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    Clinical Trial Results:
    Direct comparison of intra-articular saline injections with an education plus exercise program for treatment of knee osteoarthritis symptoms: A randomised, open label, controlled, evidence based trial

    Summary
    EudraCT number
    		 2019-000809-71
    Trial protocol
    		 DK  
    Global end of trial date
    01 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Dec 2021
    First version publication date
    22 Dec 2021
    Other versions
    Summary report(s)
    		 Scientific article

    Trial information

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    Trial identification
    Sponsor protocol code
    APPI2-PT-2019-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03843931
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Parker Institute, Frederiksberg Hospital
    Sponsor organisation address
    Ndr. Fasanvej 57, Copenhagen, Denmark, 2000
    Public contact
    Primary/ Principal Investigator, The Parker Institute, Bispebjerg and Frederiksberg Hospital, The Capital Region of Denmark, 45 38164155, henning.bliddal@regionh.dk
    Scientific contact
    Primary/ Principal Investigator, The Parker Institute, Bispebjerg and Frederiksberg Hospital, The Capital Region of Denmark, 45 38164155, henning.bliddal@regionh.dk
    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
    01 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare a widely used education plus exercise program (the GLA:D program) with intra-articular saline injections as treatments of knee OA symptoms
    Protection of trial subjects
    The trial was open-label and any adverse event reported by the participants were handled by scheduling an appointment with an investigator
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2019
    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
    Denmark: 206
    Worldwide total number of subjects
    206
    EEA total number of subjects
    206
    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)
    67
    From 65 to 84 years
    133
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between 30 July 2019 and 17 September 2020, participants were recruited from the OA outpatient’s clinic at Bispebjerg-Frederiksberg Hospital, Denmark

    Pre-assignment
    Screening details
    		 544 individuals were prescreened by telephone, of which 207 were ineligible and 10 declined clinical screening. 317 had their eligibility assessed by clinical screening, of which 109 were not eligible and 2 were ineligible but were not randomised.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    As this was an open-label trial neither health professionals delivering the interventions, nor participants were blinded to treatment allocation. Outcome assessors were blinded to allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Exercise and Education
    Arm description
    		 The GLA:D program
    Arm type
    		 behavioural/exercise

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Open Label Placebo
    Arm description
    		 Intra-articular injections of 5 ml saline
    Arm type
    		 Placebo

    Investigational medicinal product name
    Natriumklorid isotonisk "SAD"
    Investigational medicinal product code
    V07AB
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    1 injection every two weeks over a period of 8 weeks; 4 injections of 5 ml in total

    Number of subjects in period 1
    		Exercise and Education Open Label Placebo
    Started
    102
    104
    Week 9
    97
    99
    Week 12
    91
    91
    Completed
    91
    91
    Not completed
    11
    13
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    1
    2
         Other reasons
    4
    6
         COVID19 trial suspension
    5
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Exercise and Education
    Reporting group description
    		 The GLA:D program

    Reporting group title
    Open Label Placebo
    Reporting group description
    		 Intra-articular injections of 5 ml saline

    Reporting group values
    		 Exercise and Education Open Label Placebo Total
    Number of subjects
    		 102 104 206
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 27 47 74
        From 65-84 years
    		 71 55 126
        85 years and over
    		 4 2 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.1 ± 8.3 66.7 ± 8.2 -
    Gender categorical
    Units: Subjects
        Female
    		 45 49 94
        Male
    		 57 55 112
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The primary analysis was performed using the intention-to- treat (ITT) population; patients were assessed and analysed as members of their randomised groups, irrespective of adherence to the treatments.

    Subject analysis sets values
    		 ITT
    Number of subjects
    206
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    74
        From 65-84 years
    126
        85 years and over
    6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    68.4 ± 8.4
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Exercise and Education
    Reporting group description
    		 The GLA:D program

    Reporting group title
    Open Label Placebo
    Reporting group description
    		 Intra-articular injections of 5 ml saline

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The primary analysis was performed using the intention-to- treat (ITT) population; patients were assessed and analysed as members of their randomised groups, irrespective of adherence to the treatments.

    Primary: change from baseline in the Knee injury and Osteoarthritis Outcome Score (KOOS) pain subscale

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    End point title
    		 change from baseline in the Knee injury and Osteoarthritis Outcome Score (KOOS) pain subscale
    End point description
    End point type
    Primary
    End point timeframe
    Week 9
    End point values
    		 Exercise and Education Open Label Placebo
    Number of subjects analysed
    102
    104
    Units: points
        arithmetic mean (confidence interval 95%)
    10.0 (7.0 to 12.9)
    7.3 (4.4 to 10.2)
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Exercise and Education v Open Label Placebo
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 6

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to week 12
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Exercise and Education
    Reporting group description
    		 The GLA:D program

    Reporting group title
    Open Label Placebo
    Reporting group description
    		 Intra-articular injections of 5 ml saline

    Serious adverse events
    		 Exercise and Education Open Label Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 99 (5.05%)
    5 / 103 (4.85%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    coloscopy
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    2 / 99 (2.02%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    0 / 99 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abscess
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Hip disarticulation
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
    Additional description: Knee pain
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Exercise and Education Open Label Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 99 (34.34%)
    40 / 103 (38.83%)
    Injury, poisoning and procedural complications
    Procedural complication
         subjects affected / exposed
    7 / 99 (7.07%)
    1 / 103 (0.97%)
         occurrences all number
    7
    1
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    5 / 99 (5.05%)
    3 / 103 (2.91%)
         occurrences all number
    5
    6
    Skin and subcutaneous tissue disorders
    Injection related reaction
         subjects affected / exposed
    0 / 99 (0.00%)
    3 / 103 (2.91%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Pain exacerbation
         subjects affected / exposed
    26 / 99 (26.26%)
    37 / 103 (35.92%)
         occurrences all number
    34
    38
    Infections and infestations
    Infection
         subjects affected / exposed
    3 / 99 (3.03%)
    0 / 103 (0.00%)
         occurrences all number
    3
    0

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34844929
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