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Trial registered on ANZCTR


Registration number
ACTRN12614001157662
Ethics application status
Approved
Date submitted
21/10/2014
Date registered
31/10/2014
Date last updated
10/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Does menopausal hormone therapy (MHT), exercise or a combination of both, improve pain and function in post-menopausal women with greater trochanteric pain syndrome (GTPS)? A randomised controlled trial.
Scientific title
Does menopausal hormone therapy (MHT), exercise or a combination of both, improve pain and function in post-menopausal women with greater trochanteric pain syndrome (GTPS)? A randomised controlled trial.
Secondary ID [1] 285119 0
Nil
Universal Trial Number (UTN)
U1111-1160-2743
Trial acronym
GLoBE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Greater Trochanteric Pain Syndrome (GTPS) 292678 0
Condition category
Condition code
Musculoskeletal 292990 292990 0 0
Other muscular and skeletal disorders
Physical Medicine / Rehabilitation 292991 292991 0 0
Physiotherapy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Once eligible for the trial, participants will be recruited and randomised into one of the following 12 week interventions:
(i) Exercise therapy, placebo transdermal cream
(ii) Sham exercise, transdermal MHT cream
(iii) Sham exercise, placebo transdermal cream
(iv) Exercise therapy, MHT transdermal cream.

Interventions
1. Menopausal hormone therapy (MHT) transdermal cream. The MHT cream is based on the Estalis continuous active ingredients. This involves supplementation of oestradiol (50mcg) and norethindrone acetate (NETA) (140mcg), a progestin. This has been chosen as it closely mimics the normal female hormone fluctuations over a monthly cycle and the progestin component provides important protection of the uterus. The active ingredients used in this cream are widely available as used commercially in a transdermal patch. A cream formula was chosen so that its appearance and texture is identical to that of the placebo alternative.

Participants will be instructed to apply 1g of cream to the skin in the inner wrist region daily for 12 weeks, rotating sides every 5 days (left and right arm). Dispensing equipment will accurately measure the correct amount to ensure accurate administration.

2. Intervention exercise therapy: Participants randomised into the intervention exercise group will be instructed in a 12 week gluteal tendon exercise program designed by clinicians expert in treating tendon pathology as there is a lack of evidence available on effective exercise therapy in GTPS. Participants will attend 4 physiotherapy sessions (baseline, 4 weeks, 8 weeks and 12 weeks post randomisation) for progression of their home exercise program and monitoring of compliance. Participants will complete their prescribed home exercise program twice daily and record their compliance with the program in an exercise diary. There is no set duration for each stage of the exercise program - progression is determined by the treating physiotherapist and is dependent on a participant's ability to complete the precribed exercises. A participant should expect their exercise session to take approximately 10-15 minutes to complete their exercise program.

Stage 1:
i. Gluteus medius strengthening: Hip Hitch with wall support and progress to hip hitch off the wall with arm support. Commence with 2 x 15second holds and increase to 4 x 40second holds before progressing to stage 2.
ii. Quadriceps strengthening: Double leg 1/4 wall squats with Hip externally rotated 20degrees, progressively increased to 1/2 wall squat. Commence with 1 set of 5 repetitions and increase to 4 sets of 5 repetitions before progressing to stage 2.
iii. Calf strengthening: Bilateral calf raise with arm support for balance. Commence with 2 sets of 5 repetitions and increase to 2 x 10 repetitions before progressing to stage 2.

Stage 2:
i. Gluteus medius strengthening: Hip Hitch with toe taps onto 7.5cm step, progressing to a 10cm step. Commence with 2 sets of 5 repetitions and increase to 2 x 15 repetitions before progressing to stage 3.
ii. Quadriceps strengthening: Sit to stand off a standard chair with arms accross chest, progressively decreasing the height of the chair as tolerated. Commence with 1 set of 5 repetitions and increase to 2 x 10 repetitions before progressing to stage 3.
iii. Calf strengthening: Sustained calf raise with toe rises on the spot, using arms for balance. Commence with 2 sets of 5 repetitions and increase to 2 x 10 repetitions before progressing to stage 3.

