<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/NCT04439669</url>
  </required_header>
  <id_info>
    <org_study_id>TYH20162222</org_study_id>
    <nct_id>NCT04439669</nct_id>
  </id_info>
  <brief_title>CRPS - Diagnostics, Pathophysiological Mechanisms, and Response to Treatment With Noninvasive Brain Stimulation</brief_title>
  <official_title>Complex Regional Pain Syndrome - Diagnostics, Pathophysiological Mechanisms, and Response to Treatment With Noninvasive Brain Stimulation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Helsinki University Central Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Turku University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Helsinki University Central Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a sham controlled, randomized, double-blind, navigated repetitive Transcranial&#xD;
      Magnetic Stimulation (nrTMS) study for the treatment of complex regional pain syndrome (CRPS&#xD;
      types 1 and 2). The investigators study factors that may contribute to development,&#xD;
      maintenance, or treatment responses with clinical, sleep, and psychiatric questionnaires and&#xD;
      clinical examinations, quantitative sensory testing and neurophysiologic recordings,&#xD;
      genetics, and MRI techniques.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      rTMS hypothetically disrupts the default networks related to chronic pain and renders the&#xD;
      brain more susceptible to drugs, rehabilitation, or cognitive behavioral therapy. In&#xD;
      addition, there is experimental evidence that rTMS releases factors that are involved in&#xD;
      endogenous top-down modulation of pain and neural plasticity. Thus, the analgesic effect of&#xD;
      rTMS may be mediated via enforcing endogenous pain control systems at the brain level, in&#xD;
      addition to its effects on neuroplastic effects.&#xD;
&#xD;
      For active, navigated stimulation targets the investigators have the parietal opercular&#xD;
      cortex overlying the secondary somatosensory cortex (&quot;S2&quot;) and the primary motor cortex (M1).&#xD;
&#xD;
      The investigators randomize participants to first receive nrTMS to the right &quot;S2&quot; or sham&#xD;
      stimulation. After ten sessions the investigators follow up the participants up to three&#xD;
      months. At three months, if the average pain is ≥5/10 in numeric rating scale (NRS), the&#xD;
      participant is offered an active, open nrTMS treatment phase depending on which treatment the&#xD;
      participant first received. If the participant benefits from the open label treatment, a&#xD;
      maintenance therapy is offered (6 months with gradually reducing nrTMS treatment frequency).&#xD;
      The symptoms and quality of life are followed with questionnaires and diaries. After the&#xD;
      maintenance period, the RN calls a structured interview at 1, 3, and 6 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 28, 2017</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2024</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>Parallel Assignment</intervention_model>
    <intervention_model_description>The patients are first randomized to receive either sham stimulation or right &quot;S2&quot; for three week period (10 stimulation sessions). Thereafter, a 3 month followup period (clinical checkup at a research visit at 1 month, RN structured telephone interviews at 2 and 3 months). If pain ≥5/10 at 3 month interview, the patient is offered an open label nrTMS treatment phase, in which the protocol depends on the first protocol of the RCT phase.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
    <masking_description>The participant does not know whether the stimulation is sham or active. The doctor or nurse giving the stimulation knows the target and whether the stimulation is sham or active. The RN and the clinician (conducting screening and 1 month clinical visit) do not know the stimulation type or target until month 3, when the code is opened.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>15-item quality of life measure</measure>
    <time_frame>Change from baseline at one month</time_frame>
    <description>Quality of life (15D questionnaire) with 15 question items with 5 alternatives in each. The scores range between 15 to 75 with 15 the best and 75 the worst quality of life.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mean pain intensity and interference</measure>
    <time_frame>Baseline, during stimulation, and two weeks after the intervention</time_frame>
    <description>Numeric rating scale (NRS, 0= no pain and 10= the worst pain imaginable)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Weekly pain intensity and interference</measure>
    <time_frame>Up to 3 months after intervention</time_frame>
    <description>Pain questionnaires (numeric rating scale (NRS, 0= no pain and 10= the worst pain imaginable)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sleep interference and quality</measure>
    <time_frame>Baseline and 1,2,and 3 months after intervention</time_frame>
    <description>Insonnia severity index (ISI). There are seven questions with scale 0 to 4 (0 with no symptoms and 4 with the worst symptoms). The scores are added up to get a total score ranging from 0 to 28. A higher score means a worse outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical neurophysiology measures</measure>
    <time_frame>Baseline and one week after intervention</time_frame>
    <description>Quantitative sensory testing (QST) with standardized reporting</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive assessment A</measure>
    <time_frame>Baseline and one month after the intervention</time_frame>
    <description>Cognitive function assessment by Cogstate, a computer based detection and identification task. Answers yes or no, standard reporting.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hand strength</measure>
    <time_frame>Baseline and one week after the intervention.</time_frame>
    <description>Hand motor function measured e.g. by Jamar (kg)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biochemical tests</measure>
    <time_frame>At baseline</time_frame>
    <description>Blood samples: inflammatory markers (e.g. high sensitivity CRP, proteomics). Standard reporting</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brain imaging: Default mode networks</measure>
    <time_frame>Baseline and one week after intervention</time_frame>
    <description>Resting state fMRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CRPS symptom severity</measure>
    <time_frame>Baseline and at one month</time_frame>
    <description>CRPS severity scale (CSS, 0=no symptoms or signs, 17=maximum score with symptoms and signs)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient global impression of change</measure>
    <time_frame>1, 2, and 3 months and through study completion, an average of 1 year</time_frame>
    <description>Global impression of change (GIC, 1=very much improved, 7= very much worse)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Screening of psychiatric symptoms and diagnostics</measure>
    <time_frame>Up to 24 weeks</time_frame>
    <description>Psychiatric interveiw (SCID II) with symptom and diagnostic description. Nine questions, answers yes or no, standard reporting. The more &quot;yes&quot;-answers, the worse the outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hand mobility</measure>
    <time_frame>Baseline and one week after intervention</time_frame>
    <description>Angles of the joints in the hand (degrees)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive assessment B</measure>
    <time_frame>Baseline and one month after the intervention</time_frame>
    <description>Wechsler Memory Scale III (WMS-III) subtest: digit span. Number of digits recalled. Standard reporting.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive assessment C</measure>
    <time_frame>Baseline and one month after the intervention</time_frame>
    <description>Wechsler Memory Scale III (WMS-III) subtest: word list. Number of words recalled. Standard reporting.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive assessment D</measure>
    <time_frame>Baseline and one month after the intervention</time_frame>
    <description>Bourdon-Wiersma (Attention and concentration): number of visual stimuli found.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive assesment E</measure>
    <time_frame>Baseline and one month after the intervention</time_frame>
    <description>Trail-Making Test (Parts A and B): time spent (seconds) for visual scanning task. Standard reporting.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA</measure>
    <time_frame>At baseline</time_frame>
    <description>DNA analysis. Standard reporting.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Transcranial Magnetic Stimulation</condition>
  <condition>Complex Regional Pain Syndrome of Upper Limb (Disorder)</condition>
  <arm_group>
    <arm_group_label>Starts with active stimulation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Active nrTMS is given to &quot;S2&quot; at the right side (10 sessions in a three week period). Thereafter, a new, open label phase will start if the average pain at 3 month follow-up is ≥5/10. Then, the nrTMS will be targeted to M1 contralateral to the side of pain. After 5 stimulation sessions the response is evaluated. If pain is still ≥510, the investigators change the target to the &quot;S2&quot; on the left side for five sessions. If there is response with pain relief, a maintenance therapy with this target is offered for 6 months with gradually reducing stimulation sessions.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Starts with sham stimulation</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Sham nrTMS will be targeted to the &quot;S2&quot; on the right side, but using a sham box/coil. Stimulation period is similar than for the active comparator. Similarly, thereafter, a new, open label phase will start if the average pain at 3 month follow-up is ≥5/10. Then, the nrTMS will be targeted to &quot;S2&quot; at the right side. After 5 stimulation sessions the response is evaluated. If pain is still ≥5/10, the investigators change the target to M1 on the contralateral side of the pain and furthermore to &quot;S2&quot; at the left side after 5 stimulation sessions, if pain is still ≥5/10.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Sham nrTMS and open phase</intervention_name>
    <description>Navigated repetitive TMS treatment (10 sessions during a three-week period) randomized to sham. In the following open phase stimulation the treatment targets are the right &quot;S2&quot;-contralateral M1-left &quot;S2&quot;.</description>
    <arm_group_label>Starts with sham stimulation</arm_group_label>
    <other_name>Starts with sham stimulation</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Active nrTMS and open phase</intervention_name>
    <description>Navigated repetitive TMS treatment (10 sessions during a three-week period) randomized to &quot;S2&quot;. In the following open phase stimulation the treatment targets are contralateral M1 and left &quot;S2&quot;. If the patient benefited from active &quot;S2&quot; stimulation, but the treatment effect faded in follow-up, the open phase stimulation starts with right &quot;S2&quot;.</description>
    <arm_group_label>Starts with active stimulation</arm_group_label>
    <other_name>Starts with active stimulation</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  CRPS 1 or 2 of the upper limb&#xD;
&#xD;
          -  Duration ≥ 6 months&#xD;
&#xD;
          -  Mean pain (NRS) intensity ≥5/10&#xD;
&#xD;
          -  Medical and other therapies have failed&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Other stimulation therapies apart from transcutaneous nerve stimulation&#xD;
&#xD;
          -  psychotic disorder&#xD;
&#xD;
          -  severe depression&#xD;
&#xD;
          -  use of strong opioids&#xD;
&#xD;
          -  epilepsy&#xD;
&#xD;
          -  any contraindication for MRI&#xD;
&#xD;
          -  abuse of alcohol or drugs&#xD;
&#xD;
          -  ongoing insurance or other entitlement cases&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Eija Kalso, Professor</last_name>
    <role>Study Chair</role>
    <affiliation>Helsinki University Hospital, Pain Clinic</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Satu Jääskeläinen, Professor</last_name>
    <role>Study Chair</role>
    <affiliation>Turku University Hospital, Dept. of Clinical Neurophysiology</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hanna Harno, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Helsinki University Hospital, Pain Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Helsinki University Hospital, Pain Clinic</name>
      <address>
        <city>Helsinki</city>
        <state>Uusimaa</state>
        <zip>00029</zip>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Turku University Hospital, Pain Clinic</name>
      <address>
        <city>Turku</city>
        <state>Varsinais-Suomi</state>
        <zip>20014</zip>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Finland</country>
  </location_countries>
  <reference>
    <citation>Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, Filipovic SR, Grefkes C, Hasan A, Hummel FC, Jaaskelainen SK, Langguth B, Leocani L, Londero A, Nardone R, Nguyen JP, Nyffeler T, Oliveira-Maia AJ, Oliviero A, Padberg F, Palm U, Paulus W, Poulet E, Quartarone A, Rachid F, Rektorova I, Rossi S, Sahlsten H, Schecklmann M, Szekely D, Ziemann U. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018). Clin Neurophysiol. 2020 Feb;131(2):474-528. doi: 10.1016/j.clinph.2019.11.002. Epub 2020 Jan 1. Erratum In: Clin Neurophysiol. 2020 May;131(5):1168-1169.</citation>
    <PMID>31901449</PMID>
  </reference>
  <reference>
    <citation>Lefaucheur JP, Andre-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM, Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipovic SR, Hummel FC, Jaaskelainen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Oliviero A, Padberg F, Poulet E, Rossi S, Rossini PM, Rothwell JC, Schonfeldt-Lecuona C, Siebner HR, Slotema CW, Stagg CJ, Valls-Sole J, Ziemann U, Paulus W, Garcia-Larrea L. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol. 2014 Nov;125(11):2150-2206. doi: 10.1016/j.clinph.2014.05.021. Epub 2014 Jun 5.</citation>
    <PMID>25034472</PMID>
  </reference>
  <reference>
    <citation>Jaaskelainen SK, Lindholm P, Valmunen T, Pesonen U, Taiminen T, Virtanen A, Lamusuo S, Forssell H, Hagelberg N, Hietala J, Pertovaara A. Variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation. Pain. 2014 Oct;155(10):2180-7. doi: 10.1016/j.pain.2014.08.029. Epub 2014 Aug 29.</citation>
    <PMID>25180011</PMID>
  </reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>March 31, 2020</study_first_submitted>
  <study_first_submitted_qc>June 17, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 19, 2020</study_first_posted>
  <last_update_submitted>May 29, 2023</last_update_submitted>
  <last_update_submitted_qc>May 29, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 31, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Helsinki University Central Hospital</investigator_affiliation>
    <investigator_full_name>Hanna Harno</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>TMS</keyword>
  <keyword>CRPS</keyword>
  <keyword>pain</keyword>
  <keyword>fMRI</keyword>
  <keyword>quality of life</keyword>
  <keyword>mood</keyword>
  <keyword>cognitive function</keyword>
  <keyword>DNA</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Complex Regional Pain Syndromes</mesh_term>
    <mesh_term>Reflex Sympathetic Dystrophy</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>The Ethics committee doesn't allow that due to privacy agreements.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04439669
org study id: TYH20162222
nct id: NCT04439669
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a sham controlled, randomized, double-blind, navigated repetitive Transcranial
      Magnetic Stimulation (nrTMS) study for the treatment of complex regional pain syndrome (CRPS
      types 1 and 2). The investigators study factors that may contribute to development,
      maintenance, or treatment responses with clinical, sleep, and psychiatric questionnaires and
      clinical examinations, quantitative sensory testing and neurophysiologic recordings,
      genetics, and MRI techniques.
rTMS hypothetically disrupts the default networks related to chronic pain and renders the
      brain more susceptible to drugs, rehabilitation, or cognitive behavioral therapy. In
      addition, there is experimental evidence that rTMS releases factors that are involved in
      endogenous top-down modulation of pain and neural plasticity. Thus, the analgesic effect of
      rTMS may be mediated via enforcing endogenous pain control systems at the brain level, in
      addition to its effects on neuroplastic effects.

      For active, navigated stimulation targets the investigators have the parietal opercular
      cortex overlying the secondary somatosensory cortex ("S2") and the primary motor cortex (M1).

      The investigators randomize participants to first receive nrTMS to the right "S2" or sham
      stimulation. After ten sessions the investigators follow up the participants up to three
      months. At three months, if the average pain is ≥5/10 in numeric rating scale (NRS), the
      participant is offered an active, open nrTMS treatment phase depending on which treatment the
      participant first received. If the participant benefits from the open label treatment, a
      maintenance therapy is offered (6 months with gradually reducing nrTMS treatment frequency).
      The symptoms and quality of life are followed with questionnaires and diaries. After the
      maintenance period, the RN calls a structured interview at 1, 3, and 6 months.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The patients are first randomized to receive either sham stimulation or right "S2" for three week period (10 stimulation sessions). Thereafter, a 3 month followup period (clinical checkup at a research visit at 1 month, RN structured telephone interviews at 2 and 3 months). If pain ≥5/10 at 3 month interview, the patient is offered an open label nrTMS treatment phase, in which the protocol depends on the first protocol of the RCT phase.
