<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/NCT03249311</url>
  </required_header>
  <id_info>
    <org_study_id>REB2017004</org_study_id>
    <nct_id>NCT03249311</nct_id>
  </id_info>
  <brief_title>Levomilnacipran in Healthy Males</brief_title>
  <official_title>Effectiveness of the Norepinephrine and Serotonin Reuptake Inhibitor Levomilnacipran in Healthy Males</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Ottawa</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Allergan</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Ottawa</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Levomilnacipran is an antidepressant currently approved in Canada to treat Major Depressive&#xD;
      Disorder (MDD). Thirty-six healthy male participants will receive escalating doses of&#xD;
      levomilnacipran, duloxetine, or placebo every 7 days (+/- 1 day) throughout a 20 - 28 day&#xD;
      period. After each dose escalation study participants will be asked to come to the clinic to&#xD;
      conduct the necessary tests - these will include tyramine pressor tests as well as blood&#xD;
      draws. The results of this study will allow the investigators to determine the dose(s) of&#xD;
      levomilnacipran at which reuptake inhibition of norepinephrine and serotonin (chemicals&#xD;
      utilized by nerve cells to transmit information to other cells) is achieved.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Levomilnacipran (Fetzima) is the active enantiomer of milnacipran (Ixel, Savella) for&#xD;
      norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake. It has an approximate&#xD;
      eight-fold greater affinity for the human NE transporter than for the 5-HT transporter. This&#xD;
      signifies that the NE transporter may be engaged to a much greater degree than the 5-HT&#xD;
      transporter at various doses, especially at lower regimens. As such, levomilnacipran&#xD;
      represents the mirror antidepressant medication of venlafaxine and duloxetine since at their&#xD;
      minimal effective doses, these medications are selective inhibitors of 5-HT reuptake and it&#xD;
      is not until daily regimens are doubled or tripled that the NE transporter gets engaged.&#xD;
&#xD;
      Levomilnacipran is effective clinically in patients with major depressive disorder (MDD) at&#xD;
      doses ranging between 40 and 120 mg/day. Given this wide effective dose range, it appears&#xD;
      essential to determine the in vivo potency of levomilnacipran and the dose at which it starts&#xD;
      inhibiting 5-HT in relation to NE reuptake in humans.&#xD;
&#xD;
      The current investigators have studied the NE reuptake blocking properties of antidepressants&#xD;
      in both healthy volunteers and patients with depression using tyramine pressor tests. This&#xD;
      peripheral model of adrenergic function involves administration of repeated intravenous&#xD;
      injections of tyramine and measurement of transient increases in systolic blood pressure&#xD;
      (SBP) that occur after a tyramine load. This approach has led to dose-dependent SBP increases&#xD;
      that are reliably reproduced one week apart in healthy volunteers who received placebo which&#xD;
      supports the use of the tyramine pressor test to assess the functional capacity of different&#xD;
      medication regimens to inhibit NE reuptake at steady state levels. Serotonin reuptake has&#xD;
      been extensively studied in human participants using the blood platelet model. In this assay,&#xD;
      whole blood 5-HT and/or platelet content is determined before and after giving reuptake&#xD;
      inhibitors. Since the 5-HT transporter is similar on 5-HT neurons in the brain and on&#xD;
      platelets, the degree of 5-HT depletion in the blood can be used as a measure of 5-HT&#xD;
      reuptake blockade in the brain. Together, these experimental approaches will identify the&#xD;
      potency of levomilnacipran for NE and 5-HT reuptake inhibition.&#xD;
&#xD;
      The purpose of this study is to determine the potency of levomilnacipran required to inhibit&#xD;
      NE and 5-HT reuptake in healthy male participants across the effective dose range of the&#xD;
      medication (40-120 mg/day).&#xD;
&#xD;
      Participants Healthy male participants will receive escalating doses of levomilnacipran,&#xD;
      duloxetine, or placebo every 4-7 days throughout a 14-23 day period. The tyramine pressor&#xD;
      procedure will be used to identify the dose at which these medications inhibit norepinephrine&#xD;
      reuptake. Serotonin reuptake inhibition will be estimated from whole blood serotonin&#xD;
      concentrations. Tyramine testing and blood draws will occur at baseline (prior to medication&#xD;
      administration) and 4 days after each dose escalation.&#xD;
&#xD;
      Participants will be assigned to one of 3 groups: levomilnacipran, duloxetine or placebo. The&#xD;
      duration of study treatment for participants in the first 2 groups will range from 22-32&#xD;
      days. These participants will receive escalating doses of levomilnacipran or duloxetine over&#xD;
      a period of 14-23 days followed by down-titrated doses over the next 8 days. The&#xD;
      investigators will offer a flexible interval for dose escalation in participants receiving&#xD;
      levomilnacipran and duloxetine to minimize side effects, improve tolerability, and maximize&#xD;
      subject retention. Participants in the placebo group will receive the levomilnacipran-matched&#xD;
      placebo capsule for 14 days.&#xD;
&#xD;
      Specific aim The objective of this study is to assess the norepinephrine and serotonin&#xD;
      reuptake inhibition capacities of levomilnacipran using the tyramine pressor procedure and&#xD;
      blood platelet model respectively. Two control groups will be included to demonstrate the&#xD;
      validity of the two experimental approaches, an active comparator group, and a placebo group.&#xD;
      Therefore, there will be three treatment arms: 1) 12 participants will be administered&#xD;
      escalating doses of levomilnacipran, 2) 12 participants will be administered escalating doses&#xD;
      of duloxetine, and 3) 12 participants will receive levomilnacipran placebo-match capsules.&#xD;
      Duloxetine will be used as an active comparator as it is an established 5-HT reuptake&#xD;
      inhibitor and a potentially effective NE reuptake inhibitor.&#xD;
&#xD;
      Assessments to be Performed Pharmacodynamic and safety evaluations: At each visit, a catheter&#xD;
      will be placed in the subject's antecubital vein. The participant will lie down and remain&#xD;
      supine until his pulse is determined to be stable (+/- approximately 5 bpm) over two&#xD;
      consecutive measurements made a minimum of 10 minutes apart. The subject's heart rate and&#xD;
      blood pressure will be recorded from the arm contralateral to the catheter. Blood samples&#xD;
      will be drawn from the catheter while the participant remains supine. The participant's heart&#xD;
      rate and blood pressure will again be recorded from the arm contralateral to the catheter.&#xD;
&#xD;
      Plasma drug levels: Plasma concentrations of levomilnacipran and duloxetine will be&#xD;
      determined from supine blood samples after each dose change to ensure that potentially&#xD;
      aberrant results are not due to poor medication compliance.&#xD;
&#xD;
      Whole blood serotonin assay: Whole blood 5-HT concentrations will be determined from supine&#xD;
      blood samples collected at regular visits.&#xD;
&#xD;
      Evaluation of tyramine pressor response: After the supine blood samples are drawn, the&#xD;
      tyramine infusion procedure will proceed as follows: 1) The participant will be connected to&#xD;
      the cardiac monitor apparatus, which automatically monitors blood pressure and heart rate. 2)&#xD;
      The participant will lie down and remain supine until his pulse is determined to be stable&#xD;
      over two consecutive measurements made a minimum of 10 minutes apart. 3) A first small dose&#xD;
      of tyramine (0.5 mg) will be administered intravenously to rule out the presence of&#xD;
      pheochromocytoma. Pheochromocytoma is a small neuroendocrine tumour which can cause elevated&#xD;
      secretion of catecholamines leading to raised blood pressure, palpitations and headaches.&#xD;
      This condition would not be detected through physical exam or laboratory tests. This dose is&#xD;
      not expected to produce any significant change in the cardiovascular parameters measured. Ten&#xD;
      minutes after the participant receives the 0.5 mg tyramine dose, the effects of two fixed&#xD;
      doses of intravenous tyramine on systolic blood pressure will be assessed. First, a 4 mg dose&#xD;
      of tyramine will be administered. Five minutes after the subject's blood pressure returns to&#xD;
      normal, a 6 mg dose will be administered. 4) Heart rate, systolic and diastolic blood&#xD;
      pressure will be recorded every 2 minutes for at least 10 minutes after the injection, or 5&#xD;
      minutes after the return of baseline blood pressure and heart rate, whichever is longer.&#xD;
&#xD;
      Safety/Monitoring procedures: A physician and research nurse coordinator will be present&#xD;
      during the entire tyramine procedure, and participants will remain on the unit for a further&#xD;
