<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/NCT01682278</url>
  </required_header>
  <id_info>
    <org_study_id>REK2012/331</org_study_id>
    <nct_id>NCT01682278</nct_id>
  </id_info>
  <brief_title>Prospective Cohort Study of Health Complaints</brief_title>
  <official_title>Amalgam Removal in Patients With Health Complaints Attributed to Amalgam Restorations: A Prospective Cohort Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>NORCE Norwegian Research Centre AS</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Bergen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Research Centre of Complementary and Alternative Medicine, Norway</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Witten/Herdecke</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>NORCE Norwegian Research Centre AS</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of this study is to evaluate if amalgam removal is associated with improved&#xD;
      self-reported health, compared to no amalgam removal. The main target group consists of a&#xD;
      group of patients with medically unexplained physical symptoms (MUPS), which they attribute&#xD;
      to dental amalgam restorations. The patients should furthermore express the wish to have&#xD;
      these amalgam fillings removed. The project is designed as a prospective cohort study,&#xD;
      consisting of three groups recruited separately. The main target group will be compared with&#xD;
      two comparison groups: one group of patients with MUPS recruited from general practice and&#xD;
      one group of healthy study patients, recruited at dental practice. The primary research&#xD;
      question is if amalgam removal is associated with improved self-reported health, compared to&#xD;
      no amalgam removal, one year after completed amalgam removal.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In Norway 5%-8% of the adult population believe that their amalgam fillings have affected&#xD;
      their health adversely; and a similar proportion of the adult population has had their&#xD;
      amalgam fillings removed for health reasons only. The Norwegian Ministry of Health and Care&#xD;
      Services has decided to fund a project comprising experimental treatment (i.e. removal of&#xD;
      amalgam fillings) for patients with health complaints which they attribute to dental amalgam.&#xD;
      The aim of this study is to evaluate the intervention by measuring health complaints and&#xD;
      quality of life before and after amalgam removal and to compare changes over time with&#xD;
      relevant patient groups. Amalgam-attributed health complaints are heterogeneous and a variety&#xD;
      of symptoms have been attributed to amalgam. Therefore, amalgam related health complaints are&#xD;
      difficult to quantify. However, amalgam-attributed health complaints are largely similar to&#xD;
      complaints experienced by patients with so called &quot;medically unexplained physical symptoms&quot;&#xD;
      (MUPS). Therefore, in order to operationalize and measure the patient's subjective health&#xD;
      complaints, the MUPS criteria and questionnaire will be applied to patients who attribute&#xD;
      their health problems to amalgam. Furthermore, this strategy allows for the inclusion of&#xD;
      patients suffering from MUPS, however without any attribution to amalgam. This group of&#xD;
      patients can serve as a comparison group with a similar symptom load, but no subjective&#xD;
      attribution to amalgam. For the interpretation of the study outcome, the natural course of&#xD;
      the health complaints in this group is of high importance.&#xD;
&#xD;
      Therefore, the project is designed as a prospective cohort study, consisting of three groups&#xD;
      recruited separately. The two comparison groups consist of one group of patients with MUPS&#xD;
      recruited from general practice and one group of healthy study patients, recruited at dental&#xD;
      practice. These study participants are recruited regardless of amalgam status. The main&#xD;
      target group consists of a group of patients with medically unexplained physical symptoms,&#xD;
      which they attribute to dental amalgam restorations. The patients should furthermore express&#xD;
      the wish to have these amalgam fillings removed (&quot;amalgam cohort&quot;). Patients with amalgam&#xD;
      attributed health complaints who suffer from medically explained disease but attribute their&#xD;
      diagnosis and course of the disease to amalgam (thus, not included in the amalgam cohort),&#xD;
