for 4 days. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Aminophylline | Patients will receive aminophylline loading dose 5mg/kg prior to transplant and will continue to receive aminophylline 1.8mg/kg Q6h for a total of 20 doses. Theophylline drug levels will be monitored daily for 4 days. Aminophylline: Aminophylline loading dose 5mg/kg prior to transplant and will continue to receive aminophylline 1.8mg/kg Q6h for a total of 20 doses. Theophylline drug levels: Theophylline drug levels will be monitored every morning from all patients for the first 4 days post- transplant. |
| 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 | Calculated Estimated Glomerular Filtration Rate (eGFR) | The investigators will measure blood creatinine on post-operative day 5 and using the Schwartz equation will calculate estimated glomerular filtration rate (GFR) to determine kidney function. | Intention to treat analysis | Posted | Mean | Standard Deviation | ml/min/1.73m2 | 5 days |
|
6 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 | Aminophylline | Patients will receive aminophylline loading dose 5mg/kg prior to transplant and will continue to receive aminophylline 1.8mg/kg Q6h for a total of 20 doses. Theophylline drug levels will be monitored daily for 4 days. Target theophylline level is 5-7mcg/ml. Aminophylline dosing will be adjusted in order to achieve desired levels as stated in the study protocol. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Agitation | Nervous system disorders | Systematic Assessment |
Small sample size
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Paul Grimm | Stanford University | 6507237903 |
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| ID | Term |
|---|---|
| D000628 | Aminophylline |
| D013806 | Theophylline |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D005029 | Ethylenediamines |
| D003959 | Diamines |
| D011073 | Polyamines |
| D000588 | Amines |
| D009930 |
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|
| Theophylline drug levels | Other | Theophylline drug levels will be monitored every morning from all patients for the first 4 days post- transplant. |
|
| Placebo | Drug | Patients will receive placebo infusion of normal saline, pre-transplant, followed by normal saline infusions matched by volume and frequency to treatment arm for a total of 20 doses. |
|
|
| 10742366 | Background | Jenik AG, Ceriani Cernadas JM, Gorenstein A, Ramirez JA, Vain N, Armadans M, Ferraris JR. A randomized, double-blind, placebo-controlled trial of the effects of prophylactic theophylline on renal function in term neonates with perinatal asphyxia. Pediatrics. 2000 Apr;105(4):E45. doi: 10.1542/peds.105.4.e45. |
| 15840666 | Background | McLaughlin GE, Abitbol CL. Reversal of oliguric tacrolimus nephrotoxicity in children. Nephrol Dial Transplant. 2005 Jul;20(7):1471-5. doi: 10.1093/ndt/gfh785. Epub 2005 Apr 19. |
| BG001 | Control | Patients will receive placebo infusion of normal saline, pre-transplant, followed by normal saline infusions matched by volume and frequency to treatment arm for a total of 20 doses. Drug levels will be monitored daily for 4 days. Theophylline drug levels: Theophylline drug levels will be monitored every morning from all patients for the first 4 days post- transplant. Placebo: Patients will receive placebo infusion of normal saline, pre-transplant, followed by normal saline infusions matched by volume and frequency to treatment arm for a total of 20 doses. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Patients will receive placebo infusion of normal saline, pre-transplant, followed by normal saline infusions matched by volume and frequency to treatment arm for a total of 20 doses. Drug levels will be monitored daily for 4 days. |
|
|
|
| Secondary | Urinary NGAL (Neutrophil Gelatinase-associated Lipocalin)/ Creatinine Ratio | urinary NGAL(Neutrophil gelatinase-associated lipocalin) is a biomarker for kidney injury. NGAL levels 12h post-transplant were found to be a marker for development of delayed graft function and need for dialysis post-transplant. NGAL levels are corrected for urine creatinine. | Participants with available data were included in the analysis. | Posted | Median | Inter-Quartile Range | ng/mg | 12 hours post transplant |
|
|
|
|
| Other Pre-specified | Presence of Fibrosis Measured on Protocol Biopsy | The investigators will use the same cores that are obtained during routine 6 months protocol biopsies to quantify the amount of fibrosis | Participants with available data were included in the analysis. | Posted | Count of Participants | Participants | 6 months |
|
|
|
|
| 0 |
| 23 |
| 0 |
| 23 |
| 9 |
| 23 |
| EG001 | Control | Patients will receive placebo infusion of normal saline, pre-transplant, followed by normal saline infusions matched by volume and frequency to treatment arm for a total of 20 doses. Drug levels will be monitored daily for 4 days. | 0 | 27 | 0 | 27 | 13 | 27 |
| tachycardia at day 1 post transplant | Cardiac disorders | Systematic Assessment |
|
| tacrolimus toxicity | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Acute kidney injury | Renal and urinary disorders | Systematic Assessment |
|
| Rejection | Renal and urinary disorders | Systematic Assessment |
|
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| Organic Chemicals |
| D014970 | Xanthines |
| D011688 | Purinones |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |
| D000470 | Alkaloids |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |