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    Clinical Trial Results:
    GRASP: Getting it Right: Addressing Shoulder Pain. Clinical and cost effectiveness of progressive exercise compared to best practice advice, with or without corticosteroid injection, for the treatment of rotator cuff disorders: a 2x2 factorial randomised controlled trial

    Summary
    EudraCT number
    		 2016-002991-28
    Trial protocol
    		 GB  
    Global end of trial date
    12 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jun 2021
    First version publication date
    28 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    N/A
    Additional study identifiers
    ISRCTN number
    		 ISRCTN16539266
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1185-3750
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Old Road, Headington, Oxford, United Kingdom,
    Public contact
    Dr Sally Hopewell, Oxford Clinical Trials Research Unit, sally.hopewell@csm.ox.ac.uk
    Scientific contact
    Dr Sally Hopewell, Oxford Clinical Trials Research Unit, sally.hopewell@csm.ox.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary research objective is to assess whether: An individually tailored progressive exercise programme, that includes behavioural change strategies, led by a physiotherapist provides greater improvement in shoulder pain and function over 12 months post-randomisation than a best practice advice session with a physiotherapist supported by high quality materials; and whether an injection into the shoulder (a subacromial corticosteroid injection) provides greater improvement in shoulder pain and function over 12 months post-randomisation than no injection. This will be assessed by the the pain and function levels of each participant over 12 months after entering the trial.
    Protection of trial subjects
    A Data Monitoring and Ethics Committee (DMEC) was responsible for monitoring the trial’s progress and providing independent advice. It advised the chair of the TSC if, at any time, in its view, the trial should have been be stopped for ethical reasons, including concerns about participant safety. The DMEC was comprised of an independent clinician, health service researchers, a specialist physiotherapist and a statistician.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 The best practice advice session with a physiotherapist was selected as the comparator because it is consistent with current clinical practice guidelines regarding the self-management advice that should be provided to people with rotator cuff disorders. In addition, we used a no-injection comparison as finding an inert robust placebo is challenging and, given the existing evidence on the short term benefit of corticosteroid injection, we believed that it was unethical and undesirable to progress a placebo arm in a large phase III trial.
    Actual start date of recruitment
    02 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 708
    Worldwide total number of subjects
    708
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    512
    From 65 to 84 years
    192
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 708 participants were recruited between 10 March 2017 to 2 May 2019 from 20 UK NHS primary care-based musculoskeletal and related physiotherapy services.

    Pre-assignment
    Screening details
    		 A total of 2287 patients were screened and assessed to see whether they met the GRASP trial eligibility criteria (see Table 5) of whom 1284 (56%) were eligible and 708 agreed to participate

    Period 1
    Period 1 title
    DefineOverall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    It was not possible to blind physiotherapists or study participants once treatment allocation was revealed. Where practical, team members were blinded until after data analysis was complete. Trial statisticians had access to treatment assignment during the study for the purposes of data monitoring and safety. Data entry personnel entered data from anonymised questionnaires, which included some details on treatments received.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Progressive Exercise
    Arm description
    		 Progressive exercise programme: individually tailored progressive home exercise programme prescribed and supervised by a physiotherapist involving up to six face-to-face sessions over 16 weeks. Preceeded by either corticosteroid injection or no corticosteroid injection depending on randomisation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methylprednisolone acetate
    Investigational medicinal product code
    Other name
    triamcinolone acetonide, as per local treatment protocols.
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    Single injection of Methylprednisolone acetate (up to 40 mg) or triamcinolone acetonide (up to 40 mg), as per local treatment protocols. Depo-Medrone 40mg https://www.medicines.org.uk/emc/product/8957/smpc#gref or Kenalog Intra-articular / Intramuscular injection https://www.medicines.org.uk/emc/product/6748/pil#gref

    Arm title
    		 Best Practice Advice
    Arm description
    		 Best practice advice: one face-to-face session with a physiotherapist and home exercise programme supported by high quality self-management materials. Preceeded by either corticosteroid injection or no corticosteroid injection depending on randomisation.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methylprednisolone acetate
    Investigational medicinal product code
    Other name
    triamcinolone acetonide, as per local treatment protocols.
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    Single injection of Methylprednisolone acetate (up to 40 mg) or triamcinolone acetonide (up to 40 mg), as per local treatment protocols. Depo-Medrone 40mg https://www.medicines.org.uk/emc/product/8957/smpc#gref or Kenalog Intra-articular / Intramuscular injection https://www.medicines.org.uk/emc/product/6748/pil#gref