      will be included in a separate case series (&quot;amalgam - case series&quot;, to be registered as a&#xD;
      separate study).&#xD;
&#xD;
      Patients in the &quot;amalgam cohort&quot; will have all amalgam fillings removed according to&#xD;
      pre-defined criteria. Amalgam removal will be performed by the patient's regular dentist or&#xD;
      another dentist chosen by the patient. After completed removal, patients in the amalgam&#xD;
      groups will be examined at a Regional Dental Center of Competence. The costs of amalgam&#xD;
      removal will be reimbursed according to pre-defined rules.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 2012</start_date>
  <completion_date type="Actual">June 30, 2021</completion_date>
  <primary_completion_date type="Actual">November 2018</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Self-reported health complaints - General index</measure>
    <time_frame>1 year follow-up after completed amalgam removal</time_frame>
    <description>Primary outcome is the general index from &quot;Self-reported health complaints&quot; (used by Sjursen et al 2011) at 1 year follow-up after completed amalgam removal. Changes from baseline to 1 year follow-up after amalgam removal of the amalgam cohort will be compared with changes in the MUPS-cohort from baseline to 2 year follow-up.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>GBB-24, total score</measure>
    <time_frame>1 and 5 year follow-up after completed amalgam removal</time_frame>
    <description>Change score at 1 and 5 year follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SF-36 Health Survey</measure>
    <time_frame>1 and 5 year follow-up after completed amalgam removal</time_frame>
    <description>Change score at 1 and 5 year follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Munich amalgam checklist</measure>
    <time_frame>1 and 5 year follow-up after completed amalgam removal</time_frame>
    <description>Change score at 1 and 5 year follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cantril Ladder Scale</measure>
    <time_frame>1 and 5 year follow-up after completed amalgam removal</time_frame>
    <description>Change score at 1 and 5 year follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Integrative Medicine Outcomes Scale</measure>
    <time_frame>1 and 5 year follow-up after completed amalgam removal</time_frame>
    <description>Change score at 1 and 5 year follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diagnostic criteria for BDS</measure>
    <time_frame>1 and 5 year follow-up after completed amalgam removal</time_frame>
    <description>Fulfillment of diagnostic criteria for BDS at baseline and follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Whiteley index</measure>
    <time_frame>1 and 5 year follow-up after completed amalgam removal</time_frame>
    <description>Change score at 1 and 5 year follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HADS</measure>
    <time_frame>1 and 5 year follow-up after completed amalgam removal</time_frame>
    <description>Change score at 1 and 5 year follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reclassification of symptoms</measure>
    <time_frame>1 and 5 year follow-up after completed amalgam removal</time_frame>
    <description>Reclassification of symptoms from MUPS to symptoms from explained organic disease at follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentration of mercury in plasma</measure>
    <time_frame>1 year follow-up after completed amalgam removal</time_frame>
    <description>Change from baseline to 1 and 5 year follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentration of cytokines in plasma</measure>
    <time_frame>1 year follow-up after completed amalgam removal</time_frame>
    <description>Change from baseline to 1 and 5 year follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported health complaints - General index</measure>
    <time_frame>5 year follow-up after completed amalgam removal</time_frame>
    <description>Change from baseline to 5 year follow-up</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Health resource use</measure>
    <time_frame>1 and 5 year follow-up after completed amalgam removal</time_frame>
    <description>Change from baseline to 1 and 5 year follow-up</description>
  </other_outcome>
  <other_outcome>
    <measure>Sick leave</measure>
    <time_frame>1 and 5 year follow-up after completed amalgam removal</time_frame>
    <description>Change from baseline to 1 and 5 year follow-up</description>
  </other_outcome>
  <other_outcome>
    <measure>Costs</measure>
