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Trial registered on ANZCTR


Registration number
ACTRN12617001522303
Ethics application status
Approved
Date submitted
26/10/2017
Date registered
1/11/2017
Date last updated
28/05/2019
Date data sharing statement initially provided
17/05/2019
Date results information initially provided
17/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
An N-of-1 trial to assess the effectiveness of Manual Lymphatic Drainage
with and without Non-thermal Laser in lipedema.
Scientific title
An N-of-1 clinical trial to assess the effectiveness of Manual Lymphatic Drainage with and without cold laser therapy for pain relief in women with lipedema.
Secondary ID [1] 293225 0
Nil known
Universal Trial Number (UTN)
U1111-1204-2762
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lipedema 305252 0
Condition category
Condition code
Alternative and Complementary Medicine 304561 304561 0 0
Other alternative and complementary medicine
Cardiovascular 304594 304594 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Manual lymphatic drainage massage is a light but very specific massage therapy designed to reduce lymph swelling by stimulating lymphatic drainage. The therapist, Angela Balinski, is trained in the anatomy and physiology of the lymphatic system and the safe use of MLD to facilitate lymph drainage of the vessels.
The non-thermal laser treatment is used to treat acute and chronic pain, and to relieve swelling and inflammation, all symptoms associated with lipedema and lymphoedema. The laser is applied to the hard, painful areas of the affected limb to increase the softness of the tissue, thereby increasing the amount of fluid that can move out of tissue. Again, the therapist is trained in the application of the laser device. The low-level laser device to be used in this study (model LTU-904; Serial Number L20541) is manufactured by Riancorp Pty Ltd, Henley beach South Australia. It is approved for use by the Therapeutic Goods Administration (AUST R 163516) as a class 11a medical device. The device is a portable rechargeable battery powered unit. It emits a 904-nanometer beam. The average output is 5 milliwatts. The laser goes to a 2 cm depth and 2 cm width. Points of pain or fibrosis or scarring are treated by applying the beam for one minute per point.
The trial is designed as a single-blind, randomised, controlled n-of-1 trial. The trial participant will attend weekly clinic sessions for eight weeks. Weeks 1 and 8 will be assessment sessions. Weeks 2-7 are one hour treatment clinics where the participant will receive either manual lymphatic drainage massage (MLD) for 30 minutes plus active laser therapy for 10 minutes or MLD (30 minutes) plus placebo laser therapy (10 minutes). The six treatment sessions are divided into 3 active laser sessions and 3 placebo laser sessions according to the randomisation plan prepared by an independent statistician. All laser sessions (both active and placebo) are accompanied by MLD treatment. Each weekly clinic session will be separated by a one-week washout.
One participant will be recruited from the body of patients in Ms Angela Balinski’s complementary medicine practice. All clinic sessions will be conducted at Ms Balinski's practice premises.
Intervention code [1] 299482 0
Treatment: Devices
Intervention code [2] 299499 0
Treatment: Other
Comparator / control treatment
The placebo therapy consists of the laser device without power. The indicator light will be covered to avoid power detection. As the laser device is non-thermal, the participant should detect no difference in the application of either the active or non-active therapy.
Control group
Placebo

