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Trial registered on ANZCTR


Registration number
ACTRN12621000175875
Ethics application status
Approved
Date submitted
23/10/2020
Date registered
18/02/2021
Date last updated
28/10/2024
Date data sharing statement initially provided
18/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
MEMOIR: a clinical trial of memantine and Graded Motor Imagery for Complex Regional Pain Syndrome
Scientific title
MEMOIR: a randomised factorial placebo-controlled trial to evaluate the effects of memantine and Graded Motor Imagery on pain intensity and pain interference in Complex Regional Pain Syndrome
Secondary ID [1] 302420 0
None
Universal Trial Number (UTN)
Trial acronym
MEMOIR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Complex Regional Pain Syndrome 319221 0
Condition category
Condition code
Neurological 317184 317184 0 0
Other neurological disorders
Physical Medicine / Rehabilitation 317191 317191 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention 1: Memantine
Target dose of 40mg/day or maximum tolerated dose, administered in 10mg tablets, twice daily. Total duration of treatment = 16 weeks. The treatment regime comprises 4 weeks up-titration (5mg/day for 4 days; 10mg/day for 4 days; 15mg/day for 4 days, 20mg/day for 4 days; 25mg/day for 4 days; 30mg/day for 4 days; 35mg/day for 4 days) 8 weeks maintenance dose (40mg/day) and 4 weeks wash-out (35 mg/day for 4 days; 30mg/day for 4 days; 25 mg/day for 4 days; 20mg/day for 4 days; 15 mg/day for 4 days; 10mg/day for 4 days; 5mg/day for 4 days). Participants will be provided with a pill cutters to allow halving of tablets during the up-titration and wash-out periods. Adherence to memantine will be measured via daily self-report medication diaries and via pill counting in returned medication kits.

Intervention 2: Graded Motor Imagery (GMI)
A progressive rehabilitation program thought to sequentially activate brain regions associated with motor planning and execution.
Participants will receive 7, 1-hour sessions delivered over 16 weeks via Telehealth by an experienced physiotherapist/occupational therapist/exercise physiologist directly to the participant's home. The first 4 sessions will be scheduled approximately fortnightly and the final 3 sessions will be scheduled approximately every 3 weeks. Participants will be prescribed approximately 1 hour of home activities daily.
The treatment program includes implicit and explicit motor imagery; mirror therapy; simple, complex and functional graded movements; goal-setting; and pain education. Participants will complete activities at a self-directed pace following a standard progression protocol with mandatory advancement at each Telehealth treatment session.
Participants will be provided with an education book (developed specifically for this study), access to an E-learning platform with educational and rehabilitation activities, access to the Recognise App, Recognise Flash Cards and Mirror Box (NOI, Adelaide).
Participant adherence will be measured via session attendance and self-report therapy diaries. The clinician will undergo approximately 20 hours of online training in Graded Motor Imagery, pain education, goal setting and specifically for familiarisation with the treatment protocol. The clinician will be provided with a clinician manual and have access to clinical supervision.
Clinician fidelity to the treatment curriculum will be measured via evaluation of recorded Telehealth sessions 1, 2 and 4.

There are 4 arms in this 2x2 factorial trial:
Arm 1. Memantine plus GMI
Arm 2. Memantine plus usual care
Arm 3. Placebo memantine plus GMI
Arm 4. Placebo memantine plus usual care
Intervention code [1] 318711 0
Treatment: Drugs
Intervention code [2] 318712 0
Rehabilitation
Intervention code [3] 318713 0
Behaviour
Comparator / control treatment
Control 1: Placebo memantine
The memantine placebo tablets are indistinguishable from active memantine in sight, smell, taste and touch. The composition of the placebo memantine tablets is 95.0-98.0% microcrystalline cellulose, 1.5-2.5% colloidal silicon dioxide, 0.5-2.0% sodium starch glycolate and 0.3-1.0% sodium steady fumarate. Placebo memantine will be administered according to the same dosage schedule as the active drug. Total duration of treatment = 16 weeks (4 weeks up-titration, 8 weeks maintenance, 4 weeks wash-out). Adherence to placebo memantine will be measured via daily self-report medication diaries and via pill counting in returned medication kits.

