<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/NCT01675648</url>
  </required_header>
  <id_info>
    <org_study_id>Lofex00428</org_study_id>
    <nct_id>NCT01675648</nct_id>
  </id_info>
  <brief_title>Lofexidine for Inpatient Opiate Detox in Singapore</brief_title>
  <official_title>A Double-blind Randomised Controlled Clinical Trial of Lofexidine Versus Diazepam in the Management of the Opioid Withdrawal Syndrome During Inpatient Detoxification in Singapore</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institute of Mental Health, Singapore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Singapore Clinical Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Institute of Mental Health, Singapore</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In Singapore, opiate substitution medication e.g. methadone is only licensed for use with&#xD;
      specific population. The standard treatment is one week of detoxification assisted with&#xD;
      diazepam and symptomatic treatment followed by one week of rehabilitation. However, diazepam&#xD;
      is highly addictive and widely abused among heroin users and pharmacologically, does not&#xD;
      reduce the physical and psychological craving for opioids which can trigger relapse. Many&#xD;
      opiate patients undergoing inpatient detoxification leave prematurely (i.e. PID: patient&#xD;
      initiated discharge) because of the severity of unpleasant withdrawal symptoms. The purpose&#xD;
      of the study is to establish an alternative medication to reduce opiate withdrawal symptoms&#xD;
      for use in Singapore by evaluating the clinical efficacy of Lofexidine versus Diazepam in the&#xD;
      management of the opiate withdrawal syndrome during inpatient detoxification.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Design: This is a randomized, double-blind (double-dummy design) phase IV clinical&#xD;
      trial. Patients will be receiving 10 days of Lofexidine plus Diazepam placebo or Diazepam&#xD;
      plus Lofexidine placebo. All the patients are expected to complete the 2-weeks inpatient&#xD;
      detoxification programme at the NAMS ward. Up to 122 patients (61 in each randomized arm)&#xD;
      will be enrolled into the study to ensure that at least 43 patients in each arm complete Day&#xD;
      4 of study treatment programme.&#xD;
&#xD;
      Efficacy Assessments: The primary efficacy outcome measure will be the Objective Opiate&#xD;
      Withdrawal Scale (OOWS) scores (range = 0-13) on Day 3 and Day 4 of the treatment phase. The&#xD;
      second efficacy outcome measure will be the Short Opiate Withdrawal Scale (SOWS), Opiate&#xD;
      Craving visual analogue scale and Pupil size on Day 3 and Day 4, time to dropout (length of&#xD;
      stay on the ward) and emotional/psychological symptoms measured every 3 days. Our expected&#xD;
      study outcomes are as following:&#xD;
&#xD;
        -  Significantly lower mean scores on the Objective Opiate Withdrawal Scale (OOWS) on day 3&#xD;
           and 4 of detox among patients in the lofexidine arm relative to those in the&#xD;
           benzodiazepine arm&#xD;
&#xD;
        -  Significantly lower mean scores on the Subjective experience of opiate withdrawal scale&#xD;
           (SOWS)on day 3 and 4 of detox among patients in the lofexidine arm relative to those in&#xD;
           the benzodiazepine arm&#xD;
&#xD;
        -  Significantly larger pupil size on day 3 and 4 of detox among patients in the lofexidine&#xD;
           arm relative to those in the benzodiazepine arm&#xD;
&#xD;
        -  Significantly lower mean craving score on the Visual Analogue Scale on day 3 and 4 of&#xD;
           detox among patients in the lofexidine arm relative to those in the benzodiazepine arm&#xD;
&#xD;
        -  Significantly longer stay (days) on the ward among patients in the lofexidine arm&#xD;
           relative to those in the benzodiazepine arm&#xD;
&#xD;
        -  Significantly lower anxiety and depression score on the MAP among patients in the&#xD;
           lofexidine arm relative to those in the benzodiazepine arm&#xD;
&#xD;
      Safety Assessment and Monitoring: After signing the informed consent, the subject will&#xD;
      undergo screening assessments to determine eligibility for study enrollment; the screen tests&#xD;
      include FBC, LFT, Renal function and 12-lead ECG, and urine pregnancy test if female. A&#xD;
      complete physical examination will be performed on the first day of screening. From Day 1&#xD;
      till discharge, Vital Signs (e.g. pulse rate, body temperature, blood pressure and&#xD;
      respiratory rate) will be closely monitored by the study nurses at the ward, i.e. immediately&#xD;
      prior to each lofexidine dose and in addition, 2 hours after the first dose of each dosing&#xD;
      day. Should patients show signs of hypotension, the nurse will inform the investigators and&#xD;
      they will determine whether or not it is necessary to terminate the patients' participation&#xD;
      in the trial. Patients will be required to repeat a 12-lead ECG test when they complete the&#xD;
      study or if they drop out of the study. If there is any significant finding from the repeat&#xD;
      ECG, it will be followed through by the investigators until resolved. All the adverse events&#xD;
