Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000550909
Ethics application status
Approved
Date submitted
3/04/2020
Date registered
11/05/2020
Date last updated
10/10/2022
Date data sharing statement initially provided
11/05/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessing a new treatment for Functional Neurological Symptoms Disorder (FNSD): a randomised controlled trial.
Scientific title
Effect of Nocebo-Hypothesis Cognitive Behavioural Therapy (NH-CBT) on physical functioning in patients with Functional Neurological Symptoms Disorder (Motor Type): a randomised controlled trial
Secondary ID [1] 300742 0
Health Research Council of New Zealand Reference Number: 20/045
Universal Trial Number (UTN)
U1111-1249-5358
Trial acronym
NHCBT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Functional Neurological Symptoms Disorder 316570 0
Condition category
Condition code
Neurological 314809 314809 0 0
Other neurological disorders
Physical Medicine / Rehabilitation 315295 315295 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The current intervention is based on the idea that functional neurological symptoms occur as the result of a nocebo effect. In other words, a subconscious belief/representation of being neurologically damaged produces symptoms.
The intervention is administered on an individual basis. It includes an explanation of the “nocebo hypothesis” to the patients within the context of a personalised psychosocial formulation of their symptoms by a clinical psychologist. Physical therapy then follows, incorporating video recording and feedback to show the patient that their functioning can improve when they are distracted (e.g. by music). These therapy elements are designed in order to weaken people's belief that they are neurologically damaged, and give a clear alternative explanatory account of causation. The physical therapy elements of the treatment will be delivered by rehabilitation professional, including a physiotherapist.
Patients will receive written information about their diagnosis and treatment, consistent with the education given to them. Dependent on individual patient need (e.g. type and severity of symptoms), the following equipment may potentially be used: mobility aids (e.g. walking frame), parallel bars, treadmill, portable electromyography biofeedback unit.
The intervention will be delivered face to face over 8 weeks (minimum of 3 hours up to a maximum of 25 hours total duration, session duration 45 - 90 minutes). The frequency and scheduling will depend on the patient’s stamina and needs. Sessions will follow a standardized script/format and will be part of either an inpatient or outpatient treatment.
All therapists in this trial have to study a therapy manual and receive a training in the treatment content and procedure. Therapists are required to attend supervision frequently with a licensed supervisor experienced in CBT for patients with functional neurological symptoms. All initial therapy sessions will be video-taped, and the first physical therapy session will also be audio-taped. We will design a rating scale to assess treatment fidelity and its two components, therapist adherence and treatment specificity, for both the NH-CBT and the control intervention. We will assess therapist competence with a validated rating scale. Session records of a randomly selected sample (30% of the intention-to-treat [ITT] sample) will be rated by an independent, blinded rater.
The majority of sessions will occur at the ISIS (Rehabilitation) Centre, Wakari Hospital, Dunedin, for both inpatient and outpatient treatment, although some sessions will occur in community settings for some patients, predominantly when they are in the latter stages of treatment.
Intervention code [1] 317066 0
Rehabilitation
Intervention code [2] 317384 0
Treatment: Other
Comparator / control treatment
The active control treatment is based on (but not identical to) an established physical therapy intervention (for functional neurological symptoms) embedded in psychoeducation (see PHYSIO4FMD trial, Nielsen et al 2019). There will be some initial supportive counselling and basic information giving with a psychologist. Subsequent physical therapy will largely consist of ‘movement retraining’ (i.e. increasingly establishing symptom free components of movement), tailored to the individual, but adhering to the key principle of employing strategies that redirect the patient’s focus of motor attention, e.g. they might focus on the goal of the task rather than the mechanics of movement, or their reflection in a mirror. Neither highly engrossing distractors nor the use of video feedback will be permitted.
Materials / equipment used will be otherwise identical to the intervention condition, except there will be no use of a tablet for video feedback, or a portable EMG biofeedback unit.
Patients will receive written information about their diagnosis and treatment, consistent with the education given to them in the control condition.
Treating staff type (by training), location, duration of sessions and overall treatment duration will be identical to the intervention condition.

