Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02874066 |
| Other study ID # |
201606016MIPC |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
March 13, 2017 |
| Est. completion date |
December 25, 2018 |
Study information
| Verified date |
February 2019 |
| Source |
National Taiwan University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Hepatitis C virus (HCV) infection is common in patients receiving hemodialysis. The uptake of
antiviral therapy for these patients is limited in the era of interferon (IFN) plus ribavirin
(RBV), probably because the sustained virologic response (SVR) rates are low and the risk of
treatment-related adverse events (AEs) are high. In the era of IFN-free direct acting
antiviral agents (DAAs), several studies have indicated high rates of SVR and excellent
safety profiles to treat patients with severe renal impairment. With regard to
ombitasvir/paritaprevir/ritonavir plus dasabuvir (PrOD) treatment, a phase 2 study (RUBY-1)
study has shown 90% of SVR in treatment-naive HCV-1 patients with chronic kidney disease
(CKD) stage 4 or 5. Among the HCV-1b patients, who received PrOD for 12 weeks, all 7 patients
achieved SVR. Although the data confirmed the excellent safety and efficacy in HCV-1b
patients with severe renal impairment, the patient number was small and the data with regard
to treatment-experienced patients was lacking. Therefore, we aimed to evaluated the safety
and efficacy of ProD for 12 weeks in treatment-naive and treatment-experienced HCV-1b
patients receiving hemodialysis.
Description:
Overview Hepatitis C virus (HCV) infection remains a major co-morbidity in hemodialysis
patients. The incidence and prevalence rates of HCV infection in hemodialysis patients are
much higher than those in the general population, and are attributed to high rates of
nosocomial HCV transmission. With regard to HCV genotype distribution, HCV genotype 1 (GT-1)
infection is the most prevalent type of infection worldwide and the genotype distribution in
HCV-infected individuals receiving hemodialysis (HD) is similar to that observed in
HCV-infected individuals with normal renal function.Compared to non-HCV infected hemodialysis
patients, HCV-infected patients have increased risks of liver-related morbidity and
mortality.10 Although HCV-infected hemodialysis patients who receive renal transplantation
have survival advantages over those who remain on maintenance dialysis, these patients still
have poor patient and graft survival, as well as have poor responses to interferon
(IFN)-based therapy. In contrast, hemodialysis patients who eradicate HCV infection have
improved biochemical, virologic and histologic responses, whether on maintenance dialysis or
after renal transplantation.
Clinical experience of IFN-based Therapy Approximately one third of hemodialysis patients
with chronic HCV infection achieve sustained virological response (SVR) by conventional IFN
or peginterferon monotherapy. In addition 18-30% of patients receiving IFN-based monotherapy
prematurely discontinued treatment due to adverse events (AEs). Although the addition of
ribavirin to IFN further improves the SVR rate in HCV-infected patients with normal renal
function, ribavirin has been considered contraindicated to treat HCV-infected hemodialysis
patients because of concern for life-threatening hemolytic anemia. Recently, pilot studies
have indicated the feasibility of adding low-dose ribavirin (200 mg three times per week to
daily 400 mg, adjusted to achieve a target concentration of 10-15 μmol/L), to IFN for
treatment of HCV-infected hemodialysis patients. Generally, the SVR rate and the premature
discontinuation rate due to null-response, severe anemia, and/or heart failure for
combination therapy are 56% and 22%, respectively.Based on these small-scale studies,
low-dose ribavirin (daily 200 mg) was approved in August 2011 by the U.S. Food and Drug
Administration to treat HCV-infected hemodialysis patients.Two recent well-conducted
randomized control studies to compare the efficacy and safety of combination therapy with
peginterferon alfa-2a (135 μg/week) plus low-dose ribavirin (RBV) (200 mg/day) or monotherapy
with peginterferon (135 μg/week) for 48 and 24 weeks in treatment-naïve HCV GT-1 and GT-2
infected individuals receiving hemodialysis showed that the SVR rates of combination therapy
groups were greater than those of monotherapy groups (64% versus 34%, p < 0.001 for HCV GT-1;
74% versus 44%, p < 0.001 for HCV GT-2), respectively. Although the SVR rate of combination
therapy with peginterferon plus low-dose ribavirin is higher than that of peginterferon
monotherapy. About 70-75% of these patients experienced clinically significant anemia which
needed high dose of erythropoiesis stimulating agents (ESAs) to keep the hemoglobin level
within the safety range. Although telaprevir (TVR)-based triple therapy has been used to
treat 4 HCV-1 patients receiving hemodialysis who were not responsive to prior peginterferon
plus RBV with good efficacy, the added on-treatment adverse events (AEs) and the pill burden
precluded the widespread use of this agent.