Stage 3:
i. Gluteus medius strengthening: Hip Hitch with hip swing. Commence with hip hitch sustained hold on the affected (stance) limb. Complete hip swings 10deg fowards and backwards 5 times with the contralateral leg. Increase this to 2 sets of 15 contralateral hip swings before progressing to advanced exercises.
ii. Quadriceps strengthening: Sit to stand off a standard chair with bias to affected leg by positioning it more posteriorly to the unaffected leg. Commence with 2 x 5 repetitions and increase to 4 x 5 repetitions before progressing to advanced exercises.
iii. Calf strengthening: Single leg calf raise using arms for balance. Commence with 2 x 5 repetitions and increase to 4 x 5 repetitions before progressing to advanced exercises.

Advanced exercises:
i. Gluteus medius strengthening: Single leg wall squat. 2 sets of 5 repetitions.
ii. Quadriceps strengthening: Step ups. 2 sets of 10 repetitions.
iii. Calf strengthening:Single leg calf raise using arms for balance. 2 sets of 15 repetitions.


In addition, a booklet that features photos and explanations of each exercise will be given to each participant for further reference. These exercises will be completed twice daily. Participants will document program adherence to exercise and MHT in a diary. Any adverse reactions will immediately be referred to a medical practitioner for assessment. All participants will continue normal activities but will be asked to record medication use (analgesic or anti-inflammatory) for their tendinopathy (e.g. NSAIDs) and cease adjunct treatments/physical treatment (physiotherapy, dry needling, accupuncture etc.).

Failure to improve: Participants will be offered cross over to both active interventions if their global rating of change score is below 0 (worsened symptoms) at 12 weeks. If in GLoBE exercise and placebo cream, they will cross over to intervention cream and continue GLoBE exercise. If in sham exercise and placebo cream, they will cross over to GLoBE exercise and intervention cream, if in sham exercise and intervention cream, they will cross over to GLoBE exercise and continue intervention cream once cleared to do so by study medical practitioners. Results for this group will be analysed and presented separately.

Intervention code [1] 289969 0
Treatment: Drugs
Intervention code [2] 289970 0
Rehabilitation
Comparator / control treatment
1. Placebo transdermal cream: Participants will be instructed to apply 1g of cream to the skin daily for 12 weeks (dispensing equipment will accurately measure the correct amount to ensure accurate administration). This cream will be of identical appearance and consistency as the intervention cream however, it will be completely inert (will not contain active ingredients).

2. Sham exercise therapy: The control group will receive a 12 week sham exercise program not focused on the rehabilitation of gluteal tendons, but still instructed by a physiotherapist. Participants will attend 4 physiotherapy sessions (baseline, 4 weeks, 8 weeks and 12 weeks post randomisation) for progression of their home exercise program and monitoring of compliance. Participants will complete their prescribed home exercise program twice daily and record their compliance with the program in an exercise diary. There is no set duration for each stage of the exercise program - progression is determined by the treating physiotherapist and is dependent on a participant's ability to complete the precribed exercises. A participant should expect their exercise session to take approximately 10-15 minutes to complete their exercise program.

Stage 1:
i. Gluteus medius strengthening: Seated gluteal squeezes. Commence with 2 sets of 5 repetitions and increase to 2 x 10 repetitions before progressing to stage 2 exercises.
ii. Quadriceps strengthening: Quadriceps over fulcrum. Commence with 2 sets of 5 repetitions and increase to 2 x 10 repetitions before progressing to stage 2 exercises.
iii. Calf strengthening: Single leg seated calf raise. Commence with 2 sets of 5 repetitions and increase to 2 x 10 repetitions before progressing to stage 2 exercises.

Stage 2:
i. Gluteus medius strengthening: Seated hip abduction. Commence with 2 sets of 5 repetitions and increase to 2 x 10 repetitions before progressing to stage 3 exercises.
ii. Quadriceps strengthening: Seated knee extension. Commence with 2 sets of 5 repetitions and increase to 2 x 10 repetitions before progressing to stage 3 exercises.
iii. Calf strengthening: Bilateral seated calf raise. Commence with 2 sets of 5 repetitions and increase to 2 x 10 repetitions before progressing to stage 3 exercises.

