Cytochrome P450-2D6 Screening Among Elderly Using Antidepressants (CYSCE)

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by University of Groningen
Sponsor:
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
Prof. Dr. Bob Wilffert, University of Groningen
ClinicalTrials.gov Identifier:
NCT01778907
First received: January 22, 2013
Last updated: March 17, 2014
Last verified: March 2014
  Purpose

Depression is common among elderly with an estimated prevalence of 5%. Due to ageing the national burden will double in the coming decade. Antidepressants as TCAs and SSRIs are effective in reducing symptoms, especially in people with severe depression. To optimize treatment efficacy and reduce side effects, the Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association developed guidelines for dose-adaptation, for instance for antidepressants such as nortriptyline and venlafaxine based on their main relevant genotype (CYP2D6) accompanied by Therapeutic Drug Monitoring. Such personalized drug dosing based on pharmacogenetic information at the start of therapy can speed up the titration phase of antidepressants to establish an adequate maintenance dose. However, pharmacogenetic screening programs are expensive and evidence on effects and costs of such a program among elderly antidepressant starters from randomized controlled studies is lacking. The investigators will conduct a pragmatic randomized controlled trial to determine the effects and costs of pharmacogenetic screening information to optimize drug dosing in depressed elderly patients who start with nortriptyline or venlafaxine.

Objective: The primary objective is to determine the effects of pharmacogenetic screening for CYP2D6 on the time to reach adequate blood levels as an accepted proxy for adequate treatment. Secondary objectives include adverse drug reactions and cost-effectiveness

Study design: pragmatic randomized controlled intervention study


Condition Intervention Phase
Depression
Depressive Disorder
Poor Metabolizer Due to Cytochrome P450 CYP2D6 Variant
Intermediate Metabolizer Due to Cytochrome P450 CYP2D6 Variant
Ultrarapid Metabolizer Due to Cytochrome P450 CYP2D6 Variant
Other: Genotype information accompanied by a drug dosing advice
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Screening
Official Title: Effects and Cost-Effectiveness of Pharmacogenetic Screening Among Elderly Starters With Antidepressants: A Pragmatic Randomized Controlled Trial

Resource links provided by NLM:


Further study details as provided by University of Groningen:

Primary Outcome Measures:
  • Serum drug levels of nortriptyline or venlafaxine [ Time Frame: After 2, 4 and 6 weeks treatment started, after the 6th week sampling continues every 2 weeks untill adequate serum drug level is reached with an expected average of 8 weeks ] [ Designated as safety issue: No ]

    Serum drug levels will be assessed by 'dried blood spot' analysis, blood will be obtained by a fingerprick.

    Adequate serum drug levels is defined as: serum drug levels within the therapeutic window (for nortriptyline 50-150 µg/L, for venlafaxine 200-400 µg/L in combination with stable drug dosing for at least 3 weeks.



Secondary Outcome Measures:
  • Adverse drug events Questionnaire [ Time Frame: At start of treatment and from that moment on, every 2 weeks untill adequate drug serum levels are reached with an expected average of 8 weeks ] [ Designated as safety issue: No ]
    Adverse drug events will be assessed by a self-reported questionnaire (ASEC). Two different questionnaires will be used, one for the side-effects of venlafaxine and another one for nortriptyline. Both are based one the ASEC questionnaire.

  • Quality of life questionnaire [ Time Frame: After 2, 4 and 6 weeks treatment started and if adequate serum drug levels are not reached in 6 weeks, every 2 weeks, untill adequate serum drug levels are reached with an expected average of 8 weeks ] [ Designated as safety issue: No ]
    Quality of life will be assessed by the EQ5D questionnaire. This information will also be used for a cost-effectiveness analysis.

  • Productivity Questionnaire [ Time Frame: After 2, 4 and 6 weeks treatment started and if adequate serum drug levels are not reached in 6 weeks, every 2 weeks, untill adequate serum drug levels are reached with an expected average of 8 weeks ] [ Designated as safety issue: No ]
    Effects on productivity by means of the Short Form-Health and Labour Questionnaire, part Labour. This information will also be used for a cost-effectiveness analysis.

  • Self reported Severity of depression Questionnaire [ Time Frame: After 2, 4 and 6 weeks treatment started and if adequate serum drug levels are not reached in 6 weeks, every 2 weeks, untill adequate serum drug levels are reached with an expected average of 8 weeks ] [ Designated as safety issue: No ]
    Severity of depression by means of the QIDS-SR.

  • Drug use [ Time Frame: At inclusion, after 2, 4 and 6 weeks after inclusion and if adequate serum drug levels are not reached in 6 weeks, every 2 weeks, untill adequate serum drug level is reached with an expected average of 8 weeks ] [ Designated as safety issue: No ]
    Drug use, including exact dosing and duration of prescription will be assessed by self reported drug use by the patient. This information will also be used for a cost-effectiveness analysis.

  • Data on health care associated resource use [ Time Frame: After 2, 4 and 6 weeks treatment started and if adequate serum drug levels are not reached in 6 weeks, every 2 weeks, untill adequate serum drug levels are reached with an expected average of 8 weeks ] [ Designated as safety issue: No ]
    Data on health care associated resource use (e.g. visits to the specific specialists including diagnoses; drug use including exact dosing and durations of prescriptions; hospitalizations, inclusive exact intensities of care; and lab values if relevant). This information will also be used for a cost-effectiveness analysis.


Estimated Enrollment: 750
Study Start Date: February 2013
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Normal genotype- control (NG-C)
In the external control group, an advice for dose adaptation based on patients serum drug levels will be given to the physician according to current daily practice. Allocation to this arm is not based on randomization.
No Intervention: Deviating genotype -control (DG-C)
In the internal control group, an advice for dose adaptation based on patients serum drug levels will be given to the physician according to current daily practice
Experimental: Deviating genotype (DG-I)
In the intervention group, genotype information accompanied by a drug dosing advice will be given to the treating physician. Blood level of the drug will be communicated by a dedicated research team to the treating physician according to daily practice.
Other: Genotype information accompanied by a drug dosing advice
Dosing advices for deviating genotypes (Poor Metabolizer, Intermediate Metabolizer, Ultrarapid Metabolizer)based on the guidelines of the Royal Dutch Pharmacists Association (KNMP).

Detailed Description:

This study is a multicenter randomized controlled trial in which psychiatric elderly care centers participate in the Netherlands. Deviating genotypes are expected to be found in ~30% of the population, therefore the study consist out of two parts. First a basic study in which ~750 patients, starting with nortriptyline or venlafaxine will be genotyped to identify patients with deviating genotypes (Poor, Intermediate or Ultrarapid Metabolizers). Second in the main study 150 patients with a deviating genotype are randomly allocated to two study arms one with and one without information on the genotype. From the extensive metabolizers('normal'genotype) 75 patients are allocated to a third arm as an external control.

  Eligibility

Ages Eligible for Study:   60 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Major depression according to DSM-IV (296.2x, 296.3x) criteria for which the treating psychiatrist decided to start drug treatment with either nortriptyline or venlafaxine.
  • Competent to understand the informed consent procedure

Exclusion Criteria:

  • Use of clinically relevant CYP2D6 inhibitors
  • Use of clinically relevant CYP2D6 inducers
  • Use of other drugs that affect plasma levels as co-medication
  • Serious hepatic failure
  • Patients for which drug treatment with venlafaxine is started and a GFR < 30 ml/min.
  • Patients with the very rare genotype: Intermediate Metabolizer with duplications (IMDUP).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01778907

Contacts
Contact: Bob Wilffert, Prof. Dr 003150-3639166 b.wilffert@rug.nl
Contact: Lisette Berm, MSc 003150-3638709 e.j.j.berm@rug.nl

Locations
Netherlands
Jeroen Bosch Ziekenhuis Recruiting
's-Hertogenbosch, Netherlands, 5200ME
Principal Investigator: R van Marum, Dr.         
Reinier van Arkel groep Recruiting
's-Hertogenbosch, Netherlands, 5201DZ
Principal Investigator: L Breuning, Dr.         
GGz inGeest Recruiting
Amsterdam, Netherlands, 1070BB
Principal Investigator: M Stek, Prof. Dr.         
Parnassia Recruiting
Den Haag, Netherlands, 2552KS
Contact: R Kok, Dr         
Principal Investigator: R Kok, Dr.         
University Medical Centre Groningen Recruiting
Groningen, Netherlands
Principal Investigator: R Oude Voshaar, Prof. Dr.         
Lentis Recruiting
Groningen, Netherlands
Contact: M Boshuisen, Dr.         
Principal Investigator: Marjolein Boshuisen, Dr.         
GGZ-NHN Recruiting
Heiloo, Netherlands, 1851NG
Principal Investigator: T Dhondt, Dr.         
GGZ Friesland Recruiting
Leeuwarden, Netherlands
Contact: H.C.P. Venema, Dr.         
Principal Investigator: H.C.P. Venema, Dr.         
Sponsors and Collaborators
University of Groningen
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
Principal Investigator: Bob Wilffert, Prof. Dr. University of Groningen
Principal Investigator: Eelko Hak, Prof. Dr. University of Groningen
  More Information

No publications provided

Responsible Party: Prof. Dr. Bob Wilffert, University of Groningen
ClinicalTrials.gov Identifier: NCT01778907     History of Changes
Other Study ID Numbers: RUG11003
Study First Received: January 22, 2013
Last Updated: March 17, 2014
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by University of Groningen:
Pharmacogenetics
Depression
Depressive Disorder
Cytochrome P-450 CYP2D6
Antidepressive Agents, Tricyclic
Antidepressive Agents, Second-Generation
Poor Metabolizer Due to Cytochrome P450 CYP2D6 Variant
Intermediate Metabolizer Due to Cytochrome P450 CYP2D6 Variant
Ultrarapid Metabolizer Due to Cytochrome P450 CYP2D6 Variant
Multicenter studies

Additional relevant MeSH terms:
Depression
Depressive Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders
Antidepressive Agents
Antidepressive Agents, Tricyclic
Antidepressive Agents, Second-Generation
Psychotropic Drugs
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 22, 2014