    <time_frame>1 and 5 year follow-up after completed amalgam removal</time_frame>
    <description>Change from baseline to 1 and 5 year follow-up</description>
  </other_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">118</enrollment>
  <condition>Health Complaints Attributed to Dental Amalgam Restorations</condition>
  <arm_group>
    <arm_group_label>Amalgam cohort</arm_group_label>
    <description>Patients with medically unexplained physical symptoms attributed to dental amalgam restorations which the patient wish to have removed.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>MUPS-cohort</arm_group_label>
    <description>Patients with medically unexplained physical symptoms without attribution to amalgam and no explicit wish to remove amalgam.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dental cohort</arm_group_label>
    <description>Healthy comparison group: Subjectively healthy without diagnosed chronic disease or prescribed medication.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Removal of dental amalgam restorations</intervention_name>
    <description>Patients in the &quot;amalgam cohort&quot; will have all dental amalgam restorations removed and replaced with other restorative materials used in modern dentistry. Amalgam removal will be performed by the patient's regular dentist or another dentist chosen by the patient.</description>
    <arm_group_label>Amalgam cohort</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Serum&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        The study population will be selected from primary care clinics and dental clinics in&#xD;
        Norway.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria (all groups):&#xD;
&#xD;
          -  permanent residents in Norway&#xD;
&#xD;
          -  able to comply with the protocol&#xD;
&#xD;
        Amalgam Cohort:&#xD;
&#xD;
          -  Health complaints attributed (by the patient) to dental amalgam restorations&#xD;
&#xD;
          -  duration of the health complaints attributed to amalgam restorations (by the patient)&#xD;
             at least 3 months&#xD;
&#xD;
          -  presence of at least one amalgam filling&#xD;
&#xD;
          -  the patient has expressed a wish to have all amalgam fillings removed&#xD;
&#xD;
          -  patient examined by patient's physician and dentist according to guidelines from the&#xD;
             Norwegian Directorate of Health&#xD;
&#xD;
          -  diagnosed diseases adequately treated&#xD;
&#xD;
          -  patient's general practitioner/family physician and dentist assess that the patient's&#xD;
             general health and dental health most likely will not deteriorate due to participation&#xD;
             in the project&#xD;
&#xD;
          -  patient's dentist assess that there are no major risks for dental complications&#xD;
             following amalgam removal (e.g. need for root canal treatments or extractions)&#xD;
&#xD;
          -  subjective symptoms without corresponding objective findings after medical&#xD;
             examination(s), including symptoms not explained by patient's diagnoses,&#xD;
&#xD;
          -  moderate or severe functional impairment (assessed by the physician)&#xD;
&#xD;
        MUPS-cohort:&#xD;
&#xD;
          -  duration of unspecific health complaints at least 3 months&#xD;
&#xD;
          -  subjective symptoms without corresponding objective findings after medical&#xD;
             examination(s), including symptoms not explained by patient's diagnoses&#xD;
&#xD;
          -  moderate or severe functional impairment (assessed by the physician)&#xD;
&#xD;
          -  diagnosed diseases adequately treated&#xD;
&#xD;
          -  no attribution to amalgam and no explicit wish to remove amalgam&#xD;
&#xD;
        Dental cohort:&#xD;
&#xD;
          -  subjectively healthy without diagnosed chronic disease or prescribed medication&#xD;
&#xD;
        Exclusion Criteria (all groups):&#xD;
&#xD;
          -  pregnancy (or planned pregnancy) and lactation&#xD;
&#xD;
          -  life threatening disease&#xD;
&#xD;
          -  patients with ongoing cancers, severe cardiopulmonary, neurological, or psychiatric&#xD;
             diseases (assessed by GP)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lars Björkman, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>NORCE Norwegian Research Centre AS</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Uni Health</name>
      <address>
        <city>Bergen</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Norway</country>
  </location_countries>
  <results_reference>
