Disorder of Transplanted Kidney, Hepatitis C, Renal Insufficiency, Chronic
Conditions
Brief summary
The purpose of this study is to determine whether patients treated for chronic hepatitis C (HCV) with zepatier (grazoprevir/elbasvir) prior to kidney transplant will have a stronger immune response compared to patients treated after kidney transplant. 25 patients with chronic kidney disease (CKD) and HCV will be treated with zepatier and 25 kidney transplant recipients with chronic kidney disease will be treated with zepatier. Blood markers of immune function will be monitored in both groups to determine their response to therapy.
Detailed description
The study will be a pilot, prospective, single-center, open-label, non-randomized, non-controlled, parallel clinical trial. 25 HCV genotype 1 infected patients post transplant will be enrolled in the study. Recruitment will be conducted through the renal transplant and nephrology outpatient clinics at the University of Maryland. The post-transplant cohort will include renal transplant recipients of both living donor and deceased donor organs infected with HCV prior to their transplantation with GFRs \<50 with active HCV viremia. These patients will be recruited from the University of Maryland's multidisciplinary transplant nephrology clinic or infectious disease clinic. Screening All patients will be screened at the Institute of Human Virology (IHV) Clinical Research Unit. At this visit, all patients will have screening labs drawn and a history and physical examination performed. Additional requirements will be genotype testing prior to enrollment, but after transplant and disease staging within 12 months of enrollment by liver biopsy, elastography, or biochemical testing. For those who do not have a genotype or disease staging within the specified time frame, genotyping and elastography will be repeated as part of the study screening work up. Eligibility will be determined based upon these results within 6 weeks of starting the study drugs. Given the reduced efficacy of this regimen in patients with genotype 1a with the presence of baseline NS5A resistance-associated variants (RAVs), the investigators will screen patients for RAVs in patients with HCV genotype 1a at the time of enrollment. Any patient with genotype 1a HCV found to have NS5A RAVs will undergo 16 weeks of therapy according to current treatment guidelines. Starting therapy Study drugs will be administered starting on day 0 after a history and physical examination is performed and safety labs are checked. All patients will sign an informed consent as approved by our Institutional Review Board (IRB) prior to administration of study drugs. Study visits during treatment Patients will be followed every 4 weeks while they are receiving study drugs. HCV viral load (VL), safety labs and hepatic panel will be performed at each of these visits. Patients will also be advised about study adherence and monitored for adverse events. Safety and adverse event monitoring At each study visit, research nurses will inquire about adverse events that may or may not be related to study drugs. Any unfavorable medical occurrences will be recorded, whether or not considered related to the patient's participation in the research, temporally associated with the patient's participation in the research. Adverse events (AEs) classified as grade 3 or higher will be reported to the IRB and principal investigator. Any grade 3 or 4 AEs and all serious adverse events (SAEs) will be reviewed as they occur by the study team. Safety labs will also be drawn at these visits. Levels of immunosuppressive agents will also be determined at these visits as appropriate. The need for dose modification of the patient's immunosuppression in the time between visits will be recorded. End of treatment visit Patients will be seen 12 weeks after starting study drugs (or 16 weeks in the case of genotype 1a patients with baseline NS5A RAVs) for an end of study visit. HCV VL, safety labs and hepatic panel will be performed at this visit. Patients will also be counseled about study adherence and the investigators will inquire about adverse events. Post treatment follow up visits Patients will be followed every 4 weeks for 12 weeks after they complete treatment. HCV VL, safety labs and a hepatic panel will be performed at these visits.
