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    Clinical Trial Results:
    Autologous Stem Cells in Achilles Tendinopathy (ASCAT)- A phase II, single centre, proof of concept study

    Summary
    EudraCT number
    2013-000966-12
    Trial protocol
    GB  
    Global end of trial date
    12 Sep 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Nov 2019
    First version publication date
    27 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    12/0419
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02064062
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCL
    Sponsor organisation address
    Joint Research Office, UCL Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    Goldberg, Royal National Orthopaedic Hospital, +44 208 3853042, andrew.goldberg@ucl.ac.uk
    Scientific contact
    Goldberg, Royal National Orthopaedic Hospital, +44 208 3853042, andrew.goldberg@ucl.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 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to determine safety by showing that there are no serious adverse reactions to autologous stem cells injected into tendon. The secondary objectives are: • To show that autologous bone marrow derived culture expanded MSCs can improve clinical outcomes (as measured by clinical scores). • To gain experience in using Ultrasound Tissue Characterisation (UTC) and assess usefulness of UTC as an outcome measurement (evaluated through a comparison with convention ultrasound measures and inter-rater reliability).
    Protection of trial subjects
    Analgesia and anaesthesia where appropriate
    Background therapy
    No placebo arm. This was a first in man study of an active treatment.
    Evidence for comparator
    N/A
    Actual start date of recruitment
    16 Sep 2015
    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
    United Kingdom: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    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)
    10
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment was difficult due to several factors including patient population, referral restrictions and competing trials. 1st consent was 16/9/2015, last consent 26/1/2018. The 10 patients in ASCAT were based nationwide and travelled to RNOH for this treatment.

    Pre-assignment
    Screening details
    16 were screened: 3 were screen fails (ineligible) and 13 were enrolled. Of those 13, 3 patients didn’t grow enough cells so were not treated.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Active arm - active treatment
    Arm description
    There was only a single arm in which MSC were harvested and cultured. Implanted into Achilles tendon for 10 participants and then follow up at 6, 12 and 24 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Autologous bone marrow derived culture-expanded mesenchymal stem cells (MSCs)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Implantation
    Dosage and administration details
    All participants received a single injection of ATIMP at a dose level of between 4-20x10e6 cells in 1ml of DMEM. IMP was supplied in a single vial, containing between 4-20x10e6 cells in 1.0ml of DMEM. The content of the vial was drawn into a syringe and injected along the length of the achilles tendon at the area of greatest degeneration starting 1cm distal to the degeneration (as deemed by ultrasound findings) and finishing 1cm proximal to normal structure under ultrasound control in the outpatient setting.

    Number of subjects in period 1
    Active arm - active treatment
    Started
    10
    Completed
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    Inclusion • Aged ≥18 and ≤ 70 • Participants with chronic midportion Achilles tendinopathy (as defined by pain in region of AT and tender swelling in mid portion of AT (no tenderness over bony attachment to heel) with symptoms for longer than 6 months who have failed conservative treatment (at least a full course of physiotherapy) and for whom surgery is being considered • Females of CBP must be willing to use two forms of effective contraception from the time of consent to 6 months post-injection. Exclusion • Previous bony surgery at or in proximity to the harvest site • Pregnancy or lactation • Current use of steroids, anti-TNF drugs, methotrexate, or ciprofloxacin • Positive for HBV, HCV, HIV 1 and 2, syphilis and HTLV • Previous AT surgery on the tendon to receive MSC implantation • Inflammatory arthritis • Known or suspected underlying haematological malignancy • Other active malignancy in the past 3 years • Bovine or antibiotic allergy

    Reporting group values
    Treatment Total
    Number of subjects
    10 10
    Age categorical
    All subjects
    Units: Subjects
        Adults (18-64 years)
    10 10
    Gender categorical
    Units: Subjects
        Male and female
    10 10

    End points

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    End points reporting groups
    Reporting group title
    Active arm - active treatment
    Reporting group description
    There was only a single arm in which MSC were harvested and cultured. Implanted into Achilles tendon for 10 participants and then follow up at 6, 12 and 24 weeks

    Primary: Serious adverse reactions

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    End point title
    Serious adverse reactions [1]
    End point description
    Incidence of serious adverse reactions
    End point type
    Primary
    End point timeframe
    Time of bone marrow harvest to 6 months post-treatment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No serious adverse reactions occurred in any of the subjects so there was no data to analyse for the primary endpoint
    End point values
    Active arm - active treatment
    Number of subjects analysed
    10 [2]
    Units: Serious adverse reaction
        number (not applicable)
    10
    Notes
    [2] - No serious adverse reactions occurred in any of the 10 subjects
    No statistical analyses for this end point

    Secondary: Incidence of success at 6 months - MOXFQ, EQ-VAS, VISA-A. VAS-pain and SAS

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    End point title
    Incidence of success at 6 months - MOXFQ, EQ-VAS, VISA-A. VAS-pain and SAS
    End point description
    Incidence of success at 6 months, where success is defined as achieving a minimally important clinical difference. These were defined for selected outcomes as: - VISA-A: increase of 12 or more points - VAS pain: reduction of 15 or more points (on 0-100 scale) - MOXFQ pain: decrease of 12 or points . The following outcomes based on clinical scores were evaluated: • MOXFQ • EQ5D 5L • EQ-VAS • VISA-A • VAS Pain score • Stanmore Sporting Activity Score (SAS) The first set of analyses of the secondary endpoints compared the changes in clinical scores from baseline to each of the subsequent time periods.The mean and standard deviation were used as summary statistics for most scores, although the median and inter-quartile range were preferred for the EQ-5d. Also reported were the mean changes in scores between timepoints, along with corresponding confidence intervals. Baseline changes to 24wk timepoint are included here. P-values were also reported (not included here).
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks post treatment
    End point values
    Active arm - active treatment
    Number of subjects analysed
    10 [3]
    Units: Change in score from baseline to 6 month
    arithmetic mean (confidence interval 95%)
        MOXFQ walking
    -30 (-43 to -16)
        MOXFQ pain
    -28 (-39 to -17)
        MOXFQ social
    -19 (-30 to -9)
        EQ-VAS
    13 (7 to 19)
        VISA-A
    22 (12 to 32)
        VAS pain
    -23 (-42 to -5)
        SAS
    2.0 (0.6 to 3.4)
    Notes
    [3] - 10 subjects were analysed for MOXFQ and VISA-A and VAS pain, 8 subjects for EQ_VAS and 9 for SAS
    No statistical analyses for this end point

    Secondary: Changes in conventional ultrasound measurements from baseline to 24 weeks

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    End point title
    Changes in conventional ultrasound measurements from baseline to 24 weeks
    End point description
    Changes in the ultrasound variables measured on a continuous scale from baseline to each subsequent timepoint were analysed at equivalent timepoints and using equivalent methods to those described for the clinical scores. Baseline changes to 24wk timepoint are included here.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks post treatment
    End point values
    Active arm - active treatment
    Number of subjects analysed
    5
    Units: Mean change
    arithmetic mean (confidence interval 95%)
        Max AP thickness of the tendon
    -0.8 (-1.3 to -0.2)
        Lesion distance
    10 (-15 to 34)
        % disorganised
    -3 (-25 to 19)
    No statistical analyses for this end point

    Secondary: Incidence of success at 6 months - EQ-5D

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    End point title
    Incidence of success at 6 months - EQ-5D
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks post-treatment
    End point values
    Active arm - active treatment
    Number of subjects analysed
    9
    Units: Median score change: baseline to 6 month
        median (inter-quartile range (Q1-Q3))
    0.16 (0.00 to 0.36)
    No statistical analyses for this end point

    Secondary: Changes in conventional ultrasound measurements from baseline to 24 weeks

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    End point title
    Changes in conventional ultrasound measurements from baseline to 24 weeks
    End point description
    Changes in the ultrasound variables measured on a continuous scale from baseline to each subsequent timepoint were analysed at equivalent timepoints and using equivalent methods to those described for the clinical scores. Baseline changes to 24wk timepoint are included here.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks post treatment
    End point values
    Active arm - active treatment
    Number of subjects analysed
    5
    Units: Mean change
    median (inter-quartile range (Q1-Q3))
        Focal change
    0.0 (0.0 to 0.0)
        % thickness
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Changes in conventional ultrasound measurement of neovascularisation from baseline to 24 weeks

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    End point title
    Changes in conventional ultrasound measurement of neovascularisation from baseline to 24 weeks
    End point description
    Neovascularisation was measured on an ordinal scale, and changes from baseline were analysed using the Wilcoxon matched-pairs test.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks post treatment
    End point values
    Active arm - active treatment
    Number of subjects analysed
    5
    Units: Severity
        Absent (baseline)
    1
        Absent (24 weeks)
    1
        Mild (baseline)
    4
        Mild (24 weeks)
    4
        Moderate (baseline)
    0
        Moderate (24 weeks)
    0
        Significant (baseline)
    0
        Significant (24 weeks)
    0
    No statistical analyses for this end point

    Secondary: Inter-observer agreement for conventional ultrasound measurements

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    End point title
    Inter-observer agreement for conventional ultrasound measurements
    End point description
    Measurements of the conventional US parameters were made by two radiologists, and calculations of the inter-rater reliability of the US measurements were made. The reliability of continuous measurements was evaluated using intra-class correlation (ICC). The reliability of ordinal measurements was made using the weighted kappa statistic (ie. neovascularisation). Due to the relatively small trial sample size, data from all four timepoints combined was included in each analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks post treatment
    End point values
    Active arm - active treatment
    Number of subjects analysed
    2 [4]
    Units: Mean of ICC/weighted kappa (ie.neovasc)
    arithmetic mean (confidence interval 95%)
        Max AP thickness
    0.95 (0.87 to 0.98)
        Lesion distance
    0.89 (0.76 to 0.95)
        Focal change
    0.41 (0.00 to 0.71)
        % thickness
    0.38 (0.00 to 0.69)
        Neovascularisation
    0.82 (0.50 to 1.00)
    Notes
    [4] - At certain timepoints data by 1st radiologist was complete for only 2 subjects; n varies from 2 - 5.
    No statistical analyses for this end point

