Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000260527
Ethics application status
Approved
Date submitted
13/02/2024
Date registered
15/03/2024
Date last updated
3/09/2024
Date data sharing statement initially provided
15/03/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Targeted care for chronic plantar heel pain: Shockwave therapy for bone marrow lesions (the BALSA trial)
Scientific title
Efficacy of shockwave therapy for pain in participants with a bone marrow lesion phenotype of chronic plantar heel pain: the BALSA trial.
Secondary ID [1] 311466 0
nil known
Universal Trial Number (UTN)
U1111-1303-7626
Trial acronym
BALSA (Bone mArrow Lesions and ShockwAve)
Linked study record
NA

Health condition
Health condition(s) or problem(s) studied:
chronic plantar heel pain 332769 0
Condition category
Condition code
Musculoskeletal 329488 329488 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Shockwave & advice
Three sessions of radial shockwave, directed at the plantar calcaneus, will be provided at weekly intervals, delivered using the same branded machine (EMS Swiss DolorClast Master Touch). Visualising the bone marrow lesion (BML) location on MRI is not required as all lesions must be in a plantar location and therefore accessible to topical shockwave application. However shockwave application will be directed to the most painful aspect of the plantar heel, marked prior to application with an indelible pen. Each session will last less than 20 minutes and details of treatment (machine settings, total session energy dose, maximum energy intensity, participant response) will be recorded on a treatment log for each participant.

Treatment parameters will be as per industry (EMS) and societal recommended guidelines (International Society for Medical Shockwave Treatment, ISMST) with intensity ranging from 2-4 bar pressure for a minimum of 2000 pulses using a 15mm diameter applicator head, at a frequency ranging from 4-10Hz based on comfort. As is standard clinical practice, the intent is to deliver the highest tolerable energy based on a progressive increase in bar pressure, a term referred to by ISMST as ‘pain-adapted dosing’.

As well as aiming for maximum bar pressure, we will seek to deliver a minimum total energy treatment dose across all 3 sessions. For this study for the purpose of quantifying a per protocol energy dose, we will target a minimum total energy dose of 500 mJ/mm^2. The Master Touch unit can convert bar pressure into energy flux density (mJ/mm^2), which when multiplied by the number of pulses delivered, computes the total sessional energy dose. To reach 500 mJ/mm^2 across 3 sessions, an average bar pressure above 2.2 is required. This places this dose in a clinically therapeutic range. If it is evident that the cumulative dose is going to be short of the targeted 500 mJ/mm^2, the clinician may increase the number of pulses in subsequent sessions (e.g. to 2500), however the priority is always to deliver the maximum peak energy dose. If participants do not receive the minimum dose across the 3 sessions, a 4th ‘top-up’ session will be offered. If a top-up session is required, this will be matched with a top-up session to an equal number of participants in the sham group. Sessions will be booked in consecutive weeks in advance however we will allow missed sessions to be caught up with treatment gaps not exceeding 2 weeks.

An advice sheet detailing flare management, footwear and activity recommendations will be provided to both groups.

Intervention code [1] 327916 0
Treatment: Devices
Comparator / control treatment
Sham shockwave & advice
A placebo shockwave applicator will be used to deliver three sessions of radial shockwave at weekly intervals for a total of 3 sessions, matched to the active treatment for session duration. The placebo applicator will deliver no energy output but is designed to mimic the active applicator with sound and vibration output. Device set up and participant positioning and instructions will be standardised to match the active treatment. For onsite staff, only the treating clinician will be aware of allocation status. They will fit the appropriate treatment applicator only at the moment allocation status is revealed, just prior to delivering the treatment. The handpiece is fitted out of sight from the participant, who is positioned prone with the lower body curtained off during the session. The handpieces are otherwise identical in appearance. Attendance and any participant response will be recorded on a treatment log.