At 16 weeks post-commencement of control treatment, control participants will be offered the intervention condition if they have not achieved full symptom remission.
Control group
Active

Outcomes
Primary outcome [1] 323174 0
Physical functioning, as measured by the Short Form 36 - Physical Functioning subscale (self-rated)
Timepoint [1] 323174 0
Baseline, then 8 weeks (primary time point), 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [1] 381063 0
Somatic symptom severity, as measured by a modified version of the Patient Health Questionnaire-15 (self-rated)
Timepoint [1] 381063 0
Baseline, then 8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [2] 381064 0
Patient perception of change, as measured by the Clinical Global Impression Scale of Improvement scale (CGI-I)(self-rated)
Timepoint [2] 381064 0
8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [3] 381065 0
Mobility, as measured by the 10 metre Walk Test (10MWT)(observer rated)
Timepoint [3] 381065 0
Baseline, then 8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [4] 381067 0
Mobility, as measured by the Functional Mobility Scale (observer rated)
Timepoint [4] 381067 0
Baseline, then 8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [5] 381069 0
Health care utilisation, as measured by hospital and GP data regarding presentations to services, as well as questions 7 and 8 from the Client Service Receipt Inventory (CSRI) (self-rated)
Timepoint [5] 381069 0
Baseline, then 16 weeks post-commencement of intervention.
Secondary outcome [6] 381071 0
Illness perception, as measured by the Brief Illness Perception Questionnaire (B-IPQ)(self-rated)
Timepoint [6] 381071 0
Baseline, then 8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [7] 381074 0
Health-related quality of life, as measured by the Short Form 36 (SF36)(self-rated).
Timepoint [7] 381074 0
Baseline, then 8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [8] 381075 0
Quality of life, measured using the EQ-5D-5L (self-rated).
Timepoint [8] 381075 0
Baseline, then 8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [9] 381076 0
Fatigue, as measured by the Vitality Scale of the Short Form 36 (SF36)(self-rated).
Timepoint [9] 381076 0
Baseline, then 8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [10] 381077 0
Catastrophic thinking about symptoms, as measured by the Symptom Catastrophising Scale (self-rated).
Timepoint [10] 381077 0
Baseline, then 8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [11] 381078 0
Anxiety, as measured by the Generalised Anxiety Disorder scale (GAD-7)(self-rated).
Timepoint [11] 381078 0
Baseline, then 8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [12] 381079 0
Depression, as measured by the Patient Health Questionnaire-9 (PHQ-9)(self-rated).
Timepoint [12] 381079 0
Baseline, then 8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [13] 381080 0
Dissociation, as measured by the Brief Dissociative Experiences Scale (DES-B)(self-rated).
Timepoint [13] 381080 0
Baseline, then 8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [14] 381081 0
Symptom disability, as measured by the Pain Disability Index (self-rated).
Timepoint [14] 381081 0
Baseline, then 8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [15] 381082 0
Therapeutic alliance, as measured by the Work Alliance Inventory - Short Form (WAI-SF)(self-rated).
Timepoint [15] 381082 0
8 weeks post-commencement of intervention.
Secondary outcome [16] 381083 0
Adverse events in therapy (particularly ruptures in the therapeutic alliance), as measured by the Inventory for the balanced assessment of Negative Effects of Psychotherapy (INEP)(self-rated).
Timepoint [16] 381083 0
8 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [17] 381084 0
Adverse events in therapy (particularly physical injury and near misses), as measured by Severity Assessment Code rating for adverse event reporting (observer rated)
Timepoint [17] 381084 0
8 weeks and 24 weeks (control group only) post-commencement of intervention.
Secondary outcome [18] 381683 0
Functional Neurological Symptoms, as measured by the Simplified Functional Movement Disorder Rating Scale (S-FMDRS)(observer rated)
Timepoint [18] 381683 0
Baseline, then 8 weeks, 16 weeks and 24 weeks (control group only) post-commencement of intervention.

Eligibility
Key inclusion criteria
Patients that will be included in our trial will have to meet the following criteria:
• aged 18 or older
• have been assessed by a neurologist including the appropriate medical investigation (e.g. imaging), and that assessment will have resulted in a formal diagnosis of FNSD (i.e. they meet DSM-V diagnostic criteria), or will have clearly identified functional neurological symptoms (according to Fahn-Williams / Gupta-Lang criteria).
• have consented to participate
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded from the trial if they meet the following criteria:
• they have a diagnosis of complex regional pain syndrome (CRPS)
• they have a diagnosis of Dissociative Identity Disorder (DID)
• they have a diagnosis of Post-Traumatic Stress Disorder (PTSD) with high severity and significant dissociation.
• they require inpatient mental health treatment during the trial.
• they receive psychopharmacotherapy and change their treatment regimen from four weeks before baseline assessment until the final assessment.
• according to the clinical judgement of the lead investigator, there are concerns about their ability to participate fully in the trial, e.g. they have active and extensive self-harm, or frequent admissions for inpatient mental health treatment in the last two months
• they sustain significant physical trauma during the period of the trial (inside or outside of the treatment setting), and therefore cannot participate in the physical therapy.
• their English language proficiency is low.
• they do not have the capacity to consent to participating in the trial
• they have previously received either NH-CBT or the active control treatment

