Primary objective:To show that concomitant use of telaprevir (1125 mg BID) does not lead to a relevant decrease (> 20%) in the paroxetine parameter AUC0-24h compared to paroxetine alone.Secondary objectives:To determine the ratio of the geometric…
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Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Viral infectious disorders
- Mood disorders and disturbances NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Geometric Mean Ratio (GMR) of the area under the curve (AUC) of paroxetine in
combination with telaprevir versus paroxetine alone.
Secondary outcome
Geometric Mean Ratio (GMR) of paroxetine Cmax en C24h of paroxetine in
combination with telaprevir versus paroxetine alone.
Adverse events of combined use of paroxetine 20mg QD with telaprevir-containing
HCV treatment.
HCV RNA response at week 4 of telaprevir-containing HCV treatment with
concomitant use of paroxetine.
Telaprevir pharmacokinetics (AUC0-12h, Cmax C12h) of telaprevir in combination
with paroxetine.
Background summary
HCV infected patients are often in need for an antidepressant. First,
depression is common in patients with HCV infection. Second, PEG-interferon
alfa causes depressive symptoms in a large proportion of patients. Inadequate
treatment of depression during HCV treatment has a negative effect on adherence
to HCV treatment, with suboptimal response as a potential result.
The introduction of Direct Acting Antivirals such as telaprevir has greatly
improved treatment outcome of HCV infected patients. Tela-previr, however,
causes some significant drug-drug interactions and hence co-administration of
other medications should preferably only be done based on clinical evidence
that such a combination is safe.
Telaprevir has been studied with one antidepressant, escitalopram: plasma
concentrations of the antidepressant were reduced by 35% and without dose
adjustment this may lead to inadequate treatment of depressive symptoms. Dose
titration of escitalopram may be needed but it may take several weeks before a
patient has reached a therapeutic dose.
There is a need for more data on telaprevir drug interactions with other
antidepressants. First, the data above show that a negative in-teraction occurs
with escitalopram and dose-titration of the antide-pressant may take too long
to prevent the (re-)occurrence of depres-sive symptoms. Second, not all
patients benefit from escitalopram and those with (prior) treatment failure on
escitalopram may require an alternative agent. Third, although escitalopram is
generally well-tolerated, side effects may occur and necessitate treatment
discon-tinuation. Finally, especially in the previous intravenous drug users on
methadone, escitalopram might not be the antidepressant of choice, since
escitalopram as well as methadone are drugs that can lead to QTc interval
prolongation and have a risk of Torsades de Pointes.
For a number of reasons, paroxetine may be a good candidate for use together
with telaprevir-containing HCV treatment. First, paroxetine has been shown to
prevent depressive symptoms in patients initiating HCV treatment with elevated
depressive symptoms at baseline. Sec-ond, paroxetine is an inhibitor of and is
metabolized by CYP2D6 while telaprevir is an inhibitor of and is metabolized by
CYP3A, and therefore no drug-drug interaction is expected. Third, paroxetine is
one of the most widely prescribed antidepressants with a well-established
efficacy and safety profile.
Study objective
Primary objective:
To show that concomitant use of telaprevir (1125 mg BID) does not lead to a
relevant decrease (> 20%) in the paroxetine parameter AUC0-24h compared to
paroxetine alone.
Secondary objectives:
To determine the ratio of the geometric means (medians) of the par-oxetine PK
parameters Cmax and C24h for the combination therapy of telaprevir (1125 mg
BID) and paroxetine (20 mg QD) versus paroxet-ine (20 mg QD) alone.
To determine the short-term safety of combined use of paroxetine 20mg QD with
telaprevir-containing HCV treatment.
To assess the short-term HCV RNA response of telaprevir-containing HCV
treatment (week 4 response) with concomitant use of paroxetine.
To assess telaprevir pharmacokinetics 1125 mg BID (AUC0-12h, Cmax, C12h) when
co-administered with paroxetine 20mg QD.
Study design
An Investigator-initiated open label two-period, one-sequence, non-randomized,
multi-centre, phase II study
Study burden and risks
The study will be performed in HCV infected patients who will be treated with
telaprevir containing HCV treatment. Patients are already on antidepressant
therapy with paroxetine or should have an indication for antidepressant therapy
(with paroxetine). We chose to conduct this study in this population because
these patients will be treated with telaprevir and paroxetine anyway and will
be exposed to these drugs in regular care.
Since no drug-drug interaction is expected between telaprevir and paroxetine we
think it is safe to perform this study in HCV infected patients on paroxetine.
No decreased concentrations of either paroxetine or telaprevir are expected and
therefore an adverse effect on antiviral or antidepressant therapy is unlikely
to occur.
The burden of participation in the trial is limited. We only perform a minimal
change in the standard treatment regimen, since included patients are already
on antidepressant therapy with paroxetine and are eligible for start of a
TVR-containing regimen for treatment of their HCV infection. To further limit
the burden, study visits are mostly planned in accordance with the regular
visiting scheme for HCV treatment. Two visits are specifically planned for this
study; two confinements for the duration of 9 hours each.
Patients may experience adverse events of paroxetine and telaprevir.
Telaprevir may cause skin reactions. Patients are being asked to contact their
physician immediately if they experience any skin reaction.
The needles used for blood sampling may cause sligth discomfort at the
injection site.
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
1. Subject is at least 18 and not older than 65 years of age at screening.;2. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.;3. Subject has a chronic HCV infection with genotype 1. ;4. Subject is eligible for telaprevir containing HCV treatment.;5. Subject is on a stable dose of 20 mg paroxetine QD for at least 4 weeks.
Exclusion criteria
1. Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.;2. Pregnant female (as confirmed by an HCG test performed less than 6 weeks before Day -1) or breast-feeding female. Female subjects of childbearing potential without adequate contracep-tion, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal) intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout.;3. Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion. ;4. Inability to understand the nature and extent of the trial and the procedures required.;5. Participation in a drug trial within 60 days prior to the first dose of telaprevir.;6. Use of relevant concomitant medication, as assessed by a hos-pital pharmacist (member of the study team). ;7. Hemoglobin < 12 g/dL (females) or < 13 g/dL (males) (7.4 respectively 8.0 mM). ;8. Poor- or ultrarapid metabolizer CYP2D6
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-005372-34-NL |
| CCMO | NL43778.091.13 |