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    Summary
    EudraCT Number:2015-005421-40
    Sponsor's Protocol Code Number:RCSI-1764
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-03-07
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedIreland - HPRA
    A.2EudraCT number2015-005421-40
    A.3Full title of the trial
    The use of topical Glyceryl Trinitrate (GTN) and eccentric exercises in the treatment of mid portion Achilles Tendinopathy: a randomised placebo controlled trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The use of a patch with medication (called Glyceryl trinitrate) and an exercise program (called eccentric exercises) in the treatment of Achilles tendon pain
    A.3.2Name or abbreviated title of the trial where available
    The NEAT trial
    A.4.1Sponsor's protocol code numberRCSI-1764
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02499484
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorRoyal College of Surgeons in Ireland
    B.1.3.4CountryIreland
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportHealth Research Board
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRoyal College of Surgeons Ireland
    B.5.2Functional name of contact pointSchool of Physiotherapy
    B.5.3 Address:
    B.5.3.1Street Address123 St Stephens Green
    B.5.3.2Town/ cityDublin
    B.5.3.3Post codeDublin 2
    B.5.3.4CountryIreland
    B.5.4Telephone number353014022397no
    B.5.5Fax numbernononono
    B.5.6E-mailphysiotherapy@rcsi.ie
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Nitro-Dur
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNitro-Dur
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Transdermal patch
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPTransdermal use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTransdermal patch
    D.8.4Route of administration of the placeboCutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Achilles tendinopathy
    E.1.1.1Medical condition in easily understood language
    pain with tenderness in the Achilles tendon, but not at the attachment to the heel bone
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10050471
    E.1.2Term Achilles tendon pain
    E.1.2System Organ Class 100000004859
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10050129
    E.1.2Term Achilles tendon thickening
    E.1.2System Organ Class 100000004859
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10000435
    E.1.2Term Achilles tendon injury
    E.1.2System Organ Class 100000004863
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10000433
    E.1.2Term Achilles tendinitis
    E.1.2System Organ Class 100000004859
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10000441
    E.1.2Term Achilles tendonitis
    E.1.2System Organ Class 100000004859
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this research is to determine if the addition of topical GTN over 24 weeks to a 12 week exercise program improves clinical outcomes more than placebo GTN for people with Achilles tendinopathy
    E.2.2Secondary objectives of the trial
    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).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria:
    1. Current diagnosis of Achilles tendinopathy
    2. 18 years of age and old
    3. Achilles pain of 3 months or more
    4. Mid-portion Achilles tenderness and thickening on palpation
    E.4Principal exclusion criteria
    1. Previous corticosteroid injection to the affected tendon in the past 3 months
    2. Symptoms of less than 3 months duration
    3. Previous use of topical GTN for Achilles tendinopathy
    4. Contra-indication to GTN therapy
    5. Current pregnancy, breastfeeding or planning pregnancy
    6. VISA-A score > 80
    7. Previous surgery to the affected Achilles tendon
    8. Seronegative spondyloarthropathy with Achilles enthesitis
    9. Previous performance of a heavy load eccentric exercise program of the Achilles in the last 6 months
    10. Inability to perform the exercise program due to serious illness, such as unstable angina/blood pressure, myocardial infarction in past three months, cardiomyopathy, uncontrolled metabolic disease, recent ECG changes, advanced respiratory disease or third degree heart block.
    11. Staff or students of Connolly Hospital, Blanchardstown.
    E.5 End points
    E.5.1Primary end point(s)
    Participants will perform the exercise program for 12 weeks and will use the patch for 24 weeks. They will complete final assessment after 24 weeks use of the patch. The primary endpoint is the VISA-A scale. 24 weeks after commencing the trial participants will cease to use the topical medication (GTN). The VISA-A will be administered at baseline, week 6, 12 and 24. The primary outcome will be the Victoria Institute of Sport Assessment, Achilles (VISA-A) scale, which measures the impact of Achilles tendinopathy on individuals’ lifestyle.
    The VISA-A is a valid, reliable and user friendly self-report index of severity of Achilles tendinopathy, can be easily administered in clinical practice (Robinson et al, 2001) and has been used as an outcome measure in other tendinopathy trials (Tumilty et al, 2012).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The VISA-A will be administered at baseline, week 6, 12 and 24.
    E.5.2Secondary end point(s)
    Secondary endpoints are the secondary outcome measures, outlined below:

