Platelet Rich Plasma Versus Placebo for the Treatment of Greater Trochanteric Pain Syndrome (HiPPO Trial)
Platelet Rich Plasma Versus Placebo for the Treatment of Greater Trochanteric Pain Syndrome (HiPPO Trial)
Greater Trochanteric Pain Syndrome (GTPS), also known as Trochanteric Bursitis, is a painful
 condition predominantly affecting middle aged women. It is characterised by pain in the
 lateral hip exacerbated by movement and lying on the affected side. GTPS encompasses
 different conditions including gluteus medius/minimus tendinopathy and bursal inflammation.
 The treatment for this condition begins with conservative treatments of analgesia and
 physiotherapy, which normally results in a resolution of symptoms. If this fails then steroid
 injections have been shown to be effective. If this is not successful patients are offered
 surgery. Steroid injections however may only be effective in the short term and sometimes
 patients require repeat injections. Platelet rich plasma (PRP) is plasma taken from the blood
 of the patient that has been treated so that it has a higher than usual concentration of
 platelets in it. It has been postulated to promote healing in damaged or inflamed tissues.
 Platelets contain a variety of growth factors, which are involved in healing. It has been
 used in a variety of orthopaedic conditions such as lateral elbow epicondylitis, patellar
 tendonitis, rotator cuff pathology and planter fasciitis. Studies have shown varying effects
 of PRP in these conditions with most promise in plantar fasciitis and patellar tendonitis.
 These conditions are similar to GTPS. A recent review of treatments for GTPS concluded that
 more research into PRP efficacy in GTPS is required. We hypothesise that PRP is effective in
 treating GTPS in patients who have not responded to conservative management (analgesia and
 physiotherapy). This is an area that lacks research and could be valuable to those suffering
 from GTPS. Further study is required as PRP could be used as instead of steroid injections or
 if steroid treatments have failed and this could prevent patients from suffering further or
 needing surgery.

 The investigators propose a randomised control trial comparing a normal saline injection with
 a PRP injection in patients with GTPS, diagnosed by MRI scan, who have not responded to
 conservative treatments. Patients will receive either PRP or normal saline under ultrasound
 guidance by a consultant rheumatologist. Sample size calculation has shown that the
 investigators will need to recruit a total of 100 patients who will be randomised into either
 arm (50 in each arm). The recruitment period will last 2 years with the whole trial aiming to
 finish in 4 years from the proposed start date. Neither patients or the study team members
 assessing the outcomes will know which treatment the patient received. Patients will be
 followed up at 3, 6 and 12 months. The primary outcome measure will be a patient reported
 outcome measure (PROM) i-HOT12 (international hip outcome tool) which is a valid and reliable
 scoring system that assesses patient's ability to return to an active lifestyle through
 obtaining subjective measures of symptoms, as well as determining emotional and social health
 status.

 This will be alongside secondary outcome measures Visual Analogue Pain Score, Modified Harris
 Hip Score and EQ-5D collected. The proposal was discussed with a group of patients who
 previously had treatment with Platelet Rich Plasma (PRP) injection for hip pain. A discussion
 was had with regards the setup of a study and they were enthusiastic about this. A patient
 information sheet was shown to them and modified as per their comments. Their advice was
 obtained with regards the setup of this study, the randomisation into placebo arm, followup
 frequency and the outcome measures. In particular, patients suggested that if placebo was not
 working then a switch over to treatment arm should be discussed sooner than the initially
 planned one year. This has been taken into account and six month has been agreed. The
 proposal was also discussed in the NRES committee who are satisfied with the proposal.
 Ethical approval has been granted and the study is registered with Health Research Authority
 England.
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.

 Hypothesis: PRP is an effective treatment for greater trochanteric pain syndrome.

 5. Project Plan

 Population: Patients with GTPS Intervention: Platelet rich plasma (PRP) injection into
 trochanteric area under ultrasound guidance Comparator - Placebo of normal saline Outcome:
 Validated patient reported outcome measures (iHOT-12), Visual Analogue Score for pain (VAS),
 Modified Harris Hip Score (mHHS) and quality of life outcome (EQ-5D 3L) will be collected at
 baseline, 3, 6 and 12 months will be compared within and between the PRP and normal saline
 arms.

