Title: Platelet Rich Plasma (PRP) in Achilles Tendon Rupture (ATR) Healing
Funder: Department of Health (England)

Abstract: HYPOTHESISPRP application as an adjunct to standard care will achieve improved musculotendinous function and patient recovery after acute Achilles tendon rupture (ATR) in adultsAIMS1)Evaluate the clinical efficacy of PRP in acute ATR in terms of mechanical muscle-tendon function2)Evaluate the clinical efficacy of PRP in acute ATR in terms of patient reported functional recovery pain and quality of life3)Identify the key components of PRP that contribute to its mechanism of action4)Explore the immunohistochemical response of the healing tendon to PRP at the cellular and tissue levelSTUDY DESIGNMulti-centre blinded randomised placebo-controlled trial of PRP in Achilles tendon rupture. Two sub-studies are embedded within the main study to contribute to the understanding of its mechanism in tendon healing:1) Biological components in PRP: cells concentrations (PRP and blood) platelets activation (CD62P marker) and growth factor concentration in PRP2) PRP immunohistochemical response in the tendon tissue in comparison to control (16 participants): needle biopsy at week 6POPULATIONAll patients aged 18-70 with diagnosed acute ATR within 7 days of injury who are suitable for non-surgical treatment. Exclusion criteria: Previous ATR diabetes vessel disease renal or liver failure blood disorders refusing blood anticoagulation serious disease unable to give informed consent.INTERVENTIONSParticipants will be randomly assigned to intervention via a remote randomisation system using permuted blocks of random size stratified by site and age to minimise imbalance in mobility and tendon health. Participants will be randomised to:1)Treatment group: PRP injection to the tendon rupture gap2)Control group: sham injection (local anaesthetic to skin and needle introduction to tendon)Both groups will then follow a standardised casting and rehabilitation protocol. Detailed guidance will be given to participants and their physiotherapists to standardise functional progress within practical boundaries.We have demonstrated feasibility of recruitment blinding control injection and practicality of the interventions and efficacy signals in a pilot study (2). A go/no-go feasibility assessment will be conducted in the 10th month of recruitment when approximately 50 patients have been recruited. The predicted site and patient recruitment rates intervention compliance and safety will be assessed and discussed with the data monitoring committee trial steering committee and reported to the EME Board.PRIMARY OUTCOMEHeel-Rise Endurance Test (HRET): a validated objective physical test to measure calf muscle-Achilles tendon capacity to work (Joules) at 24 weeks(12). This is calculated by calibrated instruments and software and is then converted into a limb symmetry index (LSI)(%) comparing injured and uninjured limbs to normalise each participant’s performance.SECONDARY OUTCOME 1)Achilles Tendon Rupture Score (ATRS): a validated patient-reported outcome measure of muscle strength fatigue pain and function(3) 2)Daily pain diary for 2 weeks (Visual Analogue Scale: VAS) 3)Patient Specific Functional Scale (PSFS): a patient-reported tool that focuses on patients’ own functional recovery goals (4) 4)SF-12: health-related quality of life scale 5)PRP components analysis: cell count Growth Factors (TGF VEGF PDGF IGF & FGF) analysis and platelet activation (CD62P) 6)Immunohistochemical analysis: pain receptors angiogenesis collagen and proliferation markersASSESSMENTS & FOLLOW UPPre-injury ATRS PSFS and SF-12 will be recorded in the clinic at baseline and over the telephone at weeks 4 7 13. Pain diary returned after 2 weeks. At 24 weeks in clinic these are repeated and a trained blinded physiotherapist will record HRETPRP and blood samples collection at baseline16 participants will have needle biopsy at week 6. Our pilot study demonstrated the acceptability and safety of this technique(2)Continuous collection of adverse eventsSAMPLE SIZEThe sample size has been calculated to detect a standardised difference of 0.5 in the HRET work measured by the LSI at 24 weeks post randomisation based on previous trial data indicating a clinically important difference of 10% and SD of 20 (1) with 214 patients (107 per arm) with 90% power 2-sided 5% significance level and allowing for 20% loss to follow-up.STATISTICAL ANALYSISIf the primary outcome (HRET LSI at 24 weeks) is normally distributed then the two groups will be compared using a t-test ANCOVA adjusting for stratification factors (primary analysis) and ANCOVA adjusting for additional prognostic factors in a multivariate framework. If there are severe departures from normality the first approach will be transformation. If the data cannot be transformed to normality then the Mann-Whitney U test will be used with no adjustment for any factors. Patterns of missing data will be explored (i.e missing at random or missing completely at random). We will use multiple imputation technique to test the sensitivity of findings to missing data.ECONOMIC BENEFITATR has a large socioeconomic impact on both patients and the NHS. The average absence from work is 12 weeks (5) with most patients requiring phased return to work. Accelerating tendon healing may have major socioeconomic benefit. PRP may also offer a biological alternative to surgical repair that costs 5-10 times more. The study will add to the science of PRP therapies for musculoskeletal injuries treatment protocols.PROJECT TIMETABLEOur pilot study and a survey of 7 recruiting sites data indicated 51 ATR/site/year with 72.1% treated non-surgically. With 30% recruitment the anticipated recruitment rate is 1/month/site. With staggered site recruitment patient recruitment and follow-up will take 32 months. Project total is 35 months.EXPERTISEOur unit has successfully conducted a pilot study of PRP in acute ATR(1). Our team co-ordinates several multi-centre placebo controlled trials in acute traumatic and elective orthopaedic conditions. Our team brings together clinical expertise in trauma and orthopaedic surgery haematology biology radiology physiotherapy and statistics together with extensive clinical trials basic and translational science expertise. Public/patient involvement has been embedded into the design and running of the trial


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL