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Trial registered on ANZCTR


Registration number
ACTRN12618000431224
Ethics application status
Approved
Date submitted
6/03/2018
Date registered
26/03/2018
Date last updated
16/02/2022
Date data sharing statement initially provided
1/04/2019
Date results information initially provided
1/04/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Analysing genes, blood, urine and clinical outcomes in people with frozen shoulder, rotator cuff tears and osteoarthritis
Scientific title
Transcriptome-wide alterations in gene expression of the glenohumeral joint capsule in people undergoing arthroscopic surgery for adhesive capsulitis, rotator cuff tears and osteoarthritis compared to people with non-inflammatory shoulder instability
Secondary ID [1] 294255 0
None
Universal Trial Number (UTN)
Trial acronym
BiSP - Biomarkers in Shoulder Pain
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Adhesive capsulitis 306935 0
shoulder instability 306936 0
rotator cuff tear 325295 0
shoulder osteoarthritis 325296 0
Condition category
Condition code
Musculoskeletal 306035 306035 0 0
Other muscular and skeletal disorders
Musculoskeletal 322695 322695 0 0
Osteoarthritis

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
All participants receive general anaesthetic and interscalene block, and will be placed in the beach chair or lateral position consistent with published guidelines. During the arthroscopy by an orthopaedic surgeon, two punch biopsies the size of rice grain will be collected under direct arthroscopic vision from the anterior capsule and rotator interval of the glenohumeral joint. Tissue samples are immediately placed in a vial containing RNAlaterTM stabilization solution (ThermoFisher).

Participants' shoulders from the AC group will be accessed with three arthroscopic portals and saline arthroscopic fluid at room temperature inserted into the joint space. Biopsies will be taken by the surgeon and rotator interval release conducted via an incision of the anterior capsule with the radiofrequency probe in the 1.00 to 5.30 position. Range of motion will be compared to the unaffected shoulder and a limited posterior capsule release performed by reversing the arthroscopic view if ranges are not equal. The operation time is approximately 60 minutes.
Intervention code [1] 300550 0
Diagnosis / Prognosis
Comparator / control treatment
Participants' shoulders in the instability group will be evaluated under anaesthetic by an orthopaedic surgeon to determine the stability pattern of the glenohumeral joint, with clinical findings considered alongside pre-operative MRI findings. The joint space will be accessed by the surgeon with arthroscopic portals and biopsies collected. The labral tear will be prepared with liberator probes and shaver, and capsulolabral reduction and fixation anteriorly +/- posteriorly with anchors according to the injury pattern. The operation time is approximately 60 minutes.
Control group
Active

Outcomes
Primary outcome [1] 305062 0
Exploratory study of gene expression using RNA-seq on tissue samples collected from the anterior glenohumeral joint capsule
Timepoint [1] 305062 0
Intra-operative tissue sample
Primary outcome [2] 305241 0
Exploratory biomarker gene analysis using plasma and urine samples.
Timepoint [2] 305241 0
Shortly before surgery
Secondary outcome [1] 344040 0
Shoulder pain and function assessed by the Oxford Shoulder Score
Timepoint [1] 344040 0
Preoperatively and 12-months postoperatively.
Secondary outcome [2] 344041 0
Active range of shoulder movement visually estimated by orthopaedic surgeon
Timepoint [2] 344041 0
Preoperatively and 12-months post-operatively
Secondary outcome [3] 344334 0
Oxford Shoulder Instability Score
Timepoint [3] 344334 0
Preoperatively and 12-months postoperatively
Secondary outcome [4] 344335 0
Upper limb symptoms and function assessed by the Quick DASH
Timepoint [4] 344335 0
Preoperatively and 12-months postoperatively
Secondary outcome [5] 344336 0
Shoulder pain, function and instability assessed by the American Shoulder and Elbow Society Score
Timepoint [5] 344336 0
Preoperatively and 12-months postoperatively
Secondary outcome [6] 344337 0
Quality of life assessed by the EQ-5D-5L
Timepoint [6] 344337 0
Preoperatively and 12-months postoperatively