    Arm title
    		 Corticosteroid Injection
    Arm description
    		 Subacromial corticosteroid injection. The corticosteroid injected was either methylprednisolone acetate (up to 40 mg) or triamcinolone acetonide (up to 40 mg), as per local treatment protocols. The local anaesthetic was either 1% lidocaine (up to 5 mL) or 0.5% bupivacaine hydrochloride (up to 10 mL). Followed by either progressive exercise programme or best practice advice depending on randomisation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methylprednisolone acetate
    Investigational medicinal product code
    Other name
    triamcinolone acetonide, as per local treatment protocols.
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    Single injection of Methylprednisolone acetate (up to 40 mg) or triamcinolone acetonide (up to 40 mg), as per local treatment protocols. Depo-Medrone 40mg https://www.medicines.org.uk/emc/product/8957/smpc#gref or Kenalog Intra-articular / Intramuscular injection https://www.medicines.org.uk/emc/product/6748/pil#gref

    Arm title
    		 No Corticosteroid Injection
    Arm description
    		 No subacromial corticosteroid injection. Followed by either progressive exercise programme or best practice advice (as described above) depending on randomisation.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Progressive Exercise Best Practice Advice Corticosteroid Injection No Corticosteroid Injection
    Started
    356
    352
    360
    348
    Completed
    343
    339
    352
    330
    Not completed
    13
    13
    8
    18
         Lost to follow-up
    13
    13
    8
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Progressive Exercise
    Reporting group description
    		 Progressive exercise programme: individually tailored progressive home exercise programme prescribed and supervised by a physiotherapist involving up to six face-to-face sessions over 16 weeks. Preceeded by either corticosteroid injection or no corticosteroid injection depending on randomisation.

    Reporting group title
    Best Practice Advice
    Reporting group description
    		 Best practice advice: one face-to-face session with a physiotherapist and home exercise programme supported by high quality self-management materials. Preceeded by either corticosteroid injection or no corticosteroid injection depending on randomisation.

    Reporting group title
    Corticosteroid Injection
    Reporting group description
    		 Subacromial corticosteroid injection. The corticosteroid injected was either methylprednisolone acetate (up to 40 mg) or triamcinolone acetonide (up to 40 mg), as per local treatment protocols. The local anaesthetic was either 1% lidocaine (up to 5 mL) or 0.5% bupivacaine hydrochloride (up to 10 mL). Followed by either progressive exercise programme or best practice advice depending on randomisation.

    Reporting group title
    No Corticosteroid Injection
    Reporting group description
    		 No subacromial corticosteroid injection. Followed by either progressive exercise programme or best practice advice (as described above) depending on randomisation.

    Reporting group values
    		 Progressive Exercise Best Practice Advice Corticosteroid Injection No Corticosteroid Injection Total
    Number of subjects
    		 356 352 360 348 708
    Age categorical
    Participant age at randomisation
    Units: Subjects
        18-35 years
    		 31 24 30 25 55
        36 years and above
    		 325 328 330 323 653
    Age continuous
    Participant age at randomisation (continuous)
    Units: years
        arithmetic mean (standard deviation)
    		 56.2 ( 12.7 ) 54.7 ( 13.5 ) 55.3 ( 13.4 ) 55.6 ( 12.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 173 176 178 171 349
        Male
    		 183 176 182 177 359
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Included in the analysis is all participants with at least one follow-up time point SPADI outcome and the baseline variables used in the model (682/total randomised 708)

    Subject analysis sets values
    		 ITT
    Number of subjects
    708
    Age categorical
    Participant age at randomisation
    Units: Subjects
        18-35 years
    52
        36 years and above
    630
    Age continuous
    Participant age at randomisation (continuous)
    Units: years
        arithmetic mean (standard deviation)
    55.8 ( 13.0 )
    Gender categorical
    Units: Subjects
        Female
    330
        Male
    352

    End points

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    End points reporting groups
    Reporting group title
    Progressive Exercise
    Reporting group description
    		 Progressive exercise programme: individually tailored progressive home exercise programme prescribed and supervised by a physiotherapist involving up to six face-to-face sessions over 16 weeks. Preceeded by either corticosteroid injection or no corticosteroid injection depending on randomisation.

