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    Clinical Trial Results:
    The use of topical Glyceryl Trinitrate (GTN) and eccentric exercises in the treatment of mid portion Achilles Tendinopathy: a randomised placebo controlled trial

    Summary
    EudraCT number
    		 2015-005421-40
    Trial protocol
    		 IE  
    Global end of trial date
    01 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Apr 2022
    First version publication date
    28 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RCSI-1764
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02499484
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Royal College of Surgeons Ireland
    Sponsor organisation address
    111 St Stephens Green, dublin, Ireland, Dublin 2
    Public contact
    School of Physiotherapy, Royal College of Surgeons Ireland, 353 014022397no, sponsorship@rcsi.ie
    Scientific contact
    School of Physiotherapy, Royal College of Surgeons Ireland, 353 014022397no, paulkirwin@rcsi.ie
    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
    09 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Dec 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective The primary objective of this research is to determine if the addition of topical GTN over 24 weeks to a 12 week exercise programme improves clinical outcomes more than placebo GTN for people with Achilles Tendinopathy. Secondary Objective To determine at which time point (week 6, 12 or 24) changes in clinical outcomes occur in those with Achilles tendinopathy undergoing a programme of topical GTN and eccentric exercise. To determine which baseline measures and patient specific factors can predict response to treatment (GTN and eccentric exercise)
    Protection of trial subjects
    By way of a phone interview, the principal investigator informed the potential participants of the nature of the study in order to ascertain their willingness to be involved or to decline participation. Potential participants were screened for inclusion and exclusion criteria at this point. All those who declined to participate or did not fulfill the inclusion criteria received their treatment as normal in the hospital physiotherapy department. Participants that were willing to partake in the study were posted an envelope containing a Participant Information Leaflet on the nature and purpose of the study, a consent letter for review, which was then signed in the presence of the principal investigator at time of initial assessment and an appointment to attend for their initial assessment. In addition, patients could withdraw from the study at any time without providing a reason and this did not have any affect on their clinical care.
    Background therapy
    		 N/A
    Evidence for comparator
    		 n/a
    Actual start date of recruitment
    02 Feb 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Ireland: 76
    Worldwide total number of subjects
    76
    EEA total number of subjects
    76
    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)
    75
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial aimed to recruit 240 subjects (120 in each treatment arm) that presented to Connolly Hospital Physiotherapy department with Achilles tendinopathy. The original sample size was 76 and although the protocol in use at the time of recruitment stipulated that 240 patients be recruited, the investigator reverted to the original sample size (76)

    Pre-assignment
    Screening details
    		 All patients referred to Connolly Hospital Physiotherapy department with a diagnosis of Achilles tendinopathy were considered eligible for the trial (once they met eligibility criteria). A pre-screening phone interview initially took place with potential subjects & an in person screening visit followed (at hospital site).

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The principal investigator performing visit assessments was fully blinded. Unblinded personnel performed the randomisation and prescribing of the investigational medicinal product for each subject. Subjects were unaware of the treatment allocation (as the Percutol and placebo tubes were not identical, they were wrapped in a covering which obscured the details). At each assessment timepoint, subjects were advised not to bring their medication so as not to unblind the investigator.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Glyceryl Trinitrate (GTN)
    Arm description
    		 0.5cm Glyceryl Trinitrate to be delivered to subjects. The topical GTN to be used for the purpose of this trial was Percutol. This delivered the GTN in ointment form. Participants were instructed to measure 0.5cm of Percutol ointment by applying 0.5cm of Percutol to a paper applicator/strip, which had the amount required indicated in a circular outline, measuring approximately the same size as a pea.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glyceryl Trinitrate Ointment
    Investigational medicinal product code
    Other name
    Percutol
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical
    Dosage and administration details
    Subjects applied 0.5cm of the GTN once daily (for a 12-14 hour duration per day) for a total of 24 weeks.

    Arm title
    		 Placebo Arm
    Arm description
    		 Participants were instructed in how to measure 0.5cm of aqueous cream and applied 0.5cm of the aqueous cream to a paper applicator/strip, which had the amount required indicated in a circular outline, measuring approximately the same size as a pea.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Aqueous Cream
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical
    Dosage and administration details
    The placebo ointment to be used in this trial was aqueous cream, contained in a 100g collapsible tube. Subjects applied this daily (for a 12-14 hour duration each day) for a total of 24 weeks.

