<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/NCT01699997</url>
  </required_header>
  <id_info>
    <org_study_id>RF-2010-2311148</org_study_id>
    <nct_id>NCT01699997</nct_id>
  </id_info>
  <brief_title>Oxytocin as Adjunctive Therapy for Schizophrenia</brief_title>
  <official_title>The Use of Oxytocin as Adjunctive Therapy for the Treatment of Schizophrenia: a Randomized, Double Blind Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>IRCCS Centro San Giovanni di Dio Fatebenefratelli</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>IRCCS Centro San Giovanni di Dio Fatebenefratelli</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: A large body of research has shown that Oxytocin (OXT) is an important prosocial&#xD;
      peptide and there is also initial evidence that the central OXT system is altered in several&#xD;
      mental disorders that are characterized by severe social disturbances and deficits, such as&#xD;
      anxiety disorders with prominent social dysfunction (e.g., schizophrenia), mood disorders and&#xD;
      borderline personality disorder. OXT may reduce psychotic symptoms and may diminish certain&#xD;
      social cognition deficits that are not improved by current antipsychotic medications.&#xD;
&#xD;
      Aims: The project has two main aims, listed below:&#xD;
&#xD;
        1. To assess the efficacy of intranasal OXT in reducing negative symptoms in patients with&#xD;
           schizophrenia in association with second-generation antipsychotics (SGA);&#xD;
&#xD;
        2. To use an Emotional Priming Paradigm task to assess pre- and post-treatment change in&#xD;
           the patients general cognitive and emotional status.&#xD;
&#xD;
      Study Design: Randomized, double-blind, placebo-controlled, cross over design. Materials and&#xD;
      methods: Patients involved in the study will be recruited in six centres in the north of&#xD;
      Italy. Each subject (aged 18-45, with a duration of the disorder no longer than 10 years)&#xD;
      will be enrolled after a screening phase. 80 patients will be randomly assigned to either 40&#xD;
      IU OXT once daily or vehicle placebo, in addition to their pre-study antipsychotic medication&#xD;
      regimen: all reasonable attempts maintain the same SGA dosages throughout the study will be&#xD;
      made. The study ratio is 1:1. The total study duration for each individual subject will be&#xD;
      approximately 8 months, which includes an up to 7-day screening period, a baseline&#xD;
      randomization visit, and a four month long cross-over treatment period. Subjects will be&#xD;
      trained by researchers about the self-administration of intranasal OXT. A trustworthy&#xD;
      caregiver will be trained as well. Each patient will receive every morning a SMS text message&#xD;
      on his mobile phone as a reminder for OXT administration.&#xD;
&#xD;
      Before starting the treatment, all patients will be assessed with standardized assessment&#xD;
      instruments and will undergo an in depth neuropsychological assessment; additional&#xD;
      evaluations, including safety evaluations, will be performed at 4 and 8 month follow-ups.&#xD;
&#xD;
      The primary outcome measure will be the negative score in the Positive and Negative Syndrome&#xD;
      Scale (PANSS) performed at 2,4,6 and 8 months since the start of the treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The project has two main aims:&#xD;
&#xD;
        1. Aims of the cross-over study To assess the efficacy of intranasal OXT in reducing&#xD;
           negative symptoms in patients with SZ (as evaluated with PANSS), in association with&#xD;
           standard Second Generation Antipsychotics (SGA)treatment; recruited patients will be&#xD;
           aged 18-45 years and will have a disorder duration of no longer than 10 years.&#xD;
&#xD;
        2. Aims of the neuropsychological assessment To use an Emotional Priming Paradigm (EPP)&#xD;
           task to assess pre- and post-treatment change in the patients general cognitive and&#xD;
           emotional status.&#xD;
&#xD;
      The investigators aim at treating a large sample size of patients with schizophrenia,&#xD;
      consisting exclusively of patients with a limited disorder duration and rather young age, for&#xD;
      a sufficiently long period of time. Our rationale for employing a longer treatment period&#xD;
      than used in previous and on-going trials is to ascertain the possibility of a positive OXT&#xD;
      dose-response relationship, which would be observable, however, with longer treatment&#xD;
      exposure. Moreover, only patients with a disorder onset of 10 years or less will be enrolled.&#xD;
&#xD;
      They will then be standardized in terms of AP treatment and randomized to OXT or placebo for&#xD;
      8 months.&#xD;
&#xD;
      OXT is a hormone that is naturally present in the human body, and recent studies have&#xD;
      suggested that patients with SZ show low levels of this neuropeptide. It is therefore&#xD;
      hypothesized that the treatment proposed in this project might balance apparently lower OXT&#xD;
      levels in these patients.&#xD;
&#xD;
      Finally, another innovative aspect of this project is the attention at ameliorating patients&#xD;
      adherence to treatment by supporting them with a reminder program (automatic SMS will be sent&#xD;
      every morning to remind patients the daily OXT self-administration) and involving a&#xD;
      trustworthy caregiver who will be trained in OXT administration and will be asked to monitor&#xD;
      the patient compliance by recording each self-administration on a written form.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2014</start_date>
  <completion_date type="Actual">November 2015</completion_date>
  <primary_completion_date type="Actual">April 2015</primary_completion_date>
  <phase>Phase 2</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>Change in PANSS negative score, as measured at T0 and at 2,4,6 and 8 months.</measure>
    <time_frame>8 months</time_frame>
    <description>Using the PANSS negative score as primary end-point, the investigators expect to observe a reduction in PANSS negative subscale scores in the treated group ranging from 0.9 to 2, with an effect size Cohens d=0.45, in agreement with the results of a previous study, in which authors who observed a reduction of 1.7 with an effect size Cohens d= 0.5. The investigators also expect that OXT will have a positive influence on the patients quality of life and reduction of PANSS positive subscale score. Correlations between OXT plasma levels, symptoms, and response to treatment will be evaluated to identify respondent and non-respondent patient groups</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>PANSS total score change.</measure>