Stage 3:
i. Gluteus medius strengthening: Standing lateral flexion with feet shoulder width apart. Commence with 2 sets of 5 repetitions and increase to 2 x 10 repetitions before progressing to advanced exercises.
ii. Quadriceps strengthening: Seated knee extension with red theratubing. Commence with 2 sets of 5 repetitions and increase to 2 x 10 repetitions before progressing to advanced exercises.
iii. Calf strengthening: Sustained seated calf raise with toe rises on the spot, with hands on chair arms for support. Commence with 2 sets of 5 repetitions and increase to 2 x 10 repetitions before progressing to advanced exercises.

Advanced exercises:
i. Gluteus medius strengthening: Standing lateral flexion with feet together. 2 x 10 repetitions.
ii. Quadriceps strengthening: Seated knee extension with green theratubing. 2 x 10 repetitions.
iii. Calf strengthening: Seated bilateral calf raise with pulses. 2 x 10 repetitions with three pulses each repetition.
Control group
Placebo

Outcomes
Primary outcome [1] 292852 0
VISA-G questionnaire: A gluteal tendon outcome measure that quantifies pain with tendon loading. This questionnaire contains a visual analogue score for pain, four questions related to pain, one question related to difficulty with moving after sitting and two activity related questions.
Timepoint [1] 292852 0
Baseline, 3 and 12 months post randomisation
Primary outcome [2] 292855 0
Global rating of change questionnaire
Timepoint [2] 292855 0
Baseline, 3 and 12 months post randomisation
Primary outcome [3] 293472 0
AQoL-8D
Timepoint [3] 293472 0
Baseline, 3 and 12 months post randomisation
Secondary outcome [1] 310087 0
Assessment of Success of Blinding - exercise component. Success of blinding of participants to what treatment arm they received will be assessed with the following
question:
“This trial compares the effect of two exercise programs, a new program and a standard program. Are you aware of which exercise program you received? “
The participant can tick one of 3 options:
YES
NO
UNSURE.
If yes, which exercise program do you think you have received?
Why?
Timepoint [1] 310087 0
One week post randomisation.
Secondary outcome [2] 310088 0
Assessment of Success of Blinding - transdermal cream component. Success of blinding of participants to what treatment arm they received will be assessed with the following
question:
“This trial compares the effect of two transdermal creams, a hormone therapy cream and a placebo cream. Are you aware of which transdermal cream you have received? “
The participant can tick one of 3 options:
YES
NO
UNSURE.
If yes, which cream do you think you received?
Why?
Timepoint [2] 310088 0
One week post randomisation
Secondary outcome [3] 310994 0
The Lateral Hip Pain Questionnaire
Timepoint [3] 310994 0
Baseline, 3 and 12 months post randomisation
Secondary outcome [4] 311112 0
Primary outcome: Hip dysfunction and Osteoarthritis Outcome Score (HOOS)
Timepoint [4] 311112 0
Basline, 3 months and 12 months post randomisation
Secondary outcome [5] 311114 0
Primary Outcome: Oxford Hip Score (OHS).
Timepoint [5] 311114 0
Baseline, 3 months and 12 months post randomisation

Eligibility
Key inclusion criteria
Included participants must be post-menopausal, determined by >12 months of menstruation cessation and/or a serum oestradiol of 0-120pmol/L and an FSH of >20IU/L; have a clinical diagnosis of GTPS; have lateral hip pain reproduction on 3/5 clinical tests (trendenburg test, FABER, palpation of the greater trochanter, resisted external de-rotation test, modified resisted external de-rotation test) and have sufficient English skills to be able to read and understand the information and consent form due to the risks involved with participating in the study.
Minimum age
40 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded by the medical practitioner if they are known to have an adverse reaction to any form of hormone therapy or have used any form of female hormone supplementation within the last 3 months; have a high risk of DVT / PE; are a current smoker; have an HbA1c >7% and/or fasting glucose > 6mmol/L; have a history of stroke, severe menstrual migraine, endometrial sarcoma, breast cancer, severe hyperlipidaemia, chronic liver disease, lupus; have had a hysterectomy; have current cholecystitis or undiagnosed abnormal uterine bleeding. Additionally, participants will be excluded if they have had a platelet-rich plasma (PRP), autologous blood injection (ABI) or corticosteroid injection (CSI) in the hip region in the last 3 months and or have any musculoskeletal, neurological and cardiorespiratory conditions affecting a their ability to participate in the study.

