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Trial registered on ANZCTR


Registration number
ACTRN12616000629437
Ethics application status
Approved
Date submitted
15/03/2016
Date registered
16/05/2016
Date last updated
9/05/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
DEFROST: A clinical trial testing metformin as a treatment for frozen shoulder or shoulder tendinopathy.
Scientific title
Dimethylbiguanide (Metformin) Efficacy in FROzen Shoulder and Tendinopathy
Secondary ID [1] 288241 0
None
Universal Trial Number (UTN)
U1111-1178-0606
Trial acronym
DEFROST
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Frozen Shoulder 297171 0
Shoulder tendinopathy 297172 0
Condition category
Condition code
Musculoskeletal 297387 297387 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention group will receive metformin tablets at a dose of 1000mg to 2000mg per day for 3 months. Participants will initially take 500mg metformin or placebo twice daily, increasing to 1000mg twice daily after 10 days. (Participants who are unable to tolerate 2000mg per day may take a reduced dose of 1500mg daily instead, but no less.) Participants will have a diary to record that the drug has been taken, pain levels, pain relief and activity levels each day for the 3 months. Drug tablet return will be assessed by the hospital clinical trials pharmacist.
Intervention code [1] 293528 0
Treatment: Drugs
Comparator / control treatment
The control group will receive identical placebo tablets daily for 3 months and be otherwise identically treated. The placebo contains the following USP grade Excipients:

Microcrystalline Cellulose
Colloidal Silicon Dioxide,
Sodium Starch Clycolate,
Sodium Strearyl Fumarate

Control group
Placebo

Outcomes
Primary outcome [1] 296937 0
Proportion of participants with VAS pain score 2 or less out of 10.

Timepoint [1] 296937 0
The primary timepoint is 3 months. In addition, measurements will be taken at baseline, 6 and 12 months from commencement of participation in trial.
Secondary outcome [1] 319738 0
Functionality: Proportion of participants reaching clinically important improvement with change greater than 20 points on the Shoulder Pain And Disability Index (SPADI).
Timepoint [1] 319738 0
Baseline, 3, 6 and 12 months from commencement of participation in trial.
Secondary outcome [2] 320662 0
Validated shoulder functional assessments (ASES (American Shoulder and Elbow surgeons shoulder assessment), OSS (Oxford Shoulder Scores) and VAS (Visual Analogue Scale Pain Assessment Score)) will be made.
Timepoint [2] 320662 0
0, 3, 6 and 12 months from commencement of participation in trial.
Secondary outcome [3] 323747 0
Range of motion (flexion, abduction, external rotation (in adduction), measured supine with a goniometer, internal rotation (in midline posteriorly)) will be measured. (Goniometer measurement to be performed supine with one hip flexed and both arms to be rotated simultaneously. External rotation in adduction to be meaured with elbows fixed by side and flexed to 90 degrees; internal rotation (in midline posteriorly) measured standing).
Timepoint [3] 323747 0
0, 3, 6 and 12 months from commencement of participation in trial.
Secondary outcome [4] 323748 0
To screen longitudinal sera samples from the enrolled participants for miRs implicated in fibrosis as markers for diagnosis, disease progression and/or treatment efficacy in patients with frozen shoulder or shoulder tendinopathy.
Expression of circulating fibrosis-related miRs: Let-7d, miR-26a, miR-29b, miR-30a, miR-192, miR-200, miR-21, miR-29a, miR-221, miR-222.
Timepoint [4] 323748 0
0, 3, 6 and 12 months from commencement of participation in trial.

Eligibility
Key inclusion criteria
Inclusion criteria for frozen shoulder:
* Patients aged between 40 and 70;
* Patients with unilateral shoulder pain (spontaneous or following minor trauma);
* Patients with pain at end of shoulder range of movement (ROM) in all directions with pain on the visual analogue scale (VAS) of greater than 4 out of 10;
* Patients with loss of glenohumeral ROM in at least 2 of 3 planes (flexion, abduction, extension);
* Patients with loss of greater than 20 per cent or 30 degrees external rotation in adduction compared with asymptomatic side;
* Patients with symptom duration of less than 6 months;
* Patients with normal x-ray;
* Patients with normal glucose tolerance ie not diabetic or recognised prediabetic;
* Patients taking background analgesics, non-steroidals, nutraceuticals (fish oil, glucosamine etc) will be allowed (to be continued at normal doses); and
* Patients who are willing to give written informed consent and are willing to comply with the study.