      will be documented and followed through until resolved during the study period. The Regular&#xD;
      Study Safety Reports inclusive of patients' recruitment, AE/SAE will be generated&#xD;
      periodically and sent to an Independent Date &amp; Safety Monitoring Committee (DSMC) for review,&#xD;
      the DSMC comprise addiction medicine experts from outside of IMH. Individual patients or the&#xD;
      entire study will be discontinued if there is any major safety finding.&#xD;
&#xD;
      Sample Size and Statistical methods: The estimate of 122 subjects (61 per group) for the&#xD;
      sample size is based on the following assumptions - mean (SE) OOWS scores on day 4 of 2.4&#xD;
      (0.4000) and 3.9 (2.7713) for the lofexidine and diazepam groups respectively (which implies&#xD;
      an expected absolute treatment effect of 1.5), a power of 80%, and allowing for 30% of the&#xD;
      patients dropping out before their evaluation on day 4. Thirty percent dropout implies that&#xD;
      86 subjects (43 per group) are required to evaluate the benefit of lofexidine over diazepam.&#xD;
      The primary efficacy analysis will be done using the ITT dataset and the safety profile will&#xD;
      be described using the safety dataset. All analysis will be conducted by independent&#xD;
      statisticians (SCRI).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">July 2015</completion_date>
  <primary_completion_date type="Actual">July 2015</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>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To evaluate differences in OOWS (Objective Opiate Withdrawal Scale)</measure>
    <time_frame>on day 3 and day 4 during inpatient dotex</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>To evaluate differences in SOWS (Short Opiate Withdrawal Scale)</measure>
    <time_frame>on day 3 and day 4 during inpatient detox</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate differences in pupil sizes</measure>
    <time_frame>on days 3 and 4 of inpatient detox</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate differences in craving on the Visual Analogue Scale</measure>
    <time_frame>on days 3 and 4 of inpatient detox</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate differences in time to drop-out (length of stay on the ward)</measure>
    <time_frame>time to drop-out</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate differences in emotional/psychological symptoms</measure>
    <time_frame>every 3 days</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>To evaluate the safety of Lofexidine with opiate dependent patients undergoing inpatient detoxification in Singapore</measure>
    <time_frame>during 14 days of inpatient detox</time_frame>
    <description>Drop of blood pressure and low pulse rate will be our main safety outcome measures among all the adverse events in both the groups; it will be reported in tabular form.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">112</enrollment>
  <condition>Opiate Dependent Patients Who Are Undergoing Inpatient Detoxification in Singapore</condition>
  <arm_group>
    <arm_group_label>Lofexidine &amp; Diazepam Placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Initial Lofexidine dosage starts from 0.8mg per day, it will be gradually increased by increments of 0.4 to 0.8mg per day up to a maximum of 2.2mg daily. After 3 peak dose days, the dosage will be gradually decreased by 0.2 to 0.6mg per day till to 0.2mg of the last lofexidine dosage in Day 10.&#xD;
The Diazepam placebo will be administrated to the patients with the same frequency, time and number tablets of diazepam in the active comparator arm.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Diazepam &amp; Lofexidine Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The initial dosage of Diazepam is 10 mg per day on Day 1&amp;2, the dosage will be increased to 15 mg per day on Day 3&amp;4, subsequently decreased to 10mg per day on Day 5, 5mg per day on Day 6&amp;7, 2mg per day on Day 8&amp;9&amp;10.&#xD;
The Lofexidine placebo will be administrated to the patients with the same frequency, time and number tablets of lofexidine in the experimental arm.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lofexidine</intervention_name>
    <arm_group_label>Lofexidine &amp; Diazepam Placebo</arm_group_label>
    <other_name>BritLofex 0.2mg</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Diazepam</intervention_name>
    <arm_group_label>Diazepam &amp; Lofexidine Placebo</arm_group_label>
    <other_name>Apo-Diazepam 5mg and 2mg</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo for Lofexidine</intervention_name>
    <arm_group_label>Diazepam &amp; Lofexidine Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo for Diazepam</intervention_name>
    <arm_group_label>Lofexidine &amp; Diazepam Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients who meet the DSM-IV criteria for a diagnosis of opiate dependence (as&#xD;
             diagnosed by a NAMS psychiatrist).&#xD;
&#xD;
          2. Individuals are voluntarily undergoing inpatient opiate withdrawal treatment at the&#xD;
             National Addictions Management Service (NAMS).&#xD;
&#xD;
          3. Agreeable to participating in the clinical trial and will provide written consent.&#xD;
&#xD;
