<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02256943</url>
  </required_header>
  <id_info>
    <org_study_id>133/12</org_study_id>
    <nct_id>NCT02256943</nct_id>
  </id_info>
  <brief_title>Genetic Determinants of Amitriptyline Efficiency for Pain Treatment</brief_title>
  <official_title>Effects of Amitriptyline on Central Pain Processing in Healthy Volunteers Depending on CYP Pharmacogenetics</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Insel Gruppe AG, University Hospital Bern</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Washington</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ludwig-Maximilians - University of Munich</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Aalborg University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Insel Gruppe AG, University Hospital Bern</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Low dose tricyclic antidepressant drugs are routinely administered co-analgesics in pain&#xD;
      medicine. Amitriptyline is largely considered as a gold standard. Amitriptyline underlies&#xD;
      cytochrome CYP2D6 and CYP2D19 metabolism. CYP2D6 is highly polymorphic; numerous genetic&#xD;
      variants result in 4 major classes characterizing enzymatic activity: poor metabolizers,&#xD;
      intermediate metabolizers, extensive metabolizers and ultrarapid metabolizers. It is not&#xD;
      known to which extent metabolizer classes determine pain outcomes or side-effects. As only&#xD;
      one in three pain patients is considered to be a responder to amitriptyline's co-analgesic&#xD;
      effect, prediction of treatment efficacy with a fast and easy to perform bedside test may&#xD;
      contribute to the patients quality of life. The aim of this study is to determine the&#xD;
      influence of cytochrome variants on experimental pain, drug related side-effects and finally&#xD;
      identification of active metabolites.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background&#xD;
&#xD;
      Pain is defined as an ongoing unpleasant sensory experience, which can be classified&#xD;
      according to three major, although overlapping, etiologies: nociceptive, inflammatory and&#xD;
      neuropathic pain.&#xD;
&#xD;
      Antidepressants are widely used as co-analgesics in the management of chronic pain. An&#xD;
      overview of different substances and their relation to their mechanism of action is presented&#xD;
      in the review of Dharmashaktu et al. Low-dose tricyclic antidepressants are well established&#xD;
      in the treatment of neuropathic pain. Amitriptyline and imipramine are two widely used&#xD;
      substances of this group. The hypoalgesic effect of amitriptyline is mainly mediated by&#xD;
      inhibiting serotoninergic and noradrenergic reuptake. When administered at night time,&#xD;
      amitriptyline's sedating effect enhances sleep quality, considered as an important&#xD;
      improvement in quality of life in chronic pain patients.&#xD;
&#xD;
      Tricyclic antidepressants undergo biotransformation in the liver with CYP2D6 catalyzing&#xD;
      hydroxylation, whereas CYP2C19 mediates demethylation of the parent drug. The demethylated&#xD;
      metabolites are partially tricyclic drugs by themselves, such as nortriptyline and&#xD;
      desipramine, which are demethyl-metabolites of amitriptyline and imipramine. It is unknown&#xD;
      whether the analgesic effect of amitriptyline is mediated through its precursor or the&#xD;
      metabolites.&#xD;
&#xD;
      The CYP2D6 gene is highly polymorphic and the numerous genetic variants result in 4 major&#xD;
      metabolizer classes characterizing enzyme activity: poor metabolizers (PM) with no enzyme&#xD;
      activity, intermediate metabolizers (IM) with reduced enzyme activity, (EM) extensive&#xD;
      metabolizers carrying two functionally active alleles and ultrarapid metabolizers (UM)&#xD;
      carrying a gene duplication or multi-duplication resulting in increased enzyme activity.&#xD;
&#xD;
      CYP2D6 PMs have higher plasma concentrations of the parent drug than EMs and are, therefore,&#xD;
      more likely to experience dose-dependent adverse drug reactions. In 50 psychiatric patients&#xD;
      receiving amitriptyline 150 mg/d, carriers of two functional CYP2D6 alleles (EMs) had a&#xD;
      significantly lower risk of side effects than IM (12.1% vs. 76.5%). The lowest risk was&#xD;
      observed for carriers of two functional CYP2D6 alleles combined with only one functional&#xD;
      CYP2C19 allele. The combination of normal (fast) CYP2C19 and slightly diminished CYP2D6&#xD;
      function leads to high concentrations of toxic intermediate metabolites and an increase of&#xD;
      adverse events. On the other hand, CYP2D6 UMs may be at risk for sub-therapeutic&#xD;
      concentrations resulting in poor therapeutic response. Thus, genetically determined&#xD;
      differences in blood concentrations of antidepressants make dose adjustments advisable.&#xD;
      However, these findings and dose recommendations have only been evaluated for psychiatric&#xD;
      patients and no investigation on antidepressants as low-dosed co-analgesics are available up&#xD;
      to now.&#xD;
&#xD;
      Quantitative sensory tests (QST) have been intensively used for more than three decades to&#xD;
      explore the central processing of painful stimuli in patients and healthy volunteers. QST&#xD;
      were developed to assess the responses to sensory stimuli, providing psychophysical methods&#xD;
      for the assessment of the nociceptive system. In addition, large cohorts of healthy&#xD;
      volunteers have been investigated using QST measures to produce reference values.&#xD;
&#xD;
      QST measures are based on a multimodal and multi-tissue approach, combining different pain&#xD;
      modalities applied to different tissues in order to gather sufficient and discriminative&#xD;
      information about the human nociceptive system. QST will be our tool to characterize&#xD;
      analgesic efficacy of amitriptyline. QST offers the unique opportunity of experimentally&#xD;
      induced pain being quantitatively measured by psychophysical, behavioural and&#xD;
      neurophysiological responses.&#xD;
&#xD;
      Objective&#xD;
&#xD;
      We test the hypothesis that the extensive and ultrarapid CYP2D6 metabolizers are associated&#xD;
      with a higher analgesic effect of amitriptyline, compared to the poor and intermediate&#xD;
      metabolizers, as assessed by quantitative sensory tests. Plasma concentrations of&#xD;