    <time_frame>8 months</time_frame>
    <description>The secondary end-point will be the PANSS total score</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Brief Assessment of Cognitive deficits in Schizophrenics (BACS) score change</measure>
    <time_frame>8 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Reading the Mind in the Eyes Test (RMET) score change.</measure>
    <time_frame>8 months</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Schizophrenia</condition>
  <arm_group>
    <arm_group_label>Oxytocin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Each treatment will consist of 10 insufflations (5/nostril alternating between nostrils) of OXT Spray, which contains approximately 40 international units (IU) of OXT</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo vial</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Each treatment will consist of 10 insufflations (5/nostril alternating between nostrils) of placebo Spray, which contains all OXT Spray ingredients except for oxytocin.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxytocin</intervention_name>
    <description>Intranasal spray with 40 IU of OXT</description>
    <arm_group_label>Oxytocin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Intranasal spray with placebo solution</description>
    <arm_group_label>Placebo vial</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with a diagnosis of SZ, according to DSM-IV criteria, for at least one year,&#xD;
             evaluated with SCID/P&#xD;
&#xD;
          -  A minimum PANSS total score of 55 (indicating moderate severity, due to ongoing AP&#xD;
             treatment) .&#xD;
&#xD;
          -  A minimum CGI-S score of 4&#xD;
&#xD;
          -  Age between 18 and 45 years&#xD;
&#xD;
          -  A disorder duration of no longer than 10 years&#xD;
&#xD;
          -  Women of childbearing age must test negative for pregnancy at the time of enrolment.&#xD;
&#xD;
        All patients must:&#xD;
&#xD;
          -  be on a therapeutic dose of a SGA (or a maximum 2 SGAs) with no major dose changes for&#xD;
             at least 4 weeks.&#xD;
&#xD;
          -  have the ability to provide informed consent&#xD;
&#xD;
          -  be able to use a nasal spray&#xD;
&#xD;
          -  reside in the service catchment area&#xD;
&#xD;
          -  show evidence of no alcohol or substance dependence in the last year&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of mental retardation&#xD;
&#xD;
          -  Diagnosis of organic mental disorder&#xD;
&#xD;
          -  History of no response to treatment with clozapine&#xD;
&#xD;
          -  History of hypersensitivity to OXT or vehicle&#xD;
&#xD;
          -  Alcohol or substance dependence in the last year&#xD;
&#xD;
          -  Presence of, or history of clinically significant allergic rhinitis as assessed by the&#xD;
             treating clinician&#xD;
&#xD;
          -  Being pregnant or breastfeeding&#xD;
&#xD;
          -  Having given birth in the past 6 months or breast-feeding in the past 3 months&#xD;
&#xD;
          -  Low literacy as indicated by an inability to read and understand the consent form&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Giovanni de Girolamo, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>IRCCS Fatebenefratelli, Brescia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Statistical Unit, Institute of Biomathematics, University of Urbino</name>
      <address>
        <city>Urbino</city>
        <state>Pesaro Urbino</state>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IRCCS Fatebenefratelli</name>
      <address>
        <city>Brescia</city>
        <zip>25125</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Mental Health</name>
      <address>
        <city>Desenzano</city>
        <zip>25024</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institute of Neuroscience, National Research Council</name>
      <address>
        <city>Milan</city>
        <zip>20129</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Mental Health</name>
      <address>
        <city>Padua</city>
        <zip>35124</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Psychiatric Clinic, University of Pisa</name>
      <address>
        <city>Pisa</city>
        <zip>56100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Psychiatric Clinic, University of Udine</name>
      <address>
        <city>Udine</city>
        <zip>33100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <link>
    <url>http://www.irccs-fatebenefratelli.it/</url>
    <description>This is the website of the Coordinating Centre</description>
  </link>
  <verification_date>February 2016</verification_date>
  <study_first_submitted>October 2, 2012</study_first_submitted>
  <study_first_submitted_qc>October 3, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 4, 2012</study_first_posted>
  <last_update_submitted>February 23, 2016</last_update_submitted>
  <last_update_submitted_qc>February 23, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 24, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>IRCCS Centro San Giovanni di Dio Fatebenefratelli</investigator_affiliation>
    <investigator_full_name>Giovanni de Girolamo, M.D.</investigator_full_name>
    <investigator_title>Responsible of Psychiatric Epidemiology and Evaluation Unit</investigator_title>
  </responsible_party>
  <keyword>Schizophrenia</keyword>
  <keyword>Oxytocin</keyword>
  <keyword>RCT</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Schizophrenia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Oxytocin</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>August 2, 2022</submitted>
    <returned>July 12, 2023</returned>
  </pending_results>
  <!-- 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/NCT01699997
org study id: RF-2010-2311148
nct id: NCT01699997
lead sponsor: 
has dmc: Yes
Background: A large body of research has shown that Oxytocin (OXT) is an important prosocial
      peptide and there is also initial evidence that the central OXT system is altered in several
      mental disorders that are characterized by severe social disturbances and deficits, such as
      anxiety disorders with prominent social dysfunction (e.g., schizophrenia), mood disorders and
      borderline personality disorder. OXT may reduce psychotic symptoms and may diminish certain
      social cognition deficits that are not improved by current antipsychotic medications.