An advice sheet designed specifically for this trial detailing flare management, post treatment session advice, footwear and simple activity recommendations will be provided to both groups.
Control group
Placebo

Outcomes
Primary outcome [1] 337292 0
Pain
Timepoint [1] 337292 0
Baseline, 4 months (primary endpoint) & 12-months post-baseline assessment.
Secondary outcome [1] 431364 0
Foot related physical function
Timepoint [1] 431364 0
Baseline, 4- & 12-months post-baseline assessment.
Secondary outcome [2] 431365 0
Global rating of change- pain.
Timepoint [2] 431365 0
4 and 12-months post-baseline assessment.
Secondary outcome [3] 431366 0
Change in size of bone marrow lesion size (mm^2)
Timepoint [3] 431366 0
BML areal size measured at baseline and 4-months post-baseline assessment.
Secondary outcome [4] 431367 0
Quality of life
Timepoint [4] 431367 0
Baseline, 4- & 12-months post-baseline assessment.
Secondary outcome [5] 431369 0
Safety
Timepoint [5] 431369 0
4- & 12-months post-baseline assessment and monitored continuously in-between.
Secondary outcome [6] 432255 0
Global rating of change- activity and participation.
Timepoint [6] 432255 0
4- & 12-months post-baseline assessment.

Eligibility
Key inclusion criteria
Inclusion: (i) aged >=18yrs, (ii) pain under the heel on most days aggravated by weightbearing, for at least 3 months, (iii) pain level > 30 on a 100mm pain visual analogue scale (VAS, 0 no pain, 100 worst possible pain), (iv) plantar calcaneal BML on PD-FS sagittal MRI > 22mm^2 (22mm^2 is the Least Significant Change, as calculated from our preliminary data).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion: (i) other lower limb pain or injury affecting mobility or participation in the past 3 months, (ii) past foot surgery or fracture involving the ankle, hind or midfoot, excluding avulsion injuries confirmed on X-ray, (iii) injection into the heel in last 3 months (iv) previous shockwave treatment, (v) diabetes or inflammatory disease, (vi) fibromyalgia, (vii) contraindication to MRI^, (viii) currently receiving professional treatment*, (ix) lower limb neurological disease, (x) vascular disease affecting lower limbs, (xi) sciatica in last 6 months, (xii) contraindication to having shockwave treatment (Table 1), (xiii) past or current bisphosphonate use, and (xiv) unwilling or unable to commit to full treatment course or complete questionnaires online.
*Discontinuing current treatment with a 2-week washout for non-steroidal anti-inflammatory use, 6-weeks for glucocorticoid use, or 3-week wash-out for conservative professional interventions such as manual therapy, would void this exclusion. Participants who maintain a stable approach in the preceding 6 weeks to ongoing self-administered treatments such as footwear or orthotic use or exercise, may continue with those interventions and maintain eligibility.
^Although not an absolute contra-indication, we will exclude pregnant participants. If there is any doubt about pregnancy status we will request participants undergo a urine pregnancy screening test before proceeding to MRI.


Table 1. Contraindications to shockwave therapy
Anti-coagulant therapy, haemhorrhagic conditions
Local infection
Wound/ skin lesions
Malignancy
Impaired circulation/ ischaemic conditions
Prosthetic device in treatment area