Outcomes
Primary outcome [1] 303784 0
Pain intensity using 100mm visual analogue scale (VAS)
Timepoint [1] 303784 0
Pain intensity will be measured at the same time on a daily basis for the eight weeks of the trial. Each of these 56 time points are considered primary time points as the data will be plotted on a time series graph to enable correlation with the treatment phases and washout phases of the trial.
Secondary outcome [1] 340132 0
Universal Pain Assessment Scale (UPAT) consisting of a numerical scale from 0 - 10.
Timepoint [1] 340132 0
Pre-treatment assessment is completed by the participant at each of clinics 2 to 7. Post-treatment assessment is completed by the participant after completion of each treatment session.
Secondary outcome [2] 340133 0
Patient Specific Scale (PSS): Up to five daily activities that the participant identifies as being difficult or are unable to perform due to the lipedema are scored on a numerical scale from 1-10 .
Timepoint [2] 340133 0
Pre-treatment assessment is completed by the participant at each clinics 2 to 7. Post-treatment assessment is completed by the participant via email 3 days after each treatment session.
Secondary outcome [3] 340134 0
General Health Questionnaire (GHQ– 12): This is a 12-item questionnaire to assess the participant’s general health status. The participant is asked to rate each item according to a choice of four specified statements.
Timepoint [3] 340134 0
Pre-treatment assessment is completed by the participant at each clinics 2 to 7. Post-treatment assessment is completed by the participant via email 3 days after each treatment session.
Secondary outcome [4] 340135 0
Breakthrough analgesic medication usage
Timepoint [4] 340135 0
The participant will record the name, dosage size and total daily dosage of all analgaesic medication used during the trial period.

Eligibility
Key inclusion criteria
Female; aged between 18 and 85 years; participants of childbearing age who agree to continue using birth control measures for the duration of the study; pain associated with swelling in at least one limb; diagnosis of lipedema.
Minimum age
18 Years
Maximum age
85 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Cancer; cardiac disease; kidney disease; epilepsy; participants who are lactating, pregnant or planning to become pregnant; participants unwilling to comply with the study protocol; any other condition, which in the opinion of the investigators could compromise the study

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)
The participant in this N-of-1 trial will receive both active and placebo laser therapy. Blinding is achieved by (1) masking of the power indicator light on the device; (2) the lack of heat generated by the non-thermal device in both the active and inactive modes; and (3) the application of the identical procedures during both active and placebo phases.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be generated by a statistical software package (Stata) and conducted by an independent academic researcher who is not associated with the study.
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
Other
Other design features
The power of an n-of-1 trial is achieved through comparison of multiple exposures of the treatments. The minimum number of exposures required for an N-of-1 trial is two, this trial has three exposures and withdrawals (placebo condition), which increases the validity of the findings. The sequence will take the form of an AB BA AB design with a 1 week washout period between each phase.
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
As per the n-of-1 design, one participant will be recruited to the trial. Unlike conventional group RCTs, group sample size and associated statistical power are not as relevant in n-of-1 trials as the trials are not designed to show statistical differences between groups. Indeed, there is no need to control for the type I or type II error in the current trial, as it is not designed to show a statistical difference. The power of an n-of-1 trial is achieved through comparison of multiple exposures of the treatments. The minimum number of exposures required for an N-of-1 trial is two, this trial has three exposures and withdrawals (placebo condition), which increases the validity of the findings.

The primary method of analysing the data will be by systematic visual graphing of the pain scales (i.e. the daily 100mm VAS and weekly UPAT). This method is recommended by the CONSORT Collaboration, Extension for N-of-1 Trials (CENT).The primary research question is whether pain is reduced for the patient, which will be evident from the patient’s reports on which intervention worked best, and reinforced by the visual graph.

Recruitment
Recruitment status
Completed
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 postcode(s) [1] 17945 0
6031 - Banksia Grove

Funding & Sponsors
Funding source category [1] 297858 0
Commercial sector/Industry
Name [1] 297858 0
Australian Traditional Medicine Society
Address [1] 297858 0
12/27 Bank St, Meadowbank NSW 2114
Country [1] 297858 0
Australia
Primary sponsor type
Individual
Name
Associate Professor Sandra Grace
Address
School of Health and Human Sciences,
Southern Cross University
Military Rd,
Lismore NSW 2480
Country
Australia
Secondary sponsor category [1] 296894 0
None
Name [1] 296894 0
Address [1] 296894 0
Country [1] 296894 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298903 0
Southern Cross University Human Research Ethics Committee
Ethics committee address [1] 298903 0
Military Rd,
Lismore NSW 2480
Ethics committee country [1] 298903 0
Australia
Date submitted for ethics approval [1] 298903 0
22/08/2017
Approval date [1] 298903 0
26/10/2017
Ethics approval number [1] 298903 0
ECN-17-174

Summary
Brief summary
The project aims to assess whether manual lymphatic drainage (MLD) with non-thermal laser is more effective than MLD alone for reducing pain and swelling in a 43-year old female patient with bilateral lipedema-like symptoms of the legs.

