Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000183785
Ethics application status
Approved
Date submitted
10/01/2022
Date registered
2/02/2022
Date last updated
18/07/2024
Date data sharing statement initially provided
2/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Does the inclusion of transcranial direct current stimulation of the brains motor cortex improve outcomes when combined with rehabilitation following Anterior Cruciate Ligament (ACL) reconstruction.
Scientific title
The efficacy of Transcranial direct current stimulation during rehabilitation following Anterior Cruciate Ligament (ACL) reconstruction on functional outcomes and return to play timelines. A double-blind randomised controlled trial (The TACL study)
Secondary ID [1] 306155 0
None
Universal Trial Number (UTN)
U1111-1273-1361
Trial acronym
TACL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anterior Cruciate Ligament Rupture 324861 0
Condition category
Condition code
Musculoskeletal 322293 322293 0 0
Other muscular and skeletal disorders
Injuries and Accidents 322404 322404 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Exercise rehabilitation
Participants will follow the Melbourne ACL rehabilitation guide that details the rehabilitation requirements for each phase. The rehabilitation protocol to be followed will be provided by one of five different physiotherapists working at SportsMed Subiaco, but each participant will be followed through via the same physiotherapist, and participants will attend for supervised rehabilitation and program upgrades at the following timepoints (some flexibility based on participants schedule): 2 weeks post-op, 4 weeks post-op, 6 weeks post-op, 8 weeks post-op, 12 weeks post-op and then monthly until they achieve the final exit criteria to return to play with assessments performed by an independent investigator not completing participant rehabilitation.
Rehabilitation duration will vary from between 15 minutes to 60 minutes depending on the stage of the program and the physical demands of this individual. Participants will record exercise adherence using the Physitrack software. Exercises will initially start with body weight exercises (e.g., bridging or sit to stand), progress into more complex movements (e.g., deadlifts) and machine resistance training (e.g., leg press) before incorporating running, agility and sport specific exercises.
Participants will be provided complimentary access to the gym at SportsMed Subiaco to complete their rehabilitation. Alternatively, if they have an existing gym membership we will provide the supervised consultation to set/ upgrade the program at SportsMed Subiaco and allow them to use their own gym membership if more convenient. Modifications to exercise rehabilitation can be incorporated into the initial rehabilitation program as required, especially within Phase One of the Melbourne ACL rehabilitation guide 2.0.

Transcranial direct current stimulation (tDCS)
All participants will have a screening session with a medical doctor (CW) to assess relevant medical history, medication use and suitability for tDCS. Participants will then be instructed in how to use the tDCS device.
Transcranial direct current stimulation is a safe, non-invasive form of brain stimulation which passes a weak direct electrical current (typically <2 mA, c.f., 800-900mA for ECT) between an anodal and cathodal electrode placed on the scalp and has an excellent safety profile. Generally, cortical excitability is increased with the application of anodal tDCS (anode applied to the target cortical region). There is evidence that tDCS application to the primary motor cortex may promote an increase in muscular maximal voluntary contraction and possibly muscular endurance, improve balance performance, gait retraining, multi-task performance and motor learning of sport specific skills and tasks. The potential benefits of tDCS application align with ACL rehabilitation goals, namely preventing the loss of/regaining muscular strength, regaining and improving neuromuscular control and the re-introduction of sport specific movements and tasks.
Single session and repeated tDCS are widely used in research involving both healthy participants and those with pain disorders, stroke, neurocognitive disorders and neuropsychiatric disorders. Both single session and repeated tDCS have been shown to be safe when applied with stimulation parameters in line with published guidelines for the safe use of tDCS. Adverse effects associated with tDCS are either rare or mild (commonly reported sensations include mild tingling or itching of the scalp).
Given the location of the quadriceps/knee representation in the primary motor cortex, participants will have an anodal electrode applied to the vertex of the scalp, overlying the bilateral lower limb primary motor cortex (M1) representation. This area can be located using the International 10/20 system (an internationally recognised method to describe scalp electrode locations). The cathode will be applied to the contralateral shoulder (i.e. opposite shoulder to the injured lower limb).
Participants will receive tDCS at 2 milliamps (mA) for 20 minutes, during which time rehabilitation exercises will commence (tDCS is considered to be online, referring to rehabilitation occurring while stimulation is being applied, however rehabilitation exercises will continue after the completion of 20 minutes of tDCS). The tDCS device will be fitted by the onsite physiotherapist. For maximal benefit tDCS application during rehabilitation will be encouraged up to three times per week during the intervention period at a similar time of day.
Intervention code [1] 322561 0
Treatment: Other
Intervention code [2] 322562 0
Rehabilitation
Comparator / control treatment
Exercise rehabilitation
Participants will follow the Melbourne ACL rehabilitation guide that details the rehabilitation requirements for each phase. The rehabilitation protocol to be followed will be provided by one of five different physiotherapists working at SportsMed Subiaco, but each participant will be followed through via the same physiotherapist, and participants will attend for supervised rehabilitation and program upgrades at the following timepoints (some flexibility based on participants schedule): 2 weeks post-op, 4 weeks post-op, 6 weeks post-op, 8 weeks post-op, 12 weeks post-op and then monthly until they achieve the final exit criteria to return to play with assessments performed by an independent investigator not completing participant rehabilitation.
Rehabilitation duration will vary from between 15 minutes to 60 minutes depending on the stage of the program and the physical demands of this individual. Participants will record exercise adherence using the Physitrack software.
Participants will be provided complimentary access to the gym at SportsMed Subiaco to complete their rehabilitation. Alternatively, if they have an existing gym membership we will provide the supervised consultation to set/ upgrade the program at SportsMed Subiaco and allow them to use their own gym membership if more convenient. Modifications to exercise rehabilitation can be incorporated into the initial rehabilitation program as required, especially within Phase One of the Melbourne ACL rehabilitation guide 2.0.

