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CRPS - Diagnostics, Pathophysiological Mechanisms, and Response to Treatment With Noninvasive Brain Stimulation

Primary Purpose

Transcranial Magnetic Stimulation, Complex Regional Pain Syndrome of Upper Limb (Disorder)

Status
Active
Phase
Not Applicable
Locations
Finland
Study Type
Interventional
Intervention
Sham nrTMS and open phase
Active nrTMS and open phase
Sponsored by
Helsinki University Central Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Transcranial Magnetic Stimulation focused on measuring TMS, CRPS, pain, fMRI, quality of life, mood, cognitive function, DNA

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • CRPS 1 or 2 of the upper limb
  • Duration ≥ 6 months
  • Mean pain (NRS) intensity ≥5/10
  • Medical and other therapies have failed

Exclusion Criteria:

  • Other stimulation therapies apart from transcutaneous nerve stimulation
  • psychotic disorder
  • severe depression
  • use of strong opioids
  • epilepsy
  • any contraindication for MRI
  • abuse of alcohol or drugs
  • ongoing insurance or other entitlement cases

Sites / Locations

  • Helsinki University Hospital, Pain Clinic
  • Turku University Hospital, Pain Clinic

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Starts with active stimulation

Starts with sham stimulation

Arm 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.

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.

Outcomes

Primary Outcome Measures

15-item quality of life measure
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.

Secondary Outcome Measures

Mean pain intensity and interference
Numeric rating scale (NRS, 0= no pain and 10= the worst pain imaginable)
Weekly pain intensity and interference
Pain questionnaires (numeric rating scale (NRS, 0= no pain and 10= the worst pain imaginable)
Sleep interference and quality
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.
Clinical neurophysiology measures
Quantitative sensory testing (QST) with standardized reporting
Cognitive assessment A
Cognitive function assessment by Cogstate, a computer based detection and identification task. Answers yes or no, standard reporting.
Hand strength
Hand motor function measured e.g. by Jamar (kg)
Biochemical tests
Blood samples: inflammatory markers (e.g. high sensitivity CRP, proteomics). Standard reporting
Brain imaging: Default mode networks
Resting state fMRI
CRPS symptom severity
CRPS severity scale (CSS, 0=no symptoms or signs, 17=maximum score with symptoms and signs)
Patient global impression of change
Global impression of change (GIC, 1=very much improved, 7= very much worse)
Screening of psychiatric symptoms and diagnostics
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.
Hand mobility
Angles of the joints in the hand (degrees)
Cognitive assessment B
Wechsler Memory Scale III (WMS-III) subtest: digit span. Number of digits recalled. Standard reporting.
Cognitive assessment C
Wechsler Memory Scale III (WMS-III) subtest: word list. Number of words recalled. Standard reporting.
Cognitive assessment D
Bourdon-Wiersma (Attention and concentration): number of visual stimuli found.
Cognitive assesment E
Trail-Making Test (Parts A and B): time spent (seconds) for visual scanning task. Standard reporting.
DNA
DNA analysis. Standard reporting.

Full Information

First Posted
March 31, 2020
Last Updated
May 29, 2023
Sponsor
Helsinki University Central Hospital
Collaborators
Turku University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04439669
Brief Title
CRPS - Diagnostics, Pathophysiological Mechanisms, and Response to Treatment With Noninvasive Brain Stimulation
Official Title
Complex Regional Pain Syndrome - Diagnostics, Pathophysiological Mechanisms, and Response to Treatment With Noninvasive Brain Stimulation
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 28, 2017 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Helsinki University Central Hospital
Collaborators
Turku University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Transcranial Magnetic Stimulation, Complex Regional Pain Syndrome of Upper Limb (Disorder)
Keywords
TMS, CRPS, pain, fMRI, quality of life, mood, cognitive function, DNA

