Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000118808
Ethics application status
Approved
Date submitted
21/11/2020
Date registered
5/02/2021
Date last updated
16/01/2024
Date data sharing statement initially provided
5/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Therapeutic ultrasound treatment for women with inflammatory conditions of the lactating breast
Scientific title
The effectiveness of therapeutic ultrasound treatment on the size of breast hardness area in women with inflammatory conditions of the lactating breast
Secondary ID [1] 302025 0
Nil known
Universal Trial Number (UTN)
U1111-1256-8464
Trial acronym
Linked study record
Not applicable

Health condition
Health condition(s) or problem(s) studied:
Breast engorgement 318603 0
Lactational blocked ducts 320161 0
Lactational mastitis 320162 0
Breast abscess 320163 0
Condition category
Condition code
Reproductive Health and Childbirth 316621 316621 0 0
Breast feeding
Inflammatory and Immune System 318104 318104 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Therapeutic ultrasound plus a standard treatment.
Arm 1: High intensity therapeutic ultrasound (2 Wcm2).
Arm 2: Low intensity therapeutic ultrasound (1 Wcm2).

Therapeutic ultrasound (TUS) is non-invasive cutaneously delivered high frequency ultrasound energy, that is delivered via a sound head that is moving continuously.

A women’s health physiotherapist, with over 6 years experience of using TUS to treat women with ICLBs, will provide the intervention face-to-face at the recruitment sites: 1) A public tertiary women's hospital; 2) private women's health physiotherapy practices; and 3) the community (at the participant’s home). The physiotherapist is a staff member at recruitment site 1) and at one of recruitment sites 2).
All participants will receive a standard treatment, comprising education and advice addressing ICLB risk factors and the common supportive measures outlined in the literature. In addition, all participants will receive up to 3 consecutive days of TUS treatment to their affected breast, which could be either high intensity TUS (arm 1), low intensity TUS (arm 2) or sham TUS (arm 3: comparator/control). Day 1 of treatment will be prioritised for the same day as recruitment, or as soon as appropriate. A standardised script will be used, asking participants to adhere to the standard treatment and not try different treatments or change what they are doing, and informed consent gained. Participants will be asked to remove clothing covering the breast and will be appropriately positioned lying down and draped with towels, allowing optimal exposure of the affected breast. To mitigate the risk of overheating, intact sensation will be confirmed prior to TUS application and participants will be given a TUS standard warnings and safety summary sheet prior to and for reference throughout the intervention. The physiotherapist will have 1 TUS machine (Astar Physiogo 300) with 3 sound heads clearly labelled A, B or C. These will correspond to pre-set programs (A, B and C) on the TUS machine. One program will be set to deliver high intensity TUS (2 Wcm2), one to deliver low intensity TUS (1 Wcm2) and one to deliver sham TUS. This will be done by a non-trial member and the sham sound head will be altered by the electrophysical company prior to the physiotherapist receiving them, thus, blinding both the physiotherapist and participant to the intervention. The physiotherapist will be able to turn down the intensity for safety. Active TUS will be applied at 1 MHz frequency in continuous mode, reflective of the majority of Australian physiotherapy practice.
Aqueous gel will be placed on the 4 cm2 sound head and the physiotherapist will apply the TUS over the area of breast swelling/hardness/tightness, using consistent light pressure and overlapping linear strokes, extending towards the axilla and nipple. Participants will be instructed not to inform the physiotherapist if they feel heat, to maintain blinding, unless it becomes more than a comfortable warmth. Duration of application will be dependent on the size of the affected area, which will be measured using the sound head, prior to TUS application. Areas of up to and including 8 cm2 (2 ultrasound heads) will receive 10 minutes of treatment; areas of greater than 8 cm2 and less than 16 cm2 (within 3 sound heads) will receive 15 minutes; and areas of 16 cm2 (4 sound heads) or greater, will receive 20 minutes of TUS treatment.
The standard treatment will be delivered via 3 different mediums: 1) video: 3-4 minutes duration, played for participants on a tablet during day 1 TUS intervention (the video will be on the trial's website for participant's later reference); 2) hard paper copy: As an infographic, with a) a laminated copy for participants to view on day 1 during the intervention and b) a pamphlet for them to take home; and 3) electronic copy of the infographic (on the trial's website; the URL will be given to all participants). The educational material/infographic is designed specifically for this study.
Participants will be encouraged to breastfeed or express prior to the intervention, to ensure their breasts are as soft as possible, and then again as soon as possible/comfortable (or within 20 to 30 minutes) post intervention. Intervention fidelity will be assessed via an online secure survey (REDCap) comprising yes/no and slider scale questions checking compliance with the different aspects of the standard treatment, and an open text response question asking about any additional treatments used/trialled. Participants will use a QR code or customised email link to access their survey. Four extra slider scale and accompanying open text questions will be included in the survey at the end of the intervention, asking participants about their satisfaction and experience with aspects of the trial (see secondary outcomes).
Participants may be contacted at 3 and 6 months post their participation in the trial, via email or phone, to ask a few questions about ICLB recurrences.
Intervention code [1] 318326 0
Treatment: Devices
Comparator / control treatment
Arm 3: Sham therapeutic ultrasound (0 Wcm2) plus a standard treatment.