Transcranial direct current stimulation (tDCS)
All participants will have a screening session with a medical doctor (CW) to assess relevant medical history, medication use and suitability for tDCS. Participants will then be instructed in how to use the tDCS device.
Transcranial direct current stimulation is a safe, non-invasive form of brain stimulation which passes a weak direct electrical current (typically <2 mA, c.f., 800-900mA for ECT) between an anodal and cathodal electrode placed on the scalp and has an excellent safety profile. Generally, cortical excitability is increased with the application of anodal tDCS (anode applied to the target cortical region). There is evidence that tDCS application to the primary motor cortex may promote an increase in muscular maximal voluntary contraction and possibly muscular endurance, improve balance performance, gait retraining, multi-task performance and motor learning of sport specific skills and tasks. The potential benefits of tDCS application align with ACL rehabilitation goals, namely preventing the loss of/regaining muscular strength, regaining and improving neuromuscular control and the re-introduction of sport specific movements and tasks.
Single session and repeated tDCS are widely used in research involving both healthy participants and those with pain disorders, stroke, neurocognitive disorders and neuropsychiatric disorders. Both single session and repeated tDCS have been shown to be safe when applied with stimulation parameters in line with published guidelines for the safe use of tDCS. Adverse effects associated with tDCS are either rare or mild (commonly reported sensations include mild tingling or itching of the scalp).
Given the location of the quadriceps/knee representation in the primary motor cortex, participants will have an anodal electrode applied to the vertex of the scalp, overlying the bilateral lower limb primary motor cortex (M1) representation. This area can be located using the International 10/20 system (an internationally recognised method to describe scalp electrode locations). The cathode will be applied to the contralateral shoulder (i.e. opposite shoulder to the injured lower limb).
Participants in the sham group will have tDCS applied for 30 seconds, then ramped down to no stimulation which is a method that has been shown to reliably blind participants. The tDCS device will be fitted by the onsite physiotherapist. For maximal benefit tDCS application during rehabilitation will be encouraged up to three times per week during the intervention period at a similar time of day.
Control group
Placebo

Outcomes
Primary outcome [1] 330054 0
Motor cortex excitability measured using Transcranial Magnetic Stimulation (TMS).