Clinical experience of IFN-free therapy by ombitasvir/paritaprevir/ritonavir plus dasabuvir
in HCV GT-1 patients The recent introduction of IFN-free direct acting antiviral agents
(DAAs) has made a paradigm shift with regard to the medical treatment for HCV-infected
individuals, based on the excellent efficacy and safety in ordinary patients. Among the
various IFN-free DAA regimens, treatment with ombitasvir/paritaprevir/ritonavir plus
dasabuvir (PrOD) has been approved in 2014 to treat patients with chronic HCV GT-1 infection.
Treatment with PrOD plus weight-based ribavirin for 12 weeks achieved an SVR12 rate of 96.2%
and 96.3% in treatment-naïve and treatment-experienced non-cirrhotic HCV GT-1 patients,
respectively (SAPPHIRE-I and SAPPHIRE-II). Furthermore, the SVR12 rates in those with GT-1a
and GT-1b were 95.3% and 98.0% in treatment-naïve patents, and 96.0% and 96.7% in
treatment-experienced patients, respectively. Among treatment-experienced HCV-1 patients, the
SVR rates of PrOD plus RBV were comparable in those with various prior treatment responses by
peginterferon plus RBV (relapse: 95.3%; partial response: 100%, null response: 95.2%).36
Among treatment-naïve and treatment-experienced compensated cirrhotic HCV GT-1 patients,
treatment with PrOD plus RBV for 12 or 24 weeks achieved and SVR rate of 91.8% and 95.%,
respectively (TURQUOISE-II).37 The SVR12 rates in HCV GT-1b cirrhotic patients were similar
in those receiving 12 and 24 weeks of treatment (98.5% versus 100%); the SVR12 rate in HCV
GT-1a cirrhotic patients receiving 24 week of treatment was greater than those receiving 12
weeks of treatment (94.2% versus 88.6%), particularly for prior non-responders to
peginterferon plus RBV (92.9% versus 80%). The PEARL-III and PEARL-IV studies compared the
SVR12 rates in treatment-naïve non-cirrhotic HCV GT-1b and HCV GT-1a patients receiving PrOD
with/without RBV for 12 weeks.37 The SVR12 rate of PrOD without RBV was similar to that of
PrOD with RBV in HCV GT-1b patients (99.0% versus 99.5%). However, the SVR12 rate in HCV
GT-1a patients receiving PrOD with RBV was marginally higher than those receiving PrOD
without RBV (97.0% versus 90.2%). The PEARL-II study further confirmed that in
treatment-experienced non-cirrhotic HCV GT-1b patients, treatment with PrOD without RBV for
12 weeks had comparable SVR12 rate to PrOD with RBV therapy (100% versus 96.6%). In
TURQUOISE-III study, PrOD without RBV for 12 weeks achieved an SVR12 rate of 100% in
treatment-naïve and treatment-experienced compensated cirrhotic HCV GT-1b patients. With
regard to safety, PrOD with/without RBV showed excellent safety profiles with few patients
experiencing serious adverse events (SAEs) and prematurely treatment discontinuation. The
constitutional AEs in patients receiving PrOD based treatment showed were slightly higher
than those receiving placebo. Furthermore, most of these symptoms were mild in grades. About
5% of the non-cirrhotic patients and about 8% of the cirrhotic patients receiving PrOD plus
RBV had an on-treatment hemoglobin level of < 10 g/dL; and none of the non-cirrhotic patients
and about 2% of the compensated cirrhotic patients receiving PrOD had an on-treatment
hemoglobin level of < 10 g/dL, respectively.35-40 In addition, the on-treatment AST/ALT
elevation of more than 5 times the upper limit of normal (ULN) were 0.6%-1.7% and 0.5% in
non-cirrhotic patients receiving PrOD with and without RBV; and were 2.9% and 2.0% in
compensated cirrhotic patients receiving PrOD with and without RBV, respectively. The
on-treatment total bilirubin elevation of more than 3 times ULN were 2.4%-5.7% and 0.5% in
non-cirrhotic patients receiving PrOD with and without RBV; 13.5% and 0% in compensated
cirrhotic patients receiving PrOD with and without RBV, respectively.35-40 Based on the above
evidence, treatment with PrOD for 12 weeks is recommended for treatment-naïve and
treatment-experienced HCV GT-1b patients, regardless of cirrhosis or not. Treatment with PrOD
plus RBV for 12 weeks is recommended for HCV GT-1a patients, except for compensated cirrhotic
HCV GT-1a null responders to prior therapy where treatment with PrOD plus RBV for 24 weeks is
recommended.