As per description of intervention(s) / exposure above:
A women’s health physiotherapist, with over 6 years experience of using TUS to treat women with ICLBs, will provide the comparator/control treatment face-to-face at the recruitment sites: 1) A public tertiary women's hospital; 2) private women's health physiotherapy practices; and 3) the community (at the participant’s home). The physiotherapist is a staff member at recruitment site 1) and at one of recruitment sites 2).
All participants will receive up to 3 consecutive days of TUS treatment to their affected breast, which could be either high intensity TUS (intervention arm 1), low intensity TUS (intervention arm 2) or sham TUS (arm 3: comparator/control). Day 1 of treatment will be prioritised for the same day as recruitment, or as soon as appropriate. A standardised script will be used, asking participants to adhere to the standard treatment and not try different treatments or change what they are doing, and informed consent gained. Participants will be asked to remove clothing covering the breast and will be appropriately positioned lying down and draped with towels, allowing optimal exposure of the affected breast. To mitigate the risk of overheating, intact sensation will be confirmed prior to TUS application and participants will be given a TUS standard warnings and safety summary sheet prior to and for reference throughout the treatment. The physiotherapist will have 1 TUS machine (Astar Physiogo 300) with 3 sound heads clearly labelled A, B or C. These will correspond to pre-set programs (A, B and C) on the TUS machine. One program will be set to deliver high intensity TUS (2 Wcm2), one to deliver low intensity TUS (1 Wcm2) and one to deliver sham TUS. This will be done by a non-trial member and the sham sound head will be altered by the electrophysical company prior to the physiotherapist receiving them, thus, blinding both the physiotherapist and participant to the treatment. The physiotherapist will be able to turn down the intensity for safety.
Aqueous gel will be placed on the 4 cm2 sound head and the physiotherapist will apply the TUS over the area of breast swelling/hardness/tightness, using consistent light pressure and overlapping linear strokes, extending towards the axilla and nipple. Participants will be instructed not to inform the physiotherapist if they feel heat, to maintain blinding, unless it becomes more than a comfortable warmth. Duration of application will be dependent on the size of the affected area, which will be measured using the sound head, prior to TUS application. Areas of up to and including 8 cm2 (2 ultrasound heads) will receive 10 minutes of treatment; areas of greater than 8 cm2 and less than 16 cm2 (within 3 sound heads) will receive 15 minutes; and areas of 16 cm2 (4 sound heads) or greater, will receive 20 minutes of TUS treatment.
The standard treatment will be delivered via 3 different mediums: 1) video: 3-4 minutes duration, played for participants on a tablet during day 1 TUS intervention (the video will be on the trial's website for participant's later reference); 2) hard paper copy: As an infographic, with a) a laminated copy for participants to view on day 1 during the intervention and b) a pamphlet for them to take home; and 3) electronic copy of the infographic (on the trial's website; the URL will be given to all participants). The educational material/infographic is designed specifically for this study.
Participants will be encouraged to breastfeed or express prior to the treatment, to ensure their breasts are as soft as possible, and then again as soon as possible/comfortable (or within 20 to 30 minutes) post treatment. Intervention fidelity will be assessed via an online secure survey (REDCap) comprising yes/no and slider scale questions checking compliance with the different aspects of the standard treatment, and an open text response question asking about any additional treatments used/trialled. Participants will use a QR code or customised email link to access their survey. Four extra slider scale and accompanying open text questions will be included in the survey at the end of the intervention, asking participants about their satisfaction and experience with aspects of the trial (see secondary outcomes).
Participants may be contacted at 3 and 6 months post their participation in the trial, via email or phone, to ask a few questions about ICLB recurrences.
Control group
Placebo