Where a participant meets inclusion criteria and has not had a PRP, ABI or CSI in the hip region in the last 3 months, but is excluded from the hormone intervention on medical grounds, they will be randomised into a single arm (intervention exercise or sham exercise).

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 recruited through local physiotherapy clinics and via referral from medical practitioners or healthcare professionals. Further advertising on community noticeboards, social media, and the Gumtree advertising service will also be conducted. Interested volunteers will contact Charlotte Ganderton (PhD candidate), who will provide further information on the trial and phone screen participants (to assess their eligibility for the trial). Contact details will be obtained from interested and eligible volunteers.

All participants will be phone screened to rule out any obvious exclusion criteria. Those that are deemed eligible via phone screen will be assessed by a medical practitioner to ensure there are no contraindications to the use of MHT. If it is deemed medically and clinically appropriate for the participant to be included in the trial according to the outlined inclusion and exclusion criteria, the medical practitioner will refer the participant to undergo an 12 lead ECG and blood sampling (fasting cholesterol, trigs, glucose, liver function tests, HDL/LDL, Fe studies, HbA1c, TFT, FSH and oestadiol) to confirm the participant does not display any contra-indications or risk factors for the use of MHT.

Once eligible for the trial, participants will be recruited and randomised into one of the following 12 week interventions: (i) Exercise therapy, placebo cream; (ii) Sham exercise, MHT cream; (iii) Sham exercise, placebo cream or (iv) Exercise therapy, MHT cream.

Randomisation of participants into one of the four treatment groups will be completed by an individual external to the research team. Randomisation will be done by the contacting an off-site trial administrator who will hold the randomisation schedule, and will not be involved in assessing, enrolling or treating participants.

A researcher at La Trobe University who will have no contact with participants will generate a randomisation schedule prior to trial commencement. The randomization sequence will be generated using a web based randomization program (http://www.randomisation.com) and will be stratified for treating practitioner. After randomisation, this individual will be responsible for contacting:
1. The treating physiotherapist on the trial to indicate which exercise program the participant has been allocated to.
2. NOVA Compounding Pharmacy Forrest Hill who will be responsible for making both the intervention transdermal cream and the placebo transdermal cream.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A block randomisation sequence (random block lengths) will be
generated with a web-based randomisation program, with stratification for treating practitioner.
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
Factorial
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Sample size: Due to the innovative nature of the research, there are no data on which to base a power analysis. However, a recent RCT by Coombes et al. (2013) looking at the effects of corticosteroid injection and physiotherapy on unilateral lateral epicondylalgia, included 165 participants (63 female, mean age of 49.7(8.1)). Several similarities between this study and our proposed study exist. It is a 2 x 2 factorial design study; the tendon pathology associated with the lateral epicondylalgia is similar to that of the gluteal tendinopathy involved in GTPS; the age and gender of study participants are similar to those proposed in our study and the intervention incorporates both a medical and a conservative exercise intervention. Thus, 120 female participants (30 for each group) was determined as a sufficient number (while also accounting for potential drop-outs)..


Statistical analysis will use intention to treat principles. A mixed model ANCOVA will be undertaken, adjusting for baseline values of the dependent variables to determine the difference between groups for primary outcomes. In addition, a responder analysis will be undertaken to determine clinical significance. Participants who achieve an increase in VISA-G scores greater than the minimal detectable change score (10 points) will be categorised as ‘responders’. The difference between the proportions of responders and non-responders in the four groups will then be analysed with risk ratios, risk differences and numbers needed to treat.

Adverse events, medications taken, co-interventions, compliance with the exercise program and success of blinding will be recorded.