      amitriptyline and its metabolites will be analysed as co-variates for drug efficacy.&#xD;
&#xD;
      Two sub-studies, one peak-level, single-dose administration and one steady-state, repeated&#xD;
      dose administration, are needed to assess the pharmacokinetics of amitriptyline and its&#xD;
      active metabolites.&#xD;
&#xD;
      Statistics are provided by José A. Biurrun Manresa.&#xD;
&#xD;
      Methods&#xD;
&#xD;
      Two consecutive randomized placebo-controlled two-way crossover sub-studies on amitriptyline&#xD;
      will be conducted in consenting, healthy, male volunteers. Both sub-studies have the same&#xD;
      aim: to determine the association between CYP2D6 genotype, drug response measured by QST and&#xD;
      plasma concentrations of amitriptyline and its metabolites. The first sub-study will be&#xD;
      conducted with a single high dose of amitriptyline (100 mg). The second sub-study will be&#xD;
      conducted with repeated low doses of amitriptyline (25 mg) once a day for 10 days.&#xD;
&#xD;
      In both sub-studies the same experimental procedures and statistical analyses will be&#xD;
      performed. The only difference between the sub-studies is the dose of amitriptyline and the&#xD;
      duration of drug intake.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2014</start_date>
  <completion_date type="Actual">January 2019</completion_date>
  <primary_completion_date type="Actual">May 2018</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Nociceptive withdrawal reflex</measure>
    <time_frame>During measurement, expected to be ca. 2-3 minutes</time_frame>
    <description>Measure of involuntary electromyographic amplitude</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacogenetic information on CYP2D6 metabolism</measure>
    <time_frame>At baseline, i.e. on day 1</time_frame>
    <description>Laboratory measurement (genotyping)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in plasmatic metabolite level</measure>
    <time_frame>Throughout study duration, expected to be ca. 20 days</time_frame>
    <description>Metabolite level in plasma</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">48</enrollment>
  <condition>Chronic Pain</condition>
  <arm_group>
    <arm_group_label>Amitriptyline first, Placebo second</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Amitriptyline first, Placebo second</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo first, Amitriptyline second</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Placebo first, Amitriptyline second</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Amitriptyline</intervention_name>
    <description>100 mg single dose</description>
    <arm_group_label>Amitriptyline first, Placebo second</arm_group_label>
    <arm_group_label>Placebo first, Amitriptyline second</arm_group_label>
    <other_name>Tryptizol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tolterodine</intervention_name>
    <description>Placebo 1 mg single dose</description>
    <arm_group_label>Amitriptyline first, Placebo second</arm_group_label>
    <arm_group_label>Placebo first, Amitriptyline second</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy&#xD;
&#xD;
          -  Male&#xD;
&#xD;
          -  &gt;7 Metabolic Equivalents&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          -  Chronic pain syndrome&#xD;
&#xD;
          -  Drug abuse&#xD;
&#xD;
          -  Alcohol abuse&#xD;
&#xD;
          -  Suspicion of neurologic dysfunction at tested sites&#xD;
&#xD;
          -  Ongoing treatment with antidepressants&#xD;
&#xD;
          -  Ongoing treatment with analgesics&#xD;
&#xD;
          -  Pretreatment with any CYP3A inducers or inhibitors&#xD;
&#xD;
          -  Known allergy to tested drugs&#xD;
&#xD;
          -  Elevated eye pressure&#xD;
&#xD;
          -  Obstructive uropathy&#xD;
&#xD;
          -  Heart disease&#xD;
&#xD;
          -  Pulmonary disease&#xD;
&#xD;
          -  Neurological disease&#xD;
&#xD;
          -  Psychiatric illness&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ulrike Stamer, Professor</last_name>
    <role>Study Chair</role>
    <affiliation>Bern University Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Pascal H Vuilleumier, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Bern University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dep. of Anesthesiology, Bern University Hospital</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <reference>
    <citation>Dharmshaktu P, Tayal V, Kalra BS. Efficacy of antidepressants as analgesics: a review. J Clin Pharmacol. 2012 Jan;52(1):6-17. doi: 10.1177/0091270010394852. Epub 2011 Mar 17.</citation>
    <PMID>21415285</PMID>
  </reference>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>September 29, 2014</study_first_submitted>
  <study_first_submitted_qc>October 1, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 6, 2014</study_first_posted>
  <last_update_submitted>January 23, 2019</last_update_submitted>
  <last_update_submitted_qc>January 23, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 24, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pharmacogenetics of Amitriptyline</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chronic Pain</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Amitriptyline</mesh_term>
    <mesh_term>Tolterodine Tartrate</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02256943
org study id: 133/12
nct id: NCT02256943
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
Low dose tricyclic antidepressant drugs are routinely administered co-analgesics in pain
      medicine. Amitriptyline is largely considered as a gold standard. Amitriptyline underlies
      cytochrome CYP2D6 and CYP2D19 metabolism. CYP2D6 is highly polymorphic; numerous genetic
      variants result in 4 major classes characterizing enzymatic activity: poor metabolizers,
      intermediate metabolizers, extensive metabolizers and ultrarapid metabolizers. It is not
      known to which extent metabolizer classes determine pain outcomes or side-effects. As only
      one in three pain patients is considered to be a responder to amitriptyline's co-analgesic
      effect, prediction of treatment efficacy with a fast and easy to perform bedside test may
      contribute to the patients quality of life. The aim of this study is to determine the
      influence of cytochrome variants on experimental pain, drug related side-effects and finally
      identification of active metabolites.
Background

