Clinical trial NCT01841502: Interaction Between Paroxetine and Telaprevir
Official title: The ROLE of ParoXetine in Patients Taking Telaprevir-based Hepatitis C Therapy: Lack of a Drug-drug Interaction? (ROLEX)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Hepatitis C Infection
Depression
Keywords: telaprevir
paroxetine
interaction
pharmacokinetics
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Janssen, LP
First posted: 2013-04-26
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: Hepatitis C (HCV) infected patients are often in need for an antidepressant. The introduction of Direct Acting Antivirals such as telaprevir has greatly improved treatment outcome of HCV infected patients.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. There is a need for more data on telaprevir drug interactions with other antidepressants.

For a number of reasons, paroxetine may be a good candidate for use together with telaprevir-containing HCV treatment.

The interaction between paroxetine and telaprevir has not been studied before.

Detailed description: HCV infected patients are often in need for an antidepressant. 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. Telaprevir, 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 interaction occurs with escitalopram and dose-titration of the antidepressant may take too long to prevent the (re-)occurrence of depressive 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 discontinuation. 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. Second, 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.

Eligibility criteria: Inclusion Criteria:

* Subject is at least 18 and not older than 65 years at screening.
* Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
* Subject has a chronic HCV infection with genotype 1.
* Subject is eligible for telaprevir containing HCV treatment.
* Subject is on a stable dose of 20 mg paroxetine once daily for at least 4 weeks.

Exclusion Criteria:

* Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
* Pregnant female (as confirmed by a human chorionic gonadotropin (HCG) test performed less than 6 weeks before Day -1) or breast-feeding female. Female subjects of childbearing potential without adequate contraception, 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.
* Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
* Inability to understand the nature and extent of the trial and the procedures required.
* Participation in a drug trial within 60 days prior to the first dose of telaprevir.
* Use of relevant concomitant medication, as assessed by a hospital pharmacist (member of the study team).
* Hemoglobin \< 12 g/dL (females) or \< 13 g/dL (males) (7.4 respectively 8.0 mM).
* Poor- or ultrarapid metabolizer CYP2D6 (based on genetic testing)

Primary outcomes:
measure: paroxetine area under the curve (AUC)
timeFrame: day -1 and day 14
Secondary outcomes:
measure: paroxetine Cmax and C24
timeFrame: Day -1 and Day 14
measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
timeFrame: Day -1 to Day 28
measure: short term HCV RNA response
timeFrame: week 4
measure: telaprevir area under the curve (AUC)
timeFrame: Day 14
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Academic Medical Centre Amsterdam
city: Amsterdam
country: Netherlands
facility: GGD Amsterdam
city: Delft
country: Netherlands
facility: Reinier de Graaf Groep
city: Groningen
country: Netherlands
facility: University Medical Centre Groningen
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
city: Rotterdam
country: Netherlands
facility: Maasstadziekenhuis
city: Utrecht
country: Netherlands
facility: University Medical Centre Utrecht
Study officials:
affiliation: Radboud University Medical Center
name: David Burger, PharmD, PhD
role: PRINCIPAL_INVESTIGATOR
References: