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Trial registered on ANZCTR


Registration number
ACTRN12619000494134p
Ethics application status
Submitted, not yet approved
Date submitted
13/03/2019
Date registered
26/03/2019
Date last updated
26/03/2019
Date data sharing statement initially provided
26/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Intermittent infusion of lidocaine, magnesium sulphate and ketamine in the treatment of neuropathic pain, Chronic Regional Pain Syndrome and fibromyalgia. A pilot study.
Scientific title
Does intermittent infusion of lidocaine, magnesium sulphate and ketamine provide sustained analgesia in the treatment of neuropathic pain, Chronic Regional Pain Syndrome and fibromyalgia. A pilot study.
Secondary ID [1] 297712 0
nil known
Universal Trial Number (UTN)
U1111-1230-0230
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neuropathic Pain 312023 0
Complex Regional Pain Syndrome 312024 0
Fibromyalgia 312025 0
Condition category
Condition code
Anaesthesiology 310590 310590 0 0
Pain management
Neurological 310631 310631 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will receive a series of 4 infusions given once weekly in the Pain Medicine Department at Sir Charles Gairdner Hospital. Each infusion will consist of a loading dose of 2mg/kg lidocaine, 0.25mg/kg ketamine and 25mg/kg MgSO4 administered over 20 minutes. This will be followed by a maintenance infusion of 2mg/kg/hr lidocaine, 0.25mg/kg/hr ketamine and 25mg/kg/hr MgSO4 for a further 3 hours. Patients will receive a total of 8mg/kg lidocaine, 1mg/kg ketamine and 100mg/kg MgSO4 over a period of 200 minutes. As this is a pilot study the doses may be adjusted as required depending of development of adverse effects.
Intervention code [1] 313945 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 319435 0
Change in average pain score as measured by the Brief Pain Inventory (BPI) questionnaire between baseline and six weeks following the final (4th) infusion.
Timepoint [1] 319435 0
9 weeks post baseline.
Secondary outcome [1] 368184 0
Change in average pain score as measured by the Brief Pain Inventory (BPI) questionnaire between baseline and 12 weeks following the final (4th) infusion.
Timepoint [1] 368184 0
15 weeks post baseline
Secondary outcome [2] 368186 0
Change in pain interference as measured by the BPI questionnaire between baseline and 6 weeks following the final (4th) infusion
Timepoint [2] 368186 0
9 weeks post baseline
Secondary outcome [3] 368187 0
Change in pain interference as measured by the BPI questionnaire between baseline and 12 weeks following the final (4th) infusion
Timepoint [3] 368187 0
15 weeks post baseline
Secondary outcome [4] 368191 0
Change in Depression, Anxiety and Stress Scale 21 (DASS21) total score between baseline and six weeks following the final (4th infusion).
Timepoint [4] 368191 0
9 weeks post baseline
Secondary outcome [5] 368192 0
Change in DASS21 total score between baseline and 12 weeks following the final (4th infusion).
Timepoint [5] 368192 0
15 weeks post baseline
Secondary outcome [6] 368193 0
Change in Patient Self Efficacy Questionnaire (PSEQ) score between baseline and six weeks following the final (4th infusion).
Timepoint [6] 368193 0
9 weeks post baseline
Secondary outcome [7] 368195 0
Change in PSEQ score between baseline and 12 weeks following the final (4th infusion).
Timepoint [7] 368195 0
15 weeks post baseline
Secondary outcome [8] 368196 0
Change in Pain Catastrophising Scale (PCS) score between baseline and six weeks following the final (4th infusion).
Timepoint [8] 368196 0
9 weeks post infusion
Secondary outcome [9] 368197 0
Change in PCS score between baseline and 12 weeks following the final (4th infusion).
Timepoint [9] 368197 0
15 weeks post infusion
Secondary outcome [10] 368198 0
Patient Global Rating of Change (GRoC) score at six weeks post the final (4th) infusion. Measured on a 7 point Likert Scale from -3 (Very much Worse) to +3 (Very Much Improved).
Timepoint [10] 368198 0
9 weeks post baseline
Secondary outcome [11] 368199 0
Patient Global Rating of Change (GRoC) score at 12 weeks post the final (4th) infusion. Measured on a 7 point Likert Scale from -3 (Very much Worse) to +3 (Very Much Improved).
Timepoint [11] 368199 0
15 weeks post baseline
Secondary outcome [12] 368200 0
Percentage of patients with reduced dose of analgesic medications compared to baseline at 6 weeks following final (4th infusion). Analgesic medications will be classified as any opioid, non-steroidal anti-inflammatory (NSAID) or COX-2 inhibitor, analgesic antidepressant (tricyclic antidepressant, duloxetine, venlafaxine, desvenlafaxine), antineuropathic anticonvulsant medication (pregabalin, gabapentin, carbamazepine, lamotrigine, topiramate). Medications and doses will be assessed from the medication list on the follow up electronic Persistent Pain Outcomes Collaboration (ePPOC) questionnaire.
Timepoint [12] 368200 0
9 weeks post baseline
Secondary outcome [13] 368201 0
Percentage of patients with reduced dose of analgesic medications compared to baseline at 12 weeks following final (4th infusion). Analgesic medications will be classified as any opioid, non-steroidal anti-inflammatory (NSAID) or COX-2 inhibitor, analgesic antidepressant (tricyclic antidepressant, duloxetine, venlafaxine, desvenlafaxine), antineuropathic anticonvulsant medication (pregabalin, gabapentin, carbamazepine, lamotrigine, topiramate). Medications and doses will be assessed from the medication list on the follow up electronic Persistent Pain Outcomes Collaboration (ePPOC) questionnaire.
Timepoint [13] 368201 0
15 weeks post baseline
Secondary outcome [14] 368332 0
Requirement for temporary or permanent cessation of infusion or reduction in rate of administration secondary to patient reported or haemodynamic (hypotension, bradycardia, tachycardia, new arrhythmia)effects. The decision to temporarily cease the infusion will be made by the treating nurse. The decision to recommence at a reduce rate or cease completely will be made by the treating doctor.
Timepoint [14] 368332 0
Will be expressed as percentage of total infusions at the completion of the trial.
Secondary outcome [15] 368333 0
Maximum change in systolic blood pressure. The maximum change in systolic blood pressure from baseline (prior to commencement of infusion) during each infusion will be calculated.
Timepoint [15] 368333 0
Will be reported as mean (+/- standard deviation) of all infusions.
Secondary outcome [16] 368334 0
Maximum change in heart rate. The maximum change in heart rate from baseline (prior to commencement of infusion) during each infusion will be calculated.
Timepoint [16] 368334 0
Will be reported as mean (+/- standard deviation) of all infusions.
Secondary outcome [17] 368336 0
Patient reported adverse effects. Patients will be asked to report any adverse effects they deem secondary to the infusion.
Timepoint [17] 368336 0
Patients will be asked following each of the four infusions and at 2 weeks and 4 weeks following the final (4th) infusion.

Eligibility
Key inclusion criteria
Age > 18 years
Peripheral neuropathic pain (painful peripheral polyneuropathy, post herpetic neuralgia, trigeminal neuralgia, post surgical, post traumatic) OR Complex Regional Pain Syndrome (CRPS) OR Fibromyalgia
Average pain intensity greater than or equal to 6/10 despite oral analgesic medications
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Pregnancy or breastfeeding
- History of seizure disorder
-Conduction abnormality on 12 lead ECG – PR >200ms, QRS >120ms, QTc >440ms
- Heart Failure – NYHA III / IV
- Chronic Liver Impairment – albumin < 30g/L OR INR >1.3
- Chronic Renal Impairment - eGFR <60ml/min/1.73m2
- Cognitive impairment deemed sufficient enough to preclude informed consent
- English language deemed insufficient to enable informed consent
- Known allergy or intolerance of proposed study medications
- Ongoing compensation/litigation claims

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Nil - it is an open label pilot trial
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The size of 30 patients represents a sample deemed sufficient to assess tolerability of the protocol and give a rough estimate of efficacy accepting the unblended nature. Assuming a baseline average pain (SD) of 8 (2) it also has approximately 90% power to detect a 30% reduction in pain with an alpha of 0.01.

All treated patients will be used to assess tolerability. Assessment of efficacy will be analysed both including all data as well as limited to patients completing the full 4 infusions. A p-value of 0.01 will be used to define statistical significance. Data on efficacy will be assessed for normality using Shapiro-Wilk test and analysed using either Student T-test of Mann-Whitney U test as appropriate.