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
masking description: The participant does not know whether the stimulation is sham or active. The doctor or nurse giving the stimulation knows the target and whether the stimulation is sham or active. The RN and the clinician (conducting screening and 1 month clinical visit) do not know the stimulation type or target until month 3, when the code is opened.
measure: 15-item quality of life measure
time frame: Change from baseline at one month
description: Quality of life (15D questionnaire) with 15 question items with 5 alternatives in each. The scores range between 15 to 75 with 15 the best and 75 the worst quality of life.
measure: Mean pain intensity and interference
time frame: Baseline, during stimulation, and two weeks after the intervention
description: Numeric rating scale (NRS, 0= no pain and 10= the worst pain imaginable)
measure: Weekly pain intensity and interference
time frame: Up to 3 months after intervention
description: Pain questionnaires (numeric rating scale (NRS, 0= no pain and 10= the worst pain imaginable)
measure: Sleep interference and quality
time frame: Baseline and 1,2,and 3 months after intervention
description: Insonnia severity index (ISI). There are seven questions with scale 0 to 4 (0 with no symptoms and 4 with the worst symptoms). The scores are added up to get a total score ranging from 0 to 28. A higher score means a worse outcome.
measure: Clinical neurophysiology measures
time frame: Baseline and one week after intervention
description: Quantitative sensory testing (QST) with standardized reporting
measure: Cognitive assessment A
time frame: Baseline and one month after the intervention
description: Cognitive function assessment by Cogstate, a computer based detection and identification task. Answers yes or no, standard reporting.
measure: Hand strength
time frame: Baseline and one week after the intervention.
description: Hand motor function measured e.g. by Jamar (kg)
measure: Biochemical tests
time frame: At baseline
description: Blood samples: inflammatory markers (e.g. high sensitivity CRP, proteomics). Standard reporting
measure: Brain imaging: Default mode networks
time frame: Baseline and one week after intervention
description: Resting state fMRI
measure: CRPS symptom severity
time frame: Baseline and at one month
description: CRPS severity scale (CSS, 0=no symptoms or signs, 17=maximum score with symptoms and signs)
measure: Patient global impression of change
time frame: 1, 2, and 3 months and through study completion, an average of 1 year
description: Global impression of change (GIC, 1=very much improved, 7= very much worse)
measure: Screening of psychiatric symptoms and diagnostics
time frame: Up to 24 weeks
description: Psychiatric interveiw (SCID II) with symptom and diagnostic description. Nine questions, answers yes or no, standard reporting. The more "yes"-answers, the worse the outcome.
measure: Hand mobility
time frame: Baseline and one week after intervention
description: Angles of the joints in the hand (degrees)
measure: Cognitive assessment B
time frame: Baseline and one month after the intervention
description: Wechsler Memory Scale III (WMS-III) subtest: digit span. Number of digits recalled. Standard reporting.
measure: Cognitive assessment C
time frame: Baseline and one month after the intervention
description: Wechsler Memory Scale III (WMS-III) subtest: word list. Number of words recalled. Standard reporting.
measure: Cognitive assessment D
time frame: Baseline and one month after the intervention
description: Bourdon-Wiersma (Attention and concentration): number of visual stimuli found.
measure: Cognitive assesment E
time frame: Baseline and one month after the intervention
description: Trail-Making Test (Parts A and B): time spent (seconds) for visual scanning task. Standard reporting.
measure: DNA
time frame: At baseline
description: DNA analysis. Standard reporting.
arm group label: Starts with active stimulation
arm group type: Active Comparator
description: Active nrTMS is given to "S2" at the right side (10 sessions in a three week period). Thereafter, a new, open label phase will start if the average pain at 3 month follow-up is ≥5/10. Then, the nrTMS will be targeted to M1 contralateral to the side of pain. After 5 stimulation sessions the response is evaluated. If pain is still ≥510, the investigators change the target to the "S2" on the left side for five sessions. If there is response with pain relief, a maintenance therapy with this target is offered for 6 months with gradually reducing stimulation sessions.
