Platelet rich plasma injection for acute Achilles tendon rupture: PATH-2 randomised, placebo controlled, superiority trial

Objective To determine whether an injection of platelet rich plasma improves outcomes after acute Achilles tendon rupture. Design Randomised, placebo controlled, two arm, parallel group, participant and assessor masked, superiority trial. Setting Secondary care trauma units across 19 hospitals in the United Kingdom’s health service. Participants Recruitment commenced in July 2015 and follow-up was completed in March 2018. 230 adults aged 18 years and over were included, with acute Achilles tendon rupture presenting within 12 days of injury and managed with non-surgical treatment. Exclusions were injury at the insertion or musculotendinous junction, major leg injury or deformity, diabetes mellitus, platelet or haematological disorder, systemic corticosteroids, anticoagulation treatment, and other contraindicating conditions. Interventions Participants were randomised 1:1 to platelet rich plasma (n=114) or placebo (dry needle; n=116) injection. All participants received standard rehabilitation care (ankle immobilisation followed by physiotherapy). Main outcomes and measures Primary outcome was muscle tendon function at 24 weeks, measured objectively with the limb symmetry index (injured/uninjured×100) in maximal work done during the heel rise endurance test (an instrumented measure of repeated single leg heel rises until fatigue). Secondary outcomes included patient reported function (Achilles tendon rupture score), quality of life (short form 12 version 2®), pain (visual analogue scale), goal attainment (patient specific functional scale), and adverse events. A central laboratory analysed the quality and content of platelet rich plasma. Analyses were by modified intention to treat. Results Participants were 46 years old on average, and 57 (25%) of 230 were female. At 24 weeks, 202 (88%) participants completed the heel rise endurance test and 216 (94%) the patient reported outcomes. The platelet rich plasma was of good quality, with expected growth factor content. No difference was detected in muscle tendon function between participants receiving platelet rich plasma injections and those receiving placebo injections (limb symmetry index, mean 34.7% (standard deviation 17.7%) v 38.5% (22.8%); adjusted mean difference −3.9% (95% confidence interval −10.5% to 2.7%)) or in any secondary outcomes or adverse event rates. Complier average causal effect analyses gave similar findings. Conclusions There is no evidence to indicate that injections of platelet rich plasma can improve objective muscle tendon function, patient reported function, or quality of life after acute Achilles tendon rupture compared with placebo, or that they offer any patient benefit. Trial registration isrctn.com identifier: ISRCTN54992179</p

Platelet-rich plasma in Achilles tendon healing 2 (PATH-2) trial: statistical analysis plan for a multicentre, double-blinded, parallel-group, placebo-controlled randomised clinical trial.

BACKGROUND: There has been a recent steep growth in platelet-rich plasma (PRP) use for musculoskeletal conditions, but findings from high quality clinical trial data are lacking in the literature. Here, we describe the statistical analysis plan (SAP) for the Platelet-rich plasma in Achilles Tendon Healing 2 (PATH-2) trial. METHODS: PATH-2 is a pragmatic, parallel-group, multi-centre, double-blinded, randomised, placebo-controlled, superiority trial. The study aims to evaluate the clinical efficacy of PRP in acute Achilles tendon rupture in terms of muscle-tendon function. Patients are identified in the orthopaedic/trauma outpatient clinic. The primary outcome is muscle-tendon work capacity from the Heel Rise Endurance Test result, expressed as the Limb Symmetry Index (work, in joules), at 24 weeks post randomisation. Multivariate linear regression adjusting for the stratification factors (centre and age) and additional prognostic factors will be used to investigate the adjusted effect of the intervention. The analysis will be by modified intention-to-treat. Sensitivity analysis will assess the internal validity of the trial results by performing a per-protocol analysis. Safety will be summarised by treatment arm for all patients who started treatment. Secondary patient-reported outcome measures will be analysed using linear mixed effects models to allow all data collected at all follow-up points to be considered. Missing data will be summarised and reported by treatment arm. Missing data imputation will be performed, if appropriate. DISCUSSION: The PATH-2 trial will be reported in accordance with the CONSORT statement. This SAP publication will avoid bias arising from prior knowledge of the study results. Any changes or deviations from the current SAP will be described and justified in the final report. TRIAL REGISTRATION: ISRCTN registry: ISRCTN54992179 , assigned 12 January 2015. ClinicalTrials.gov: NCT02302664, received 18 November 2014. UK Clinical Research Network Study Portfolio Database: ID 17850

Platelet rich plasma in regenerative tendon repair mechanobiological interactions and clinical application

Tendon injury prevalence in both athletic and occupational settings is on the increase. Tendon healing properties are poor, despite the complex biological process triggered by the injury, which makes those injuries incapacitating for months. A significant proportion of these injuries remain difficult to treat, and many patients suffer from decreased performance and longstanding sequelae. While mechanical stabilization has been a hallmark of tendon surgical management, orthobiologics are playing an increasing role in optimizing tendon healing. Platelet rich Plasma (PRP), which is a volume of autologous plasma having platelet concentration above baseline, has been suggested as an accelerant orthobiological agent rich in supraphysiological concentration of growth factors. However, strong evidence of its mode of action and of its clinical efficacy is lacking. The purpose of this thesis is to identify the role of PRP in tendon regeneration in in-vitro and clinical studies. Firstly, the viability and biological components of clinically-prepared PRP were studied in novel experiments. This PRP was used in linked in-vitro studies to investigate the possible mechanism of PRP effect on the injured Achilles tendon cells and tissues. Cell count, viability, proliferation and DNA content were studied. The clinical application of PRP in Achilles tendon rupture was assessed in a randomised clinical pilot study using a combination of PROMs, objective outcome measures and a novel imaging modality called functional ultrasound elastography. This non-invasive technique was developed in a healthy-tendons volunteer study and its feasibility in ruptured tendons was assessed in the pilot trial. In another unique study, the immunohistochemical response to PRP was assessed in biopsies taken under US guidance at week 6 and compared to control to explore the possible mechanism of PRP effects. The findings confirmed that PRP is a viable activatable autologous blood product rich in growth factors. The results also confirmed that leukocytes and platelets are present in very high concentration with reversal of lymphocyte neutrophil ratio. Elastography volunteer study confirmed that FUSE is feasible using clinically applicable ultrasound scan. The improved algorithm allowed visualisation of localised strain within the studied tissues. The clinical application of PRP in Achilles tendon rupture revealed positive efficacy signal that PRP led to faster healing, improved pain and earlier restoration of function. However, the findings of this pilot trial were indicative and not confirmative. Immunohistochemistry analysis showed that PRP enhanced the maturity of the healing tendon tissues by promoting better collagen I deposition, improved Collagen III/Collagen I ratio, reduced cellularity, better vascular structure and higher GAGs content when compared with control. The finding may explain the clinical improvement observed in these patients at week 6 onwards. Linked in-vitro studies showed that autologous PRP with its cellular components, which include platelets, leukocytes and erythrocytes, has the ability to stimulate tendon cell migration to the injury site and stimulate proliferation in the injured human tendon. Additionally, it may maintain tissue viability in the hypoxic environment that follows tendon injury. Promoting migration and proliferation of cells and maintain tissue viability may play an important role to accelerate tendon healing. The findings of this project has informed the design of a phase II large multi-centre randomised controlled trial and helped secure major funding from the National Institute of Health Research (NIHR). This trial will set the scene for PRP use in tendon treatment.</p