Recruitment
Recruitment status
Active, not 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)
VIC

Funding & Sponsors
Funding source category [1] 289728 0
University
Name [1] 289728 0
La Trobe University
Address [1] 289728 0
La Trobe University
Melbourne
Victoria
Australia
3086
Country [1] 289728 0
Australia
Primary sponsor type
University
Name
La Trobe University
Address
School of Allied Health
Faculty of Health Sciences
Department of Physiotherapy
La Trobe University
Bundoora
Victoria
3086
Country
Australia
Secondary sponsor category [1] 288424 0
Commercial sector/Industry
Name [1] 288424 0
Mornington Peninsula Sports Physicians
Address [1] 288424 0
Mornington Clinic
Suite 5, Level 1
315 Main St
Mornington
Victoria, 3931

Frankston Clinic
Suite 1
20 Clarendon St
Frankston,
Victoria, 3199
Country [1] 288424 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291465 0
La Trobe University Human Ethics Committee
Ethics committee address [1] 291465 0
La Trobe University Melbourne
Bundoora
Victoria
Australia
3086
Ethics committee country [1] 291465 0
Australia
Date submitted for ethics approval [1] 291465 0
16/07/2014
Approval date [1] 291465 0
15/10/2014
Ethics approval number [1] 291465 0
HEC14-055

Summary
Brief summary
Greater trochanteric pain syndrome (GTPS) causes severely debilitating pain on the outside of the hip, resulting in limited activity, employment and decreased capacity to exercise. The pain of GTPS has been shown to be as severe and debilitating as osteoarthritis of the hip in those waiting for hip replacement. It most commonly affects post-menopausal women and limits capacity for physical activity that is critical for older women to achieve healthy ageing. In addition to tendon injury, ageing women suffer a myriad of conditions and diseases that burden both the individual and society, all of which can be ameliorated by physical activity (cardiovascular disease, obesity and osteoporosis). Conservative management is the first line treatment, although evidence is limited and the condition can be resistant to treatment. Thus, the aim of this study is to investigate the effect of menopausal hormone therapy and exercise on pain and function in post-menopausal women with GTPS. Eighty women will be recruited and randomised to one of four groups: (i) Exercise therapy, placebo MHT cream; (ii) Sham exercise, MHT cream; (iii) Sham exercise, placebo MHT cream or (iv) Exercise therapy, MHT cream. Interventions will be 12 weeks in duration and outcomes (6 questionnaires) will be examined at baseline, 3 months, and 12 months. We hypothesise that as tendon cells contain hormone-specific receptors, supplemental hormones may be beneficial for reducing pain and dysfunction measured by a clinical significant change in VISA-G scores (using responder analysis).
Trial website
Trial related presentations / publications
Public notes
This study will establish guidelines for exercise prescription and menopausal hormone therapy, improve outcomes of patients with GTPS and lay foundations for larger randomised controlled trials for exercise and hormone therapy intervention in postmenopausal women with GTPS.

Contacts
Principal investigator
Name 50518 0
Ms Rachael McMillan
Address 50518 0
La Trobe University
School of Allied Health
Faculty of Health Science
Department of Physiotherapy
Bundoora 3086
Victoria
Australia
Country 50518 0
Australia
Phone 50518 0
+61 3 94791389
Fax 50518 0
Email 50518 0
globe.hip@latrobe.edu.au
Contact person for public queries
Name 50519 0
Ms Rachael McMillan
Address 50519 0
La Trobe University
School of Allied Health
Faculty of Health Science
Department of Physiotherapy
Bundoora 3086
Victoria
Australia
Country 50519 0
Australia
Phone 50519 0
+61 3 94791389
Fax 50519 0
Email 50519 0
globe.hip@latrobe.edu.au
Contact person for scientific queries
Name 50520 0
Ms Rachael McMillan
Address 50520 0
La Trobe University
School of Allied Health
Faculty of Health Science
Department of Physiotherapy
Bundoora 3086
Victoria
Australia
Country 50520 0
Australia
Phone 50520 0
+61 3 94791389
Fax 50520 0
Email 50520 0
globe.hip@latrobe.edu.au

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary