Chronic Kidney Disease, Hepatitis C
Conditions
Keywords
CKD, HCV
Brief summary
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
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.
Interventions
DRUGSofosbuvir/Ledipasvir FDC
12 weeks treatment with Harvoni
Sponsors
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percent Change in Proteinuria | Baseline and 24 weeks (12 weeks after completion of Harvoni) | % change in proteinuria from baseline (timepoint week 0) through timepoint week 24, which was 12 weeks after completion of Harvoni. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With ≥25% Reduction in Proteinuria | 24 weeks | 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. |
| Mean Time in Weeks to Maximum Reduction in Proteinuria | 52 weeks | 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. |
| Median Change in eGFR From Baseline to Timepoint Week 24 | 24 weeks | 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 \[if black\] |
| Change in Urinary β-2microglobulin Levels Before Therapy | 24 weeks | 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. |
| Change in Urinary β-2microglobulin Levels After Therapy | 24 weeks | 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. |
| Median Change in eGFR From Baseline to Timepoint Week 52 | 52 weeks | 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 \[if black\] |
Countries
United States
Participant flow
Recruitment details
14 patients were recruited and signed informed consent
Participants by arm
| Arm | Count |
|---|---|
| 12 Weeks Treatment With Sofosbuvir/Ledipasvir (400mg/90mg) Sofosbuvir/Ledipasvir (400mg/90mg) FDC: 12 weeks treatment with Harvoni for patients with Hepatitis C (HCV) and HCV-associated CKD
Subjects were followed for one year after treatment initiation | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | 12 Weeks Treatment With Sofosbuvir/Ledipasvir (400mg/90mg) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Baseline HCV RNA | 1,573,500 IU/mL |
| CKD stage 1 | 3 Participants |
| CKD stage 2 | 2 Participants |
| CKD stage 3 | 5 Participants |
| Congestive heart failure | 1 Participants |
| Coronary artery disease | 2 Participants |
| Diabetes mellitus | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| HCV genotype 1a | 3 Participants |
| HCV genotype 1b | 4 Participants |
| HCV genotype 4 | 2 Participants |
| HCV genotype mixed | 1 Participants |
| Hypertension | 9 Participants |
| Prior PEG-IFN/ribavirin treatment | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United States | 10 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 7 / 10 |
| serious Total, serious adverse events | 1 / 10 |
Outcome results
Primary
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.
Time frame: Baseline and 24 weeks (12 weeks after completion of Harvoni)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 12 Weeks Treatment With Sofosbuvir/Ledipasvir (400mg/90mg) | The Percent Change in Proteinuria | -14 percentage change from baseline |
Secondary
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.
Time frame: 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 12 Weeks Treatment With Sofosbuvir/Ledipasvir (400mg/90mg) | Change in Urinary β-2microglobulin Levels After Therapy | 57 mcg/L |
Secondary
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.
Time frame: 24 weeks
Population: Data were not collected and the outcome cannot be reported. Values for urinary β-2microglobulin were obtained at baseline and not at screening. Thus we are unable to report a change in urinary β-2microglobulin levels BEFORE therapy with ledipasvir/sofosbuvir - however, we are able to report the changes after therapy as followup values were done.
Secondary
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.
Time frame: 52 weeks
Population: Because 3 patients had rising proteinuria they are not included in this analysis, which only looks at the mean time to reduction in proteinuria in the 7 patients who had any reductions in proteinuria. This includes the 3 patients who had -25% change in proteinuria and 4 patients who had smaller negative changes (reductions) in proteinuria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 12 Weeks Treatment With Sofosbuvir/Ledipasvir (400mg/90mg) | Mean Time in Weeks to Maximum Reduction in Proteinuria | 39.4 weeks | Standard Deviation 12.7 |
Secondary
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 \[if black\]
Time frame: 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 12 Weeks Treatment With Sofosbuvir/Ledipasvir (400mg/90mg) | Median Change in eGFR From Baseline to Timepoint Week 24 | 1 mL/min/1.73m^2 |
Secondary
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 \[if black\]
Time frame: 52 weeks
Population: Sofosbuvir/Ledipasvir FDC: 12 weeks treatment with Harvoni (10 total dosed on protocol)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 12 Weeks Treatment With Sofosbuvir/Ledipasvir (400mg/90mg) | Median Change in eGFR From Baseline to Timepoint Week 52 | -4 mL/min/1.73m^2 |
Secondary
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.
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 12 Weeks Treatment With Sofosbuvir/Ledipasvir (400mg/90mg) | Number of Participants With ≥25% Reduction in Proteinuria | 3 Participants |