Ignite Creation Date:
2024-05-06 @ 8:59 AM
Last Modification Date:
2024-10-26 @ 12:08 PM
Study NCT ID:
NCT02874066
Status:
COMPLETED
Last Update Posted:
2019-07-19
First Post:
2016-08-17
Brief Title:
PrOD for Non-Cirrhotic Patients With HCV-1b Receiving Hemodialysis
Sponsor:
National Taiwan University Hospital
Organization:
National Taiwan University Hospital
Study Overview
Official Title:
ParitaprevirRitonavirOmbitasvir Plus Dasabuvir for Treatment-Naive and Treatment-Experienced Non-Cirrhotic Patients With Hepatitis C Virus Genotype 1b Receiving Hemodialysis
Status:
COMPLETED
Status Verified Date:
2019-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PIVOTAL
Brief 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 ombitasvirparitaprevirritonavir 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
Detailed 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 functionCompared to non-HCV infected hemodialysis patients HCV-infected patients have increased risks of liver-related morbidity and mortality10 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 μmolL to IFN for treatment of HCV-infected hemodialysis patients Generally the SVR rate and the premature discontinuation rate due to null-response severe anemia andor heart failure for combination therapy are 56 and 22 respectivelyBased on these small-scale studies low-dose ribavirin daily 200 mg was approved in August 2011 by the US Food and Drug Administration to treat HCV-infected hemodialysis patientsTwo recent well-conducted randomized control studies to compare the efficacy and safety of combination therapy with peginterferon alfa-2a 135 μgweek plus low-dose ribavirin RBV 200 mgday or monotherapy with peginterferon 135 μgweek 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 0001 for HCV GT-1 74 versus 44 p 0001 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 ombitasvirparitaprevirritonavir 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 ombitasvirparitaprevirritonavir 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 962 and 963 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 953 and 980 in treatment-naïve patents and 960 and 967 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 953 partial response 100 null response 95236 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 918 and 95 respectively TURQUOISE-II37 The SVR12 rates in HCV GT-1b cirrhotic patients were similar in those receiving 12 and 24 weeks of treatment 985 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 942 versus 886 particularly for prior non-responders to peginterferon plus RBV 929 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 withwithout RBV for 12 weeks37 The SVR12 rate of PrOD without RBV was similar to that of PrOD with RBV in HCV GT-1b patients 990 versus 995 However the SVR12 rate in HCV GT-1a patients receiving PrOD with RBV was marginally higher than those receiving PrOD without RBV 970 versus 902 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 966 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 withwithout 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 gdL 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 gdL respectively35-40 In addition the on-treatment ASTALT elevation of more than 5 times the upper limit of normal ULN were 06-17 and 05 in non-cirrhotic patients receiving PrOD with and without RBV and were 29 and 20 in compensated cirrhotic patients receiving PrOD with and without RBV respectively The on-treatment total bilirubin elevation of more than 3 times ULN were 24-57 and 05 in non-cirrhotic patients receiving PrOD with and without RBV 135 and 0 in compensated cirrhotic patients receiving PrOD with and without RBV respectively35-40 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 ombitasvirparitaprevirritonavir 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
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 μmolL to IFN for treatment of HCV-infected hemodialysis patients Generally the SVR rate and the premature discontinuation rate due to null-response severe anemia andor heart failure for combination therapy are 56 and 22 respectivelyBased on these small-scale studies low-dose ribavirin daily 200 mg was approved in August 2011 by the US Food and Drug Administration to treat HCV-infected hemodialysis patientsTwo recent well-conducted randomized control studies to compare the efficacy and safety of combination therapy with peginterferon alfa-2a 135 μgweek plus low-dose ribavirin RBV 200 mgday or monotherapy with peginterferon 135 μgweek 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 0001 for HCV GT-1 74 versus 44 p 0001 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 ombitasvirparitaprevirritonavir 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 ombitasvirparitaprevirritonavir 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 962 and 963 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 953 and 980 in treatment-naïve patents and 960 and 967 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 953 partial response 100 null response 95236 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 918 and 95 respectively TURQUOISE-II37 The SVR12 rates in HCV GT-1b cirrhotic patients were similar in those receiving 12 and 24 weeks of treatment 985 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 942 versus 886 particularly for prior non-responders to peginterferon plus RBV 929 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 withwithout RBV for 12 weeks37 The SVR12 rate of PrOD without RBV was similar to that of PrOD with RBV in HCV GT-1b patients 990 versus 995 However the SVR12 rate in HCV GT-1a patients receiving PrOD with RBV was marginally higher than those receiving PrOD without RBV 970 versus 902 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 966 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 withwithout 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 gdL 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 gdL respectively35-40 In addition the on-treatment ASTALT elevation of more than 5 times the upper limit of normal ULN were 06-17 and 05 in non-cirrhotic patients receiving PrOD with and without RBV and were 29 and 20 in compensated cirrhotic patients receiving PrOD with and without RBV respectively The on-treatment total bilirubin elevation of more than 3 times ULN were 24-57 and 05 in non-cirrhotic patients receiving PrOD with and without RBV 135 and 0 in compensated cirrhotic patients receiving PrOD with and without RBV respectively35-40 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 ombitasvirparitaprevirritonavir 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None