Inclusion criteria for shoulder tendinopathy:
* Patients aged between 40 and 70:
* Patients with unilateral shoulder pain, pain with rotator cuff (supraspinatus and/or infraspinatus) contraction against resistance, loss of ROM not to exceed 20 per cent in any direction, by comparison with asymptomatic side;
* Patients with normal x-ray;
* Patients with ultrasound or magnetic resonance imaging (MRI) evidence of in-tact but "heterogeneous" rotator cuff;
* Patients with normal glucose tolerance;
* Patients taking background analgesics, non-steroidals, nutraceuticals (fish oil, glucosamine etc) will be allowed (to be continued at stable doses); and
* Patients who are willing to give written informed consent and are willing to comply with the study.
Minimum age
40 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Patients with a rotator cuff disruption on ultrasound or MRI (ie full thickness or partial thickness cuff tear);
* Patients who have a known abnormality in glucose tolerance including impaired glucose tolerance, impaired fasting glucose, type 1 or type 2 diabetes mellitus;
* Patients with impaired renal function (estimated glomerular filtration rate (eGFR) less than 45mL per minute);
* Patients who have symptoms of frozen shoulder which have been present for more than 6 months;
* Patients who have had previous shoulder surgery, hydrodilatation or manipulation under anaesthesia procedure;
* Patients who have had a steroid injection into the affected shoulder
* Patients who have taken oral steroids within the last 3 months;
* Patients who are taking fluoroquinolones antibiotics, such as ciprofloxacin, levofloxacin, moxifloxacin;
* Women lactating, pregnant, or of child bearing potential who are not willing to avoid pregnancy during the study;
* Patients who have had an acute coronary syndrome (including myocardial infarction or unstable angina), peripheral vascular disease, transient ischaemic attack (TIA) or acute stroke within the preceding 6 months;
* Patients with clinically significant active cardiovascular disease including stable/unstable angina or heart failure (New York Heart Association (NYHA) class III and IV) at the discretion of the investigator;
* Patients with a history of pulmonary embolism within the last 3 months;
* Patients with planned major surgery, including dental surgery, during the study treatment period;
* Patients with planned radiological investigations requiring contrast within the study treatment period;
* Patients who have suspected or known abuse of narcotics or alcohol;
* Patients who have received an investigational new drug within the last 30 days;
* Patients with a cognitive impairment, intellectual disability, mental illness or history of psychological illness or condition such as to interfere with their ability to understand the requirements of the study and to answer clinical questions in the opinion of the coordinating investigator;
* Patients with a condition or illness that in the investigator's opinion would be unsuitable for participation in the study (due to limitations with active participation, compliance with the study drug treatment or follow-up).

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)
Allocation will be concealed. Bottles containing 120 tablets will be supplied with identical packaging and labelling and will be allocated using a randomisation schedule supplied by a University statistician (Kolling Institute). The packaged drugs will be delivered to RNSH pharmacy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
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
Phase 2 / Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
SAMPLE SIZE ESTIMATION
Assuming: 1) 5 per cent significance and 80 per cent power; 2) 50 per cent of treatment group achieve the patient-acceptable pain VAS at 3 months; and 3) 30 per cent of control group achieve this reduction, we will need 91 in each group. Including 10 per cent extra for dropouts, we will require 100 participants per arm. For our primary outcome, shoulder pain and disability index (SPADI), we assume 60 per cent of Treatment group will improve greater than 20 points at 3 months and 30 per cent of treatment group will achieve this, we obtain over 90 per cent power with 100 participants in each arm.

Therefore, 400 participants in total will be recruited.

Baseline characteristics will be compared using the chi2 and Mann-Whitney U statistics for categoric and quantitative data, respectively. At the end of the study, each outcome will be analysed separately and independently in the first instance. Differences in score data (VAS, SPADI, American Shoulder and Elbow Surgeons Standardised Shoulder Assessment (ASES), Oxford Shoulder Scores (OSS)) between treatments will be assessed using log-rank tests (two-tailed alpha = 0.05) at each time point separated by shoulder disorder (tendinopathy/frozen shoulder). An appropriate post hoc test (eg Bonferoni for continuous data or Benjamini-Hochberg correction for non parametric data) will be used where multiple time points are included in the test. A mixed model logistic regression clustered by shoulder disorder and time as independent dummy variables will be performed on the full set of data. Results will be reported as odds ratios with 95 per cent confidence intervals.
ROM measurements will be assessed by mixed model linear regression with the same dummy variables. Differences in micro ribonucleic acid (microRNA) (miR) expression levels between treatments will be assessed by ttests (two-tailed alpha = 0.05) at each time point after any necessary normalising transformation. Associations between miR expression levels and clinical parameters will be performed initially by Spearman’s rank correlations for each shoulder condition separately. If scatter plots show clustering (age, body mass index (BMI) etc), partial correlations corrected for clustering variable(s) will be used.


