Hepatitis C Clinical Trial
Official title:
A Prospective Cohort Study to Improve HCV Care Using Multidisciplinary Approach to the Treatment of Chronic Hepatitis C in Dialysis Patients: The MATCH-D Study
Hepatitis C virus (HCV) infects an estimated 185 million individuals worldwide and 3.4
million to 4.4 million people in the United States. Approximately 80% of acutely infected HCV
patients progress to chronic infection, 20% of whom develop cirrhosis within 25 years, with
25% of patients with cirrhosis developing hepatocellular carcinoma and/or decompensated liver
disease. Hepatitis C virus is the primary cause of liver transplantation in the United
States.
There are 6 known genotypes of HCV. The most common genotypes in the United States are
genotype 1 (subtypes 1a and 1b), 2, and 3, which together comprise 97% of all infections.
In chronic kidney disease (CKD) patients, the prevalence of HCV infection is higher than in
the general population. Patients with impaired kidney function have limited therapeutic
options. The US Food and Drug Administration (FDA) recently approved Elbasvir/Grazopevir for
treatment of genotype 1 and 4 infection in CKD patients including those on hemodialysis.
At our institution, the Multidisciplinary Approach to the Treatment of Chronic Hepatitis C
(MATCH) Initiative is a program which was first implemented to increase screening, diagnosis
and treatment of HCV by actively incorporating primary care providers (PCP) at every step of
the HCV care process. Following implementation of MATCH, early data indicates, marked
increase in screening high risk and baby-boomer cohorts, as well as safe and effective
treatment of HCV cases at the primary provider setting. The initiative proved that active
participation of PCPs in the care of HCV reduced the treatment lag by 71% compared to
traditional care of referring HCV cases to specialized care (Gastroenterology or Hepatology)
while keeping similar SVR. We intend to expand the program to improve quality of care for HCV
patients in dialysis center. We propose active involvement of dialysis clinical staff
including nephrologist, to increase HCV screening rate, promote timely diagnosis and
treatment of CHC in patient with end-stage renal disease.
This study is being conducted to evaluate real-world effectiveness of HCV DAA therapy in CHC
hemodialysis patients when the DAA-treatment is managed and monitored by the clinical staff
of hemodialysis center.
Primary objective: To determine sustained virologic response (SVR) rates attained with
open-label Zepatier administered through hemodialysis center under the supervision of a
nephrologist in chronic hepatitis C infected (CHC) patient currently on hemodialysis.
Secondary objective:
1. To estimate prevalence of HCV infection, severity of fibrosis (using non-invasive
measures), and HCV detection rate in patients with End stage renal disease on
hemodialysis.
2. To calculate the average treatment-lag time (time from HCV diagnosis to submission of
treatment approval).
This study is being conducted to evaluate real-world effectiveness of HCV DAA therapy in CHC
hemodialysis patients when the DAA-treatment is managed and monitored by the nephrologist of
hemodialysis center.
Hepatitis C virus (HCV) infects an estimated 185 million individuals worldwide (1) and 3.4
million to 4.4 million people in the United States.(2) Approximately 80% of acutely infected
HCV patients progress to chronic infection, 20% of whom develop cirrhosis within 25 years,
with 25% of patients with cirrhosis developing hepatocellular carcinoma and/or decompensated
liver disease.(3) Hepatitis C virus is the primary cause of liver transplantation in the
United States.(4) There are 6 known genotypes of HCV. The most common genotypes in the United
States are genotype 1 (subtypes 1a and 1b), 2, and 3, which together comprise 97% of all
infections.(5) Since the discovery of HCV in 1989 (6) strategies to cure the infection have
evolved dramatically. A cure is defined as a sustained virologic response (SVR) and consists
of undetectable levels of plasma HCV RNA 12 or 24 weeks after therapy completion.(7)
Treatment of HCV has evolved rapidly and has led to improved rates of SVR.
Although these highly effective therapies for hepatitis C virus (HCV) infection have
revolutionized treatment, only a few patients are able to receive treatment.(8) Barriers
arising at multiple levels, from diagnosis to specialist referral, that still need to be
overcome to move toward disease eradication.(9) In chronic kidney disease (CKD) patients, the
prevalence of HCV infection is higher than in the general population. Testing for HCV in
hemodialysis patients should be repeated every 6 months.(10) The national study on
dialysis-associated diseases was published in 2002 and represents the infection statistics
from dialysis center nationwide.(11) The overall estimated prevalence of HCV antibody in this
study was 7.8%.
In addition, patients with impaired kidney function have limited therapeutic options. The US
Food and Drug Administration (FDA) recently approved Elbasvir/Grazopevir for treatment of
genotype 1 and 4 infection in CKD patients including those on hemodialysis.