Primary outcomes for each of the underlying pathologies (peripheral neuropathic pain, CRPS, fibromyalgia) and secondary outcomes will be presented with descriptive statistics but not analysed with inferential tests.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 13372 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 25975 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 302237 0
Hospital
Name [1] 302237 0
Sir Charles Gairdner Hospital
Address [1] 302237 0
Hospital Ave, Nedlands WA 6009
Country [1] 302237 0
Australia
Primary sponsor type
Individual
Name
Daniel Ellyard
Address
Department of Pain Management
Sir Charles Gairdner Hospital
Hospital Ave, Nedlands WA 6009
Country
Australia
Secondary sponsor category [1] 302091 0
None
Name [1] 302091 0
Address [1] 302091 0
Country [1] 302091 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 302915 0
Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee
Ethics committee address [1] 302915 0
Level 2, A block
Sir Charles Gairdner Hospital
Hospital Ave
Nedlands WA 6009
Ethics committee country [1] 302915 0
Australia
Date submitted for ethics approval [1] 302915 0
14/02/2019
Approval date [1] 302915 0
Ethics approval number [1] 302915 0

Summary
Brief summary
Intermittent infusions utilising lidocaine, magnesium or ketamine are routinely used in the management of neuropathic pain and fibromyalgia. These three treatments are utilised for treatment of the same condition without any current evidence to compare efficacy or to guide clinicians in the most appropriate therapy for a given patient.

The current paradigm in the management of pain utilises multimodal analgesia, in which analgesics with different mechanisms of action are used in combination to harness presumed additive (and hopefully synergistic) effects and limit dose related adverse effects. However studies of analgesics are only infrequently examined in combination, which leads to a lack of information regarding the additive nature of any effects (positive or negative).

Within the Sir Charles Gairdner Hospital (SCGH) Pain Management Department, patients are admitted as day stay patients for brief (1-2 hour) infusions of either lidocaine or ketamine, usually repeated on a weekly basis for a series of three infusions.

The aim of this pilot study is to assess the efficacy and tolerability of an infusion utilising a combination of lidocaine, magnesium sulphate and ketamine in the treatment of neuropathic pain, CRPS and fibromyalgia. Data will be used to identify appropriate doses and guide the creation of a later comparative study.

This study will be an open label pilot study. 30 patients with peripheral neuropathic pain, CRPS or fibromyalgia will be recruited from the Pain Management Department at SCGH. Patients will receive four intermittent infusions utilising a combination of lidocaine, magnesium sulphate and ketamine.

Patients will be assessed for intra-infusion adverse effects and on a fortnightly basis for 6 weeks and then at 3 months following the final infusion. Data will be collected via phone interview as well as utilising the ePPOC questionnaire which includes multiple pain measures (BPI, DASS21, PSEQ,PCS, GRoC and medication usage) and is routinely used in the Pain Management Department at SCGH to assess efficacy of therapy.

Following completion of the study, data obtained along with data from a prior audits of lidocaine and ketamine infusions for the treatment of neuropathic pain will be used to design a double blind comparative study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 91834 0
Dr Daniel Ellyard
Address 91834 0
Department of Pain Management
Lower Ground, G Block
Sir Charles Gairdner Hospital
Hospital Ave
Nedlands WA 6009
Country 91834 0
Australia
Phone 91834 0
+61 8 6457 3333
Fax 91834 0
Email 91834 0
Daniel.Ellyard@health.wa.gov.au
Contact person for public queries
Name 91835 0
Dr Daniel Ellyard
Address 91835 0
Department of Pain Management
Lower Ground, G Block
Sir Charles Gairdner Hospital
Hospital Ave
Nedlands WA 6009
Country 91835 0
Australia
Phone 91835 0
+61 8 6457 3333
Fax 91835 0
Email 91835 0
Daniel.Ellyard@health.wa.gov.au
Contact person for scientific queries
Name 91836 0
Dr Daniel Ellyard
Address 91836 0
Department of Pain Management
Lower Ground, G Block
Sir Charles Gairdner Hospital
Hospital Ave
Nedlands WA 6009
Country 91836 0
Australia
Phone 91836 0
+61 8 6457 3333
Fax 91836 0
Email 91836 0
Daniel.Ellyard@health.wa.gov.au

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 data for each of the primary and secondary outcomes as well as safety data.
When will data be available (start and end dates)?
Following publication of the trial. It will be available for a period of 15 years.
Available to whom?
researchers who provide a methodologically sound proposal
Available for what types of analyses?
achieve the aims in the approved proposal
How or where can data be obtained?
Provision of electronic database file (excel) of data
What supporting documents are/will be available?
No other documents available
Summary results
No Results