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Eligible participants will undergo baseline assessment by an independent assessor, before being randomly assigned to one of the study arms. Allocation will be concealed in sealed opaque sequentially number envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation will be conducted by a research associate not affiliated with the study. Randomization will be obtained by an online service which uses a pseudorandom number algorithm (e.g. www.randomization.com).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
If participants in the control group have not achieved full symptom remission at 16 weeks post-commencement of intervention, they will receive NH-CBT for a maximum of 25 more hours. They will then be assessed again, using largely the same measures
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The power analysis for our trial was run with G*Power 3.1.9.4. In a previous trial, our control treatment reached moderate effect (f=0.33) at 6-month follow-up on the SF36 physical function subscale, our primary outcome (Nielsen et al, 2017) For this trial we conservatively assume a small group*time interaction effect (f=0.10) under consideration of our three measurements and a test-retest reliability of r=0.5. A power analysis for a mixed-effect ANOVA with an alpha error probability of 0.05 and a power of 0.80 results in an optimal total sample size of 164.

Statistical analyses will be run with IBM SPSS Statistics. All of our analyses will be based on intention-to-treat principle. Multiple imputation procedure offered by IBM SPSS Statistics will be used to replace missing values. Group*time interaction effects as well as main group and time effects for our primary and secondary outcomes will be analysed with mixed-effect univariate ANOVAs with one within group factor (baseline, post-treatment, 6-month follow-up) and one between-group factor (NH-CBT versus control intervention). Significant interaction effects will be broken down with Bonferroni-corrected post hoc pairwise comparisons of cell means.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
25/05/2020
Actual
19/06/2020
Date of last participant enrolment
Anticipated
31/10/2022
Actual
Date of last data collection
Anticipated
20/02/2023
Actual
Sample size
Target
164
Accrual to date
38
Final
Recruitment outside Australia
Country [1] 22430 0
New Zealand
State/province [1] 22430 0
Otago

Funding & Sponsors
Funding source category [1] 305193 0
University
Name [1] 305193 0
University of Otago
Country [1] 305193 0
New Zealand
Primary sponsor type
Individual
Name
Dr Matt Richardson
Address
Department of Psychological Medicine
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 305747 0
Individual
Name [1] 305747 0
Dr Maria Kleinstaeuber
Address [1] 305747 0
Department of Psychological Medicine
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country [1] 305747 0
New Zealand
Other collaborator category [1] 281265 0
Individual
Name [1] 281265 0
Dr Dana Wong
Address [1] 281265 0
School of Psychology and Public Health
La Trobe University
Plenty Road and Kingsbury Drive
Bundoora
VICTORIA 3086
Country [1] 281265 0
Australia
Other collaborator category [2] 281266 0
Individual
Name [2] 281266 0
Professor Paul Glue
Address [2] 281266 0
Department of Psychological Medicine
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country [2] 281266 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305548 0
Health and Disability Ethics Committee
Ethics committee address [1] 305548 0
Ethics committee country [1] 305548 0
New Zealand
Date submitted for ethics approval [1] 305548 0
02/04/2020
Approval date [1] 305548 0
14/04/2020
Ethics approval number [1] 305548 0
20/STH/56

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 100750 0
Dr Matt Richardson
Address 100750 0
Department of Psychological Medicine
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 100750 0
New Zealand
Phone 100750 0
+64 27 458 5634
Fax 100750 0
Email 100750 0
[email protected]
Contact person for public queries
Name 100751 0
Matt Richardson
Address 100751 0
Department of Psychological Medicine
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 100751 0
New Zealand
Phone 100751 0
+64 27 458 5634
Fax 100751 0
Email 100751 0
[email protected]
Contact person for scientific queries
Name 100752 0
Matt Richardson
Address 100752 0
Department of Psychological Medicine
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 100752 0
New Zealand
Phone 100752 0
+64 27 458 5634
Fax 100752 0
Email 100752 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).
When will data be available (start and end dates)?
Immediately following publication; no end date.
Available to whom?
Researchers who provide a methodologically sound proposal for re-analyses.
Available for what types of analyses?
For re-analyses, if their aim is covered by the purpose described and agreed on in the patient information sheet and informed consent.
How or where can data be obtained?
Proposals should be directed to the Principal Investigator ([email protected]). To gain access, data requestors will need to sign a data access agreement. Data are not publicly available because informed consent provided by participants of this study is committed to a defined purpose.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7489Study protocol  [email protected]



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseNocebo-Hypothesis Cognitive Behavioral Therapy (NH-CBT) for Persons With Functional Neurological Symptoms (Motor Type): Design and Implementation of a Randomized Active-Controlled Trial.2020https://dx.doi.org/10.3389/fneur.2020.586359
N.B. These documents automatically identified may not have been verified by the study sponsor.