<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/NCT02993289</url>
  </required_header>
  <id_info>
    <org_study_id>H-16029763</org_study_id>
    <nct_id>NCT02993289</nct_id>
  </id_info>
  <brief_title>Is Detoxification Needed in Medication-overuse Headache?</brief_title>
  <acronym>DEFINE3</acronym>
  <official_title>Is Detoxification Needed in Medication-overuse Headache?: A Randomized Controlled Trial of 3 Treatment Strategies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Danish Headache Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Danish Headache Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Medication-overuse headache (MOH) is a disabling condition, yet treatable. According to&#xD;
      European guidelines and based on evidence, multidisciplinary detoxification is the first&#xD;
      choice of treatment for MOH. However, consensus about the details in such detoxification&#xD;
      programs is lacking. Contrary, other headache specialists believe more in treating chronic&#xD;
      headache with medication overuse with single-therapy of prophylaxis and no withdrawal of&#xD;
      acute medication, based on randomized controlled double-blinded placebo trial with&#xD;
      prophylaxes. Only a single RCT has compared single-therapy with prophylaxis to&#xD;
      detoxification. However there was no significant difference.&#xD;
&#xD;
      AIM:&#xD;
&#xD;
        1. To compare three different treatment protocols in order to improve the therapy of MOH.&#xD;
&#xD;
        2. To test several baseline variables for being potential predictors for good treatment&#xD;
           outcome.&#xD;
&#xD;
        3. To examine the role of epigenetics in MOH.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">October 24, 2016</start_date>
  <completion_date type="Anticipated">November 30, 2023</completion_date>
  <primary_completion_date type="Actual">July 2, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Reduction in headache days per month in group A and C compared to group B.</measure>
    <time_frame>Six months follow-up</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Reduction in headache days per month</measure>
    <time_frame>Two and 12 months follow-up and 4 years</time_frame>
    <description>Group A and C versus group B.&#xD;
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).&#xD;
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reduction in days/month with use of analgesics and/or migraine medication.</measure>
    <time_frame>Two, 6 and 12 months follow-up and 4 years</time_frame>
    <description>Group A and C versus group B.&#xD;
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).&#xD;
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Responders based on reduction in headache days / month (percentage with more than 30%, 50% and 75%).</measure>
    <time_frame>Two, 6 and 12 months follow-up and 4 years</time_frame>
    <description>Group A and C versus group B.&#xD;
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).&#xD;
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reduction in headache intensity.</measure>
    <time_frame>Two, 6 and 12 months follow-up and 4 years</time_frame>
    <description>Group A and C versus group B.&#xD;
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).&#xD;
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).&#xD;
This outcome will be presented as 1) Total headache intensity per month, and as 2) Visual Analogue Scale (VAS).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Descriptive report of self-reported adverse effects of treatments.</measure>
    <time_frame>Two, 6 and 12 months follow-up</time_frame>
    <description>Group A and C versus group B.&#xD;
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).&#xD;
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Headache Under-Response to Treatment (HURT)-score.</measure>
    <time_frame>Two, 6 and 12 months follow-up</time_frame>
    <description>Group A and C versus group B.&#xD;
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).&#xD;
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Drop-out rate.</measure>
    <time_frame>One, 2, 4, 6, 9 and 12 months follow-up and 4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Hospital Anxiety and Depression Scale (HADS).</measure>
    <time_frame>Six and 12 months follow-up</time_frame>
    <description>Group A and C versus group B.&#xD;
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).&#xD;
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Quality of Life (QoL) score.</measure>
    <time_frame>Six and 12 months follow-up</time_frame>
    <description>Group A and C versus group B.&#xD;
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).&#xD;
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Severity of Dependence Score (SDS).</measure>
    <time_frame>Six and 12 months follow-up</time_frame>
    <description>Group A and C versus group B.&#xD;
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).&#xD;
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Perceived Stress Score (PSS).</measure>
    <time_frame>Twelve months follow-up.</time_frame>
    <description>Group A and C versus group B.&#xD;
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).&#xD;
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient's satisfaction questionnaire</measure>
    <time_frame>Two, 6 and 12 months follow-up</time_frame>
    <description>Group A and C versus group B.&#xD;
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).&#xD;
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Difference in DNA-profile between patients with MOH and controlgroups.</measure>
    <time_frame>Baseline</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Difference in methylation levels and RNA sequence analysis in patients with MOH undergoing treatment compared to controls.</measure>
    <time_frame>From baseline to 6 months follow-up</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Analysis of association between methylation levels and treatment outcome defined as 1) reduction in headache days per month at 6 months and 12 months and 2) percent of cured vs. percent of relapsers after 12 months.</measure>
    <time_frame>At 6 and 12 months follow-up</time_frame>
  </other_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Anticipated">115</enrollment>
  <condition>Medication Overuse Headache</condition>
  <arm_group>
    <arm_group_label>Detoxification and pharmacological prophylactic treatment</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Group A: Two months detoxification program combined with pharmacological prophylactic treatment from start.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pharmacological prophylactic treatment</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Pharmacological prophylactic treatment from start without detoxification.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Detoxification</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Two months detoxification program with postponed pharmacological prophylactic treatment after ended detoxification.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group 1: Episodic migraine</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group 2: Healthy volunteers</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Different well-known treatments</intervention_name>
    <arm_group_label>Detoxification</arm_group_label>
    <arm_group_label>Detoxification and pharmacological prophylactic treatment</arm_group_label>
    <arm_group_label>Pharmacological prophylactic treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Patients with medication-overuse headache:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Confirmed MOH diagnosis according to the ICHD-III beta (1).&#xD;
&#xD;
          -  Eligible for outpatient treatment based on type of medication overuse (without massive&#xD;
             pure opioids and barbiturates overuse), and personal resources and motivation.&#xD;
&#xD;
          -  Capable of completing headache diary/calendar.&#xD;
&#xD;
          -  Age ≥ 18 years old and capable of providing informed consent.&#xD;
&#xD;
          -  Medication-overuse headache based on initial tension-type headache (TTH) or migraine.&#xD;
&#xD;
          -  Signed informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severe physical illness or psychiatric disorders.&#xD;
&#xD;
          -  Addiction to alcohol or other drugs.&#xD;
&#xD;
          -  Current treatment with headache prophylaxis. Patients can be included minimum 5 weeks&#xD;
             after stop of prophylaxis.&#xD;
&#xD;
          -  Pregnancy, breastfeeding or planned pregnancy within the next 12 months.&#xD;
&#xD;
          -  Inability to provide reliable information about medical history.&#xD;
&#xD;
        Criteria for Control group 1 - Episodic migraineurs:&#xD;
&#xD;
          -  Episodic migraine, with/without concomitant tension-type headache, according to the&#xD;
             ICHD-III beta.&#xD;
&#xD;
          -  Headache days / month ≤ 6 at time of inclusion.&#xD;
&#xD;
          -  Days with analgesics / month ≤ 6 at time of inclusion.&#xD;
&#xD;
          -  Prophylactics are allowed.&#xD;
&#xD;
          -  Age ≥ 18 years old.&#xD;
&#xD;
          -  Ability to fill out headache calendar.&#xD;
&#xD;
          -  No previous medication overuse.&#xD;
&#xD;
          -  No significant co-morbid pain, physical or psychiatric disorders.&#xD;
&#xD;
          -  No addiction to alcohol or drug-abuse.&#xD;
&#xD;
          -  No pregnancy, breastfeeding or planned pregnancy within the next 12 months.&#xD;
&#xD;
        Criteria for Control group 2 - Healthy volunteers:&#xD;
&#xD;
        •≥ 2 days with headache in the past month at time of inclusion.&#xD;
&#xD;
          -  Days with analgesics / month ≤ 6 at time of inclusion.&#xD;
&#xD;
          -  Age ≥ 18 years old.&#xD;
&#xD;
          -  No significant co-morbid pain, physical or psychiatric disorders.&#xD;
&#xD;
          -  No addiction to alcohol or drug-abuse.&#xD;
&#xD;
          -  No pregnancy, breastfeeding or planned pregnancy within the next 12 months.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Danish Headache Center</name>
      <address>
        <city>Glostrup</city>
        <state>Copenhagen</state>
        <zip>2600</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>December 8, 2016</study_first_submitted>
  <study_first_submitted_qc>December 12, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 15, 2016</study_first_posted>
  <last_update_submitted>June 9, 2020</last_update_submitted>
  <last_update_submitted_qc>June 9, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 11, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Danish Headache Center</investigator_affiliation>
    <investigator_full_name>Louise Carlsen</investigator_full_name>
    <investigator_title>Medical doctor, PhD-student</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Headache Disorders, Secondary</mesh_term>
    <mesh_term>Headache</mesh_term>
  </condition_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/NCT02993289
org study id: H-16029763
nct id: NCT02993289
lead sponsor: 
has dmc: No
Medication-overuse headache (MOH) is a disabling condition, yet treatable. According to
      European guidelines and based on evidence, multidisciplinary detoxification is the first
      choice of treatment for MOH. However, consensus about the details in such detoxification
      programs is lacking. Contrary, other headache specialists believe more in treating chronic
      headache with medication overuse with single-therapy of prophylaxis and no withdrawal of
      acute medication, based on randomized controlled double-blinded placebo trial with
      prophylaxes. Only a single RCT has compared single-therapy with prophylaxis to
      detoxification. However there was no significant difference.

      AIM:

        1. To compare three different treatment protocols in order to improve the therapy of MOH.

        2. To test several baseline variables for being potential predictors for good treatment
           outcome.

        3. To examine the role of epigenetics in MOH.
allocation: Randomized
intervention model: Factorial Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Reduction in headache days per month in group A and C compared to group B.
time frame: Six months follow-up
measure: Reduction in headache days per month
time frame: Two and 12 months follow-up and 4 years
description: Group A and C versus group B.
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).
measure: Reduction in days/month with use of analgesics and/or migraine medication.
time frame: Two, 6 and 12 months follow-up and 4 years
description: Group A and C versus group B.
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).
measure: Responders based on reduction in headache days / month (percentage with more than 30%, 50% and 75%).
time frame: Two, 6 and 12 months follow-up and 4 years
description: Group A and C versus group B.
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).
measure: Reduction in headache intensity.
time frame: Two, 6 and 12 months follow-up and 4 years
description: Group A and C versus group B.
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).
This outcome will be presented as 1) Total headache intensity per month, and as 2) Visual Analogue Scale (VAS).
measure: Descriptive report of self-reported adverse effects of treatments.
time frame: Two, 6 and 12 months follow-up
description: Group A and C versus group B.
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).
measure: Changes in Headache Under-Response to Treatment (HURT)-score.
time frame: Two, 6 and 12 months follow-up
description: Group A and C versus group B.
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).
measure: Drop-out rate.
time frame: One, 2, 4, 6, 9 and 12 months follow-up and 4 years
measure: Changes in Hospital Anxiety and Depression Scale (HADS).
time frame: Six and 12 months follow-up
description: Group A and C versus group B.
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).
measure: Changes in Quality of Life (QoL) score.
time frame: Six and 12 months follow-up
description: Group A and C versus group B.
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).
measure: Changes in Severity of Dependence Score (SDS).
time frame: Six and 12 months follow-up
description: Group A and C versus group B.
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).
measure: Changes in Perceived Stress Score (PSS).
time frame: Twelve months follow-up.
description: Group A and C versus group B.
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).
measure: Patient's satisfaction questionnaire
time frame: Two, 6 and 12 months follow-up
description: Group A and C versus group B.
Group A (detoxification with prophylaxis) versus group C (detoxification with postponed prophylaxis).
Group B (single-therapy with prophylaxis) versus group C (detoxification with postponed prophylaxis).
measure: Difference in DNA-profile between patients with MOH and controlgroups.
time frame: Baseline
measure: Difference in methylation levels and RNA sequence analysis in patients with MOH undergoing treatment compared to controls.
time frame: From baseline to 6 months follow-up
measure: Analysis of association between methylation levels and treatment outcome defined as 1) reduction in headache days per month at 6 months and 12 months and 2) percent of cured vs. percent of relapsers after 12 months.
time frame: At 6 and 12 months follow-up
arm group label: Detoxification and pharmacological prophylactic treatment
arm group type: Active Comparator
description: Group A: Two months detoxification program combined with pharmacological prophylactic treatment from start.
arm group label: Pharmacological prophylactic treatment
arm group type: Active Comparator
description: Pharmacological prophylactic treatment from start without detoxification.
arm group label: Detoxification
arm group type: Active Comparator
description: Two months detoxification program with postponed pharmacological prophylactic treatment after ended detoxification.
arm group label: Control group 1: Episodic migraine
arm group type: No Intervention
arm group label: Control group 2: Healthy volunteers
arm group type: No Intervention
intervention type: Other
intervention name: Different well-known treatments
arm group label: Detoxification
arm group label: Detoxification and pharmacological prophylactic treatment
arm group label: Pharmacological prophylactic treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Denmark
responsible party type: Principal Investigator
investigator affiliation: Danish Headache Center
investigator full name: Louise Carlsen
investigator title: Medical doctor, PhD-student
mesh term: Headache Disorders, Secondary
mesh term: Headache