 Design: The trial will be a two arm single centre double blind randomised control trial. The
 study will include a two-way comparison between PRP and placebo normal saline injections for
 treating GTPS. Participants will be reviewed at baseline, 3, 6 and 12 with patient reported
 outcome measures (PROM) completed at each of these reviews.

 Setting: Hospital outpatient Target population: Participants with GTPS will be identified and
 referred for inclusion in the study by their main care provider (GP, Orthopaedic surgeon,
 Rheumatologist).

 Health technology being assessed: Platelet rich plasma injection (PRP)

 Objectives of the Trial :

 1. To test the hypothesis that PRP is effective in treating GTPS in patients who have
 failed conservative management

 2. To assess the duration of effect of PRP Outcome Measures Primary: The International Hip
 Outcome Tool - 12 (iHOT-12) PROM scores Secondary: The Visual Analogue Score for pain
 (VAS), Modified Harris Hip Score (mHHS) and the EQ-5D 3L scores

 Power and sample size:

 The primary outcome of interest is the change from baseline to 12 month follow-up for the
 12-item International Hip Outcome Tool (iHOT-12). Statistical significance is set at 5% and
 desired power at 90%, with two tailed tests applied. The minimally clinically important
 difference (MCID) for the iHOT-12 has been reported as 10 (from 100) and the standard
 deviation for the change in score from baseline as no greater than 21 by Sansone et al (23).
 We conservatively assume that change in iHOT score from baseline in the steroid group will be
 no more than 10 and the change in the iHOT score form baseline in the PRP group will be no
 less than 27. Using these figures, a minimal sample size at follow up of 66 (33 in each
 group) will be required. Pilot data obtained by our team suggest that the refusal to
 participate rate should be no more than 25% and the dropout rate no more than 35% over 12
 months. Refusal rates tend to be low in this patient group given the chronic nature of the
 condition and the fact that patients will only be approached once conservative management has
 failed. Thus, we will need to approach 135.4 (round up to 136) patients, and recruit 102
 patients to achieve our target sample size.

 Difference between current and planned care pathway: None

 Dissemination Plan:

 To ensure that the outputs from the research informs policy and practice and thereby
 maximises the benefit to patients and the NHS, the following dissemination strategy has been
 developed using evidence for translating knowledge into practice. From research evidence we
 know that research is most effectively disseminated using multiple vehicles, ideally with
 face to face interaction. So, in addition to giving written feedback to study participants,
 dissemination activities will include development of links with key organisations such as
 NICE, NHS Information Centre, NHS Commissioning Board and Quality Observatories to contribute
 to and capitalise on their networks. In addition, media and national and international
 medical conferences. Furthermore, Publications including Full, Executive Summary and Plain
 English summary reports of the research, peer review journals and local NHS newsletters and
 A5 laminate.
Inclusion Criteria:

 1. Over 18 years of age

 2. Symptoms consistent with GTPS present for at least 6 months

 3. Radiological diagnosis of GTPS using MRI, or ultrasound scan if MRI contraindicated

 4. Failed conservative management in any other care setting

 5. Patient is willing and able to provide written informed consent.

 Exclusion Criteria:

 1. Lacks capacity to provide consent

 2. Has hip joint osteoarthritis requiring treatment on a plain radiograph

 3. Presence of confounding pathologies of the hip MRI

 4. Any extensive surgery or deformity of the hip on X-ray.

 5. Presence of systemic disorders -coagulopathy, active infection, immune system
 disorders, peripheral neuropathy, malignancy, unresolved fractures.

 6. Had any surgical treatment specifically targeted at GTPS e.g. bursectomy/Ilio-tibial
 band lengthening

 7. Pregnancy

 8. Anti-coagulant therapy eg warfarin, rivaroxaban, apixaban, dabigatran

 9. Haemaglobin <10g/dL or platelets < 150,000/ul

 10. Unable to safely stop anti-platelet/NSAID medications eg. Recent cardiac stenting

 11. Has lumbar-sacral spine pathology or a recent history of acute hip trauma

 12. Has a recent history of acute sciatica

 13. Is not able to attend or comply with treatment or follow-up scheduling

 14. Participates in any other clinical trial