At our institution, the Multidisciplinary Approach to the Treatment of Chronic Hepatitis C
(MATCH) Initiative is a program which was first implemented to increase screening, diagnosis
and treatment of HCV by actively incorporating primary care providers (PCP) at every step of
the HCV care process. Following implementation of MATCH, early data indicates, marked
increase in screening high risk and baby-boomer cohorts, as well as safe and effective
treatment of HCV cases at the primary provider setting. The initiative proved that active
participation of PCPs in the care of HCV reduced the treatment lag by 71% compared to
traditional care of referring HCV cases to specialized care (Gastroenterology or Hepatology)
while keeping similar SVR. (13) We intend to expand the program to improve quality of care
for HCV patients in dialysis center. We propose active involvement of dialysis clinical staff
including nephrologist, to increase HCV screening rate, promote timely diagnosis and
treatment of CHC in patient with end-stage renal disease.
Rationale of the study- We will perform a phase IV study to prove real world effectiveness of
Zepatier in successful treatment of CHC in patients on chronic hemodialysis at hemodialysis
centers, when administered under the supervision of a nephrologist. The study will be
conducted in the selected collaborative hemodialysis centers.
Zepatier Open-label Zepatier (grazoprevir 100 mg and elbasvir 50 mg) will be administered in
this study.(14, 15) Zepatier is a fixed-dose combination tablet without ribavirin. GZR is an
HCV NS3/4a inhibitor while EBR is an HCV NS5A inhibitor. Both grazoprevir and elbasvir are
direct-acting antivirals, which together form an effective therapy for HCV and reduce the
likelihood and effects of long-term liver-related HCV complications.
Zepatier has been evaluated globally in multiple phase I, II, and III trials to treat HCV.
(14, 15) Randomized, placebo-controlled trials have been carried out, which led to FDA
approval for Zepatier as a treatment for genotype 1 and 4 HCV.
As of July 1, 2015, a diverse population of over 1000 HCV patients has been exposed to
Zepatier either as a single agent or in combination with ribavirin or sofosbuvir in phase
I/II/III studies. Zepatier has been generally well tolerated at doses of 50-100 mg GZR and 50
mg EBR orally once daily. It has been comparably effective across all subgroups it has been
tested in, including non-cirrhotic and/or treatment-naïve subjects. (14, 15) Headaches,
fatigue, and nausea represent the most common adverse drug reactions with Zepatier.3,4 Other
drug-related adverse events have included arthralgia, insomnia, diarrhea, dizziness, pyrexia,
and asthenia. (14, 15) Drug-related serious adverse events are uncommon, but include allergic
reactions, possible adverse interactions with other medications, or elevated liver enzymes.
In past Zepatier trials, the majority of the adverse events were reversible. These adverse
events are usually mild or moderate events.
The dosage in our study (100/50 mg daily) is a commonly attainable dose in clinical practice.
Zepatier has shown to be safe for subjects with chronic kidney disease or who are on
hemodialysis. Less than 1% of Zepatier is excreted renally. In Merck's C-SURFER, a phase 1
randomized, controlled Zepatier trial, subjects with advanced kidney disease tolerated the
drug well for the required 12 weeks without dose adjustments. (16) Zepatier trials have
demonstrated a 94-100% success rate achieving HCV RNA levels of <15 IU/ml after 12 weeks of
treatment (SVR-12) among genotype 1 HCV patients. (14, 15) This is a prospective cohort phase
IV study using multidisciplinary approach for the treatment of hepatitis C in hemodialysis
patients. Hemodialysis centers will be used to deliver all HCV related care.
The study will be conducted in the selected collaborative hemodialysis centers in
Philadelphia. In addition to the standard of care (SOC), all subjects with CHC will be
evaluated for HCV DAA therapy: review of clinical records, assessment of the degree of liver
fibrosis using FibroScan, baseline HCV virological tests, HIV and HBV screening, etc.
Baseline and follow-up laboratory tests and FibroScan imaging will be performed at the
Einstein lab or an alternative laboratory if requested by the patient. Baseline clinical
evaluation and follow up focused H/P will be done by the nephrologist at the dialysis unit..
The study coordinator is a MATCH-D navigator and is responsible for compiling supporting
documents for HCV DAA treatment request and fax it to a designated fax number (to mimic
faxing to the payers in real world scenario). Local specialty pharmacy pharmacist (also a
part of the MATCH-D group) will be responsible for providing hepatitis C treatment education
to approved patients, ensure delivery of DAA therapy and monitoring for any drug related
adverse events.
MATCH-D group will comprise of a study coordinator, study investigators, nephrologist,
specialty pharmacy pharmacist, and dialysis unit . The group will meet weekly to review cases
and provide recommendations on diagnosis, DAA selection and assist with HCV treatment This
study will be divided to 3 phases.
1. Training study team, dialysis center clinical staff (Quarterly refresher)
2. Identifying hepatitis C patient and evaluation for treatment
3. Treatment and follow up Phase 1: Training study team and dialysis center clinical staff
education All collaborative hemodialysis centers coordinator and the study team will be
educated for HCV screening, work-up, treatment and study protocol in the first month of
study. There will be refresher course every 3 months.