      Aims: The project has two main aims, listed below:

        1. To assess the efficacy of intranasal OXT in reducing negative symptoms in patients with
           schizophrenia in association with second-generation antipsychotics (SGA);

        2. To use an Emotional Priming Paradigm task to assess pre- and post-treatment change in
           the patients general cognitive and emotional status.

      Study Design: Randomized, double-blind, placebo-controlled, cross over design. Materials and
      methods: Patients involved in the study will be recruited in six centres in the north of
      Italy. Each subject (aged 18-45, with a duration of the disorder no longer than 10 years)
      will be enrolled after a screening phase. 80 patients will be randomly assigned to either 40
      IU OXT once daily or vehicle placebo, in addition to their pre-study antipsychotic medication
      regimen: all reasonable attempts maintain the same SGA dosages throughout the study will be
      made. The study ratio is 1:1. The total study duration for each individual subject will be
      approximately 8 months, which includes an up to 7-day screening period, a baseline
      randomization visit, and a four month long cross-over treatment period. Subjects will be
      trained by researchers about the self-administration of intranasal OXT. A trustworthy
      caregiver will be trained as well. Each patient will receive every morning a SMS text message
      on his mobile phone as a reminder for OXT administration.

      Before starting the treatment, all patients will be assessed with standardized assessment
      instruments and will undergo an in depth neuropsychological assessment; additional
      evaluations, including safety evaluations, will be performed at 4 and 8 month follow-ups.