      15 min after all Tyramine Pressor Test procedures have completed for monitoring. There is&#xD;
      access to an automated external defibrillator (AED), and a crash cart with supporting staff&#xD;
      in case of emergency.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 2, 2018</start_date>
  <completion_date type="Anticipated">May 1, 2022</completion_date>
  <primary_completion_date type="Actual">December 31, 2019</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>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Primary End Point</measure>
    <time_frame>24 months</time_frame>
    <description>The degree of norepinephrine reuptake in response to the increasing levels of the study medication will be assessed and compared between three treatment groups.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Secondary End Points</measure>
    <time_frame>24 months</time_frame>
    <description>The degree of serotonin reuptake in response to the increasing levels of the study medication will be assessed and compared between three treatment groups.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">36</enrollment>
  <condition>None (i.e. Healthy Volunteers)</condition>
  <arm_group>
    <arm_group_label>Levomilnacipran</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be randomly assigned to receive levomilnacipran, duloxetine, or placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Duloxetine (Cymbalta)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will be randomly assigned to receive levomilnacipran, duloxetine, or placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Levomilnacipran Placebo-matched capsules</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will be randomly assigned to receive levomilnacipran, duloxetine, or placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levomilnacipran</intervention_name>
    <description>Escalating doses of 40 to 120mg/day every 7 days (+/- 1 day) throughout a 20-26 day period.</description>
    <arm_group_label>Levomilnacipran</arm_group_label>
    <other_name>Fetzima</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Duloxetine</intervention_name>
    <description>Escalating doses of 40 to 120mg/day every 7 days (+/- 1 day) throughout a 20-26 day period.</description>
    <arm_group_label>Duloxetine (Cymbalta)</arm_group_label>
    <other_name>Cymbalta</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <description>Escalating doses of 40 to 120mg/day every 7 days (+/- 1 day) throughout a 20-26 day period.</description>
    <arm_group_label>Levomilnacipran Placebo-matched capsules</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male participants between 18 and 40 years-old&#xD;
&#xD;
          -  Written informed consent signed by the participant&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Lifetime personal history of diagnosis of major depressive disorder according to the&#xD;
             DSM-V (American Psychiatric Association, 2013) using the Structured Clinical Interview&#xD;
             for DSM-V Axis I Disorders, Research Version, Non-patient Edition (SCID-5-RV for&#xD;
             DSM-V; First et al., 2015)&#xD;
&#xD;
          -  A history of suicidal ideation and behaviour, including self-harm and/or harm to&#xD;
             others.&#xD;
&#xD;
          -  A history of substance abuse and/or dependence.&#xD;
&#xD;
          -  A positive drug screen for illicit drugs&#xD;
&#xD;
          -  Substantial alcohol use&#xD;
&#xD;
          -  Current use of Monoamine Oxidase Inhibitors (MAOIs), including the antibiotic&#xD;
             linezolid and the thiazine dye methylthioninium chloride (methylene blue)&#xD;
&#xD;
          -  Current use of serotonin-precursors (such as L-tryptophan, oxitriptan)&#xD;
&#xD;
          -  Current use of serotonergic drugs (triptans, certain tricyclic antidepressants,&#xD;
             lithium, tramadol, St. John's Wort)&#xD;
&#xD;
          -  Concomitant use of NSAIDS, ASA, and other anticoagulants.&#xD;
&#xD;
          -  Current use of Thioridazine&#xD;
&#xD;
          -  Current use of CYP1A2 Inhibitors&#xD;
&#xD;
          -  Current use of Triptans (5HT1 Agonists)&#xD;
&#xD;
          -  Blood pressure greater than 140/90 and/or a pulse rate greater than 90 bpm&#xD;
&#xD;
          -  Recent history of myocardial infarction, cerebrovascular accident, cardiac&#xD;
             arrhythmias, or unstable heart disease.&#xD;
&#xD;
          -  Evidence of significant physical illness contraindicating the use of levomilnacipran&#xD;
             and duloxetine found on the physical exam or in the laboratory data obtained during&#xD;