    Secondary: Association between UTC and ultrasound measurements

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    End point title
    Association between UTC and ultrasound measurements
    End point description
    The association between conventional ultrasound and UTC measurements was examined to establish the usefulness of UTC as an outcome measurement. The final outcome related to the UTC measurements, which quantified the percentage of fibres in four different categories: • Type 1: aligned fibrillar structure (straight fibres) • Type 2: wavy fibres (aligned but not as aligned as type 1) • Type 3: haphazard fibre aligned • Type 4: amorphoric material or no fibres Type 1 + 2 values were summed together representing ‘organised’ tissue, and type 3 + 4 were summed together representing ‘disorganised tissue”. The % disorganised tissue was analysed. The UTC measurement analysed was the percentage of disorganised tissue. The conventional US measurements were made by two radiologists. However, there was more complete data from the second radiologist, and thus only data from this radiologist was included in these analyses. Only the changes between baseline and each subsequent timepo
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks post treatment.
    End point values
    Active arm - active treatment
    Number of subjects analysed
    4 [5]
    Units: Correlation coefficient
    number (not applicable)
        Max AP thickness (baseline to 6 weeks)
    0.60
        Lesion distance (baseline to 6 weeks)
    -0.15
        Focal change (baseline to 6 weeks)
    -0.09
        % thickness (baseline to 6 weeks)
    -0.09
        max AP thickness (baseline to 12 weeks)
    0.67
        Lesion distance (baseline to 12 weeks)
    0.10
        Focal change (baseline to 24 weeks)
    0
        % thickness (baseline to 12 weeks)
    0.41
        Max AP thickness (baseline to 24 weeks)
    0.00
        Lesion distance (baseline to 24 weeks)
    0.00
        Focal change (baseline to 12 weeks)
    0.41
        % thickness (baseline to 24 weeks)
    0
    Notes
    [5] - 6 for the baseline to 6 wk comparison, 5 for the baseline to 12 wk and 4 for the baseline to 24 wk
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs were recorded from the time of the bone marrow harvest until the final follow up visit (24 weeks post treatment).
    Adverse event reporting additional description
    Patient were questioned on adverse events on a telephone call 48 h after harvest and at each subsequent follow up visit.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    all patients treated
    Reporting group description
    -

    Serious adverse events
    all patients treated
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    all patients treated
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 10 (10.00%)
    Musculoskeletal and connective tissue disorders
    Injury
    Additional description: Patient injured toe whilst hoovering.
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Feb 2015
    Revised protocol, patient alert card and PIS Cover letter: To correct inconsistency regarding the timing of the follow up phone call to patients post treatment. Amendment to allow the trial team to send Patient Information Sheets to potential patients by post prior to their first outpatient visit. Informed consent procedure changed from; At least 24 hours will be given for consideration by the patient before consenting to take part. to Adequate time will be given for consideration by the patient before consenting to take part. Section 9 - Recording and reporting of adverse events and reactions – The AE definition has been amended and timeline for recording AEs has been changed from ‘following consent’ to after the bone marrow harvest’.
    11 Dec 2015
    To include dosing range for cell numbers of 4-20 x 10e6 rather than absolute value of 20 x 10e6.
    26 May 2016
    Updates to protocol: 1. Addition of the use of participant identification centre (PICs) 2. Addition of the use of a sports activity questionnaire 3. Dosing period changed from approx. 5 weeks to approx. 5-6 weeks Updates to protocol and PIS: 4. To document that bone marrow harvest may be done under local or general anaesthesia (rather than just local) depending on patient preference (as per routine practice). 5. Risks of general anaesthesia added. 6. To add statement that pregnancy will be assessed by self-declaration at initial screening followed by urine pregnancy tests within 7 days of bone marrow harvest and ATIMP administration. Other changes 7. Addition of the use of an advert. 8. Protocol outline created to send to PIC sites to provide information about the trial.
    05 Jul 2017
    Update to IMPD to include the option to cryopreserve cells in the event that cells grow too quickly and the surgery cannot be rescheduled for an earlier date. Cells which have not undergone more than 10 population doublings can be cryopreserved for further re-seeding and expansion closer to administration date. The protocol and PIS updated to clarify that the timing between bone harvest and implantation is an approximation (stated as approximately 5 weeks).

    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.
    Complex logistics to manage cell harvest, culture and implantation as well as the full gamut of clinical assessments required per patient.
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