Primary objective: To evaluate if adequate exposure to ribavirin can be achieved after a dose adjustment based on the AUC0-4h from a first dose of ribavirin.Secondary:• To evaluate how many patients need a dose adjustment to achieve adequate…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The exposure (AUC) to ribavirin.
Secondary outcome
Laboratory safety and side-effects
Background summary
Currently, the standard treatment for patients with chronic hepatitis C virus
(HCV) consists of peginterferon (PEG-IFN) in combination with ribavirin (RBV).
Sustained viral response (SVR), defined as undetectable HCV RNA 6 months after
treatment, is achieved in 50-80% of patients. Unfortunately, still 30-50% of
patients relapse or remain virological non-responders.
For a number of difficult to treat diseases, such as HIV, therapeutic drug
monitoring (TDM) has been introduced to optimize treatment response rates. TDM
is defined as tailoring medication doses to the individual patient based on
(repeated) measurements of (plasma) drug concentrations. Although some suggest
to monitor clinical signs and symptoms to maintain adequate SVR rates in
patients with chronic HCV, recent data have demonstrated the usefulness of TDM
of RBV to improve treatment response. Due to a large interpatient variability
in RBV plasma concentrations, the RBV dose is not a good predictor of a
sustained viral response (SVR), even though it is based on body weight, but
plasma concentrations early after start of treatment are. There is, however, no
consensus on the appropriate time of monitoring of RBV plasma concentrations as
it may take 4-8 weeks before RBV reaches steady-state. Furthermore, there is no
consensus yet on the target level and most appropriate pharmacokinetic
parameter (Cmax, Cmin, AUC) for RBV. Finally, there is no evidence based
information whether interventions such as dose adjustments or counseling for
nonadherence, are effective in improving RBV plasma concentrations and, thus,
SVR.
A recent study has illustrated the importance of adequate plasma RBV
concentrations achieved very early after the start of treatment. The exposure
to RBV after the first dose was predictive of SVR7. In this study, RBV plasma
concentrations were determined during the first dose interval of 12h through
intensive blood sampling. An abbreviated RBV area under the plasma
concentration vs. time curve (AUC) determined over 4 hours had a positive
predictive value (PPV) of 80% and a negative predictive value (NPV) of 79% for
predicting SVR. Patients with an AUC0-4h >= 1.755 mg.h/L had a significantly
better chance of achieving SVR than patients with an AUC0-4h under this
threshold. Given the importance of early adequate exposure to RBV and the
possibility to adjust this early in or even before the treatment period, makes
it an attractive and potentially highly effective TDM intervention.
We want to know if sufficient exposure to RBV can be achieved after a dose
adjustment which is based on an abbreviated AUC after a first dose of RBV.
Study objective
Primary objective:
To evaluate if adequate exposure to ribavirin can be achieved after a dose
adjustment based on the AUC0-4h from a first dose of ribavirin.
Secondary:
• To evaluate how many patients need a dose adjustment to achieve adequate
exposure to ribavirin
• To evaluate if there are subgroups of HCV infected patients who more often
need a dose adjustment to achieve sufficient exposure to ribavirin
• To evaluate the safety and tolerability of a dose adjustment of ribavirin in
(formerly) HCV infected patients
Study design
This is an open-label, prospective, phase-IIa trial in 40 (formerly) HCV
infected patients who have previously been treated with PEG-IFN and RBV.
After meeting the inclusion criteria and passing the exclusion criteria,
subjects will receive a dose of RBV based on body weight on Day 1
Blood samples will be taken to measure plasma concentrations of RBV and the
area under the concentration time curve will be calculated:
• If exposure to RBV is adequate (AUC0-4h >= 1.755 mg.h/L), there will not be a
dose adjustment on Day 29
• If exposure to RBV is not adequate (AUC0-4h < 1.755 mg.h/L), the RBV dose
will be adjusted on Day 29
On Day 29 subjects will receive another dose of RBV, adjusted or not. Again
blood samples will be taken to measure plasma concentrations of RBV and the
AUC0-4h will be calculated.
The total duration of the study will be 4 weeks.
Intervention
Two times a single dose of ribavirin will be given and blood will taken to
determine the ribavirin concentration and other biochemical parameters
Study burden and risks
Subjects will come to the hospital for screening and will be admitted for half
a day twice.
Subject will receive a single dose of ribavirin twice. Side effects of
ribavirin might occur, but the chance is small since it is a single dose. In
addition the subjects have been treated with ribavirin for at least for weeks
twice a day and they will receive two extra doses of ribavirin which is
negligible when compared to the number of doses they have received before, and
thus, no additional harm is expected.
Geert Grooteplein Zuid 10
6525 GA Nijmegen
NL
Geert Grooteplein Zuid 10
6525 GA Nijmegen
NL
Listed location countries
Age
Inclusion criteria
1. Subject is at least 18 years at screening.
2. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
3. Subject has been treated with RBV and PEG-IFN for a chronic HCV infection for at least 4 weeks
4. Female subject is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or female subject is of childbearing potential practicing adequate contraception, e.g. intrauterine device, hormonal contraceptives, all in combination with condom use by the sexual partner; double barrier method, vasectomized partner, or total abstinence.
They must agree to take precautions in order to prevent a pregnancy throughout the entire study and until four months after the end of this study.
5. Male subject is practicing one of the following methods of birth control during this study with RBV and for seven months after the end of the study: condoms, is vasectomized or total abstinence from sexual intercourse. Next to that, the female sexual partner should practice an adequate contraception method.
Exclusion criteria
1. Inability to understand the nature and extent of the trial and the procedures required.
2. Participation in a drug trial within 60 days prior to the first dose.
3. RBV use within 90 days prior to the first dose.
4. Pregnancy or a pregnant partner (unless subject agrees to use condoms)
5. Breastfeeding
6. Hemoglobinopathies (e.g. thalassemia, sickle-cell anaemia)
7. Serious adverse events with former treatment with RBV
8. A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months
9. A history of severe psychiatric condition, particularly severe depression, suicidal ideation or suicide attempt.
10. Hemoglobin (Hb) < 7.5 mmol/L (female) or < 8.0 mmol/L (male)
11. Creatinine clearance < 50 mL/min
12. CD4-count < 200 cells/mm3
13. Signs of progressive liver disease, such as
•Decompensated cirrhosis (Child-Pugh grade B or C), and/or
•Bilirubin > 35 µmol/L or albumin <38 g/L or PTT >4 sec or platelets < 90 x 109/L
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-020371-22-NL |
| CCMO | NL33793.091.10 |