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)
A blinded study assistant will generate the allocation schedule off-site. The participant and treating staff will be informed of allocation by telephone after baseline measures have been collected.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation block randomised in groups of 6, using REDCap.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving 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
Efficacy
Statistical methods / analysis
Effects on the primary outcome of change in FHSQ pain at 4- and 12-months from baseline will be determined by linear mixed models with group allocation, time and their interaction as fixed effects, and participant ID as a random effect. Our primary hypothesis is powered for pain at 4-months, as we expect most change to occur by then and we are clinically interested in changing the early trajectory of CPHP.
Our primary and secondary analyses will be intention-to-treat, however we will also conduct a secondary per protocol analysis for i) study participants who receive the minimum targeted total energy dose of 500mJ/mm^2, and ii) study participants who receive a bar pressure in at least one session of 3 or greater, for the primary outcome of pain at 4 months. To preserve blinding, analyses will be conducted on the 4 and 12-month data only once the final 12-month data is collected.
Other pre-specified stratification analyses will be performed to examine which subgroups may respond better to treatment, specifically considering the variables of BMI (less than or equal to 28, or greater than 28 kg/m^2), and BML lesion size (less than or equal to 100, or greater than 100mm^2). These cut-points have been used or established from our prior work, and limiting the sub-groups to these values will help preserve cell balance and size. It is anticipated that sub-groups with lower BMI and larger lesions will respond better to treatment.
The primary analysis for pain at 4-months will not be adjusted for age, sex or BMI but if baseline imbalances exist that are greater than 10% we will conduct a sensitivity analysis adjusting for those variables. We will also conduct a sensitivity analysis adjusting for baseline FHSQ pain level.
In separate exploratory mediation analyses we will assess the effect of group allocation on pain outcomes based on change in BML size (mm^2), as well as change in MRI co-pathology for plantar fascia thickness and PD-weighted signal within the plantar fascia. To detect a change in BML size of 100mm^2, a size demonstrated as important in CPHP disease risk dose response modelling, using a SD of 160mm^2 and our current sample size of 90, our power would be 0.83.
Mixed effects linear models can handle missing data, however we will inspect the data to determine the nature of any missingness (e.g. time points, reasons, participant groups). We will apply techniques such as inverse probability weighting or multiple imputation methods to address missingness, where appropriate.
Statistical significance will be specified at p < 0.05 for a two-tailed test.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
10/07/2024
Actual
2/09/2024
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
31/12/2025
Actual
Sample size
Target
90
Accrual to date
8
Final
Recruitment in Australia
Recruitment state(s)
TAS
Recruitment postcode(s) [1] 42004 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 315750 0
Charities/Societies/Foundations
Name [1] 315750 0
Royal Hobart Hospital Research Foundation
Country [1] 315750 0
Australia
Primary sponsor type
University
Name
Menzies Institute for Medical Research, University of Tasmania
Address
Country
Australia
Secondary sponsor category [1] 317864 0
None
Name [1] 317864 0
Address [1] 317864 0
Country [1] 317864 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314609 0
University of Tasmania Human Research Ethics Committee
Ethics committee address [1] 314609 0
Ethics committee country [1] 314609 0
Australia
Date submitted for ethics approval [1] 314609 0
13/02/2024
Approval date [1] 314609 0
26/02/2024
Ethics approval number [1] 314609 0
29837

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

Contacts
Principal investigator
Name 132166 0
Dr Jason Rogers
Address 132166 0
Menzies Institute for Medical Research, 17 Liverpool St, Hobart TAS 7000
Country 132166 0
Australia
Phone 132166 0
+61 3 6220 8525
Fax 132166 0
Email 132166 0
[email protected]
Contact person for public queries
Name 132167 0
Jason Rogers
Address 132167 0
Menzies Institute for Medical Research, 17 Liverpool St, Hobart TAS 7000
Country 132167 0
Australia
Phone 132167 0
+61 3 6220 8525
Fax 132167 0
Email 132167 0
[email protected]
Contact person for scientific queries
Name 132168 0
Jason Rogers
Address 132168 0
Menzies Institute for Medical Research, 17 Liverpool St, Hobart TAS 7000
Country 132168 0
Australia
Phone 132168 0
+61 3 6220 8525
Fax 132168 0
Email 132168 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?
Non-re-identifiable individual participant outcome data, including composite scores for all covariates and additional measures.
When will data be available (start and end dates)?
After publication, with no end-date specified.
Available to whom?
Mediated access will be made available on reasonable request to researchers who provide a study plan for intended use.
Available for what types of analyses?
IPD meta-analyses, any other approved purpose as outlined in the access request.
How or where can data be obtained?
Access to data will be mediated by the study PI ([email protected]), provided via the University of Tasmania's Research Data Portal. This portal enables access to a Creative Commons licensed, searchable and metadata labelled database.


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.