Eligibility
Key inclusion criteria
Inclusion Criteria (AC and control):
• Adults 18 – 70 yrs
• Symptoms > 3mths
• Imaging
o MRI – exclusion of degenerative or inflammatory arthropathy, as well as stage full thickness rotator cuff tears
• Instability > 1 episode for controls, pain only a minor feature
• AC – Global loss of motion > 30%
Inclusion criteria (rotator cuff tear)
• 18 to 70 years of age
• Symptoms > 6 months (chronic tear)
• Full thickness rotator cuff tear on MRI
Inclusion criteria (shoulder arthritis)
• 18 to 85 years of age
• Primary OA
• Symptoms > 6 months
• Xray changes consistent with OA
o OA only group: without full thickness rotator cuff tear on US or MRI
o Rotator cuff arthropathy group: x-ray indicating high humeral head
Minimum age
18 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria (AC and control):
• Post surgical restricted motion
• Instability episode < 8wks prior – for control group
• Imaging – MRI features – not fulfilling criteria
Exclusion criteria (rotator cuff tear)
• Isolated subscapularis tears
• Reduced motion (<50% range) affecting daily living with clinical features of adhesive
• Massive tears (> 2 tendons)
• Prior shoulder surgery in the affected shoulder
• Intra-articular or intra-bursal corticosteroid injection within the preceding three months.
Exclusion criteria (shoulder arthritis)
• Rheumatoid arthritis or seronegative arthropathies
• Type C glenoid
• Prior shoulder surgery or significant trauma/fracture
• Intra-articular or intra-bursal corticosteroid injection within the preceding three months.

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Total RNA will be extracted from all samples using a commercially available kit (Qiagen). The quantity and quality of the extracted RNA will be measured by Agilent bioanalyser. Sequencing libraries will be generated from 1 microgram of RNA using the Truseq RNA library preparation kit (Illumina) before being converted to complimentary DNA (cDNA). cDNA libraries will then be sequenced (Illumina HiSeq). Raw read quality filtering and adapter trimming will be performed with Trimmomatic before building of the transcriptome index with Spliced Transcripts Alignment to a Reference (STAR) Software. Mapping to the human transcriptome will be performed using STAR 2-pass. Collation of individual sample counts into a m x n matrix for differential abundance testing will be performed using R. Furthermore, Gene Set Enrichment Analysis (Broad Institute) will be used to determine pathway-specific alterations in gene expression, which will give new insights into the pathogenesis of AC. Differentially expressed genes will undergo further bioinformatics analysis to identify genes that contain an export sequence motif common to all secreted proteins. In addition, differentially expressed genes encoding proteins that are exported via exosome vesicles will also be identified. Identified candidate genes will be confirmed by quantitative polymerase chain reaction (PCR). Potential biomarker genes that are significantly different between groups will guide analysis of plasma and urine samples from AC and control patients to generate information relating to specific biomarkers.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
26/02/2016
Date of last participant enrolment
Anticipated
31/03/2022
Actual
Date of last data collection
Anticipated
31/03/2023
Actual
Sample size
Target
100
Accrual to date
85
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 298893 0
Hospital
Name [1] 298893 0
Barwon Health
Country [1] 298893 0
Australia
Primary sponsor type
Hospital
Name
Barwon Health
Address
Bellerine Street, Geelong, Victoria, Australia, 3220
Country
Australia
Secondary sponsor category [1] 298107 0
Hospital
Name [1] 298107 0
St John of God Hospital
Address [1] 298107 0
Myers St, Geelong, Victoria, Australia, 3220
Country [1] 298107 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299837 0
Barwon Health Human Research Ethics Committee
Ethics committee address [1] 299837 0
Bellerine Street
Geelong, Australia, Victoria, 3220
Ethics committee country [1] 299837 0
Australia
Date submitted for ethics approval [1] 299837 0
Approval date [1] 299837 0
08/10/2015
Ethics approval number [1] 299837 0
15/15