Phase 2: Identifying hepatitis C patient and evaluation for treatment
1. Patient Screening a. Every dialysis patient will be offered HCV screening every 6 months
as standard of care.
b. HCV Ab with reflex HCV viral load will be ordered.
2. Patient Identification
1. Patients will be assessed for positive HCV Ab and detectable viral load.
2. Nephrologist will notifythe patient with the results.
3. Nephrologist will have the patient complete and sign HIPAA form.
4. Nephrologist will email patient information to the study coordinator.
5. Study coordinator is expected to keep composite record (including the above
results) of all identified patients until enrollment. This record will be utilized
at the Multidisciplinary Meeting.
6. Informed consent will be obtained by the study coordinator.
7. Basic demographic information will be collected.
3. Patient evaluation for treatment
1. Complete blood work and FibroScan imaging will be conducted at Einstein lab or an
alternative laboratory if requested by the patient.
2. Study coordinator is expected to ensure patients have all testing completed.
3. Study coordinator will ensure all patients are tested for FibroScan imaging using
the portable FibroScan® 530 Compact system. .
This trial will enroll approximately 71 compensated cirrhotic and non-cirrhotic, Genotype 1
and 4, HCV patients who are currently on hemodialysis. Non-invasive test will be used to
determine the presence or absence of cirrhosis. All excluded CHC patients will receive
standard of care. Patients who have decompensated cirrhosis or hepatoma will be referred to
the hepatology clinic and receive care by the hepatologist.
Study visits There will be 4 study visits in our study. Subjects may be asked to come early
before dialysis session to have physical examination or Fibroscan.
Screening and Informed consent
During screening period, the following procedures and activities will be performed at
hemodialysis center after the informed consent is signed:
- Review medical history and physical examination
- Review medication list
- Review laboratory data Baseline study • First laboratory tests will be performed at the
Einstein lab or an alternative laboratory if requested by the patientand include: • CBC,
CMP, PT/INR • HCV PCR Viral load
- HCV PCR genotype
- HCV NS5A RAV testing
- HBV screening: HBsAg, HBcAb
- HIV 1 / 2 Ab screening
- FibroScan
- Women of childbearing potential will have a pregnancy test at screening visit.
Phase 3: Treatment and follow up 1. Treatment a. MATCH-D group will review and
discuss identified CHC patients and determine those appropriate for DAA therapy
through the dialysis center, and those who require referral to Liver Center based
on work-up (e.g. decompensated cirrhosis).
i. Patients appropriate for dialysis center treatment and agreeable to treatment
will be enrolled in study.
b. Meeting to occur weekly c. Study coordinator will notify the nephrologist, who
saw patient, by email of the meeting decision. Subsequently, the nephrologist
should notify patient of the decision and a) refer to hepatology if needed or b)
explain need for treatment.
d. Prescription along with pertinent information (e.g. lab results, fibrosis stage,
etc.) will be compiled and sent to local specialty pharmacy by the study
coordinator for all enrolled patients.
e. Specialty pharmacy will:
1. Provide education to patients about prescribed treatment.
2. Identify potential drug interactions and notify team.
3. Oversee delivery of medications. Provide refill reminders to patients or
dialysis center staff.
4. Monitor medication adherence.
5. Keep "database" that is accessible to study coordinator and MATCH-D study
group Specialty pharmacy will be the investigational pharmacy who is
expertised in HCV care.
Initiation treatment with Zepatier All subjects will be provided with a 28-day supply of the
study drug and instructed to begin treatment once all tests are done. The study coordinator
will call the patient to ensure treatment has begun for HCV with Zepatier.
As with any scientific protocol, safety will be considered before treating the patients. The
MATCH-D team will evaluate the patient's overall condition and make a judgment on whether
initiating treatment is safe.
Zepatier for 12 weeks or 16 weeks ± Ribavirin will be used to treat HCV genotype 1, 4 in our
patients and will be supplied by Merck & Co.Inc.
Statistical Methods The data will be collected using an Excel spreadsheet and analyzed with
Stata 14.0 (Statacorp., College Town, TX). Descriptive statistics will be used to summarize
the demographic characteristics. Screening rates, treatment rates, and treatment lag (time
from detection to treatment submission) will be calculated. Categorical variables will be
compared using chi square or fischer's exact test whereas continuous variables will be
compared using student's t-test. SVR rates will also be compared with historical controls. P
value of less than 0.05 will be considered statistically significant.
Power/Sample Size:
Power of 0.8 with a p-value of 0.05 were used a priori for sample size calculation. As was
shown in C-SURFER trial recently, SVR of 99% was attained in chronic kidney disease patients
including those on dialysis. Accepting a non-inferiority margin of 5% and similar expected
SVR in our cohort, the sample size was calculated to be 71 patients.
Potential Benefits The subjects will get clinical benefits as the HCV treatment can prevent
cirrhosis and hepatocellular carcinoma in the future. This study also has a potential to
speed up treatment evaluation and the subjects may get the treatment faster.
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