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
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.
Masking
ParticipantInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Starts with active stimulation
Arm Type
Active Comparator
Arm 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 Title
Starts with sham stimulation
Arm Type
Placebo Comparator
Arm 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(s)
Sham nrTMS and open phase
Other Intervention Name(s)
Starts with sham stimulation
Intervention 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".
Intervention Type
Device
Intervention Name(s)
Active nrTMS and open phase
Other Intervention Name(s)
Starts with active stimulation
Intervention 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".
Primary Outcome Measure Information:
Title
15-item quality of life measure
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.
Time Frame
Change from baseline at one month
Secondary Outcome Measure Information:
Title
Mean pain intensity and interference
Description
Numeric rating scale (NRS, 0= no pain and 10= the worst pain imaginable)
Time Frame
Baseline, during stimulation, and two weeks after the intervention
Title
Weekly pain intensity and interference
Description
Pain questionnaires (numeric rating scale (NRS, 0= no pain and 10= the worst pain imaginable)
Time Frame
Up to 3 months after intervention
Title
Sleep interference and quality
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.
Time Frame
Baseline and 1,2,and 3 months after intervention
Title
Clinical neurophysiology measures
Description
Quantitative sensory testing (QST) with standardized reporting
Time Frame
Baseline and one week after intervention
Title
Cognitive assessment A
Description
Cognitive function assessment by Cogstate, a computer based detection and identification task. Answers yes or no, standard reporting.
Time Frame
Baseline and one month after the intervention
Title
Hand strength
Description
Hand motor function measured e.g. by Jamar (kg)
Time Frame
Baseline and one week after the intervention.
Title
Biochemical tests
Description
Blood samples: inflammatory markers (e.g. high sensitivity CRP, proteomics). Standard reporting
Time Frame
At baseline
Title
Brain imaging: Default mode networks
Description
Resting state fMRI
Time Frame
Baseline and one week after intervention
Title
CRPS symptom severity
Description
CRPS severity scale (CSS, 0=no symptoms or signs, 17=maximum score with symptoms and signs)
Time Frame
Baseline and at one month
Title
Patient global impression of change
Description
Global impression of change (GIC, 1=very much improved, 7= very much worse)
Time Frame
1, 2, and 3 months and through study completion, an average of 1 year
Title
Screening of psychiatric symptoms and diagnostics
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.
Time Frame
Up to 24 weeks
Title
Hand mobility
Description
Angles of the joints in the hand (degrees)
Time Frame
Baseline and one week after intervention
Title
Cognitive assessment B
Description
Wechsler Memory Scale III (WMS-III) subtest: digit span. Number of digits recalled. Standard reporting.
Time Frame
Baseline and one month after the intervention
Title
Cognitive assessment C
Description
Wechsler Memory Scale III (WMS-III) subtest: word list. Number of words recalled. Standard reporting.
Time Frame
Baseline and one month after the intervention
Title
Cognitive assessment D
Description
Bourdon-Wiersma (Attention and concentration): number of visual stimuli found.
Time Frame
Baseline and one month after the intervention
Title
Cognitive assesment E
Description
Trail-Making Test (Parts A and B): time spent (seconds) for visual scanning task. Standard reporting.
Time Frame
Baseline and one month after the intervention
Title
DNA
Description
DNA analysis. Standard reporting.
Time Frame
At baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: CRPS 1 or 2 of the upper limb Duration ≥ 6 months Mean pain (NRS) intensity ≥5/10 Medical and other therapies have failed Exclusion Criteria: Other stimulation therapies apart from transcutaneous nerve stimulation psychotic disorder severe depression use of strong opioids epilepsy any contraindication for MRI abuse of alcohol or drugs ongoing insurance or other entitlement cases
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eija Kalso, Professor
Organizational Affiliation
Helsinki University Hospital, Pain Clinic
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Satu Jääskeläinen, Professor
Organizational Affiliation
Turku University Hospital, Dept. of Clinical Neurophysiology
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Hanna Harno, MD, PhD
Organizational Affiliation
Helsinki University Hospital, Pain Clinic
Official's Role
Study Director
Facility Information:
Facility Name
Helsinki University Hospital, Pain Clinic
City
Helsinki
State/Province
Uusimaa
ZIP/Postal Code
00029
Country
Finland
Facility Name
Turku University Hospital, Pain Clinic
City
Turku
State/Province
Varsinais-Suomi
ZIP/Postal Code
20014
Country
Finland

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
The Ethics committee doesn't allow that due to privacy agreements.
Citations:
PubMed Identifier
31901449
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.
Results Reference
background
PubMed Identifier
25034472
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.
Results Reference
background
PubMed Identifier
25180011
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.
Results Reference
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CRPS - Diagnostics, Pathophysiological Mechanisms, and Response to Treatment With Noninvasive Brain Stimulation

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