Recruitment
Recruitment status
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)
NSW
Recruitment hospital [1] 5001 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 12490 0
2065 - Royal North Shore Hospital

Funding & Sponsors
Funding source category [1] 292622 0
Charities/Societies/Foundations
Name [1] 292622 0
Australian Orthopaedic Association (AOA) Research Foundation Ltd
Address [1] 292622 0
AOA Research Foundation Ltd
Level 12, 45 Clarence St
Sydney NSW 2000
Country [1] 292622 0
Australia
Funding source category [2] 292623 0
Commercial sector/Industry
Name [2] 292623 0
Ramsay Research Teaching Fund
Address [2] 292623 0
Kolling Institute
Northern Sydney Local Health District
Kolling Building, Level 13
St Leonards NSW 2065
Country [2] 292623 0
Australia
Funding source category [3] 292624 0
Hospital
Name [3] 292624 0
Department of Orthopaedics and Traumatic Surgery, Royal North Shore Hospital
Address [3] 292624 0
Clinical Administration 7C, Level 7
Acute Services Building
Royal North Shore Hospital
St Leonards NSW 2065
Country [3] 292624 0
Australia
Primary sponsor type
Government body
Name
Northern Sydney Local Health District - Professor David Sonnabend and Professor Lyn March
Address
PO Box 4007,
Royal North Shore LPO,
ST LEONARDS, NSW 2065
Country
Australia
Secondary sponsor category [1] 291340 0
None
Name [1] 291340 0
Address [1] 291340 0
Country [1] 291340 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294107 0
NSLHD Human Research Ethics Committee
Ethics committee address [1] 294107 0
Research Office
Kolling Building, Level 13
Royal North Shore Hospital
St Leonards NSW 2065
Ethics committee country [1] 294107 0
Australia
Date submitted for ethics approval [1] 294107 0
25/08/2015
Approval date [1] 294107 0
11/12/2015
Ethics approval number [1] 294107 0
RESP/15/239

Summary
Brief summary
The Department of Orthopaedics and Traumatic Surgery at Royal North Shore Hospital is conducting research to test a new treatment for frozen shoulder and tendinopathy. The treatment being investigated is a drug called Metformin. Metformin is currently approved to treat Type 2 diabetes. It is not currently approved to treat frozen shoulder or tendinopathy.

The aim of the study is to determine whether Metformin is effective in reducing pain and loss of movement, and speeding up recovery in patients suffering from a frozen shoulder or tendinopathy. Our investigations in the Department of Orthopaedics and Traumatic Surgery's laboratory at Royal North Shore Hospital have shown that this drug acts on the cause of the stiffness in these shoulder conditions and may be effective in reducing the pain and its duration.

Results of research undertaken in our laboratory, also suggest that blood tests may help diagnose these conditions and indicate if a patient is recovering well.

Current treatments for these conditions have limited success. It is therefore important that more research is done into new treatments, including drug treatments. Frozen shoulder and tendinopathy cause enormous pain, which can lead to loss of sleep, difficulty in dressing and toileting, and participating in occupational and recreational activities. This drug may enable patients to return to their usual activities more quickly.

This research has been initiated by the study doctor, Professor Sonnabend, who is an orthopaedic surgeon at Royal North Shore Hospital.

Patients are eligible for this study if they:
* Are aged between 40 and 70;
* Have shoulder pain in only one shoulder, which may or may not be following an injury;
* Have pain at the ends of the range of movement of their shoulder in all directions;
* Have a loss of movement in the shoulder;
* Have had symptoms for less than 3 months;
* Have an x-ray that is normal;
* Are non-diabetic.

Participants will be given either metformin or a placebo to take twice daily for 3 months. The one taken will be chosen randomly. Participants and the study doctor will not know which treatment a participant is receiving.

Participation in the study will involve 4 medical appointments at Royal North Shore Hospital, which would be at least the usual number of visits that would be made to a specialist, but in addition to the consultations, questionnaires will be completed and blood samples will be taken.

Participation in any research project is voluntary. This study will not cost participants anything.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 62482 0
Prof David Sonnabend
Address 62482 0
Department of Orthopaedics and Traumatic Surgery
Clinical Administration 7C, Level 7,
Acute Services Building
Royal North Shore Hospital
St Leonards NSW 2065
Country 62482 0
Australia
Phone 62482 0
+61 2 94631771
Fax 62482 0
+61 2 94631078
Email 62482 0
david.sonnabend@health.nsw.gov.au
Contact person for public queries
Name 62483 0
Ms Celia Miller
Address 62483 0
Department of Orthopaedics and Traumatic Surgery
Clinical Administration 7C, Level 7,
Acute Services Building
Royal North Shore Hospital
St Leonards NSW 2065
Country 62483 0
Australia
Phone 62483 0
+61 2 94631761
Fax 62483 0
+61 2 94631078
Email 62483 0
celia.miller@health.nsw.gov.au
Contact person for scientific queries
Name 62484 0
Dr Margaret Smith
Address 62484 0
Kolling Building, Level 10
Royal North Shore Hospital
St Leonards NSW 2065
Country 62484 0
Australia
Phone 62484 0
+61 2 99264807
Fax 62484 0
+61 2 94631078
Email 62484 0
mobsmith@sydney.edu.au

No information has been provided regarding IPD availability
Summary results
No Results