Interventions
DRUGPost-transplant Grazoprevir and Elbasvir
Treatment will be started in the post-transplant patients on day 0 with the combination pill zepatier, containing grazoprevir 100mg/elbasvir 50mg by mouth once daily. The medications will be continued for a total of 12 weeks (16 weeks if resistance mutations, RAVs, are detected)
Sponsors
University of Maryland, Baltimore
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
* At least 18 years of age at the time of screening * Have stable renal function for one month (30 days) prior to enrollment * Have Chronic HCV infection prior to transplantation with documented HCV viremia ≥ 1,000 IU/ml at screening and either documented HCV Ab positivity or HCV viremia ≥ 1,000 IU/ml at least 6 months prior to enrollment. * Documented genotype 1 HCV infection prior to enrollment and after their transplant in the post-transplantation cohort * HCV disease staging within 12 months prior to enrollment by liver biopsy, transient elastography, or biochemical testing * Be able to give informed consent and comply with study guidelines * Women of childbearing age will be required to have a negative pregnancy test at enrollment and use birth control throughout the duration of treatment. Inclusion Criteria Specific to the Pre-transplant Arm Patients will either be: * On the transplant waiting list followed by the University of Maryland's nephrology clinic or the Baltimore VA's nephrology clinic * On chronic hemodialysis not yet on the transplant list and followed in the University's hemodialysis center or in the University's nephrology clinic * Have chronic kidney disease with GFR \<50 Inclusion Criteria Specific to the Post-transplant Arm • Patients will have undergone renal transplantation no greater than five years prior to enrollment and will be followed in our University's nephrology and infectious disease clinic. They will all have stable renal function at the time of enrollment.
Exclusion criteria
* Documented positive hepatitis B (HBV) surface antigen, and/or HBV DNA prior to enrollment * Any prior exposure to HCV protease inhibitor therapy * HIV co-infection if on a protease inhibitor based regimen * Increase in creatinine of 15% or greater within one month (30 days) of the screening visit * Evidence of hepatocellular carcinoma at the time of enrollment * Liver disease caused by an etiology other than HCV * F4 or decompensated cirrhotic patients * Child Pugh class B or C * AST or ALT \>350 within 6 months prior to enrollment * Albumin \< 3g/dL at the time of enrollment * Platelet count \< 75 at the time of enrollment * History of clinically significant allergy or adverse event with protease inhibitors * Evidence of the acquisition of HCV at the time of or after transplantation * Pregnant or breastfeeding women * Cyclosporine; St. John's Wort; Efavirenz; Phenytoin; Carbamazepine; Bosentan; HIV protease inhibitors; modafinil; ketoconazole; or rifampin use within 7 days of enrollment * Coadministration of more than 20 mg atorvastatin; 10 mg rosuvastatin; 20 mg of fluvastatin, lovastatin or simvastatin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SVR 12 | This will be measured at post-treatment week 12 (study week 24 or week 28 for those with resistance mutations) | Sustained virologic response (SVR) will be assessed by measuring the quantitative HCV viral load 12 weeks after completing treatment. This will be a measure of circulating HCV virus in participants off therapy, 12 weeks after finishing treatment, to determine the durability of the response to the treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in T Cell Immunophenotypes | This will be collected at day 0, week 4, and week 12 | The study will involve measuring the change in T cell immunophenotypes |
| Quantification of Antiviral Cytokines | This will be collected at day 0 and week 4 | The study will involve measuring interferon gamma and TNF alpha levels |
| Change in T Cell Response | This will be collected at day 0, week 4, and week 12 | The study will involve measuring the change in T cell response by analyzing the frequency of exhaustion markers PD-1 and activation markers ICOS, CD38, CD69 at day 0, week 4, and week 12. |
| Kidney Function | This will be measured at day 0, treatment week 2, treatment week 4, treatment week 8, treatment week 12, ( treatment week 16, if applicable), post-treatment week 4 (week 16/20), and post-treatment week 12 (week 24/28) | Clinical review using labs and the patient's chart will be performed for change in kidney graft function by change in eGFR or creatinine |
| Kidney Allograft Rejection | This will be measured at post-treatment week 12 | Clinical review using labs and the patient's chart will be performed for documented episodes of kidney rejection |
| Safety as Assessed by Adverse Event Monitoring, Including Routine Lab Work | This will be measured at day 0, weeks 2, 4, 8, 12 (and 16 if resistance mutations are present) | Safety will be assessed by adverse event monitoring, including routine lab work |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Post-transplant This arm will evaluate the treatment of patients with HCV and chronic kidney disease (GFR \<50) who have had a kidney transplant using grazoprevir and elbasvir.