    Number of subjects in period 1
    		Glyceryl Trinitrate (GTN) Placebo Arm
    Started
    37
    39
    Completed
    33
    33
    Not completed
    4
    6
         Lost to follow-up
    4
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Glyceryl Trinitrate (GTN)
    Reporting group description
    		 0.5cm Glyceryl Trinitrate to be delivered to subjects. The topical GTN to be used for the purpose of this trial was Percutol. This delivered the GTN in ointment form. Participants were instructed to measure 0.5cm of Percutol ointment by applying 0.5cm of Percutol to a paper applicator/strip, which had the amount required indicated in a circular outline, measuring approximately the same size as a pea.

    Reporting group title
    Placebo Arm
    Reporting group description
    		 Participants were instructed in how to measure 0.5cm of aqueous cream and applied 0.5cm of the aqueous cream to a paper applicator/strip, which had the amount required indicated in a circular outline, measuring approximately the same size as a pea.

    Reporting group values
    		 Glyceryl Trinitrate (GTN) Placebo Arm Total
    Number of subjects
    		 37 39 76
    Age categorical
    Patients 65-84 in GTN arm
    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)
    		 36 39 75
        From 65-84 years
    		 1 0 1
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 16 14 30
        Male
    		 21 25 46

    End points

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    End points reporting groups
    Reporting group title
    Glyceryl Trinitrate (GTN)
    Reporting group description
    		 0.5cm Glyceryl Trinitrate to be delivered to subjects. The topical GTN to be used for the purpose of this trial was Percutol. This delivered the GTN in ointment form. Participants were instructed to measure 0.5cm of Percutol ointment by applying 0.5cm of Percutol to a paper applicator/strip, which had the amount required indicated in a circular outline, measuring approximately the same size as a pea.

    Reporting group title
    Placebo Arm
    Reporting group description
    		 Participants were instructed in how to measure 0.5cm of aqueous cream and applied 0.5cm of the aqueous cream to a paper applicator/strip, which had the amount required indicated in a circular outline, measuring approximately the same size as a pea.

    Primary: Victorian Institute of Sport Assessment – Achilles

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    End point title
    		 Victorian Institute of Sport Assessment – Achilles
    End point description
    VISA-A was a self administered questionnaire which rated the severity of the Achilles tendon pain, function and activity. It is currently the only validated reliable tool for assessing pain and function in Achilles tendinopathy, it is the current gold standard outcome tool.
    End point type
    Primary
    End point timeframe
    Assessed at 24 weeks
    End point values
    		 Glyceryl Trinitrate (GTN) Placebo Arm
    Number of subjects analysed
    33
    33
    Units: 0-100
        arithmetic mean (standard deviation)
    87.1 ( 13.9 )
    85.1 ( 16.8 )
    Statistical analysis title
    		 Statistical analysis of primary endpoint
    Statistical analysis description
    Data were entered into Excel Version 16 and imported to SPSS 26 for analysis. Linear regression was used to analyse the between-group difference in the primary outcome in order to compare the effectiveness of GTN versus placebo on Achilles symptoms as measured by the change in the primary outcome measure from baseline to 6 weeks, 12 weeks and 24 weeks.
    Comparison groups
    Glyceryl Trinitrate (GTN) v Placebo Arm
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.09
         upper limit
    		 9.1
    Notes
    [1] - Where baseline differences existed between the two groups, baseline scores for the outcome measures were used as the covariate in the analysis, due to baseline differences between the two groups. The independent variables selected were group allocation (GTN or placebo), and the baseline outcome measure being analysed (e.g. VISA-A at baseline). The dependent variable selected was the outcome measure being analysed at week 6, 12 and 24 (e.g. VISA-A scores at week 6, 12 and 24).

    Secondary: Numerical Rating Scale (NRS)

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    End point title
    		 Numerical Rating Scale (NRS)
    End point description
    This was a numerical rating scale (NRS) for subjects to rate their Achilles pain from zero to ten,
    End point type
    Secondary
    End point timeframe
    assessed at 24 weeks
    End point values
    		 Glyceryl Trinitrate (GTN) Placebo Arm
    Number of subjects analysed
    33
    33
    Units: 0-10
        arithmetic mean (standard deviation)
    3.2 ( 2.9 )
    2.9 ( 2.9 )
    No statistical analyses for this end point

    Secondary: Lower Extremity Functional Scale (LEFS)

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    End point title
    		 Lower Extremity Functional Scale (LEFS)
    End point description
    The LEFS is a self reported measure of functional ability in relation to their Achilles tendinopathy, which was completed by participants
    End point type
    Secondary
    End point timeframe
    Assessment at 24 weeks
    End point values
    		 Glyceryl Trinitrate (GTN) Placebo Arm
    Number of subjects analysed
    33
    33
    Units: 0-80
        arithmetic mean (standard deviation)
    72.9 ( 9.9 )
    71.9 ( 10.2 )
    No statistical analyses for this end point