             the first week of the study&#xD;
&#xD;
          -  Current use of medication that may affect voiding (ie- anticholinergics)&#xD;
&#xD;
          -  History of obstructive urinary disorders and dysuria, prostatic hypertrophy,&#xD;
             prostatitis, and other lower urinary tract obstructive disorders.&#xD;
&#xD;
          -  History of Stevens-Johnson Syndrome and Erythema multiforme.&#xD;
&#xD;
          -  Diabetes Type I and II&#xD;
&#xD;
          -  Fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase&#xD;
             insufficiency.&#xD;
&#xD;
          -  Hepatic Impairment&#xD;
&#xD;
          -  Uncontrolled narrow-angle glaucoma&#xD;
&#xD;
          -  Severe renal impairment&#xD;
&#xD;
          -  History of seizure disorder&#xD;
&#xD;
          -  Anatomically narrow ocular angles.&#xD;
&#xD;
          -  Osteoporosis or major risk for bone fractures.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Pierre Blier, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Royal's Institute of Mental Health Research</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Institute of Mental Health Research, Royal Ottawa Mental Health Centre</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1Z 7K4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <reference>
    <citation>Asnis GM, Henderson MA. Levomilnacipran for the treatment of major depressive disorder: a review. Neuropsychiatr Dis Treat. 2015 Jan 9;11:125-35. doi: 10.2147/NDT.S54710. eCollection 2015.</citation>
    <PMID>25657584</PMID>
  </reference>
  <reference>
    <citation>Auclair AL, Martel JC, Assie MB, Bardin L, Heusler P, Cussac D, Marien M, Newman-Tancredi A, O'Connor JA, Depoortere R. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety. Neuropharmacology. 2013 Jul;70:338-47. doi: 10.1016/j.neuropharm.2013.02.024. Epub 2013 Mar 13.</citation>
    <PMID>23499664</PMID>
  </reference>
  <reference>
    <citation>Blier P, Saint-Andre E, Hebert C, de Montigny C, Lavoie N, Debonnel G. Effects of different doses of venlafaxine on serotonin and norepinephrine reuptake in healthy volunteers. Int J Neuropsychopharmacol. 2007 Feb;10(1):41-50. doi: 10.1017/S1461145705006395. Epub 2006 May 11.</citation>
    <PMID>16690005</PMID>
  </reference>
  <reference>
    <citation>Aldosary F, Norris S, Tremblay P, James JS, Ritchie JC, Blier P. Differential Potency of Venlafaxine, Paroxetine, and Atomoxetine to Inhibit Serotonin and Norepinephrine Reuptake in Patients With Major Depressive Disorder. Int J Neuropsychopharmacol. 2022 Apr 19;25(4):283-292. doi: 10.1093/ijnp/pyab086.</citation>
    <PMID>34958348</PMID>
  </reference>
  <reference>
    <citation>Debonnel G, Saint-Andre E, Hebert C, de Montigny C, Lavoie N, Blier P. Differential physiological effects of a low dose and high doses of venlafaxine in major depression. Int J Neuropsychopharmacol. 2007 Feb;10(1):51-61. doi: 10.1017/S1461145705006413. Epub 2006 May 11.</citation>
    <PMID>16690006</PMID>
  </reference>
  <reference>
    <citation>First, M.B., Williams, J.B.W., Karg, R.S., &amp; Spitzer, R.L. (2015). Structured clinical interview for DSM-5-research version. Arlington: American Psychiatric Association.</citation>
  </reference>
  <reference>
    <citation>Gobbi G, Slater S, Boucher N, Debonnel G, Blier P. Neurochemical and psychotropic effects of bupropion in healthy male subjects. J Clin Psychopharmacol. 2003 Jun;23(3):233-9. doi: 10.1097/01.jcp.0000084023.22282.03.</citation>
    <PMID>12826985</PMID>
  </reference>
  <reference>
    <citation>Turcotte JE, Debonnel G, de Montigny C, Hebert C, Blier P. Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects. Neuropsychopharmacology. 2001 May;24(5):511-21. doi: 10.1016/S0893-133X(00)00220-7.</citation>
    <PMID>11282251</PMID>
  </reference>
  <reference>
    <citation>Vincent S, Bieck PR, Garland EM, Loghin C, Bymaster FP, Black BK, Gonzales C, Potter WZ, Robertson D. Clinical assessment of norepinephrine transporter blockade through biochemical and pharmacological profiles. Circulation. 2004 Jun 29;109(25):3202-7. doi: 10.1161/01.CIR.0000130847.18666.39. Epub 2004 Jun 7.</citation>
    <PMID>15184278</PMID>
  </reference>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>July 20, 2017</study_first_submitted>
  <study_first_submitted_qc>August 9, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 15, 2017</study_first_posted>
  <last_update_submitted>October 5, 2021</last_update_submitted>
  <last_update_submitted_qc>October 5, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 6, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Ottawa</investigator_affiliation>
    <investigator_full_name>Pierre Blier</investigator_full_name>