Outcomes
Primary outcome [1] 324749 0
Size of breast hardness area (in cm2), measured via tracing the area of hardness on to cling wrap with a permanent marker. Cling wrap tracings will be scanned into Adobe and the area calculated electronically. This measures area of local inflammatory symptoms.
Timepoint [1] 324749 0
Timepoint 1: baseline (day 1, pre intervention). Timepoint 2: 1 day after intervention commencement (day 2, pre day 2 intervention). Timepoint 3: 2 days after intervention commencement (day 3, pre day 3 intervention) - primary timepoint. Timepoint 4: 10 days after intervention commencement.
Secondary outcome [1] 385635 0
Breast milk sodium and potassium levels as measured by an ion selective electrode (ISE). This is to measure local and systemic inflammatory symptoms. This is a composite secondary outcome.
Timepoint [1] 385635 0
Timepoint 1: baseline (day 1, pre intervention). Timepoint 3: 2 days after intervention commencement (day 3, pre day 3 intervention). Timepoint 4: 10 days after intervention commencement.
Secondary outcome [2] 385676 0
Breast Inflammatory Symptom Severity Index (BISSI) scores - a patient reported outcome measure (copyright: Melinda Cooper, physiotherapist), with face and content validity established. This is to measure local and systemic inflammatory symptoms.
Timepoint [2] 385676 0
Timepoint 1: baseline (day 1, pre intervention). Timepoint 2: 1 day after intervention commencement (day 2, pre day 2 intervention). Timepoint 3: 2 days after intervention commencement (day 3, pre day 3 intervention). Timepoint 4: 10 days after intervention commencement.
Secondary outcome [3] 390098 0
Acceptability of participating in this study assessed using an online secure survey (REDCap). The survey is designed specifically for this study.
Timepoint [3] 390098 0
Timepoint 4: 10 days after intervention commencement.
Secondary outcome [4] 390099 0
Feasibility of participating in this study assessed using an online secure survey (REDCap). The survey is designed specifically for this study.
Timepoint [4] 390099 0
Timepoint 4: 10 days after intervention commencement.
Secondary outcome [5] 390100 0
Acceptability of the primary outcome (size of breast hardness area) assessed using an online secure survey (REDCap). The survey is designed specifically for this study.
Timepoint [5] 390100 0
Timepoint 4: 10 days after intervention commencement.
Secondary outcome [6] 390101 0
Acceptability of the secondary outcome [1] (breast milk sodium and potassium levels as measured by an ion selective electrode) assessed using an online secure survey (REDCap). The survey is designed specifically for this study.
Timepoint [6] 390101 0
Timepoint 4: 10 days after intervention commencement.
Secondary outcome [7] 417408 0
Global Rating of Change (GRC) scale
Timepoint [7] 417408 0
Timepoint 2: 1 day after intervention commencement (day 2, pre day 2 intervention),. Timepoint 3: 2 days after intervention commencement (day 3, pre day 3 intervention). Timepoint 4: 10 days after intervention commencement.

Eligibility
Key inclusion criteria
Lactating women over the age of 18, greater than 7 days postpartum, presenting with; a) at least 1 current local breast inflammatory symptom (e.g. breast pain, redness, increased temperature, swelling) AND b) at least 1 systemic inflammatory symptom (e.g. fever, chills, aching, lethargy, headache) this current episode.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
History of breast cancer or breast surgery (including breast implants), pacemaker, preterm birth, multiple birth.

