Trial of Pirfenidone to Prevent Progression in Chronic Kidney Disease

Study Overview
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Brief Summary
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Kidney disease is a global health problem, affecting more than 10% of the world's population and more than half of adults over 70 years of age in the United States. Persons with kidney disease are at higher risk for cardiovascular disease, heart failure, physical function decline, and mortality. Kidney scarring is a dominant factor in the development of kidney disease. Our group has evaluated several tests to determine the severity of scarring without requiring kidney biopsies, using MRI imaging scans and evaluating markers of scarring that we can measure in the urine. In this study we will use these measures to evaluate pirfenidone as a promising potential new treatment for patients with kidney disease.

Detailed Description
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The TOP-CKD clinical trial is a randomized, double-blind, placebo-controlled interventional study, phase 2 trial of pirfenidone vs. placebo in 200 persons with Chronic Kidney Disease (CKD) with an eGFR ≥ 20 ml/min/1.73 m2 and a risk of progression to End Stage Renal Disease (ESRD) of at least 1% over five years. Participants receive treatment for 12 months, followed by a 6 month off-treatment follow-up period. Kidney scarring, also known as fibrosis, is a dominant factor in the development of kidney disease. This study will evaluate several tests to determine the severity of scarring without requiring kidney biopsies, using MRI imaging scans and evaluating markers of scarring that we can measure in the urine. We will use these measures to evaluate pirfenidone as a promising potential new treatment for patients with CKD.

Official Title
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Trial of Pirfenidone to Prevent Progression in Chronic Kidney Disease (TOP-CKD)

Conditions
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Chronic Kidney Disease

Intervention / Treatment
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* Drug: Pirfenidone
* Drug: matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with eGFR ≥20 ml/min/1.73m2 using the CKD-EPI Creatinine equation. Four variable Kidney Failure Risk Equation (KFRE) 5 year risk score >1% Age 21 years or older. Exclusion Criteria: To be determined at the screening visit or, for laboratory data, within 3 months of the screening visit if available from clinical care. Participants with known autosomal dominant polycystic kidney disease. Use or planned use of drugs that inhibit CYP1A2 which may increase pirfenidone exposure ( for example, artemisin, atazanavir, cimetidine, ciprofloxacin, enoxacin, ethinyl estradiol, fluvoxamine, mexiletine, tacrine, thiabendazole, or zileuton). Liver disease: clinical cirrhosis by imaging or physician diagnosis; alcohol use > 14 drinks/week; or aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin concentrations > 2 times the upper limit of normal (ULN) based on thresholds set at each site's local clinical laboratory. Clinical idiopathic pulmonary fibrosis (IPF) by imaging or physician diagnosis (pirfenidone is indicated for patients with IPF). Electrocardiogram (ECG) with a QTc interval > 500 msec at screening (pirfenidone can prolong QTc). Family or personal history of long QT Syndrome. Known hypersensitivity to pirfenidone. Current use of tobacco, including cigarettes, cigars, chewing tobacco, or vaping products. (Current use is defined as any use in the past 3 months). Physical inability, claustrophobia or other contra-indication to obtaining MRI measurements. Current participation in another clinical trial (observational studies are exempted). Systemic immunosuppressive medications (<10 mg daily prednisone or inhaled steroids are exempted). Malignancy within 2 years (non-melanoma skin and localized prostate carcinoma are exempted). Institutionalized individuals (e.g. prisoners, long term care residents). Pregnancy, planning to become pregnant, or currently breast-feeding; women under 55 will need to either have a reliable method of birth control (IUD {intrauterine device}, oral contraceptive pills {OCPs}) or have no menses in the preceding 2 years. Life expectancy < 12 months as assessed by the site investigator. Plans to leave the immediate area in < 12 months. Anticipated need for dialysis or kidney transplantation within 12 months. Hospitalization within the past 30 days (24-hour observation admissions are exempted). Active alcohol or substance abuse within the last 12 months, as assessed by the site investigator. Active treatment of uncontrolled psychiatric disease, as assessed by the site investigator. Perceived inability to adhere to the medical regimen or comply with recommendations, as determined by the site investigator. Inability or unwillingness to travel to study visits. Any condition that, in the opinion of the site investigator, might be significantly exacerbated by the known side effects associated with the administration of pirfenidone.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Experimental, pirfenidone<br>Pirfenidone 267 mg capsules Randomized participants will take 5 capsules (1335 mg pirfenidone): 2 pills in the morning, 1 mid-day, and 2 in the evening, with meals. | Drug: Pirfenidone<br>* Pirfenidone vs. matching placebo<br>* Other names: ESBRIET;|
| Placebo Comparator: Placebo, pirfenidone<br>Pirfenidone placebo capsules Randomized participants will take 5 capsules (1335 mg pirfenidone): 2 pills in the morning, 1 mid-day, and 2 in the evening, with meals. | Drug: matching placebo<br>* matching placebo<br>* Other names: ESBRIET;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in kidney fibrosis, as assessed by diffusion-weighted magnetic resonance imaging (DW-MRI). | The slope of change in apparent diffusion coefficient of the cortex of the kidney on the diffusion-weighted renal MRI over 12 months. | Baseline to Month 12 | 
| Change from baseline in kidney fibrosis, as assessed by urinary markers of tubulo-interstitial fibrosis. | The slope of change of urine alpha 1 microglobulin (α1M), N-terminal procollagen type 3 peptide (PIIINP), and monocyte chemoattractant protein-1 (MCP-1) over 12 months. | Baseline to Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in kidney function, as assessed by eGFR. | Change in eGFR will be evaluated as a secondary endpoint, using linear mixed models with random intercepts and slopes. Estimates from the linear mixed models will be interpretable as annual change in slope. | Baseline to Month 18 | 
| Change from baseline in kidney function, as assessed by urine albumin to creatinine ratio (ACR). | Change in ACR will be evaluated as a secondary endpoint, using linear mixed models with random intercepts and slopes. Estimates from the linear mixed models will be interpretable as annual change in slope. Because urine concentrations of ACR are typically right-skewed, we will use a log transformation to normalize its distribution. | Baseline to Month 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fibrosis, Scarring, CKD