    <investigator_title>Endowed Research Chair and Director of Mood Disorders Research Unit</investigator_title>
  </responsible_party>
  <keyword>Levomilnacipran</keyword>
  <keyword>Antidepressant</keyword>
  <keyword>Ottawa</keyword>
  <keyword>Selective Norepinephrine Reuptake Inhibitor</keyword>
  <keyword>Healthy males</keyword>
  <keyword>Tyramine response</keyword>
  <keyword>Serotonin</keyword>
  <keyword>Norepinephrine</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Duloxetine Hydrochloride</mesh_term>
    <mesh_term>Milnacipran</mesh_term>
    <mesh_term>Levomilnacipran</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03249311
org study id: REB2017004
nct id: NCT03249311
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Levomilnacipran is an antidepressant currently approved in Canada to treat Major Depressive
      Disorder (MDD). Thirty-six healthy male participants will receive escalating doses of
      levomilnacipran, duloxetine, or placebo every 7 days (+/- 1 day) throughout a 20 - 28 day
      period. After each dose escalation study participants will be asked to come to the clinic to
      conduct the necessary tests - these will include tyramine pressor tests as well as blood
      draws. The results of this study will allow the investigators to determine the dose(s) of
      levomilnacipran at which reuptake inhibition of norepinephrine and serotonin (chemicals
      utilized by nerve cells to transmit information to other cells) is achieved.
Levomilnacipran (Fetzima) is the active enantiomer of milnacipran (Ixel, Savella) for
      norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake. It has an approximate
      eight-fold greater affinity for the human NE transporter than for the 5-HT transporter. This
      signifies that the NE transporter may be engaged to a much greater degree than the 5-HT
      transporter at various doses, especially at lower regimens. As such, levomilnacipran
      represents the mirror antidepressant medication of venlafaxine and duloxetine since at their
      minimal effective doses, these medications are selective inhibitors of 5-HT reuptake and it
      is not until daily regimens are doubled or tripled that the NE transporter gets engaged.

      Levomilnacipran is effective clinically in patients with major depressive disorder (MDD) at
      doses ranging between 40 and 120 mg/day. Given this wide effective dose range, it appears
      essential to determine the in vivo potency of levomilnacipran and the dose at which it starts
      inhibiting 5-HT in relation to NE reuptake in humans.

      The current investigators have studied the NE reuptake blocking properties of antidepressants
      in both healthy volunteers and patients with depression using tyramine pressor tests. This
      peripheral model of adrenergic function involves administration of repeated intravenous
      injections of tyramine and measurement of transient increases in systolic blood pressure
      (SBP) that occur after a tyramine load. This approach has led to dose-dependent SBP increases
      that are reliably reproduced one week apart in healthy volunteers who received placebo which
      supports the use of the tyramine pressor test to assess the functional capacity of different
      medication regimens to inhibit NE reuptake at steady state levels. Serotonin reuptake has
      been extensively studied in human participants using the blood platelet model. In this assay,
      whole blood 5-HT and/or platelet content is determined before and after giving reuptake
      inhibitors. Since the 5-HT transporter is similar on 5-HT neurons in the brain and on
      platelets, the degree of 5-HT depletion in the blood can be used as a measure of 5-HT
      reuptake blockade in the brain. Together, these experimental approaches will identify the
      potency of levomilnacipran for NE and 5-HT reuptake inhibition.

      The purpose of this study is to determine the potency of levomilnacipran required to inhibit
      NE and 5-HT reuptake in healthy male participants across the effective dose range of the
      medication (40-120 mg/day).

      Participants Healthy male participants will receive escalating doses of levomilnacipran,
      duloxetine, or placebo every 4-7 days throughout a 14-23 day period. The tyramine pressor
      procedure will be used to identify the dose at which these medications inhibit norepinephrine
      reuptake. Serotonin reuptake inhibition will be estimated from whole blood serotonin
      concentrations. Tyramine testing and blood draws will occur at baseline (prior to medication
      administration) and 4 days after each dose escalation.