          4. Males or females who are between the ages of 21-55 years. The lower limit of 21 years&#xD;
             is in place because of lack of data on younger populations. The upper limit is set at&#xD;
             55 years as the likelihood of having co-morbid physical health problems is greater.&#xD;
&#xD;
          5. Individuals who have a positive urine screen for the presence of opiates (routinely&#xD;
             given on first visit to outpatient clinic).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Are investigator site personnel directly affiliated with this study and their&#xD;
             immediate families, immediate family is defined as a spouse, parent, child or sibling,&#xD;
             whether biological or legally adopted.&#xD;
&#xD;
          2. Are currently enrolled in, or discontinued within the last 30 days from another&#xD;
             clinical trial or medical research judged not to be scientifically or medically&#xD;
             compatible with this study.&#xD;
&#xD;
          3. A history of allergy/sensitivity to clonidine, lofexidine, imidazole derivatives (e.g.&#xD;
             clotrimazole, antifungal) or alpha-2-adrenergic medications.&#xD;
&#xD;
          4. Co-dependency on alcohol, benzodiazepines or any other drug that would require&#xD;
             detoxification.&#xD;
&#xD;
          5. A history of major physical illness (cardiovascular disease, cerebrovascular disease,&#xD;
             renal impairment, liver disease, epilepsy, symptomatic HIV, Hepatitis B and/or C).&#xD;
&#xD;
          6. Patients with major psychiatric illness (e.g. psychotic disorders, major depression).&#xD;
&#xD;
          7. Patients prescribed analgesic*(*: Opioid analgesic and similar narcotic analgesics),&#xD;
             antihypertensive, antiarrhythmic, or antiretroviral medication.&#xD;
&#xD;
          8. Baseline BP &gt; 140/90 mmHg or &lt; 85/55mmHg, and/or baseline PR &lt;55beats/min.&#xD;
&#xD;
          9. Significant abnormal finding from blood tests (FBC, LFT, Renal function) and ECG&#xD;
             during screening.&#xD;
&#xD;
         10. Pregnant or breast feeding.&#xD;
&#xD;
         11. Patients are receiving and not willing to stop the drugs which may cause prolong QT&#xD;
             interval and hypotension while using concomitant with Lofexidine, e.g. thioridazine,&#xD;
             chlorpromazine, tricyclic antidepressants.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Song Guo, Ph.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>NAMS IMH Singapore</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Addictions Management Service, Institute of Mental Health, Singapore</name>
      <address>
        <city>Singapore</city>
        <zip>539747</zip>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Singapore</country>
  </location_countries>
  <verification_date>August 2015</verification_date>
  <study_first_submitted>August 16, 2012</study_first_submitted>
  <study_first_submitted_qc>August 27, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 30, 2012</study_first_posted>
  <last_update_submitted>August 26, 2015</last_update_submitted>
  <last_update_submitted_qc>August 26, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 28, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Institute of Mental Health, Singapore</investigator_affiliation>
    <investigator_full_name>Dr. Guo Song</investigator_full_name>
    <investigator_title>Consultant, Head of Research, NAMS IMH</investigator_title>
  </responsible_party>
  <keyword>Opiate dependent</keyword>
  <keyword>inpatient detoxification</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lofexidine</mesh_term>
    <mesh_term>Clonidine</mesh_term>
    <mesh_term>Diazepam</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/NCT01675648
org study id: Lofex00428
nct id: NCT01675648
lead sponsor: 
collaborator: 
has dmc: Yes
In Singapore, opiate substitution medication e.g. methadone is only licensed for use with
      specific population. The standard treatment is one week of detoxification assisted with
      diazepam and symptomatic treatment followed by one week of rehabilitation. However, diazepam
      is highly addictive and widely abused among heroin users and pharmacologically, does not
      reduce the physical and psychological craving for opioids which can trigger relapse. Many
      opiate patients undergoing inpatient detoxification leave prematurely (i.e. PID: patient
      initiated discharge) because of the severity of unpleasant withdrawal symptoms. The purpose
      of the study is to establish an alternative medication to reduce opiate withdrawal symptoms
      for use in Singapore by evaluating the clinical efficacy of Lofexidine versus Diazepam in the
      management of the opiate withdrawal syndrome during inpatient detoxification.
Study Design: This is a randomized, double-blind (double-dummy design) phase IV clinical
      trial. Patients will be receiving 10 days of Lofexidine plus Diazepam placebo or Diazepam
      plus Lofexidine placebo. All the patients are expected to complete the 2-weeks inpatient
      detoxification programme at the NAMS ward. Up to 122 patients (61 in each randomized arm)
      will be enrolled into the study to ensure that at least 43 patients in each arm complete Day
      4 of study treatment programme.

