Clinical Trial Results:
Autologous Stem Cells in Achilles Tendinopathy (ASCAT)- A phase II, single centre, proof of concept study
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Summary
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EudraCT number |
2013-000966-12 |
Trial protocol |
GB |
Global end of trial date |
12 Sep 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
27 Nov 2019
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First version publication date |
27 Nov 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
12/0419
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02064062 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
UCL
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Sponsor organisation address |
Joint Research Office, UCL Gower Street, London, United Kingdom, WC1E 6BT
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Public contact |
Goldberg, Royal National Orthopaedic Hospital, +44 208 3853042, andrew.goldberg@ucl.ac.uk
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Scientific contact |
Goldberg, Royal National Orthopaedic Hospital, +44 208 3853042, andrew.goldberg@ucl.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Sep 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Sep 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Sep 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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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).
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Protection of trial subjects |
Analgesia and anaesthesia where appropriate
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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
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 10
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Worldwide total number of subjects |
10
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EEA total number of subjects |
10
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
10
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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. | ||||||
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Pre-assignment
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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. | ||||||
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Period 1
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Period 1 title |
Treatment (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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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)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Implantation
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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.
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Baseline characteristics reporting groups
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Reporting group title |
Treatment
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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 | |||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Active arm - active treatment
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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 | ||
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End point title |
Serious adverse reactions [1] | ||||||||
End point description |
Incidence of serious adverse reactions
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End point type |
Primary
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End point timeframe |
Time of bone marrow harvest to 6 months post-treatment
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| 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 |
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| Notes [2] - No serious adverse reactions occurred in any of the 10 subjects |
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| No statistical analyses for this end point | |||||||||
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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
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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).
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End point type |
Secondary
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End point timeframe |
Baseline to 24 weeks post treatment
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| Notes [3] - 10 subjects were analysed for MOXFQ and VISA-A and VAS pain, 8 subjects for EQ_VAS and 9 for SAS |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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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.
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End point type |
Secondary
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End point timeframe |
Baseline to 24 weeks post treatment
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Incidence of success at 6 months - EQ-5D | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to 24 weeks post-treatment
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| No statistical analyses for this end point | |||||||||
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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.
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End point type |
Secondary
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End point timeframe |
Baseline to 24 weeks post treatment
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| No statistical analyses for this end point | |||||||||||||
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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.
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End point type |
Secondary
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End point timeframe |
Baseline to 24 weeks post treatment
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| No statistical analyses for this end point | |||||||||||||||||||||||
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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.
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End point type |
Secondary
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End point timeframe |
Baseline to 24 weeks post treatment
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| Notes [4] - At certain timepoints data by 1st radiologist was complete for only 2 subjects; n varies from 2 - 5. |
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| No statistical analyses for this end point | |||||||||||||||||||
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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
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End point type |
Secondary
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End point timeframe |
Baseline to 24 weeks post treatment.
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| 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 |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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Adverse events information
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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).
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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.
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Assessment type |
Systematic | ||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||
Dictionary version |
17.0
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Reporting groups
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Reporting group title |
all patients treated
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Reporting group description |
- | ||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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’.
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11 Dec 2015 |
To include dosing range for cell numbers of 4-20 x 10e6 rather than absolute value of 20 x 10e6. |
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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.
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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).
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| 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. | |||