      Pain is defined as an ongoing unpleasant sensory experience, which can be classified
      according to three major, although overlapping, etiologies: nociceptive, inflammatory and
      neuropathic pain.

      Antidepressants are widely used as co-analgesics in the management of chronic pain. An
      overview of different substances and their relation to their mechanism of action is presented
      in the review of Dharmashaktu et al. Low-dose tricyclic antidepressants are well established
      in the treatment of neuropathic pain. Amitriptyline and imipramine are two widely used
      substances of this group. The hypoalgesic effect of amitriptyline is mainly mediated by
      inhibiting serotoninergic and noradrenergic reuptake. When administered at night time,
      amitriptyline's sedating effect enhances sleep quality, considered as an important
      improvement in quality of life in chronic pain patients.

      Tricyclic antidepressants undergo biotransformation in the liver with CYP2D6 catalyzing
      hydroxylation, whereas CYP2C19 mediates demethylation of the parent drug. The demethylated
      metabolites are partially tricyclic drugs by themselves, such as nortriptyline and
      desipramine, which are demethyl-metabolites of amitriptyline and imipramine. It is unknown
      whether the analgesic effect of amitriptyline is mediated through its precursor or the
      metabolites.

      The CYP2D6 gene is highly polymorphic and the numerous genetic variants result in 4 major
      metabolizer classes characterizing enzyme activity: poor metabolizers (PM) with no enzyme
      activity, intermediate metabolizers (IM) with reduced enzyme activity, (EM) extensive
      metabolizers carrying two functionally active alleles and ultrarapid metabolizers (UM)
      carrying a gene duplication or multi-duplication resulting in increased enzyme activity.

