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Pharmacogenetics Informed Tricyclic Antidepressant Dosing (PITA) (PITA)

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ClinicalTrials.gov Identifier: NCT03548675
Recruitment Status : Recruiting
First Posted : June 7, 2018
Last Update Posted : July 25, 2018
Sponsor:
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
Radboud University

Brief Summary:
Tricyclic Antidepressants (TCA's) are the cornerstone of treatment for patients with severe Major Depressive Disorder (sMDD). Current dosing is guided by repeated measurements of blood levels. Compared to patients with a normal metabolization function, for those with increased CYP450 enzyme activity it takes longer to reach a therapeutic drug level. The consequent delay of drug efficacy is associated with a prolonged treatment period, increased risk of suicidal behaviour and eventually lower remission rates. For those with reduced CYP450 activity higher rates of side effects are expected. An innovative TCA dosing strategy, taking the genetic variants of CYP2D6 and CYP2C19 into account may help to reduce the above mentioned problems. Up till now, the current guidelines for CYP450 pharmacogenetics based TCA dosing have not been systematically evaluated for effectiveness and cost-effectiveness in larger groups of patients. Such evaluation is necessary before broad implementation of these guidelines can be advocated. In the present study 200 patients with sMDD who are treated with nortriptyline, clomipramine or imipramine, with genotypes associated with deviant CYP450 metabolizer status are randomized over two strategies: dosing based both on CYP450-genotype and blood level measurements and dosing as usual (standard doses plus blood levels). A third arm of 100 patients with normal CYP450-activity serves as a reference group (standard dosing and blood levels). We hypothesize that for patients with genotypes reflecting deviant CYP450 enzyme activity, genotype informed dosing results in faster attainment of therapeutic drug levels, lower rates of side effects, earlier symptom relief and lower levels of health- and working related costs.

Condition or disease Intervention/treatment Phase
Depressive Disorder, Major Drug: TCA treatment Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This study is a randomized controlled clinical trial.
Masking: Single (Outcomes Assessor)
Masking Description: Prescribing physicians will be unblinded for the genotype and the resulting metabolization phenotype. Outcome assessments will be performed by blinded researchers and the patients themselves (self-assessments).
Primary Purpose: Treatment
Official Title: Pharmacogenetics to Improve Personalized Antidepressant Dosing in Patients With Severe Depression;a Randomized Controlled Trial Using Tricyclic Antidepressants
Actual Study Start Date : May 23, 2018
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antidepressants

Arm Intervention/treatment
Experimental: Genotype-guided TCA treatment
Genotype guided dosing of the TCAs in patients with a PM,IM or UM phenotype based on pharmacogenetic test.
Drug: TCA treatment
All patients fulfilling inclusion criteria will be genotyped for CYP2C19 and CYP2D6 genes. Based on the genetic test results patients will be classified into a metabolisation phenotype (UM, EM, IM or PM).

Active Comparator: Standard TCA treatment (PM,IM or UM)
Standard dosing of TCA in patients with a PM,IM or UM phenotype based on pharmacogenetic test
Drug: TCA treatment
All patients fulfilling inclusion criteria will be genotyped for CYP2C19 and CYP2D6 genes. Based on the genetic test results patients will be classified into a metabolisation phenotype (UM, EM, IM or PM).

Active Comparator: Standard TCA treatment (EM)
Standard dosing of TCA in patients with EM phenotype based on pharmacogenetic test
Drug: TCA treatment
All patients fulfilling inclusion criteria will be genotyped for CYP2C19 and CYP2D6 genes. Based on the genetic test results patients will be classified into a metabolisation phenotype (UM, EM, IM or PM).




Primary Outcome Measures :
  1. Time to TCA plasma concentration in the therapeutic range [ Time Frame: During the 7 weeks treatment phase ]
    Time to TCA plasma concentration in the therapeutic range


Secondary Outcome Measures :
  1. Reduction of depressive symptoms [ Time Frame: Difference between measurements at baseline and after 7 weeks of treatment ]
    HAM-D reduction

  2. Highest level of side effects [ Time Frame: During the 7 weeks treatment phase ]
    summary measure: FIBSER

  3. Economic Evaluation (Cost Effectiveness) [ Time Frame: 26 weeks after the start of treatment ]
    Utility based on EQ5D5L measurement



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients are in- and outpatients, having a primary diagnosis of severe major depressive disorder (SCID-I diagnosis in agreement with DSM-5 criteria and a Hamilton Rating Scale for Depression score ≥ 19 (HAM-D-17-item version), aged 18-65 years, who, according to their physician, are eligible for treatment with a TCA (Nortriptyline (NOR), Clomipramine (CLOMI) or Imipramine (IMI)). The choice of the specific TCA is at the discretion of the physician in attendance.

Exclusion Criteria:

  1. Psychotic depression
  2. Bipolar I or II disorder.
  3. Schizophrenia or other primary psychotic disorder.
  4. Drug or alcohol dependence in the past 3 months.
  5. Mental Retardation (IQ < 80).
  6. For women: pregnancy or possibility for pregnancy without adequate contraceptive measures.
  7. Breastfeeding.
  8. Serious medical illness affecting the CNS, including but not restricted to M Parkinson, SLE, brain tumour, CVA.
  9. Relevant medical illness as contra-indication for TCA use, such as recent myocardial infarction.
  10. Other drugs influencing the pharmacokinetics of the TCAs as based on a list of interacting drugs. In case of psychotropic co-medication only a benzodiazepine in a dose equivalent up to 4 mg lorazepam will be allowed.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03548675


Contacts
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Contact: Joost Janzing, MD PhD +31-(0)243613489 Joost.Janzing@radboudumc.nl
Contact: Marieke Coenen, PhD +31-(0)243617752 Marieke.Coenen@radboudumc.nl

Locations
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Netherlands
Radboudumc Dept of Psychiatry Recruiting
Nijmegen, Netherlands, 6500 HB
Contact: Joost Janzing, MD, PhD    0031243666495    Joost.janzing@radboudumc.nl   
Sponsors and Collaborators
Radboud University
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
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Principal Investigator: Joost Janzing, MD PhD Radboudumc dept of Psychiatry

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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT03548675     History of Changes
Other Study ID Numbers: 848016004
First Posted: June 7, 2018    Key Record Dates
Last Update Posted: July 25, 2018
Last Verified: April 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Radboud University:
Pharmacogenetics
Antidepressive Agents

Additional relevant MeSH terms:
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Depressive Disorder
Depression
Depressive Disorder, Major
Mood Disorders
Mental Disorders
Behavioral Symptoms
Antidepressive Agents
Antidepressive Agents, Tricyclic
Psychotropic Drugs