Clinical experience of IFN-free therapy by ombitasvir/paritaprevir/ritonavir plus dasabuvir
in HCV GT-1 patients with severe renal impairment or end-stage renal disease (ESRD) The
pharmacokinetic (PK) study of ombitasvir, paritaprevir, ritonavir, and dasabuvir was
evaluated in 24 subjects with normal renal function, and with mild, moderate or severe renal
impairment (each arm 6 patients). Compared to subjects with normal renal function, the area
under the curves (AUCs) in subjects with mild renal impairment were comparable for
ombitasvir, 20% higher for paritaprevir and dasabuvir, and 42% higher for ritonavir; the AUCs
in subjects with moderate renal impairment were comparable for ombitasvir, 37% higher for
paritaprevir and dasabuvir, and 80% higher for ritonavir; the AUCs in subjects with severe
renal impairment were comparable for ombitasvir, 50% higher for paritaprevir and dasabuvir,
and 114% higher for ritonavir. All patients were well tolerated for PrOD treatment except for
mild AEs, including nausea, myalgia, and catheter-site erythema, encountered in 1 subject
with moderate renal impairment. Based on the PK study, the changes of the drug exposure were
not clinically relevant and the doses of PrOD do not require adjustment.
The phase 3b RUBY-I study evaluated the safety and efficacy of PrOD with RBV and PrOD without
RBV for 12 weeks in 13 and 7 HCV GT-1a and HCV GT-1b treatment-naïve non-cirrhotic patients
with severe renal impairment or ESRD. The interim safety analysis showed that no patients had
study drug discontinuation, no treatment-related serious adverse events (SAEs) and no
clinically significant changes in markers of liver or kidney function. With regard to
efficacy, 14 of the 20 patients completed 12 weeks of treatment and all of them achieved
end-of-treatment virologic response (EOTVR). Ten patients (8 in GT-1a and 2 in GT-1b)
completed post-treatment follow-up for 4 weeks and all achieved SVR4. Furthermore, 2 HCV
GT-1a patients completed post-treatment follow-up for 12 weeks and all achieved SVR12.
Rationale of the study design Although peginterferon monotherapy and combination therapy with
peginterferon plus low-dose RBV for 24-48 weeks have been evaluated in many studies, the
efficacy for the treatment regimens were only modest (SVR rate about 60%). In addition, the
on-treatment AEs and SAEs by IFN-based therapies were frequently encountered in HCV-infected
patients receiving hemodialysis. Of note was the pronounced on-treatment hemoglobin level
decrease in patients receiving combination therapy by peginterferon plus low-dose RBV,
necessitating significant RBV dose reduction and high-dose erythrocyte stimulating agent
(ESA) support.
By receiving IFN-free DAA therapies, HCV-infected patients have excellent SVR rates, low
on-treatment SAE and AE rates, shorter treatment duration, and low pill burdens. The PK study
of ombitasvir, paritaprevir, ritonavir and dasabuvir proves the excellent safety profiles and
dose adjustment are not needed for PrOD regimen in subjects with various degrees of renal
impairment. The interim analysis of RUBY-I study showed the excellent on-treatment and
off-therapy antiviral effects in HCV GT-1a and GT-1b infected patients receiving PrOD plus
low-dose RBV and PrOD, respectively. However, all the patients enrolled in the RUBY-I study
were treatment-naïve and were non-cirrhotic. Furthermore, only 7 patients in the RUBY-I study
were HCV GT-1b patients. Based on the excellent safety and efficacy profiles of PrOD
treatment for HCV GT-1b infected patients with normal renal function, we aim to evaluate the
safety and efficacy of PrOD for 12 weeks in treatment-naïve and treatment-experienced HCV
GT-1b non-cirrhotic patients receiving hemodialysis.