      CYP2D6 PMs have higher plasma concentrations of the parent drug than EMs and are, therefore,
      more likely to experience dose-dependent adverse drug reactions. In 50 psychiatric patients
      receiving amitriptyline 150 mg/d, carriers of two functional CYP2D6 alleles (EMs) had a
      significantly lower risk of side effects than IM (12.1% vs. 76.5%). The lowest risk was
      observed for carriers of two functional CYP2D6 alleles combined with only one functional
      CYP2C19 allele. The combination of normal (fast) CYP2C19 and slightly diminished CYP2D6
      function leads to high concentrations of toxic intermediate metabolites and an increase of
      adverse events. On the other hand, CYP2D6 UMs may be at risk for sub-therapeutic
      concentrations resulting in poor therapeutic response. Thus, genetically determined
      differences in blood concentrations of antidepressants make dose adjustments advisable.
      However, these findings and dose recommendations have only been evaluated for psychiatric
      patients and no investigation on antidepressants as low-dosed co-analgesics are available up
      to now.

      Quantitative sensory tests (QST) have been intensively used for more than three decades to
      explore the central processing of painful stimuli in patients and healthy volunteers. QST
      were developed to assess the responses to sensory stimuli, providing psychophysical methods
      for the assessment of the nociceptive system. In addition, large cohorts of healthy
      volunteers have been investigated using QST measures to produce reference values.

      QST measures are based on a multimodal and multi-tissue approach, combining different pain
      modalities applied to different tissues in order to gather sufficient and discriminative
      information about the human nociceptive system. QST will be our tool to characterize
      analgesic efficacy of amitriptyline. QST offers the unique opportunity of experimentally
      induced pain being quantitatively measured by psychophysical, behavioural and
      neurophysiological responses.

      Objective

      We test the hypothesis that the extensive and ultrarapid CYP2D6 metabolizers are associated
      with a higher analgesic effect of amitriptyline, compared to the poor and intermediate
      metabolizers, as assessed by quantitative sensory tests. Plasma concentrations of
      amitriptyline and its metabolites will be analysed as co-variates for drug efficacy.

      Two sub-studies, one peak-level, single-dose administration and one steady-state, repeated
      dose administration, are needed to assess the pharmacokinetics of amitriptyline and its
      active metabolites.

      Statistics are provided by José A. Biurrun Manresa.

      Methods

      Two consecutive randomized placebo-controlled two-way crossover sub-studies on amitriptyline
      will be conducted in consenting, healthy, male volunteers. Both sub-studies have the same
      aim: to determine the association between CYP2D6 genotype, drug response measured by QST and
      plasma concentrations of amitriptyline and its metabolites. The first sub-study will be
      conducted with a single high dose of amitriptyline (100 mg). The second sub-study will be
      conducted with repeated low doses of amitriptyline (25 mg) once a day for 10 days.

      In both sub-studies the same experimental procedures and statistical analyses will be
      performed. The only difference between the sub-studies is the dose of amitriptyline and the
      duration of drug intake.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Nociceptive withdrawal reflex
time frame: During measurement, expected to be ca. 2-3 minutes
description: Measure of involuntary electromyographic amplitude
measure: Pharmacogenetic information on CYP2D6 metabolism
time frame: At baseline, i.e. on day 1
description: Laboratory measurement (genotyping)
measure: Changes in plasmatic metabolite level
time frame: Throughout study duration, expected to be ca. 20 days
description: Metabolite level in plasma
arm group label: Amitriptyline first, Placebo second
arm group type: Active Comparator
description: Amitriptyline first, Placebo second
arm group label: Placebo first, Amitriptyline second
arm group type: Active Comparator
description: Placebo first, Amitriptyline second
intervention type: Drug
intervention name: Amitriptyline
description: 100 mg single dose
arm group label: Amitriptyline first, Placebo second
arm group label: Placebo first, Amitriptyline second
other name: Tryptizol
intervention type: Drug
intervention name: Tolterodine
description: Placebo 1 mg single dose
arm group label: Amitriptyline first, Placebo second
arm group label: Placebo first, Amitriptyline second
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Ulrike Stamer, Professor
role: Study Chair
affiliation: Bern University Hospital
last name: Pascal H Vuilleumier, MD
role: Principal Investigator
affiliation: Bern University Hospital
facility: 
country: Switzerland
citation: Dharmshaktu P, Tayal V, Kalra BS. Efficacy of antidepressants as analgesics: a review. J Clin Pharmacol. 2012 Jan;52(1):6-17. doi: 10.1177/0091270010394852. Epub 2011 Mar 17.
PMID: 21415285
responsible party type: Sponsor
mesh term: Chronic Pain
mesh term: Amitriptyline
mesh term: Tolterodine Tartrate