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)
Non-trial personnel will prepare sequentially numbered sealed opaque envelopes, signifying participant number. Inside the envelopes there will be the letter A, B or C written on the enclosed paper, signifying group allocation. The allocation sequence will be randomised, using an online computer program (www.random.org). The physiotherapist will open the envelopes sequentially, post baseline outcome measurement. The physiotherapist will have 1 TUS machine (Astar Physiogo 300), with 3 pre-set programs (A, B and C) and 3 corresponding sound heads clearly labelled, A, B or C. One will be set to deliver high intensity (2 Wcm2) TUS, one to deliver low intensity (1 Wcm2) TUS and one to deliver sham TUS.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be stratified in blocks of 9, within the sites. The online computer program (www.random.org) will be used to generate the random allocation sequences separately for each block of 9, at each of the three recruitment sites.
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
Efficacy
Statistical methods / analysis
A priori sample size calculation based on the expected difference between groups for size of breast hardness area over 3 days (unpublished data from previous study by researcher Dr Leanda McKenna) revealed a sample of n= 156 (52 per group) has 80% power to show an effect size difference f= 0.20 (based on mean difference= 2.0cm2, standard deviation (SD)= 5.0cm2), in a linear mixed model with 3 groups and 4 timepoints (G*Power V3.1.9.4). The expected difference in breast milk sodium levels produced similar mean and SD values, thus we are adequately powered for breast milk analysis.
A blinded interim analysis will be conducted by the trial’s statistician when this minimum sample size (n= 156) has been reached, specifically to assess the distribution of antibiotic use across the trial groups. If significant disproportion exists, further recruitment may be necessary to allow statistical comparison. At any time throughout the trial, women will be able to seek medical treatment, given ICLBs can rapidly progress in severity to a serious illness.
Data analysis will be blinded and completed according to intention-to-treat. Stata (StataCrop, College Station, TX) will be used to perform a generalised linear mixed model (GLMM) analysis of the relationship between the 3 different TUS treatments and the primary and secondary outcomes. Antibiotic use, for the current ICLB episode, will be entered as a fixed effect into the model. Treatment fidelity will be inspected and potentially entered into the model as confounders. Visual inspection of residual plots will be undertaken to evaluate normality and homogeneity of variance, and 95% confidence intervals and p-values will be obtained by likelihood ratio tests.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/12/2021
Actual
26/12/2021
Date of last participant enrolment
Anticipated
22/03/2025
Actual
Date of last data collection
Anticipated
31/03/2025
Actual
Sample size
Target
187
Accrual to date
56
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 17921 0
Mercy Hospital for Women - Heidelberg
Recruitment hospital [2] 21604 0
The Royal Women's Hospital - Parkville
Recruitment postcode(s) [1] 31784 0
3084 - Heidelberg
Recruitment postcode(s) [2] 36527 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 306448 0
University
Name [1] 306448 0
Curtin University PhD research support fund
Country [1] 306448 0
Australia
Funding source category [2] 307175 0
Government body
Name [2] 307175 0
Australian Government Department of Education, Skills and Employment Research Training Program Scholarship
Country [2] 307175 0
Australia
Funding source category [3] 310669 0
Hospital
Name [3] 310669 0
Mercy Health Small Grant 2021/2022
Country [3] 310669 0
Australia
Funding source category [4] 312952 0
Hospital
Name [4] 312952 0
Mercy Health Small Grant 2022/23
Country [4] 312952 0
Australia
Primary sponsor type
Individual
Name
Leanda McKenna
Address
Curtin University, Kent Street, Bentley, WA 6102
Country
Australia
Secondary sponsor category [1] 308164 0
Individual
Name [1] 308164 0
Emma Heron
Address [1] 308164 0
Curtin University, Kent Street, Bentley, WA 6102
Country [1] 308164 0
Australia
Other collaborator category [1] 281426 0
Individual
Name [1] 281426 0
Dr Adelle McArdle
Address [1] 281426 0
Monash University, Northways Road, Churchill VIC 3842
Country [1] 281426 0
Australia
Other collaborator category [2] 281427 0
Individual
Name [2] 281427 0
Prof Donna Geddes
Address [2] 281427 0
The University of Western Australia M310, 35 Stirling Highway, Crawley, WA 6009
Country [2] 281427 0
Australia
Other collaborator category [3] 281521 0
Individual
Name [3] 281521 0
Melinda Cooper
Address [3] 281521 0
MMC Physiotherapy, PO Box 785, Kyneton Vic 3444
Country [3] 281521 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306654 0
Mercy Health Human Research Ethics Committee
Ethics committee address [1] 306654 0
Ethics committee country [1] 306654 0
Australia
Date submitted for ethics approval [1] 306654 0
13/01/2021
Approval date [1] 306654 0
06/05/2021
Ethics approval number [1] 306654 0
2021-007
Ethics committee name [2] 308588 0
Curtin University Human Research Ethics Committee
Ethics committee address [2] 308588 0
Ethics committee country [2] 308588 0
Australia
Date submitted for ethics approval [2] 308588 0
11/05/2021
Approval date [2] 308588 0
18/11/2021
Ethics approval number [2] 308588 0
HRE2021-0315-01
Ethics committee name [3] 310259 0
Monash University Human Research Ethics Committee
Ethics committee address [3] 310259 0
Ethics committee country [3] 310259 0
Australia
Date submitted for ethics approval [3] 310259 0
14/05/2021
Approval date [3] 310259 0
27/05/2021
Ethics approval number [3] 310259 0
29150

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

Contacts
Principal investigator
Name 104570 0
Mrs Emma Heron
Address 104570 0
Curtin University, Kent Street, Bentley, WA 6102
Country 104570 0
Australia
Phone 104570 0
+61 3 9481 6312
Fax 104570 0
+61 3 9489 1273
Email 104570 0
[email protected]
Contact person for public queries
Name 104571 0
Leanda McKenna
Address 104571 0
Curtin University, Kent Street, Bentley, WA 6102
Country 104571 0
Australia
Phone 104571 0
+61 8 9266 3660
Fax 104571 0
+61 8 9266 0000
Email 104571 0
[email protected]
Contact person for scientific queries
Name 104572 0
Leanda McKenna
Address 104572 0
Curtin University, Kent Street, Bentley, WA 6102
Country 104572 0
Australia
Phone 104572 0
+61 8 9266 3660
Fax 104572 0
+61 8 9266 0000
Email 104572 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?




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.