Control 2: Usual care
Usual care, excluding any treatments that are listed in the study exclusion criteria. Usual care for CRPS may include pharmacological, psychological and rehabilitative treatments.
Control group
Placebo

Outcomes
Primary outcome [1] 325276 0
Average pain intensity over the previous 7 days, measured using the 11-point Numerical Pain Rating Scale
Timepoint [1] 325276 0
Week 16 post-randomisation
Primary outcome [2] 325277 0
Pain interference, measured using PROMIS Pain Interference (CAT)
Timepoint [2] 325277 0
Week 16 post-randomisation
Secondary outcome [1] 387376 0
Average pain intensity over the previous 7 days, measured using the 11-point Numerical Pain Rating Scale
Timepoint [1] 387376 0
Baseline; weekly, weeks 1-15; and weeks 26 and 52 post-randomisation
Secondary outcome [2] 387951 0
Pain interference, measured using PROMIS Pain Interference (CAT)
Timepoint [2] 387951 0
Baseline; weekly, weeks 1-15; and weeks 26 and 52 post-randomisation
Secondary outcome [3] 387952 0
Physical function, measured using PROMIS Physical Function (CAT)
Timepoint [3] 387952 0
Baseline; weeks 12, 16, 26 and 52 post-randomisation
Secondary outcome [4] 387953 0
Fatigue, measured using PROMIS Fatigue (CAT)
Timepoint [4] 387953 0
Baseline; weeks 16, 26 and 52 post-randomisation
Secondary outcome [5] 387954 0
Self-efficacy, measured using PROMIS Self Efficacy-Manage Symptoms (CAT)
Timepoint [5] 387954 0
Baseline; weeks 12, 16, 26 and 52 post-randomisation
Secondary outcome [6] 387955 0
Cognitive function, measured by PROMIS Cognitive Function Abilities Subset (CAT)
Timepoint [6] 387955 0
Baseline; weeks 12, 16, 26 and 52 post-randomisation
Secondary outcome [7] 387956 0
Depression, measured using PROMIS Depression (CAT)
Timepoint [7] 387956 0
Baseline; weeks 16, 26 and 52 post-randomisation
Secondary outcome [8] 387957 0
Severity of symptoms, measured using the CRPS Severity Score
Timepoint [8] 387957 0
Baseline; week 16 post-randomisation
Secondary outcome [9] 389397 0
Pain self-efficacy, measured using the Pain Self-Efficacy Questionnaire - Two Item Short Form
Timepoint [9] 389397 0
Baseline; weeks 12, 16, 26 and 52 post-randomisation
Secondary outcome [10] 391550 0
Adverse events, assessed via self-report, measured by the incidence of adverse effects, new medical conditions or the worsening of existing medical conditions experienced during the treatment and follow-up period. Examples of known adverse effects for memantine are confusion, dizziness, drowsiness, headache, insomnia, agitation, hallucination, vomiting and seizures.
Timepoint [10] 391550 0
Weeks 1-16, 26 and 52 post-randomisation
Secondary outcome [11] 391551 0
Adherence to study medication, assessed via a daily self-report medication diary and via pill counting in returned medication kits.
Timepoint [11] 391551 0
Daily, from randomisation to week 16 post-randomisation (diary); and end of treatment (returned kits)
Secondary outcome [12] 391554 0
Adherence to GMI therapy, assessed via a self-report therapy diary (GMI arms only)
Timepoint [12] 391554 0
Daily, from commencement of first GMI session to week 16 post-randomisation, and weeks 26 and 52 post-randomisation
Secondary outcome [13] 391555 0
Patient Global Impression of Change
Timepoint [13] 391555 0
Week 16 post-randomisation
Secondary outcome [14] 391556 0
Cost effectiveness of the interventions. The economic evaluation will be a trial-based cost-utility analysis.
Timepoint [14] 391556 0
Baseline to week 16 post-randomisation

Eligibility
Key inclusion criteria
Diagnosis of unilateral, chronic CRPS according to the Budapest research criteria, of 6 months to 5 years duration; at least moderate pain and disability measured by SF-36 items 7 and 8; English language proficiency; access to internet; willingness to provide informed consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Known allergies to NMDA receptor antagonists; taking more than 60mg/day of morphine equivalents of opioid analgesics; taking methadone; using more than 450mg/day of pregabalin or more than 1200mg/day gabapentin; using monoamine oxidase inhibitors; using more than 50mg/day of tricyclic antidepressants; having used ketamine in the preceding 4 weeks; having received lidocaine injections or infusions in the preceding 4 weeks; commencement of bisphosphonate therapy in the preceding 4 months; taking anti-arrhythmic cardiac medications; taking anti-psychotic medications; taking cisapride; taking erythromycin; taking quinolones; taking anti-tuberculous agents; taking anti-fungal agents; taking antiretrovirals; uncontrolled hypertension; moderate to severe renal impairment (defined as an estimated Glomerular Filtration Rate below 70mL/min/1.73m2); diagnosis of prolonged QTc syndrome; ventricular fibrillation; ventricular tachycardia; heart block; Torsades de Pointes; acute coronary syndrome in the preceding 3 months; NYHA Classes III-IV heart failure; implanted pacemaker or defibrillator; history of serious neurological conditions (stroke, seizure disorders, Alzheimer’s disease, paralysis); history of schizophrenia, psychosis, bipolar disorder, or clinically significant delusions, hallucinations or delirium; implanted spinal cord or nerve stimulators; females who are pregnant or lactating; females of child-bearing potential and not using reliable contraceptive method(s); males and females planning conception; significant history of illicit substance abuse or drug overuse; current use of Graded Motor Imagery; other pain that may interfere with assessment of CRPS and/or use of Graded Motor Imagery, according to the study physician; scheduled for major surgery during the treatment or follow-up period.

