Clinical trial NCT02505243: Evaluation of RIBAvirin Plasma COncentrations in Patients With Chronic Hepatitis C Infection Routinely Treated With Modern DAA Regimens
Official title: Evaluation of RIBAvirin Plasma COncentrations in Patients With Chronic Hepatitis C Infection Routinely Treated With Modern DAA Regimens
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: HCV Coinfection
Hepatitis C
Keywords: ribavirin
direct-acting antivirals
pharmacokinetics
therapeutic drug monitoring
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Erasmus Medical Center
name: University Medical Center Groningen
name: UMC Utrecht
name: Maastricht University Medical Center
First posted: 2015-07-22
Enrollment: 252
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: chronicHCV infected patients treated with direct acting antivirals (daclatasvir, simeprevir, sofosbuvir, paritaprevir, ombitasvir, dasabuvir, ledipasvir) and ribavirin.

Brief summary: The aim of this study is to evaluate RBV plasma concentrations when used in combination with newly developed DAA combinations. If possible, its correlations with SVR rates and incidence of anaemia will be assessed in HCV-patients.

Detailed description: Ribavirin (RBV) is a synthetic guanosine analogue that is used to treat patients infected with hepatitis C virus (HCV). For many years, RBV has been the cornerstone of the HCV treatment in combination with peg interferon (PEG-IFN). Since the development of direct-acting antivirals (DAA), PEG-IFN free treatment regimes became first choice of HCV treatment in the Netherlands. RBV still plays an important role in some of these regimens. The European Association for the Study of the liver (EASL) included RBV in PEG-IFN free regimens in combination with sofosbuvir, simeprevir and daclatasvir for HCV genotype (GT) 1, 3 and 4. Patients with predictors of poor response are candidates for DAA therapy combined with RBV, for instance prior null responders and/or patients with cirrhosis. For the treatment of genotype 2 (GT2) and 3 RBV is used in combination with sofosbuvir.

Chronic HCV infection is treated with combination therapy, therefore manufacturers developed combination tablets such as Gilead's Harvoni (ledipasvir + sofosbuvir) and Abbvie's 3D combination (paritaprevir, ombitasvir, dasabuvir and ritonavir). Possibly, RBV will be added to these regimes in the future when the patient is a prior null responder or suffering from cirrhosis.

As RBV is a guanine analogue it is not specific for HCV and some severe adverse effects are known. The most important adverse effect is haemolytic anaemia,which usually occurs during the first weeks of treatment (\>10% of the treated patients, depending on co-medication). Other adverse reactions that were frequently reported were: neutropenia, anorexia, depression/insomnia, headache, dizziness, dyspnea, and cough 5.

In dual (PEG-IFN + RBV) HCV therapy RBV concentrations were associated with efficacy and toxicity. Also in former studies in HCV-infected patients treated with telaprevir (TVR) or boceprevir (BOC) in combination with PEG-IFN, the plasma concentration of RBV was associated with Sustained Virologic Response (SVR) and anaemia (defined as Hb\<8,5 g/dL). We have tried to determine an optimal therapeutic range for RBV when combined with these DAAs. The plasma concentration of RBV at week 8 should be 2.2-5.3 mg/L in combination with TVR. 48% of the HCV patients in the cohort had these plasma concentrations of which 81% achieved SVR and 5.2% reported anaemia. In combination with BOC the plasma concentration should be 2.2-3.6 mg/L, 50% of patients had these concentrations. In this group 69% of patients achieved SVR and 46% anaemia. So, for these therapies, therapeutic ranges for RBV could be defined for the optimal SVR rates and the lowest incidence of anaemia 6, 7.

As TVR and BOC have now been replaced by novel DAAs, we would like to investigate this described relationship between RBV concentrations, SVR and anaemia also with the newer DAAs that were licensed in the last year (simeprevir and sofosbuvir) and that are going to be available in 2015 in The Netherlands (daclatasvir, Harvoni, Abbvie 3D combo).

The aim of this study is to evaluate RBV plasma concentrations when used in combination with newly developed DAA combinations. If possible, its correlations with SVR rates and incidence of anaemia will be assessed in HCV-patients.

Eligibility criteria: Inclusion Criteria:

* HCV-infected patients
* Patient must be treated with ribavirin. The dosage of ribavirin may vary, as the different centers have different protocols for RBV dosing.
* Patient must be treated with one or more DAAs (simeprevir, sofosbuvir, daclatasvir, ledipasvir, paritaprevir, ombitasvir, or dasabuvir).
* At least 18 years of age at start of treatment.

Exclusion Criteria:

* None

Primary outcomes:
measure: Ribavirin concentration
timeFrame: Ribavirin concentraition at week 8 of treatment
Secondary outcomes:
measure: Sustained virological response (SVR12)
timeFrame: Change from baseline virological resonse, 12 weeks after treatment.
measure: Hemoglobin concentrations
timeFrame: Change from baseline hemoglobin concentrationes, 8 weeks after treatment.
measure: Ribavirin concentration
timeFrame: Ribavirin concentraition at week 2 of treatment
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre
state: Gelderland
Study officials:
affiliation: Radboud University Medical Center
name: David Burder, PharmdD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Tilborg M, Lieveld FI, Smolders EJ, van Erpecum KJ, de Kanter CTMM, Maan R, van der Valk M, Arends JE, Dofferhoff ASM, Blokzijl H, Bijmolen M, Drenth JPH, de Knegt RJ, Burger DM; HepNed Study Group. Ribavirin steady-state plasma level is a predictor of sustained virological response in hepatitis C-infected patients treated with direct-acting antivirals. Aliment Pharmacol Ther. 2017 Nov;46(9):864-872. doi: 10.1111/apt.14288. Epub 2017 Sep 7.