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inability to achieve recruitment goals at a single center and given the current pandemic conditions
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Aim 1. To determine the effect of Allopurinol treatment on renal function (glomerular filtration rate, GFR) in pediatric chronic kidney disease (CKD) patients with high uric acid levels (hyperuricemia).
Aim 2. Establish whether Allopurinol treatment reduces Nlrp3 inflammasome and renal injury biomarkers.
Uric acid levels often rise when kidney function declines. Historically, high uric acid has not been treated unless the uric acid crystallizes in the joint space and causes clinical gout disease, more typically seen in adults. However, new research has shown that high uric acid levels are associated with the development of hypertension, inflammation, and both acute and chronic kidney injury. Adult patients on renal dialysis who have hyperuricemia also have higher mortality rates. In several adult and in one pediatric clinical trial of uric acid lowering therapy (with Allopurinol or Febuxostat), treatment has demonstrated a slower rate of renal function decline and improved blood pressure compared to placebo. The pediatric trial was a 4-month placebo controlled trial of Allopurinol, and showed positive improvement in renal function and blood pressure, but did not adequately control for potential confounders in the outcome. Two known confounders that influence renal function (glomerular filitration rate, GFR) in pediatric CKD are race and glomerular or non-glomerular disease etiology. This study is designed to control for these confounders and establish whether Allopurinol for 6 months of treatment to a goal range of 3-5 mg/dL will improve renal function compared to standard of care. The secondary outcome is to determine whether blood pressure is affected by the treatment and the magnitude of change of serum uric acid. This study will also explore whether Allopurinol treatment alters activation of the Nlrp3 inflammasome or renal injury biomarkers.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Allopurinol | Active Comparator | Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. |
|
| Standard of Care Control | No Intervention | The treatment arm will be compared to a standard of care arm. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Allopurinol | Drug | Allopurinol dosed to target uric acid levels of 3-5 mg/dL. |
|
| Measure | Description | Time Frame |
|---|---|---|
| eGFR Change | Change in Cys-C eGFR over time | The difference in Cystatin C eGFR between baseline and 6 months will be measured |
| eGFR Change | Change in Creatinine eGFR over time | The difference in Creatinine eGFR between baseline and 6 months will be measured |
| Measure | Description | Time Frame |
|---|---|---|
| Serum Uric Acid Change | Change in Serum Uric Acid | The difference in Serum Uric Acid between baseline and 6 months will be measured |
| Systolic Blood Pressure | Change in systolic blood pressure |
| Measure | Description | Time Frame |
|---|---|---|
| Serum High Sensitivity C-reactive Protein (Hs-CRP) | Compare the mean difference of serum hs-CRP from baseline to 6 months between groups | Serum hs-CRP will be measured at baseline and 6 months |
| Interleukin 18 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Cristin Kaspar, MD | Virginia Commonwealth University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Virginia Commonwealth University | Richmond | Virginia | 23298 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Allopurinol | Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. Allopurinol: Allopurinol dosed to target uric acid levels of 3-5 mg/dL. |
| FG001 | Standard of Care Control | The treatment arm will be compared to a standard of care arm. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Allopurinol | Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. Allopurinol: Allopurinol dosed to target uric acid levels of 3-5 mg/dL. |
| BG001 |
| 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 | eGFR Change | Change in Cys-C eGFR over time | Posted | Mean | Standard Deviation | ml/min/1.73m^2 | The difference in Cystatin C eGFR between baseline and 6 months will be measured |
|
6 months
Regular investigator assessment, regular laboratory testing