      The primary outcome measure will be the negative score in the Positive and Negative Syndrome
      Scale (PANSS) performed at 2,4,6 and 8 months since the start of the treatment.
The project has two main aims:

        1. Aims of the cross-over study To assess the efficacy of intranasal OXT in reducing
           negative symptoms in patients with SZ (as evaluated with PANSS), in association with
           standard Second Generation Antipsychotics (SGA)treatment; recruited patients will be
           aged 18-45 years and will have a disorder duration of no longer than 10 years.

        2. Aims of the neuropsychological assessment To use an Emotional Priming Paradigm (EPP)
           task to assess pre- and post-treatment change in the patients general cognitive and
           emotional status.

      The investigators aim at treating a large sample size of patients with schizophrenia,
      consisting exclusively of patients with a limited disorder duration and rather young age, for
      a sufficiently long period of time. Our rationale for employing a longer treatment period
      than used in previous and on-going trials is to ascertain the possibility of a positive OXT
      dose-response relationship, which would be observable, however, with longer treatment
      exposure. Moreover, only patients with a disorder onset of 10 years or less will be enrolled.

      They will then be standardized in terms of AP treatment and randomized to OXT or placebo for
      8 months.

      OXT is a hormone that is naturally present in the human body, and recent studies have
      suggested that patients with SZ show low levels of this neuropeptide. It is therefore
      hypothesized that the treatment proposed in this project might balance apparently lower OXT
      levels in these patients.

      Finally, another innovative aspect of this project is the attention at ameliorating patients
      adherence to treatment by supporting them with a reminder program (automatic SMS will be sent
      every morning to remind patients the daily OXT self-administration) and involving a
      trustworthy caregiver who will be trained in OXT administration and will be asked to monitor
      the patient compliance by recording each self-administration on a written form.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in PANSS negative score, as measured at T0 and at 2,4,6 and 8 months.
time frame: 8 months
description: Using the PANSS negative score as primary end-point, the investigators expect to observe a reduction in PANSS negative subscale scores in the treated group ranging from 0.9 to 2, with an effect size Cohens d=0.45, in agreement with the results of a previous study, in which authors who observed a reduction of 1.7 with an effect size Cohens d= 0.5. The investigators also expect that OXT will have a positive influence on the patients quality of life and reduction of PANSS positive subscale score. Correlations between OXT plasma levels, symptoms, and response to treatment will be evaluated to identify respondent and non-respondent patient groups
measure: PANSS total score change.
time frame: 8 months
description: The secondary end-point will be the PANSS total score
measure: Brief Assessment of Cognitive deficits in Schizophrenics (BACS) score change
time frame: 8 months
measure: Reading the Mind in the Eyes Test (RMET) score change.
time frame: 8 months
arm group label: Oxytocin
arm group type: Experimental
description: Each treatment will consist of 10 insufflations (5/nostril alternating between nostrils) of OXT Spray, which contains approximately 40 international units (IU) of OXT
arm group label: Placebo vial
arm group type: Placebo Comparator
description: Each treatment will consist of 10 insufflations (5/nostril alternating between nostrils) of placebo Spray, which contains all OXT Spray ingredients except for oxytocin.
intervention type: Drug
intervention name: Oxytocin
description: Intranasal spray with 40 IU of OXT
arm group label: Oxytocin
intervention type: Drug
intervention name: Placebo
description: Intranasal spray with placebo solution
arm group label: Placebo vial
criteria: 
gender: All
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: No
last name: Giovanni de Girolamo, M.D.
role: Principal Investigator
affiliation: IRCCS Fatebenefratelli, Brescia
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Italy
url: http://www.irccs-fatebenefratelli.it/
description: This is the website of the Coordinating Centre
responsible party type: Principal Investigator
investigator affiliation: IRCCS Centro San Giovanni di Dio Fatebenefratelli
investigator full name: Giovanni de Girolamo, M.D.
investigator title: Responsible of Psychiatric Epidemiology and Evaluation Unit
mesh term: Schizophrenia
mesh term: Oxytocin
submitted: August 2, 2022
returned: July 12, 2023