The trial is designed as a single-blind, randomised, controlled n-of-1 trial. The trial participant will attend weekly clinic sessions for eight weeks. Weeks 1 and 8 will be assessment sessions. Weeks 2-7 are treatment clinics where the participant will receive either manual lymphatic drainage massage (MLD) plus active laser therapy or MLD plus placebo laser therapy in a randomised sequence. The placebo therapy consists of the laser device without power.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78606 0
A/Prof Sandra Grace
Address 78606 0
Director of Research
School of Health & Human Sciences
Southern Cross University
PO Box 157,
Lismore NSW 2480
Country 78606 0
Australia
Phone 78606 0
+61 2 6620 3646
Fax 78606 0
Email 78606 0
sandra.grace@scu.edu.au
Contact person for public queries
Name 78607 0
A/Prof Sandra Grace
Address 78607 0
Director of Research
School of Health & Human Sciences
Southern Cross University
PO Box 157,
Lismore NSW 2480
Country 78607 0
Australia
Phone 78607 0
+61 2 6620 3646
Fax 78607 0
Email 78607 0
sandra.grace@scu.edu.au
Contact person for scientific queries
Name 78608 0
A/Prof Sandra Grace
Address 78608 0
Director of Research
School of Health & Human Sciences
Southern Cross University
PO Box 157,
Lismore NSW 2480
Country 78608 0
Australia
Phone 78608 0
+61 2 6620 3646
Fax 78608 0
Email 78608 0
sandra.grace@scu.edu.au

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?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – plain English summary
Research question
The aim of this study was to assess the efficacy of manual lymphatic drainage (MLD) with low level laser therapy (LLLT) in reducing pain compared to MLD alone in a 44-year old female patient with a medical diagnosis of bilateral lipedema. In this single-blind N-of-1 trial the participant was randomly exposed to the intervention and the comparator over time, therefore acting her own control. The trial was design in collaboration with the participant.

Background info
Lipedema is a disorder of adipose tissue that is characterised by hypertrophy of the lower extremities and causes pain and functional impairment. Usual treatments include manual lymphatic drainage which provides short term symptomatic relief.

Participant characteristics
The participant was a 44 year old female who reported heavy legs with swelling. Following ultrasound investigation her GP diagnosed ‘probable lipedema’. The patient was referred for MLD to help improve her lipedema-related pain and swelling.

Key results
The trend across the trial was one of decreasing pain. However, there was no discernible difference between the effects of treatment when either active or sham LLLT was applied with MLD. This trend of improvement over time was likely attributable to the combination of the MLD and the therapeutic relationship.

Limitations
In this study, the primary outcome measure was a measure of pain as this was identified by the patient as her most concerning symptom. This global assessment, chosen to reduce the burden on the participant, may have acted to blunt her assessment of the therapy. Szolnoky and colleagues (2011) employed a 10-item tool including descriptors of the characteristic experience of lipedema. These were: pressing, dull, heavy, pulling, torturing, enervating, violent, unbearable, exhausting, stabbing. This scale might have allowed a more nuanced and clinically useful evaluation of the two conditions.
In this study the Patient Specific Functional Scale (PSFS) was used to measure the participant’s perceptions of functional limitations associated with lipedema. The validity of PSFS is influenced by the choice of functions to assess. In the context of this trial the inclusion of participation in ‘high intensity training at boot camp’ was probably inappropriate and may have compromised the validity of the PSFS. An additional week of baseline scoring would have given researchers, practitioner and participant the opportunity to refine the PSFS and improved trial protocol implementation, specifically in regard to the timely collection of study data. It may have also stabilised the daily pain scores prior to the application of the interventions.