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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 | Allopurinol | Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. Allopurinol: Allopurinol dosed to target uric acid levels of 3-5 mg/dL. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome | Immune system disorders | Systematic Assessment | Patient in treatment intervention developed DRESS syndrome directly attributable to Allopurinol. Required renal replacement therapy, prolonged steroid taper and has partially recovered. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Cristin Kaspar, MD | Virginia Commonwealth University | 804-628-3866 | cristin.kaspar@vcuhealth.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 25, 2019 | May 3, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D033461 | Hyperuricemia |
| D051436 | Renal Insufficiency, Chronic |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
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| ID | Term |
|---|---|
| D000493 | Allopurinol |
| ID | Term |
|---|---|
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| The difference in clinic systolic blood pressure between baseline and 6 months will be measured |
| Diastolic Blood Pressure | Change in diastolic blood pressure | The difference in clinic diastolic blood pressure between baseline and 6 months will be measured |
Change in interleukin 18
| Serum interleukin 18 will be measured at baseline, 3 months, and 6 months |
| Serum Nlrp3 | Change in serum Nlrp3 | Serum Nlrp3 will be measured at baseline, 3 months, and 6 months |
| Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) | Change in urine NGAL | Urine NGAL will be measured at baseline, 3 months, and 6 months |
| Urine Endothelin-1 (ET-1) | Change in urine ET-1 | Urine ET-1 will be measured at baseline, 3 months, and 6 months |
| Urine Kidney Injury Molecule-1 (KIM-1) | Change in urine KIM-1 | Urine KIM-1 will be measured at baseline, 3 months, and 6 months |
| Urine N-acetyl-Beta-D-Glucosaminidase (NAG) | Change in urine NAG | Urine NAG will be measured at baseline, 3 months, and 6 months |
| Medical change caused patient to no longer meet inclusion/exclusion criteria |
|
| Standard of Care Control |
The treatment arm will be compared to a standard of care arm. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
| Primary | eGFR Change | Change in Creatinine eGFR over time | Posted | Mean | Standard Deviation | ml/min/1.73m^2 | The difference in Creatinine eGFR between baseline and 6 months will be measured |
|
|
|
|
| Secondary | Serum Uric Acid Change | Change in Serum Uric Acid | Posted | Mean | Standard Deviation | mg/dl | The difference in Serum Uric Acid between baseline and 6 months will be measured |
|
|
|
|
| Secondary | Systolic Blood Pressure | Change in systolic blood pressure | Follow up blood pressure data was not collected from one participant in the treatment group | Posted | Mean | Standard Deviation | mmHg | The difference in clinic systolic blood pressure between baseline and 6 months will be measured |
|
|
|
|
| Secondary | Diastolic Blood Pressure | Change in diastolic blood pressure | Follow up blood pressure data was not collected from one participant in the treatment group | Posted | Mean | Standard Deviation | mmHg | The difference in clinic diastolic blood pressure between baseline and 6 months will be measured |
|
|
|
|
| Other Pre-specified | Serum High Sensitivity C-reactive Protein (Hs-CRP) | Compare the mean difference of serum hs-CRP from baseline to 6 months between groups | Posted | Mean | Standard Deviation | mg/dL | Serum hs-CRP will be measured at baseline and 6 months |
|
|
|
|
| Other Pre-specified | Interleukin 18 | Change in interleukin 18 | Not Posted | Serum interleukin 18 will be measured at baseline, 3 months, and 6 months | Participants |
| Other Pre-specified | Serum Nlrp3 | Change in serum Nlrp3 | Not Posted | Serum Nlrp3 will be measured at baseline, 3 months, and 6 months | Participants |
| Other Pre-specified | Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) | Change in urine NGAL | Not Posted | Urine NGAL will be measured at baseline, 3 months, and 6 months | Participants |
| Other Pre-specified | Urine Endothelin-1 (ET-1) | Change in urine ET-1 | Not Posted | Urine ET-1 will be measured at baseline, 3 months, and 6 months | Participants |
| Other Pre-specified | Urine Kidney Injury Molecule-1 (KIM-1) | Change in urine KIM-1 | Not Posted | Urine KIM-1 will be measured at baseline, 3 months, and 6 months | Participants |
| Other Pre-specified | Urine N-acetyl-Beta-D-Glucosaminidase (NAG) | Change in urine NAG | Not Posted | Urine NAG will be measured at baseline, 3 months, and 6 months | Participants |
| 0 |
| 7 |
| 1 |
| 7 |
| 0 |
| 7 |
| EG001 | Standard of Care Control | The treatment arm will be compared to a standard of care arm. | 0 | 7 | 0 | 7 | 0 | 7 |
|
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| 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 |