    <citation>Bjorkman L, Musial F, Alraek T, Werner EL, Weidenhammer W, Hamre HJ. Removal of dental amalgam restorations in patients with health complaints attributed to amalgam: A prospective cohort study. J Oral Rehabil. 2020 Nov;47(11):1422-1434. doi: 10.1111/joor.13080. Epub 2020 Aug 30.</citation>
    <PMID>32810306</PMID>
  </results_reference>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>September 5, 2012</study_first_submitted>
  <study_first_submitted_qc>September 5, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 10, 2012</study_first_posted>
  <last_update_submitted>March 16, 2022</last_update_submitted>
  <last_update_submitted_qc>March 16, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 31, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Health complaints</keyword>
  <keyword>Amalgam</keyword>
  <keyword>Mercury</keyword>
  <keyword>Plasma</keyword>
  <keyword>Cytokine</keyword>
  <!-- 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/NCT01682278
org study id: REK2012/331
nct id: NCT01682278
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
The aim of this study is to evaluate if amalgam removal is associated with improved
      self-reported health, compared to no amalgam removal. The main target group consists of a
      group of patients with medically unexplained physical symptoms (MUPS), which they attribute
      to dental amalgam restorations. The patients should furthermore express the wish to have
      these amalgam fillings removed. The project is designed as a prospective cohort study,
      consisting of three groups recruited separately. The main target group will be compared with
      two comparison groups: one group of patients with MUPS recruited from general practice and
      one group of healthy study patients, recruited at dental practice. The primary research
      question is if amalgam removal is associated with improved self-reported health, compared to
      no amalgam removal, one year after completed amalgam removal.
In Norway 5%-8% of the adult population believe that their amalgam fillings have affected
      their health adversely; and a similar proportion of the adult population has had their
      amalgam fillings removed for health reasons only. The Norwegian Ministry of Health and Care
      Services has decided to fund a project comprising experimental treatment (i.e. removal of
      amalgam fillings) for patients with health complaints which they attribute to dental amalgam.
      The aim of this study is to evaluate the intervention by measuring health complaints and
      quality of life before and after amalgam removal and to compare changes over time with
      relevant patient groups. Amalgam-attributed health complaints are heterogeneous and a variety
      of symptoms have been attributed to amalgam. Therefore, amalgam related health complaints are
      difficult to quantify. However, amalgam-attributed health complaints are largely similar to
      complaints experienced by patients with so called "medically unexplained physical symptoms"
      (MUPS). Therefore, in order to operationalize and measure the patient's subjective health
      complaints, the MUPS criteria and questionnaire will be applied to patients who attribute
      their health problems to amalgam. Furthermore, this strategy allows for the inclusion of
      patients suffering from MUPS, however without any attribution to amalgam. This group of
      patients can serve as a comparison group with a similar symptom load, but no subjective
      attribution to amalgam. For the interpretation of the study outcome, the natural course of
      the health complaints in this group is of high importance.

      Therefore, the project is designed as a prospective cohort study, consisting of three groups
      recruited separately. The two comparison groups consist of one group of patients with MUPS
      recruited from general practice and one group of healthy study patients, recruited at dental
      practice. These study participants are recruited regardless of amalgam status. The main
      target group consists of a group of patients with medically unexplained physical symptoms,
      which they attribute to dental amalgam restorations. The patients should furthermore express
      the wish to have these amalgam fillings removed ("amalgam cohort"). Patients with amalgam
      attributed health complaints who suffer from medically explained disease but attribute their
      diagnosis and course of the disease to amalgam (thus, not included in the amalgam cohort),
      will be included in a separate case series ("amalgam - case series", to be registered as a
      separate study).