      Efficacy Assessments: The primary efficacy outcome measure will be the Objective Opiate
      Withdrawal Scale (OOWS) scores (range = 0-13) on Day 3 and Day 4 of the treatment phase. The
      second efficacy outcome measure will be the Short Opiate Withdrawal Scale (SOWS), Opiate
      Craving visual analogue scale and Pupil size on Day 3 and Day 4, time to dropout (length of
      stay on the ward) and emotional/psychological symptoms measured every 3 days. Our expected
      study outcomes are as following:

        -  Significantly lower mean scores on the Objective Opiate Withdrawal Scale (OOWS) on day 3
           and 4 of detox among patients in the lofexidine arm relative to those in the
           benzodiazepine arm

        -  Significantly lower mean scores on the Subjective experience of opiate withdrawal scale
           (SOWS)on day 3 and 4 of detox among patients in the lofexidine arm relative to those in
           the benzodiazepine arm

        -  Significantly larger pupil size on day 3 and 4 of detox among patients in the lofexidine
           arm relative to those in the benzodiazepine arm

        -  Significantly lower mean craving score on the Visual Analogue Scale on day 3 and 4 of
           detox among patients in the lofexidine arm relative to those in the benzodiazepine arm

        -  Significantly longer stay (days) on the ward among patients in the lofexidine arm
           relative to those in the benzodiazepine arm

        -  Significantly lower anxiety and depression score on the MAP among patients in the
           lofexidine arm relative to those in the benzodiazepine arm

      Safety Assessment and Monitoring: After signing the informed consent, the subject will
      undergo screening assessments to determine eligibility for study enrollment; the screen tests
      include FBC, LFT, Renal function and 12-lead ECG, and urine pregnancy test if female. A
      complete physical examination will be performed on the first day of screening. From Day 1
      till discharge, Vital Signs (e.g. pulse rate, body temperature, blood pressure and
      respiratory rate) will be closely monitored by the study nurses at the ward, i.e. immediately
      prior to each lofexidine dose and in addition, 2 hours after the first dose of each dosing
      day. Should patients show signs of hypotension, the nurse will inform the investigators and
      they will determine whether or not it is necessary to terminate the patients' participation
      in the trial. Patients will be required to repeat a 12-lead ECG test when they complete the
      study or if they drop out of the study. If there is any significant finding from the repeat
      ECG, it will be followed through by the investigators until resolved. All the adverse events
      will be documented and followed through until resolved during the study period. The Regular
      Study Safety Reports inclusive of patients' recruitment, AE/SAE will be generated
      periodically and sent to an Independent Date & Safety Monitoring Committee (DSMC) for review,
      the DSMC comprise addiction medicine experts from outside of IMH. Individual patients or the
      entire study will be discontinued if there is any major safety finding.