TMS will be assessed at both Edith Cowan University and Murdoch University. TMS will assess Motor cortex excitability: delivery of non-invasive transcranial magnetic stimulation (TMS) to the brain to elicit motor response in quadriceps muscle to assess various aspects of motor cortex excitability (motor evoked potential (MEP), resting motor threshold (RMT), active motor threshold (AMT), MEP120 and short-interval intracortical inhibition (SICI)) that all indicate cortex excitability.
Timepoint [1] 330054 0
Pre-op and then post-op at weeks 2, 8, 16, 26 and 52.
Secondary outcome [1] 404747 0
Quadriceps Strength (Isometric Dynamometry)
Timepoint [1] 404747 0
Pre-op and then post-op at weeks 2, 8, 16, 26 and 52.
Secondary outcome [2] 404748 0
Hamstring strength (Isometric Dynamometry)
Timepoint [2] 404748 0
Pre-op and then post-op at weeks 2, 8, 16, 26 and 52.
Secondary outcome [3] 404749 0
Self-reported physical activity levels (Type of physical activity, duration of physical activity in minutes and intensity of physical activity with an RPE-10 scale 0-10) will be administered via a Qualtrics Survey to determine the Arbitrary Units (AU) of load for the designated physical activity. E.g., 30 minutes of running at an RPE of 6 will be reported as 180 AU of running load.
Timepoint [3] 404749 0
Pre-op and then fortnightly post-op until 1 year post-op.
Secondary outcome [4] 404750 0
Rehabilitation Adherence (Physitrack Application)
Timepoint [4] 404750 0
Adherence will be monitored for every exercise session until the return to sport.
Secondary outcome [5] 404751 0
Medication usage will be recorded by participant self-report with the survey administered via Qualtrics.
Timepoint [5] 404751 0
Pre-op and then fortnightly post-op until 1 year post-op.
Secondary outcome [6] 404752 0
Adverse events will be recorded by participant self-report with the survey administered via Qualtrics. The most common adverse event that may occur when using tDCS include skin irritation. The common adverse events from exercise rehabilitation would include muscle soreness or increased joint effusion.
Timepoint [6] 404752 0
Pre-op and then fortnightly post-op until 1 year post-op.
Secondary outcome [7] 404753 0
Success of blinding will be recorded by participant self-report with the survey administered via Qualtrics.
Timepoint [7] 404753 0
At the conclusion of the rehabilitation period (52-weeks).
Secondary outcome [8] 404761 0
Participants will also be assessed using the exit criteria for each rehabilitation stage presented within the Melbourne ACL rehabilitation guide 2.0. The main four phases of the Melbourne ACL rehabilitation guide 2.0 are 1) Recovery from surgery, 2) Strength and Neuromuscular control, 3) Running, agility and landings, and 4) Return to sport.
Timepoint [8] 404761 0
The timepoints for these assessments will take place at the discretion of the treating physiotherapist and be based on the key performance indicators presented within the Melbourne ACL rehabilitation guide 2.0 as opposed to a discrete timeline.

Eligibility
Key inclusion criteria
Participants who have suffered a non-contact, primary isolated ACL rupture during type one or two physical activity (using the IKDC classification system) without concurrent knee injury severe enough to require surgical intervention if the ACL was intact (e.g. concurrent PCL rupture or bucket handle meniscal tear would be excluded) will be eligible to participate within this study. Participants will have an ACLR using a hamstring graft. ACLR will occur within six weeks of ACL injury. Specifically:
• Over 18 years of age
• Acute non-contact, primary ACL rupture diagnosed clinically by an orthopaedic surgeon, confirmed with magnetic resonance imaging pre-surgery and confirmation of ACL rupture during surgery.
• Able to proceed to ACLR within 4 weeks of baseline neurophysiological testing
• Able to attend scheduled follow-up sessions
• Able to give consent
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Concurrent knee injuries severe enough to require surgery (e.g. concurrent PCL rupture or bucket handle meniscal tear)
• Previous lower limb surgery
• Concurrent musculoskeletal injury to the lower limb
• Pregnancy
Conditions that may impact the safety of tDCS:18
• Previous tDCS leading to adverse effects
• Skin lesions or sensitive scalp
• Neurological conditions/illness, including epilepsy/convulsion/seizure
• Previous or current implants in their body that may be triggered or heated by an electrical current (e.g. pacemaker, intracranial shunts, artificial cochlea, etc)
• Any mental implanted in their head (e.g. surgical clips, staples, shrapnel)
• Frequent or intense headaches
• Previous brain trauma or neurosurgical intervention
• Serious medical complications (e.g. advanced pulmonary, cardiac, liver or kidney disease)
• Pharmacological treatment for depression
• Neuropsychotropic drugs (e.g. antiepileptics, neuroleptics, benzodiazepines, antidepressants) or drugs with an effect on neuroplasticity (dopamine, fluoxetine or D-amphetamine, sodium or calcium channel blockers, NMDA receptor antagonists)
• History of significant alcohol or substance abuse, as identified through screening questionnaire
Conditions that may impact the safety of transcranial magnetic stimulation (TMS) use:19
• History of epilepsy (treated or untreated)
• Vascular, traumatic, tumoural, infectious, or metabolic lesion of the brain, even without history of seizure, and without anticonvulsant medication
• Administration of drugs that potentially lower seizure threshold, without concomitant administration of anticonvulsant drugs which potentially protect against seizure occurrence
• Sleep deprivation* the night before, alcoholism , as identified through screening questionnaire
• Implanted brain electrodes (cortical or deep-brain electrodes)
• Severe or recent heart disease

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 randomised into either the active tDCS or sham tDCS group using computer-generated randomisation sequencing software without restriction by the medical doctor performing the screening examination for tDCS (CW).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised into either the active tDCS or sham tDCS group using computer-generated randomisation sequencing software without restriction by the medical doctor performing the screening examination for tDCS (CW).
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
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Data analysis will be performed using SPSS. All demographic data will be presented as mean and standard deviation (SD), or the non-parametric alternative. Data from outcome measures will be presented as count, frequency, mean, SD, median and range, where appropriate. Within and between group differences will be presented using mean, SD and analysed with linear mixed models to determine the effect size and 95% confidence interval with statistical significance. The influence of potential mediators of the treatment effect (e.g age, gender, BMI, adherence, physical activity and medication usage) will be explored by including the potential treatment mediators. Statistical significance will be set at <0.05.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/04/2022
Actual
3/10/2022
Date of last participant enrolment
Anticipated
8/04/2024
Actual
12/02/2024
Date of last data collection
Anticipated
2/06/2025
Actual
Sample size
Target
26
Accrual to date
Final
26
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 310496 0
Commercial sector/Industry
Name [1] 310496 0
Orthopaedic Research Foundation of WA
Country [1] 310496 0
Australia
Funding source category [2] 310497 0
Commercial sector/Industry
Name [2] 310497 0
SportsMed Subiaco
Country [2] 310497 0
Australia
Primary sponsor type
University
Name
Edith Cowan University
Address
270 Joondalup Drive
Joondalup
WA 6027
Country
Australia
Secondary sponsor category [1] 311662 0
University
Name [1] 311662 0
Edith Cowan University
Address [1] 311662 0
270 Joondalup Drive
Joondalup
WA 6027
Country [1] 311662 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310126 0
Edith Cowan University, Human Research Ethics Committee
Ethics committee address [1] 310126 0
Ethics committee country [1] 310126 0
Australia
Date submitted for ethics approval [1] 310126 0
17/01/2022
Approval date [1] 310126 0
Ethics approval number [1] 310126 0
Ethics committee name [2] 314182 0
Murdoch University HREC
Ethics committee address [2] 314182 0
Ethics committee country [2] 314182 0
Australia
Date submitted for ethics approval [2] 314182 0
13/01/2022
Approval date [2] 314182 0
15/03/2022
Ethics approval number [2] 314182 0
2022-03176-MURPHY

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

Contacts
Principal investigator
Name 116566 0
Mr Myles Murphy
Address 116566 0
Edith Cowan University
270 Joondalup Drive
Joondalup
WA 6027
Country 116566 0
Australia
Phone 116566 0
+61 08 6304 3545
Fax 116566 0
Email 116566 0
[email protected]
Contact person for public queries
Name 116567 0
Myles Murphy
Address 116567 0
Edith Cowan University
270 Joondalup Drive
Joondalup
WA 6027
Country 116567 0
Australia
Phone 116567 0
+61 08 6304 3545
Fax 116567 0
Email 116567 0
[email protected]
Contact person for scientific queries
Name 116568 0
Myles Murphy
Address 116568 0
Edith Cowan University
270 Joondalup Drive
Joondalup
WA 6027
Country 116568 0
Australia
Phone 116568 0
+61 08 6304 3545
Fax 116568 0
Email 116568 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?
All of the de-identified IPD collected from the trial.
When will data be available (start and end dates)?
01/04/2022-01/04/2024 upon request and and available indefinitely following this via FigShare.
Available to whom?
All de-identified data will be uploaded to Figshare upon completion of the data collection and available for any usage. For data requests prior to completion of the trial, data will be released on a case-by-case basis at the discretion of the principal investigator.
Available for what types of analyses?
All de-identified data will be uploaded to Figshare upon completion of the data collection and available for any usage. For data requests prior to completion of the trial, data will be released on a case-by-case basis at the discretion of the principal investigator.
How or where can data be obtained?
All de-identified data will be uploaded to Figshare upon completion of the data collection and available for any usage. For data requests prior to completion of the trial, data will be released on a case-by-case basis at the discretion of the principal investigator.

The principal investigator can be contacted via email: [email protected]


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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

Documents added automatically
No additional documents have been identified.