    Secondary: Heel Raise for Endurance Test

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    End point title
    		 Heel Raise for Endurance Test
    End point description
    End point type
    Secondary
    End point timeframe
    assessment at 24 weeks
    End point values
    		 Glyceryl Trinitrate (GTN) Placebo Arm
    Number of subjects analysed
    33
    33
    Units: 0-100
        arithmetic mean (standard deviation)
    28.1 ( 10.3 )
    31.6 ( 13.6 )
    No statistical analyses for this end point

    Secondary: Hopping Test

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    End point title
    		 Hopping Test
    End point description
    End point type
    Secondary
    End point timeframe
    assessment at 24 weeks
    End point values
    		 Glyceryl Trinitrate (GTN) Placebo Arm
    Number of subjects analysed
    33
    33
    Units: 0-100
        arithmetic mean (standard deviation)
    77.6 ( 42.8 )
    79.8 ( 42.2 )
    No statistical analyses for this end point

    Secondary: AP Ultrasound Measure of Achilles thickness

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    End point title
    		 AP Ultrasound Measure of Achilles thickness
    End point description
    End point type
    Secondary
    End point timeframe
    assessment at 24 weeks
    End point values
    		 Glyceryl Trinitrate (GTN) Placebo Arm
    Number of subjects analysed
    33
    33
    Units: 0-20
        arithmetic mean (standard deviation)
    7.7 ( 2.4 )
    7.9 ( 2.1 )
    No statistical analyses for this end point

    Secondary: Pressure Pain Threshold (PPT) Scores

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    End point title
    		 Pressure Pain Threshold (PPT) Scores
    End point description
    End point type
    Secondary
    End point timeframe
    assessment at 24 weeks
    End point values
    		 Glyceryl Trinitrate (GTN) Placebo Arm
    Number of subjects analysed
    33
    33
    Units: 0-10
        arithmetic mean (standard deviation)
    6.3 ( 2.9 )
    5.9 ( 2.9 )
    No statistical analyses for this end point

    Secondary: Star Excursion Balance Test (SEBT) Anterior Reach

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    End point title
    		 Star Excursion Balance Test (SEBT) Anterior Reach
    End point description
    End point type
    Secondary
    End point timeframe
    assessment at 24 weeks
    End point values
    		 Glyceryl Trinitrate (GTN) Placebo Arm
    Number of subjects analysed
    33
    33
    Units: 0-120
        arithmetic mean (standard deviation)
    62.6 ( 8.4 )
    64.2 ( 6.6 )
    No statistical analyses for this end point

    Secondary: Star Excursion Balance Test (SEBT) Posteromedial Reach

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    End point title
    		 Star Excursion Balance Test (SEBT) Posteromedial Reach
    End point description
    End point type
    Secondary
    End point timeframe
    assessment at 24 weeks
    End point values
    		 Glyceryl Trinitrate (GTN) Placebo Arm
    Number of subjects analysed
    33
    33
    Units: 0-120
        arithmetic mean (standard deviation)
    97.7 ( 10.7 )
    98.7 ( 10.2 )
    No statistical analyses for this end point

    Secondary: Star Excursion Balance Test (SEBT) Posterolateral Reach

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    End point title
    		 Star Excursion Balance Test (SEBT) Posterolateral Reach
    End point description
    End point type
    Secondary
    End point timeframe
    assessment at 24 weeks
    End point values
    		 Glyceryl Trinitrate (GTN) Placebo Arm
    Number of subjects analysed
    33
    33
    Units: 0-120
        arithmetic mean (standard deviation)
    88.7 ( 9.2 )
    90.2 ( 12.7 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 3 to week 24
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Glyceryl Trinitrate Group
    Reporting group description
    		 Six adverse reactions were noted in the GTN group and four adverse events.

    Reporting group title
    Placebo Group
    Reporting group description
    		 Four adverse reactions and two adverse events occurred in the placebo

    Serious adverse events
    		 Glyceryl Trinitrate Group Placebo Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 39 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    achilles tendon rupture
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 39 (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
    		 Glyceryl Trinitrate Group Placebo Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 37 (27.03%)
    4 / 39 (10.26%)
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 39 (2.56%)
         occurrences all number
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 39 (5.13%)
         occurrences all number
    2
    2
    Eye disorders
    Eye Swelling
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Skin Irritation
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 39 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Muscle Soreness
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Ankle Swelling
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 39 (0.00%)
         occurrences all number
    1
    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
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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