    1. Numerical Rating Scale (NRS)

    Participants will be asked to rate their Achilles pain from zero to ten on a numerical rating scale (NRS). Standardized and validated pain scales provide a means of measuring a patient’s pain and of evaluating the response to treatment. Williamson and Hogart (2005) determined that NRS is valid, reliable and appropriate for use in clinical practice. Participants will be asked to verbally rate their level of perceived pain intensity on a numerical scale from 0 to 10, with zero representing “no pain” and 10 representing the “the worst pain possible”.

    2. Lower Extremity Functional Scale (LEFS).
    The LEFS is a self-report measure of functional ability in relation to their Achilles tendinopathy, which will be completed by participants. The LEFS has been shown to have good construct validity and reliability with more sensitivity to change than the SF-36. It is easy to administer and score so is applicable for research purposes and clinical decision making for individual patients (Binkley et al., 1999).

    3. Pressure Algometry
    The outcome measurement in pressure algometry is the pain detection threshold (PDT), or the point at which pressure pain is first experienced by the participant. As tenderness is one of the key clinical diagnostic criteria, algometry is an appropriate measure to quantify the pain pressure response.
    Participants will be positioned prone with the ankle at neutral position with the foot hanging off the edge of the treatment table. The thickest and most tender point of the Achilles will be identified and marked with a pen.
    The algometer will be placed against the tender point and pressure gently and steadily increased until such point that the patient experiences pressure pain. The corresponding pressure will be read and recorded. This technique will be used to objectively measure the pain detection threshold (PDT) of affected and unaffected Achilles tendons in all participants.

    4. Ultra-sound examination of the Achilles tendon.
    All Achilles tendons (both affected and unaffected sides) will undergo ultra-sound scans at baseline and weeks 6, 12 and 24. Longitudinal and transverse views will be obtained. The Achilles tendons will be measured with patients in a prone position and their heels overhanging the examination couch to enable movement of the feet (Gibbon et al, 1999; Ohberg et al, 2001). The ankles will be flexed to 90° to ensure standardised tension on the tendon and provide the best imaging during contraction of the gastrocnemius muscles.
    The tendon thickness will be measured at the thickest point in both longitudinal and transversal scans. In the longitudinal scan, abnormal Achilles tendon thickness will be measured at the thickest point, and the distance from the point of measuring to the attachment of the calcaneus will be recorded.

    5. Dynamic Balance/Proprioception testing
    The modified Star Excursion Balance Test (SEBT) will be performed to assess whether any difference exists between the 2 groups and between the affected and unaffected limbs. The SEBT has been shown to be a reliable measure of dynamic balance (Hertel et al, 2006).
    Participants will complete the test for each limb in 3 SEBT reach directions (anterior, posteromedial, and posterolateral). This 3 direction version of the SEBT has been termed the Y balance test and has been shown to be a reliable test for measuring single limb stance excursion distances while performing dynamic balance (Plisky et al, 2009). The reach distance will be measured and recorded by the principal investigator.
    6. Heel raises for endurance and hopping test
    The heel raise test for endurance will be performed on one leg at a time with the participant standing. Participants will be instructed to raise up as high as possible onto the toes and then lower the heel to the starting position and repeat this technique for as many as possible on each leg. The test will be terminated when the patient stops, or can no longer perform a heel raise. The number of heel raises and any pain associated with the test will be documented using the NRS.
    Hopping tests involve the stretch shortening cycle of the Achilles tendon and calf musculature, and therefore measure the muscle tendon units elastic properties. Participants will be instructed to perform hopping on one leg at a time, with arms by the side, in a natural rhythm. Participants will be instructed to perform 20 hops on each leg with 15 to 30 seconds rest between each side. The number of hops performed and pain associated with hopping on each side will be documented using the NRS.
    Both the heel raise to endurance and hopping test have been shown to reliable tests with good test-retest reliablility in previous studies of Achilles tendinopathy (Silbernagel et al, 2001 and 2006).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary end points will be evaluated at baseline, week 6, 12 and 24.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 80
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2016-03-07. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state240
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    none
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-03-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-12-01
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