      Sample Size and Statistical methods: The estimate of 122 subjects (61 per group) for the
      sample size is based on the following assumptions - mean (SE) OOWS scores on day 4 of 2.4
      (0.4000) and 3.9 (2.7713) for the lofexidine and diazepam groups respectively (which implies
      an expected absolute treatment effect of 1.5), a power of 80%, and allowing for 30% of the
      patients dropping out before their evaluation on day 4. Thirty percent dropout implies that
      86 subjects (43 per group) are required to evaluate the benefit of lofexidine over diazepam.
      The primary efficacy analysis will be done using the ITT dataset and the safety profile will
      be described using the safety dataset. All analysis will be conducted by independent
      statisticians (SCRI).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: To evaluate differences in OOWS (Objective Opiate Withdrawal Scale)
time frame: on day 3 and day 4 during inpatient dotex
measure: To evaluate differences in SOWS (Short Opiate Withdrawal Scale)
time frame: on day 3 and day 4 during inpatient detox
measure: To evaluate differences in pupil sizes
time frame: on days 3 and 4 of inpatient detox
measure: To evaluate differences in craving on the Visual Analogue Scale
time frame: on days 3 and 4 of inpatient detox
measure: To evaluate differences in time to drop-out (length of stay on the ward)
time frame: time to drop-out
measure: To evaluate differences in emotional/psychological symptoms
time frame: every 3 days
measure: To evaluate the safety of Lofexidine with opiate dependent patients undergoing inpatient detoxification in Singapore
time frame: during 14 days of inpatient detox
description: Drop of blood pressure and low pulse rate will be our main safety outcome measures among all the adverse events in both the groups; it will be reported in tabular form.
arm group label: Lofexidine & Diazepam Placebo
arm group type: Experimental
description: Initial Lofexidine dosage starts from 0.8mg per day, it will be gradually increased by increments of 0.4 to 0.8mg per day up to a maximum of 2.2mg daily. After 3 peak dose days, the dosage will be gradually decreased by 0.2 to 0.6mg per day till to 0.2mg of the last lofexidine dosage in Day 10.
The Diazepam placebo will be administrated to the patients with the same frequency, time and number tablets of diazepam in the active comparator arm.
arm group label: Diazepam & Lofexidine Placebo
arm group type: Active Comparator
description: The initial dosage of Diazepam is 10 mg per day on Day 1&2, the dosage will be increased to 15 mg per day on Day 3&4, subsequently decreased to 10mg per day on Day 5, 5mg per day on Day 6&7, 2mg per day on Day 8&9&10.
The Lofexidine placebo will be administrated to the patients with the same frequency, time and number tablets of lofexidine in the experimental arm.
intervention type: Drug
intervention name: Lofexidine
arm group label: Lofexidine & Diazepam Placebo
other name: BritLofex 0.2mg
intervention type: Drug
intervention name: Diazepam
arm group label: Diazepam & Lofexidine Placebo
other name: Apo-Diazepam 5mg and 2mg
intervention type: Drug
intervention name: Placebo for Lofexidine
arm group label: Diazepam & Lofexidine Placebo
intervention type: Drug
intervention name: Placebo for Diazepam
arm group label: Lofexidine & Diazepam Placebo
criteria: 
gender: All
minimum age: 21 Years
maximum age: 55 Years
healthy volunteers: No
last name: Song Guo, Ph.D
role: Principal Investigator
affiliation: NAMS IMH Singapore
facility: 
country: Singapore
responsible party type: Principal Investigator
investigator affiliation: Institute of Mental Health, Singapore
investigator full name: Dr. Guo Song
investigator title: Consultant, Head of Research, NAMS IMH
mesh term: Lofexidine
mesh term: Clonidine
mesh term: Diazepam