A Double Blind Randomised Control Trial Investigating the Efficacy of Platelet Rich Plasma Versus Placebo for the Treatment of Greater Trochanteric Pain Syndrome (HiPPO Trial)

1. What is the problem being addressed? Greater trochanteric pain syndrome (GTPS), also known as trochanteric bursitis, is a painful condition characterised by pain around the greater trochanter usually affecting middle aged women (1). It was first described, as trochanteric bursitis in 1958 (2). Further details on the clinical symptoms published in 1978 as pain over the greater trochanter on walking, squatting or climbing stairs and pain on lying on the affected side or when crossing one's legs (3). Little described tenderness over the greater trochanter over the insertion of the gluteus tendons. GTPS was a term used by Karpinski et al 1985 instead of trochanteric bursitis as patients did not exhibit typical bursitis signs of swelling, heat, crepitus or fluctuation (4). This notion has been supported by other studies (5) including a study performed by Bird et al 2001 evaluated 24 patients using MRI with the clinical picture of GTPS and found that majority of them had gluteus medius tendon pathology with only 2 patients with trochanteric bursal inflammation (1). Hence, GTPS instead of trochanteric bursitis appears to be the more accurate way of described the clinical condition which seems to have multiple facets in its pathology.
2. Why is the research important? Greater trochanteric pain syndrome (GTPS) is one of the most common causes of lateral hip pain in adults and can be a painful and debilitating condition which as a last resort requires surgery especially if it does not respond to conservative treatments. The best estimates of prevalence are from a large, community-based study with over 3000 adults aged 50 to 70 years, in which unilateral GTPS was present in 15 percent of women and 6.6 percent of men. Bilateral GTPS was reported in 8.5 and 1.9 percent of women and men, respectively. The usual age at presentation is over 50 years, and the female to male ratio is approximately 4:1. It can be associated with low back pain in 20-35%. Bilateral GTPS in particular is associated with higher 20-meter walk time and chair stand time. It can lead to substantial limitation of activity and poor quality of life. It is therefore important to look at appropriate treatment options that will lead to quicker and more long-lasting recovery.

Currently the treatment ladder for GTPS consists of conservative measures such as physiotherapy and NSAIDs. The majority of patients will settle with conservative management however if this fails then more invasive treatment options include shockwave therapy and corticosteroid injections. These second line treatments are important in preventing the need for surgery as a last resort. (6, 7, 8). Corticosteroid injection is an established second line treatment for GTPS that has been shown to be efficacious but not necessarily long term as reported by a randomised study comparing steroid . (9) This notion has been supported by numerous reviews of GTPS management (10, 11, 12, 13). It is therefore imperative to explore treatment options that have the potential for long-lasting benefits, in the form of regenerative medicine are explored. One such is the use of platelet rich plasma (PRP) which will allow regeneration of cells and more robust healing.

PRP is an autologous blood product which has been postulated to promote healing in damaged or inflamed tissues including muscles, ligaments, bones and tendons. Platelets contain a variety of elements including growth factors and cytokines which are involved in tissue healing. These include platelet derived endothelial growth factor, platelet derived growth factor, transforming growth factor, insulin like growth factor, vascular endothelial growth factor, basic fibroblast growth factor. These growth factors are present in the processes of tissue injury, inflammation and repair. Therefore the theory is the higher the concentration of platelets, the more growth factors there will be present to promote the healing process when administered directly to the area of interest (14). PRP has been applied in other fields of medicine including regenerative therapies in oral and maxillofacial surgery. (15, 16) Over the past decade or so there have been numerous studies of PRP's efficacy in treating inflammatory musculoskeletal conditions similar in pathology to GTPS, such as lateral epicondylitis, patellar tendinitis, rotator cuff pathology, achilles tendonitis and plantar fasciitis. This has been collectively reviewed by several authors with reports of mixed efficacy compared to standard treatments for these conditions with the most promise shown in plantar fasciitis and patellar tendinitis (17, 18). These reviews all report a lack of evidence to fully support or reject PRP's efficacy in these conditions, except for achilles tendonitis where PRP showed no difference compared with placebo in a randomised study (19, 20). PRP's healing or regenerative properties have shown promise in other areas of orthopaedics such as cartilage pathology (14).

The success of novel regenerative therapy in the form of PRP in a scientifically conducted clinical study will be a major advance in our current knowledge base and will have wider implications for its use in other fields of orthopaedics and will provide better understanding in developing strategies for dealing with similar issues probably even for degenerative conditions. 3. How does the existing literature support this proposal We have completed a systematic literature review which has been submitted for publication. We used NICE healthcare database advanced search (HDAS) via Athens (PubMed, MEDLINE, CINAHL, EMBASE and AMED databases) to conduct our search from their year of inception to October 2017. In total, four studies were included for analysis consisting of two randomised control trials and two case series. We also identified four additional studies from published conference abstracts (one randomised control trial and three case series). 209 patients included in these studies with a mean age ranging from 48 to 76.2 years. Majority were females with three months minimum duration of symptoms. Diagnosis was made using ultrasound or MRI. Included studies used a variety of outcome measures. Improvement was observed during the first 3 months after injection. Significant improvement was also noted when patients were followed up till 12 months post treatment. We found that there is a paucity of evidence reporting the efficacy of PRP in treatment of GTPS. The current literature has revealed that PRP injections are relatively safe and can be effective. Considering the limitations in these studies, we think more large-sample and high-quality randomised clinical trials are required in the future to provide evidence of the efficacy for PRP as a treatment in GTPS. 4. What is the research question / aims and objectives?

The aim of the trial is to investigate the clinical efficacy of the novel treatment platelet rich plasma (PRP) in treating patients with GTPS. PRP's clinical efficacy will be compared against a placebo injection of normal saline.