Effect of Harvoni on Proteinuria and eGFR in Hepatitis C Virus Associated Chronic Kidney Disease (CKD)

Study Overview
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Brief Summary
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Treatment protocol to see if people with hepatitis C (HCV) and chronic kidney disease (CKD) who are treated with Harvoni for 12 weeks have improvements in their kidney disease.

Detailed Description
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The investigators hypothesize that patients with early stage (1-3) CKD caused by HCV infection will have significantly improved proteinuria and eGFR after viral eradication with 12 weeks of treatment Harvoni (LDV/SOF). This trial data will serve as the basis to support further study of LDV/SOF in patients with early CKD. Slowing progression of CKD is a critical goal, as the increasing incidence and prevalence of advanced CKD and end stage renal disease (ESRD) places significant health burden on patients and tremendous costs on our health-care system.

Official Title
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Effect of Ledipasvir and Sofosbuvir on Proteinuria and Estimated Glomerular Filtration Rate in Patients With Early Stage (1-3) Hepatitis C Associated Chronic Kidney Disease

Conditions
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Hepatitis C, Chronic Kidney Disease

Intervention / Treatment
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* Drug: Sofosbuvir/Ledipasvir FDC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject has signed the written informed consent Male or female ≥ 18 year of age HCV genotype 1 or 4 with ribonucleic acid (HCV RNA) greater than 1000 international units (IU)/milliliter (mL), determined by HCV RNA polymerase chain reaction Roche TaqMan quantitative assay. Initial diagnosis of proteinuric chronic kidney disease occurred < 7 years prior to completion of screening Women of childbearing potential (i.e. women who have not undergone hysterectomy or bilateral oophorectomy, or no medically documented ovarian failure, and are ≤ 50 years of age) must agree to 1 medically approved contraceptive measures and have their partners agree to an additional barrier method of contraception for the duration of the study and for 4 weeks after the last administration of the study drug. Women of childbearing potential must not rely on hormone-containing contraceptive as a form of birth control during the study but may use. An intrauterine device, female barrier methods with cervical cap or diaphragm with spermicidal agent, tubal sterilization, or vasectomy in male partners. Male subjects must agree to consistently and correctly use a condom during heterosexual intercourse and avoid sperm donation for the duration of this study and for 90 days after the last dose of ledipasvir and sofosbuvir. Additionally, if their female partner is of childbearing potential (as defined above), their partner must agree to use either 1 of the non-hormonal methods of birth control listed above or a hormone-containing contraceptive for 90 days after last study drug date. Hormone-containing contraceptive options for partners include implants of levonorgestrel, injectable progesterone, oral contraceptives, contraceptive vaginal ring, or transdermal contraceptive pat Adequate organ function defined as follows platelets ≥ 50 x 109/L; hemoglobin ≥ 9 g/dL, estimated glomerular filtration rate ≥ 30mL/min/1.73m2 as estimated by CKD-Epi equation. Liver imaging to exclude hepatocellular carcinoma (HCC) is required within 6 months in any patient with cirrhosis. Has > 300mg/g creatinine proteinuria on two urine samples obtained within 30 days of starting ledipasvir and sofosbuvir. Exclusion Criteria: History of evidence of clinically significant disorder other than hepatitis C virus infection or clinically significant laboratory finding that in the investigator's judgment would pose a risk to subject safety, interfere with study procedures, or prevent completion of the study. Pregnant or lactating female Uncontrolled depression or psychiatric disease interfering with the ability to comply with the study procedures or complete the study History or presence of any form of cancer within 3 years prior to enrollment, with the exception of excised basal cell or squamous cell carcinoma of the skin, stage 0 or 1 melanoma, or cervical carcinoma in site or breast carcinoma in situ that has been excised or resected completely and is without evidence of local recurrence or metastasis. Experience life-threatening cryoglobulinemic vasculitis requiring initiation of rituximab, steroids or plasmapheresis. Concomitant use of cimetidine, trimethoprim or other drugs which can increase tubular creatinine reabsorption Uncontrolled cardiovascular or pulmonary disease Uncontrolled hypertension Known HIV infection Known hypersensitivity to ledipasvir or sofosbuvir Prior HCV treatment failure using a medication in the NS5A inhibitor class Individuals who are taking the following medications and require continuation of the medications during the proposed study period will be excluded, given known interactions with ledipasvir-sofosbuvir: Carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifampin, isoniazid, rifapentine, rosuvastatin, proton pump inhibitors, digoxin, modafinil, and St. John's wort, milk thistle, Echinacea. Having an alternate explanation of chronic kidney disease, including: Diabetic kidney disease, either by biopsy findings or duration of uncontrolled diabetes > 8 years without serologic evidence of immune-complex related kidney disease Chronic hypertensive nephropathy without proteinuria Lupus nephritis Multiple myeloma Obesity related proteinuria, BMI > 35 Ongoing nephrotoxic medication use, including NSAIDS Polycystic kidney disease Kidney biopsy showing an alternate explanation for chronic kidney disease

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 12 weeks treatment with Sofosbuvir/Ledipasvir (400mg/90mg)<br>10 patients with hepatitis C (HCV) and HCV-associated CKD that will receive 12 weeks treatment with Sofosbuvir/Ledipasvir (400mg/90mg) | Drug: Sofosbuvir/Ledipasvir FDC<br>* 12 weeks treatment with Harvoni<br>* Other names: Harvoni;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percent Change in Proteinuria | % change in proteinuria from baseline (timepoint week 0) through timepoint week 24, which was 12 weeks after completion of Harvoni. | Baseline and 24 weeks (12 weeks after completion of Harvoni) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Change in eGFR From Baseline to Timepoint Week 24 | Median change from baseline (timepoint week 0) to timepoint week 24, which was 12 weeks after completion of Harvoni. Median change in eGFR was calculated using the creatinine and cystatin C-based estimating equation. eGFR = 135 × min(SCr/κ, 1)α × max(SCr/κ, 1)-0.601 × min(Scys/0.8, 1)-0.375 × max(Scys/0.8, 1)-0.711 × 0.995Age × 0.969 [if female] × 1.08 [if black] | 24 weeks | 
| Number of Participants With ≥25% Reduction in Proteinuria | Number of participants with at least -25% change in proteinuria, calculated from baseline (timepoint week 0) to timepoint week 24, which is 12 weeks after completion of Harvoni. | 24 weeks | 
| Mean Time in Weeks to Maximum Reduction in Proteinuria | This outcome evaluated all post-baseline proteinuria values through the 52 week followup, and determined which demonstrated the greatest negative change (reduction) from baseline. We then calculate the mean time to maximum reduction of proteinuria. | 52 weeks | 
| Median Change in eGFR From Baseline to Timepoint Week 52 | Median change from baseline (timepoint week 0) to timepoint week 52, which was 40 weeks after completion of Harvoni. Median change in eGFR was calculated using the creatinine and cystatin C-based estimating equation. eGFR = 135 × min(SCr/κ, 1)α × max(SCr/κ, 1)-0.601 × min(Scys/0.8, 1)-0.375 × max(Scys/0.8, 1)-0.711 × 0.995Age × 0.969 [if female] × 1.08 [if black] | 52 weeks | 
| Change in Urinary β-2microglobulin Levels Before Therapy | Change in urinary β-2microglobulin levels before therapy with ledipasvir/sofosbuvir fixed dose combination pill. β-2microglobulin (mcg/L) change prior to initiating HCV-treatment. This outcome was not assessed. | 24 weeks | 
| Change in Urinary β-2microglobulin Levels After Therapy | Change in urinary β-2microglobulin levels after therapy with ledipasvir/sofosbuvir fixed dose combination pill β-2microglobulin (mcg/L) levels were assessed at baseline (timepoint week 0) and at timepoint week 24. Change was recorded for each patient, and presented as a median with IQR. | 24 weeks | 

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