Summary
Brief summary
Adhesive capsulitis (AC), rotator cuff tears (RCT) and osteoarthritis (OA) is a disabling and poorly understood pathological conditions of the shoulder joint. The current study aims to increase our understanding of the pathogenesis, diagnosis and clinical outcomes of people with AC, RCT and OA by investigating: 1) transcriptome-wide alterations in gene expression of the glenohumeral joint capsule compared to people with non-inflammatory shoulder instability (controls); 2) serum and urine biomarkers to better understand diagnosis and staging of AC, RCT and OA; and 3) clinical outcomes in people with AC, RCT and OA compared to controls 12-months following arthroscopic capsular release or labral repair respectively.

The study is a multi-centre, non-randomised study investigating people undergoing surgery for AC, RCT and OA compared to people undergoing arthroscopic stabilization for shoulder instability. Tissue samples collected from the anterior glenohumeral joint capsule during surgery will undergo RNA-seq to determine differences in gene expression between the study groups. Gene Set Enrichment Analysis will be used to further understand the pathogenesis of AC as well as guide serum and urine biomarker analysis. Clinical outcomes regarding pain, function and quality of life will be assessed using the Oxford Shoulder Score, Oxford Shoulder Instability Score, Quick DASH, American Shoulder and Elbow Society Score, EQ-5D-5L and active shoulder range of movement. Clinical outcomes will be collected pre-operatively and 12-months post-operatively and study groups will be compared for statistically significant differences (p<0.05).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81718 0
Prof Richard Page
Address 81718 0
Barwon Centre for Orthopaedic Research & Education (B-CORE)
St John of God Hospital Geelong
Myers St, Geelong, Victoria, Australia, 3220
Country 81718 0
Australia
Phone 81718 0
+61 3 5222 5777
Fax 81718 0
Email 81718 0
richard.page@deakin.edu.au
Contact person for public queries
Name 81719 0
Dr Stephen Gill
Address 81719 0
Barwon Centre for Orthopaedic Research & Education (B-CORE)
St John of God Hospital Geelong
Myers St, Geelong, Victoria, Australia, 3220
Country 81719 0
Australia
Phone 81719 0
+61 3 52150902
Fax 81719 0
Email 81719 0
stephen.gill2@deakin.edu.au
Contact person for scientific queries
Name 81720 0
Dr Stephen Gill
Address 81720 0
Barwon Centre for Orthopaedic Research & Education (B-CORE)
St John of God Hospital Geelong
Myers St, Geelong, Victoria, Australia, 3220
Country 81720 0
Australia
Phone 81720 0
+61 3 52150902
Fax 81720 0
Email 81720 0
stephen.gill2@deakin.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Study data will be made available upon reasonable request.
When will data be available (start and end dates)?
Study data will be made available upon reasonable request from 31 March 2023 until 31 March 2026.
Available to whom?
Appropriately qualified and interested parties.
Available for what types of analyses?
Quantitative analysis.
How or where can data be obtained?
Study data will be made available directly from the investigators upon reasonable request.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7546Study protocolPage, R.S., McGee, S.L., Eng, K. et al. Adhesive capsulitis of the shoulder: protocol for the adhesive capsulitis biomarker (AdCaB) study. BMC Musculoskelet Disord 20, 145 (2019). https://doi.org/10.1186/s12891-019-2536-x This citation is the for the adhesive capsulitis and shoulder instability participants. The protocol for the additional participants is unpublished.https://bmcmusculoskeletdisord.biomedcentral.com/articles/10.1186/s12891-019-2536-x 



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseTranscriptomic analysis of adhesive capsulitis of the shoulder.2020https://dx.doi.org/10.1002/jor.24686
N.B. These documents automatically identified may not have been verified by the study sponsor.