      Patients in the "amalgam cohort" will have all amalgam fillings removed according to
      pre-defined criteria. Amalgam removal will be performed by the patient's regular dentist or
      another dentist chosen by the patient. After completed removal, patients in the amalgam
      groups will be examined at a Regional Dental Center of Competence. The costs of amalgam
      removal will be reimbursed according to pre-defined rules.
observational model: Cohort
time perspective: Prospective
measure: Self-reported health complaints - General index
time frame: 1 year follow-up after completed amalgam removal
description: Primary outcome is the general index from "Self-reported health complaints" (used by Sjursen et al 2011) at 1 year follow-up after completed amalgam removal. Changes from baseline to 1 year follow-up after amalgam removal of the amalgam cohort will be compared with changes in the MUPS-cohort from baseline to 2 year follow-up.
measure: GBB-24, total score
time frame: 1 and 5 year follow-up after completed amalgam removal
description: Change score at 1 and 5 year follow-up
measure: SF-36 Health Survey
time frame: 1 and 5 year follow-up after completed amalgam removal
description: Change score at 1 and 5 year follow-up
measure: Munich amalgam checklist
time frame: 1 and 5 year follow-up after completed amalgam removal
description: Change score at 1 and 5 year follow-up
measure: Cantril Ladder Scale
time frame: 1 and 5 year follow-up after completed amalgam removal
description: Change score at 1 and 5 year follow-up
measure: Integrative Medicine Outcomes Scale
time frame: 1 and 5 year follow-up after completed amalgam removal
description: Change score at 1 and 5 year follow-up
measure: Diagnostic criteria for BDS
time frame: 1 and 5 year follow-up after completed amalgam removal
description: Fulfillment of diagnostic criteria for BDS at baseline and follow-up
measure: Whiteley index
time frame: 1 and 5 year follow-up after completed amalgam removal
description: Change score at 1 and 5 year follow-up
measure: HADS
time frame: 1 and 5 year follow-up after completed amalgam removal
description: Change score at 1 and 5 year follow-up
measure: Reclassification of symptoms
time frame: 1 and 5 year follow-up after completed amalgam removal
description: Reclassification of symptoms from MUPS to symptoms from explained organic disease at follow-up
measure: Concentration of mercury in plasma
time frame: 1 year follow-up after completed amalgam removal
description: Change from baseline to 1 and 5 year follow-up
measure: Concentration of cytokines in plasma
time frame: 1 year follow-up after completed amalgam removal
description: Change from baseline to 1 and 5 year follow-up
measure: Self-reported health complaints - General index
time frame: 5 year follow-up after completed amalgam removal
description: Change from baseline to 5 year follow-up
measure: Health resource use
time frame: 1 and 5 year follow-up after completed amalgam removal
description: Change from baseline to 1 and 5 year follow-up
measure: Sick leave
time frame: 1 and 5 year follow-up after completed amalgam removal
description: Change from baseline to 1 and 5 year follow-up
measure: Costs
time frame: 1 and 5 year follow-up after completed amalgam removal
description: Change from baseline to 1 and 5 year follow-up
arm group label: Amalgam cohort
description: Patients with medically unexplained physical symptoms attributed to dental amalgam restorations which the patient wish to have removed.
arm group label: MUPS-cohort
description: Patients with medically unexplained physical symptoms without attribution to amalgam and no explicit wish to remove amalgam.
arm group label: Dental cohort
description: Healthy comparison group: Subjectively healthy without diagnosed chronic disease or prescribed medication.
intervention type: Device
intervention name: Removal of dental amalgam restorations
description: Patients in the "amalgam cohort" will have all dental amalgam restorations removed and replaced with other restorative materials used in modern dentistry. Amalgam removal will be performed by the patient's regular dentist or another dentist chosen by the patient.
arm group label: Amalgam cohort
Serum
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 20 Years
maximum age: 70 Years
healthy volunteers: No
last name: Lars Björkman, PhD
role: Principal Investigator
affiliation: NORCE Norwegian Research Centre AS
facility: 
country: Norway
citation: Bjorkman L, Musial F, Alraek T, Werner EL, Weidenhammer W, Hamre HJ. Removal of dental amalgam restorations in patients with health complaints attributed to amalgam: A prospective cohort study. J Oral Rehabil. 2020 Nov;47(11):1422-1434. doi: 10.1111/joor.13080. Epub 2020 Aug 30.
PMID: 32810306
responsible party type: Sponsor