    Reporting group title
    Best Practice Advice
    Reporting group description
    		 Best practice advice: one face-to-face session with a physiotherapist and home exercise programme supported by high quality self-management materials. Preceeded by either corticosteroid injection or no corticosteroid injection depending on randomisation.

    Reporting group title
    Corticosteroid Injection
    Reporting group description
    		 Subacromial corticosteroid injection. The corticosteroid injected was either methylprednisolone acetate (up to 40 mg) or triamcinolone acetonide (up to 40 mg), as per local treatment protocols. The local anaesthetic was either 1% lidocaine (up to 5 mL) or 0.5% bupivacaine hydrochloride (up to 10 mL). Followed by either progressive exercise programme or best practice advice depending on randomisation.

    Reporting group title
    No Corticosteroid Injection
    Reporting group description
    		 No subacromial corticosteroid injection. Followed by either progressive exercise programme or best practice advice (as described above) depending on randomisation.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Included in the analysis is all participants with at least one follow-up time point SPADI outcome and the baseline variables used in the model (682/total randomised 708)

    Primary: SPADI over 12 months

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    End point title
    		 SPADI over 12 months
    End point description
    End point type
    Primary
    End point timeframe
    over 12 months
    End point values
    		 Progressive Exercise Best Practice Advice Corticosteroid Injection No Corticosteroid Injection ITT
    Number of subjects analysed
    343
    339
    352
    330
    682
    Units: Adjusted Mean
        arithmetic mean (standard error)
    28.8 ( 1.0 )
    29.4 ( 1.1 )
    28.5 ( 1.0 )
    29.6 ( 1.0 )
    29.1 ( 0.7 )
    Statistical analysis title
    		 Primary analysis for Progressive Exercise
    Statistical analysis description
    The difference in the primary outcome SPADI between the two intervention groups (Progressive Exercise and Best Practice Advice) was estimated over the 12 months period and at each data collection time point using a repeated measures linear mixed effects regression model adjusted for the fixed effects age, sex and baseline SPADI, and random intercepts by centre, physiotherapist and observations within participant.
    Comparison groups
    Progressive Exercise v Best Practice Advice
    Number of subjects included in analysis
    682
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.659 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.66
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -4.52
         upper limit
    		 3.2
    Variability estimate
    Standard error of the mean
    Notes
    [1] - Statistical significance was set at the 1% level and corresponding 99% confidence intervals (CI) for the primary outcome.
    Statistical analysis title
    		 Primary analysis for Corticosteroid Injection
    Statistical analysis description
    The difference in the primary outcome SPADI between the two intervention groups (Corticosteroid Injection and No Corticosteroid Injection) was estimated over the 12 months period and at each data collection time point using a repeated measures linear mixed effects regression model adjusted for the fixed effects age, sex and baseline SPADI, and random intercepts by centre, physiotherapist and observations within participant.
    Comparison groups
    Corticosteroid Injection v No Corticosteroid Injection
    Number of subjects included in analysis
    682
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.397 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (final values)
    Point estimate
    -1.11
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -4.47
         upper limit
    		 2.26
    Variability estimate
    Standard error of the mean
    Notes
    [2] - Statistical significance was set at the 1% level and corresponding 99% confidence intervals (CI) for the primary outcome.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    12 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    2015
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Foreseeable adverse events occurring as a result of the trial intervention(s) were not planned to be recorded as part of the trial. Instead, participants were provided with information on the potential adverse events resulting from exercise and corticosteroid injection (if applicable) including what they should do if they experience an adverse event, as would happen as part of standard NHS procedures.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Our population was predominantly white British (89.7%), this figure is higher compared with the population in England as a whole (78.7%). The prevalence of rotator cuff disorder in ethnic minority groups is not well known or understood.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32894159
    http://www.ncbi.nlm.nih.gov/pubmed/28716796
    http://www.ncbi.nlm.nih.gov/pubmed/32026827
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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