arm group label: Starts with sham stimulation
arm group type: Placebo Comparator
description: Sham nrTMS will be targeted to the "S2" on the right side, but using a sham box/coil. Stimulation period is similar than for the active comparator. Similarly, thereafter, a new, open label phase will start if the average pain at 3 month follow-up is ≥5/10. Then, the nrTMS will be targeted to "S2" at the right side. After 5 stimulation sessions the response is evaluated. If pain is still ≥5/10, the investigators change the target to M1 on the contralateral side of the pain and furthermore to "S2" at the left side after 5 stimulation sessions, if pain is still ≥5/10.
intervention type: Device
intervention name: Sham nrTMS and open phase
description: Navigated repetitive TMS treatment (10 sessions during a three-week period) randomized to sham. In the following open phase stimulation the treatment targets are the right "S2"-contralateral M1-left "S2".
arm group label: Starts with sham stimulation
other name: Starts with sham stimulation
intervention type: Device
intervention name: Active nrTMS and open phase
description: Navigated repetitive TMS treatment (10 sessions during a three-week period) randomized to "S2". In the following open phase stimulation the treatment targets are contralateral M1 and left "S2". If the patient benefited from active "S2" stimulation, but the treatment effect faded in follow-up, the open phase stimulation starts with right "S2".
arm group label: Starts with active stimulation
other name: Starts with active stimulation
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Eija Kalso, Professor
role: Study Chair
affiliation: Helsinki University Hospital, Pain Clinic
last name: Satu Jääskeläinen, Professor
role: Study Chair
affiliation: Turku University Hospital, Dept. of Clinical Neurophysiology
last name: Hanna Harno, MD, PhD
role: Study Director
affiliation: Helsinki University Hospital, Pain Clinic
facility: 
facility: 
country: Finland
citation: Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, Filipovic SR, Grefkes C, Hasan A, Hummel FC, Jaaskelainen SK, Langguth B, Leocani L, Londero A, Nardone R, Nguyen JP, Nyffeler T, Oliveira-Maia AJ, Oliviero A, Padberg F, Palm U, Paulus W, Poulet E, Quartarone A, Rachid F, Rektorova I, Rossi S, Sahlsten H, Schecklmann M, Szekely D, Ziemann U. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018). Clin Neurophysiol. 2020 Feb;131(2):474-528. doi: 10.1016/j.clinph.2019.11.002. Epub 2020 Jan 1. Erratum In: Clin Neurophysiol. 2020 May;131(5):1168-1169.
PMID: 31901449
citation: Lefaucheur JP, Andre-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM, Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipovic SR, Hummel FC, Jaaskelainen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Oliviero A, Padberg F, Poulet E, Rossi S, Rossini PM, Rothwell JC, Schonfeldt-Lecuona C, Siebner HR, Slotema CW, Stagg CJ, Valls-Sole J, Ziemann U, Paulus W, Garcia-Larrea L. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol. 2014 Nov;125(11):2150-2206. doi: 10.1016/j.clinph.2014.05.021. Epub 2014 Jun 5.
PMID: 25034472
citation: Jaaskelainen SK, Lindholm P, Valmunen T, Pesonen U, Taiminen T, Virtanen A, Lamusuo S, Forssell H, Hagelberg N, Hietala J, Pertovaara A. Variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation. Pain. 2014 Oct;155(10):2180-7. doi: 10.1016/j.pain.2014.08.029. Epub 2014 Aug 29.
PMID: 25180011
responsible party type: Principal Investigator
investigator affiliation: Helsinki University Central Hospital
investigator full name: Hanna Harno
investigator title: Principal Investigator
mesh term: Complex Regional Pain Syndromes
mesh term: Reflex Sympathetic Dystrophy
mesh term: Syndrome
sharing ipd: No
ipd description: The Ethics committee doesn't allow that due to privacy agreements.