Post-transplant Grazoprevir and Elbasvir: Treatment will be started in the post-transplant patients on day 0 with the combination pill zepatier, containing grazoprevir 100mg/elbasvir 50mg by mouth once daily. The medications will be continued for a total of 12 weeks (16 weeks if resistance mutations, RAVs, are detected) | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 1 |
Baseline characteristics
| Characteristic | Post-transplant |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants |
| Age, Continuous | 59.65 years STANDARD_DEVIATION 8.17 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Fibrosis Stage Fibrosis Stage 0-1 | 12 Participants |
| Fibrosis Stage Fibrosis Stage 2-3 | 9 Participants |
| HCV genotype post-transplant Genotype 1a | 14 Participants |
| HCV genotype post-transplant Genotype 1b | 7 Participants |
| HCV-positive donor | 19 Participants |
| Median baseline HCV RNA level | 6.24 Log international units/mL |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 19 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 | 2 Participants |
| Region of Enrollment United States | 21 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 16 Participants |
| Time from transplant | 117 days |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 21 |
| other Total, other adverse events | 21 / 21 |
| serious Total, serious adverse events | 6 / 21 |
Outcome results
Primary
SVR 12
Sustained virologic response (SVR) will be assessed by measuring the quantitative HCV viral load 12 weeks after completing treatment. This will be a measure of circulating HCV virus in participants off therapy, 12 weeks after finishing treatment, to determine the durability of the response to the treatment.
Time frame: This will be measured at post-treatment week 12 (study week 24 or week 28 for those with resistance mutations)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Post-transplant | SVR 12 | Number achieved SVR12 | 19 Participants |
| Post-transplant | SVR 12 | Number failed treatment | 1 Participants |
| Post-transplant | SVR 12 | Number missing SVR12 data | 1 Participants |
Secondary
Change in T Cell Immunophenotypes
The study will involve measuring the change in T cell immunophenotypes
Time frame: This will be collected at day 0, week 4, and week 12
Population: This study was amended to eliminate the comparator arm and focus on clinical outcomes including SVR12. No subjects were recruited in this arm, so no data was collected or is available.~The frequency of CD4+ and CD8+ effector memory, naïve, central memory and terminally differentiated effector memory cell populations were compared from day 0 to week 4 on treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Post-transplant | Change in T Cell Immunophenotypes | CD4+CCR7-CD45RO+ EM day 0 | 70.64 percentage of expressing cells | Standard Deviation 17.48 |
| Post-transplant | Change in T Cell Immunophenotypes | CD4+CCR7-CD45RO+ EM week 4 | 65.4 percentage of expressing cells | Standard Deviation 11.17 |
| Post-transplant | Change in T Cell Immunophenotypes | CD4+CCR7-CD45RO+ EM week 12 | 65.1 percentage of expressing cells | Standard Deviation 13.29 |
Secondary
Change in T Cell Response
The study will involve measuring the change in T cell response by analyzing the frequency of exhaustion markers PD-1 and activation markers ICOS, CD38, CD69 at day 0, week 4, and week 12.
Time frame: This will be collected at day 0, week 4, and week 12
Population: This study was amended to eliminate the comparator arm and focus on clinical outcomes including SVR12. No subjects were recruited in this arm, so no data was collected or is available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Post-transplant | Change in T Cell Response | PD-1 day 0 | 29.15 percentage of expressing cells | Standard Deviation 15.21 |
| Post-transplant | Change in T Cell Response | PD-1 week 4 | 21.83 percentage of expressing cells | Standard Deviation 14.52 |
| Post-transplant | Change in T Cell Response | PD-1 week 12 | 20.5 percentage of expressing cells | Standard Deviation 8.91 |
| Post-transplant | Change in T Cell Response | ICOS day 0 | 12.73 percentage of expressing cells | Standard Deviation 7.92 |
| Post-transplant | Change in T Cell Response | ICOS week 4 | 6.14 percentage of expressing cells | Standard Deviation 5.65 |
| Post-transplant | Change in T Cell Response | ICOS week 12 | 5.03 percentage of expressing cells | Standard Deviation 2.81 |
| Post-transplant | Change in T Cell Response | CD38 day 0 | 10.86 percentage of expressing cells | Standard Deviation 4.81 |
| Post-transplant | Change in T Cell Response | CD38 week 4 | 5.97 percentage of expressing cells | Standard Deviation 4.43 |
| Post-transplant | Change in T Cell Response | CD38 week 12 | 6.73 percentage of expressing cells | Standard Deviation 4.48 |
| Post-transplant | Change in T Cell Response | CD69 day 0 | 0.98 percentage of expressing cells | Standard Deviation 0.6 |
| Post-transplant | Change in T Cell Response | CD69 week 4 | 0.43 percentage of expressing cells | Standard Deviation 0.26 |
| Post-transplant | Change in T Cell Response | CD69 week 12 | 0.75 percentage of expressing cells | Standard Deviation 0.54 |
Secondary
Kidney Allograft Rejection
Clinical review using labs and the patient's chart will be performed for documented episodes of kidney rejection
Time frame: This will be measured at post-treatment week 12
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Post-transplant | Kidney Allograft Rejection | No rejection | 19 Participants |
| Post-transplant | Kidney Allograft Rejection | Borderline acute cellular rejection | 1 Participants |
| Post-transplant | Kidney Allograft Rejection | Mild antibody mediated rejection | 1 Participants |
Secondary
Kidney Function
Clinical review using labs and the patient's chart will be performed for change in kidney graft function by change in eGFR or creatinine
Time frame: This will be measured at day 0, treatment week 2, treatment week 4, treatment week 8, treatment week 12, ( treatment week 16, if applicable), post-treatment week 4 (week 16/20), and post-treatment week 12 (week 24/28)
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Post-transplant | Kidney Function | Increase in Cr >30% on treatment | yes | 5 Participants |
| Post-transplant | Kidney Function | Increase in Cr >30% on treatment | no | 16 Participants |
| Post-transplant | Kidney Function | Decrease eGFR >30% | yes | 4 Participants |
| Post-transplant | Kidney Function | Decrease eGFR >30% | no | 17 Participants |
Secondary
Quantification of Antiviral Cytokines
The study will involve measuring interferon gamma and TNF alpha levels
Time frame: This will be collected at day 0 and week 4
Population: This study was amended to eliminate the comparator arm and focus on clinical outcomes including SVR12. No subjects were recruited in this arm, so no data was collected or is available.~Analysis was done comparing IFN gamma and TNF alpha from day 0 to week 4.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Post-transplant | Quantification of Antiviral Cytokines | IFN gamma day 0 | 9.67 pg/mL | Standard Deviation 7.12 |
| Post-transplant | Quantification of Antiviral Cytokines | IFN gamma week 4 | 7.26 pg/mL | Standard Deviation 6.19 |
| Post-transplant | Quantification of Antiviral Cytokines | TNF alpha day 0 | 7.26 pg/mL | Standard Deviation 2.74 |
| Post-transplant | Quantification of Antiviral Cytokines | TNF alpha week 4 | 4.45 pg/mL | Standard Deviation 3.55 |
Secondary
Safety as Assessed by Adverse Event Monitoring, Including Routine Lab Work
Safety will be assessed by adverse event monitoring, including routine lab work
Time frame: This will be measured at day 0, weeks 2, 4, 8, 12 (and 16 if resistance mutations are present)
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Post-transplant | Safety as Assessed by Adverse Event Monitoring, Including Routine Lab Work | Any Adverse Event | Yes | 21 Participants |
| Post-transplant | Safety as Assessed by Adverse Event Monitoring, Including Routine Lab Work | Any Adverse Event | No | 0 Participants |
| Post-transplant | Safety as Assessed by Adverse Event Monitoring, Including Routine Lab Work | Any Serious Adverse Event | Yes | 6 Participants |
| Post-transplant | Safety as Assessed by Adverse Event Monitoring, Including Routine Lab Work | Any Serious Adverse Event | No | 15 Participants |
| Post-transplant | Safety as Assessed by Adverse Event Monitoring, Including Routine Lab Work | Decrease in eGFR >30% from baseline | Yes | 4 Participants |
| Post-transplant | Safety as Assessed by Adverse Event Monitoring, Including Routine Lab Work | Decrease in eGFR >30% from baseline | No | 17 Participants |
| Post-transplant | Safety as Assessed by Adverse Event Monitoring, Including Routine Lab Work | Elevated tacrolimus level while on treatment | Yes | 13 Participants |
| Post-transplant | Safety as Assessed by Adverse Event Monitoring, Including Routine Lab Work | Elevated tacrolimus level while on treatment | No | 8 Participants |