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)
Participants will be enrolled into the study after informed consent has been provided and the participant has met all inclusion criteria and none of the exclusion criteria. The participant will receive a study medication kit (active/placebo) with a unique study ID. MEMOIR researchers will use the NHMRC Clinical Trial Centre Interactive Voice Response System to inform participants of their allocation to the GMI or usual care group. Randomisation occurs at this point. Allocation to memantine or placebo groups will be concealed to participants, investigators, clinicians, medical monitors, pharmacists, outcome assessors and statisticians. Allocation to GMI or usual care groups will be concealed to medical monitors, outcome assessors and statisticians.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Random sequence allocation will be conducted in permuted blocks using a computerised random number generation by an independent statistician. The statistician will not be involved in participant recruitment, treatment or data collection. Study medication kits will be prepared according to the allocation sequence, numbered sequentially and sealed.

Allocation to the GMI/usual care arms will be controlled by two separate, additional permuted block lists: one for those participants allocated to active drug and one for those allocated to placebo.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Factorial
Other design features
Group 1. Memantine plus GMI
Group 2. Memantine plus usual care
Group 3. Placebo memantine plus GMI
Group 4. Placebo memantine plus usual care
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Data analysis will be blinded, analysed by intention-to-treat, following a prospectively published statistical analysis plan. Analysis will be conducted by an independent statistician and the research team, and checked for accuracy.

We will use a mixed-effects model to estimate the effect of allocation to intervention group on the primary outcomes; pain intensity and pain interference at 16-weeks post randomisation.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
22/03/2021
Actual
12/05/2021
Date of last participant enrolment
Anticipated
30/06/2026
Actual
Date of last data collection
Anticipated
30/06/2027
Actual
Sample size
Target
204
Accrual to date
138
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 306840 0
Government body
Name [1] 306840 0
National Health and Medical Research Council
Country [1] 306840 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Neuroscience Research Australia
Address
139 Barker St,
Randwick NSW 2031
Country
Australia
Secondary sponsor category [1] 307402 0
University
Name [1] 307402 0
University of New South Wales
Address [1] 307402 0
High St,
Kensington NSW 2052
Country [1] 307402 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307001 0
RPA Research Ethics and Governance Office, Sydney Local Health District
Ethics committee address [1] 307001 0
Ethics committee country [1] 307001 0
Australia
Date submitted for ethics approval [1] 307001 0
24/07/2020
Approval date [1] 307001 0
13/10/2020
Ethics approval number [1] 307001 0
X20-0325 & 2020/ETH01743

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

Contacts
Principal investigator
Name 105706 0
Prof James H McAuley
Address 105706 0
Neuroscience Research Australia
139 Barker Street,
Randwick NSW 2031
Country 105706 0
Australia
Phone 105706 0
+61293991266
Fax 105706 0
Email 105706 0
[email protected]
Contact person for public queries
Name 105707 0
Michael C Ferraro
Address 105707 0
Neuroscience Research Australia
139 Barker Street,
Randwick NSW 2031
Country 105707 0
Australia
Phone 105707 0
+61293991049
Fax 105707 0
Email 105707 0
[email protected]
Contact person for scientific queries
Name 105708 0
Michael C Ferraro
Address 105708 0
Neuroscience Research Australia
139 Barker Street,
Randwick NSW 2031
Country 105708 0
Australia
Phone 105708 0
+61293991049
Fax 105708 0
Email 105708 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?
De-identified individual participant data of published results will be made available upon reasonable request.
When will data be available (start and end dates)?
Data will be made available after the publication of study reports. There is no end date for the availability of study data.
Available to whom?
De-identified individual participant data will be made to interested researchers only upon reasonable request and once the proposed research project has received separate ethics approval from a Human Research Ethics Committee.
Available for what types of analyses?
Any
How or where can data be obtained?
Request to the data custodian, the Principal Investigator ([email protected])


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
9480Study protocol  [email protected]
9481Statistical analysis plan  [email protected]
9482Informed consent form  [email protected]
9483Clinical study report  [email protected]
9484Ethical approval  [email protected]
9485Analytic code  [email protected]



Results publications and other study-related documents

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