      Participants will be assigned to one of 3 groups: levomilnacipran, duloxetine or placebo. The
      duration of study treatment for participants in the first 2 groups will range from 22-32
      days. These participants will receive escalating doses of levomilnacipran or duloxetine over
      a period of 14-23 days followed by down-titrated doses over the next 8 days. The
      investigators will offer a flexible interval for dose escalation in participants receiving
      levomilnacipran and duloxetine to minimize side effects, improve tolerability, and maximize
      subject retention. Participants in the placebo group will receive the levomilnacipran-matched
      placebo capsule for 14 days.

      Specific aim The objective of this study is to assess the norepinephrine and serotonin
      reuptake inhibition capacities of levomilnacipran using the tyramine pressor procedure and
      blood platelet model respectively. Two control groups will be included to demonstrate the
      validity of the two experimental approaches, an active comparator group, and a placebo group.
      Therefore, there will be three treatment arms: 1) 12 participants will be administered
      escalating doses of levomilnacipran, 2) 12 participants will be administered escalating doses
      of duloxetine, and 3) 12 participants will receive levomilnacipran placebo-match capsules.
      Duloxetine will be used as an active comparator as it is an established 5-HT reuptake
      inhibitor and a potentially effective NE reuptake inhibitor.

      Assessments to be Performed Pharmacodynamic and safety evaluations: At each visit, a catheter
      will be placed in the subject's antecubital vein. The participant will lie down and remain
      supine until his pulse is determined to be stable (+/- approximately 5 bpm) over two
      consecutive measurements made a minimum of 10 minutes apart. The subject's heart rate and
      blood pressure will be recorded from the arm contralateral to the catheter. Blood samples
      will be drawn from the catheter while the participant remains supine. The participant's heart
      rate and blood pressure will again be recorded from the arm contralateral to the catheter.

      Plasma drug levels: Plasma concentrations of levomilnacipran and duloxetine will be
      determined from supine blood samples after each dose change to ensure that potentially
      aberrant results are not due to poor medication compliance.

      Whole blood serotonin assay: Whole blood 5-HT concentrations will be determined from supine
      blood samples collected at regular visits.

      Evaluation of tyramine pressor response: After the supine blood samples are drawn, the
      tyramine infusion procedure will proceed as follows: 1) The participant will be connected to
      the cardiac monitor apparatus, which automatically monitors blood pressure and heart rate. 2)
      The participant will lie down and remain supine until his pulse is determined to be stable
      over two consecutive measurements made a minimum of 10 minutes apart. 3) A first small dose
      of tyramine (0.5 mg) will be administered intravenously to rule out the presence of
      pheochromocytoma. Pheochromocytoma is a small neuroendocrine tumour which can cause elevated
      secretion of catecholamines leading to raised blood pressure, palpitations and headaches.
      This condition would not be detected through physical exam or laboratory tests. This dose is
      not expected to produce any significant change in the cardiovascular parameters measured. Ten
      minutes after the participant receives the 0.5 mg tyramine dose, the effects of two fixed
      doses of intravenous tyramine on systolic blood pressure will be assessed. First, a 4 mg dose
      of tyramine will be administered. Five minutes after the subject's blood pressure returns to
      normal, a 6 mg dose will be administered. 4) Heart rate, systolic and diastolic blood
      pressure will be recorded every 2 minutes for at least 10 minutes after the injection, or 5
      minutes after the return of baseline blood pressure and heart rate, whichever is longer.

      Safety/Monitoring procedures: A physician and research nurse coordinator will be present
      during the entire tyramine procedure, and participants will remain on the unit for a further
      15 min after all Tyramine Pressor Test procedures have completed for monitoring. There is
      access to an automated external defibrillator (AED), and a crash cart with supporting staff
      in case of emergency.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Single (Participant)
measure: Primary End Point
time frame: 24 months
description: The degree of norepinephrine reuptake in response to the increasing levels of the study medication will be assessed and compared between three treatment groups.
measure: Secondary End Points
time frame: 24 months
description: The degree of serotonin reuptake in response to the increasing levels of the study medication will be assessed and compared between three treatment groups.
arm group label: Levomilnacipran
arm group type: Experimental
description: Participants will be randomly assigned to receive levomilnacipran, duloxetine, or placebo
arm group label: Duloxetine (Cymbalta)
arm group type: Active Comparator
description: Participants will be randomly assigned to receive levomilnacipran, duloxetine, or placebo
arm group label: Levomilnacipran Placebo-matched capsules
arm group type: Placebo Comparator
description: Participants will be randomly assigned to receive levomilnacipran, duloxetine, or placebo
intervention type: Drug
intervention name: Levomilnacipran
description: Escalating doses of 40 to 120mg/day every 7 days (+/- 1 day) throughout a 20-26 day period.
arm group label: Levomilnacipran
other name: Fetzima
intervention type: Drug
intervention name: Duloxetine
description: Escalating doses of 40 to 120mg/day every 7 days (+/- 1 day) throughout a 20-26 day period.
arm group label: Duloxetine (Cymbalta)
other name: Cymbalta
intervention type: Drug
intervention name: Placebos
description: Escalating doses of 40 to 120mg/day every 7 days (+/- 1 day) throughout a 20-26 day period.
arm group label: Levomilnacipran Placebo-matched capsules
criteria: 
gender: Male
gender based: Yes
minimum age: 18 Years
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Pierre Blier, MD
role: Principal Investigator
affiliation: The Royal's Institute of Mental Health Research
facility: 
country: Canada
citation: Asnis GM, Henderson MA. Levomilnacipran for the treatment of major depressive disorder: a review. Neuropsychiatr Dis Treat. 2015 Jan 9;11:125-35. doi: 10.2147/NDT.S54710. eCollection 2015.
PMID: 25657584
citation: Auclair AL, Martel JC, Assie MB, Bardin L, Heusler P, Cussac D, Marien M, Newman-Tancredi A, O'Connor JA, Depoortere R. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety. Neuropharmacology. 2013 Jul;70:338-47. doi: 10.1016/j.neuropharm.2013.02.024. Epub 2013 Mar 13.
PMID: 23499664
citation: Blier P, Saint-Andre E, Hebert C, de Montigny C, Lavoie N, Debonnel G. Effects of different doses of venlafaxine on serotonin and norepinephrine reuptake in healthy volunteers. Int J Neuropsychopharmacol. 2007 Feb;10(1):41-50. doi: 10.1017/S1461145705006395. Epub 2006 May 11.
PMID: 16690005
citation: Aldosary F, Norris S, Tremblay P, James JS, Ritchie JC, Blier P. Differential Potency of Venlafaxine, Paroxetine, and Atomoxetine to Inhibit Serotonin and Norepinephrine Reuptake in Patients With Major Depressive Disorder. Int J Neuropsychopharmacol. 2022 Apr 19;25(4):283-292. doi: 10.1093/ijnp/pyab086.
PMID: 34958348
citation: Debonnel G, Saint-Andre E, Hebert C, de Montigny C, Lavoie N, Blier P. Differential physiological effects of a low dose and high doses of venlafaxine in major depression. Int J Neuropsychopharmacol. 2007 Feb;10(1):51-61. doi: 10.1017/S1461145705006413. Epub 2006 May 11.
PMID: 16690006
citation: First, M.B., Williams, J.B.W., Karg, R.S., & Spitzer, R.L. (2015). Structured clinical interview for DSM-5-research version. Arlington: American Psychiatric Association.
citation: Gobbi G, Slater S, Boucher N, Debonnel G, Blier P. Neurochemical and psychotropic effects of bupropion in healthy male subjects. J Clin Psychopharmacol. 2003 Jun;23(3):233-9. doi: 10.1097/01.jcp.0000084023.22282.03.
PMID: 12826985
citation: Turcotte JE, Debonnel G, de Montigny C, Hebert C, Blier P. Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects. Neuropsychopharmacology. 2001 May;24(5):511-21. doi: 10.1016/S0893-133X(00)00220-7.
PMID: 11282251
citation: Vincent S, Bieck PR, Garland EM, Loghin C, Bymaster FP, Black BK, Gonzales C, Potter WZ, Robertson D. Clinical assessment of norepinephrine transporter blockade through biochemical and pharmacological profiles. Circulation. 2004 Jun 29;109(25):3202-7. doi: 10.1161/01.CIR.0000130847.18666.39. Epub 2004 Jun 7.
PMID: 15184278
responsible party type: Principal Investigator
investigator affiliation: University of Ottawa
investigator full name: Pierre Blier
investigator title: Endowed Research Chair and Director of Mood Disorders Research Unit
mesh term: Duloxetine Hydrochloride
mesh term: Milnacipran
mesh term: Levomilnacipran
sharing ipd: No