Clinical trial NCT03077009: Functional Improvement and UTC of the Achilles Tendon After Sodium Hyaluronate Injection for Plantaris Syndrome
Official title: Functional Improvement and Ultrasound Tissue Characterisation of the Achilles Tendon Following Sodium Hyaluronate Injection for Plantaris Friction Syndrome
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Plantaris Friction Syndrome
Non-Insertional Achilles Tendinopathy
Lead sponsor: Fortius Clinic
Sponsor class: OTHER
First posted: 2017-03-10
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a study to assess the benefit of sodium hyaluronate (Ostenil) injection for plantaris friction syndrome (PFS) associated with midportion Achilles tendinopathy. Functional outcome scores will be recorded prior to treatment and at regular intervals up to 2 years. Changes in tendon structure will be assessed using ultrasonographic tissue characterisation (UTC). UTC will be performed prior to treatment and also at regular intervals up to 6 months following injection.

Detailed description: Introduction Midportion Achilles tendinopathy is a common source of disability, with typical features including pain, swelling and dysfunction \[Roche\]. The causes are multifactorial \[Roche\]. First line treatment is typically non operative and includes an eccentric loading program \[Alfredson-1998\], high volume injection \[Chan\], platelet rich plasma \[de Vos JAMA 2010\], sclerosing agent injections \[Alfredson-2005\] , shock wave therapy \[Lynen\]\[Saxena\] and for resistant cases, surgery \[Alfredson-2011\].

Plantaris friction syndrome (PFS) One possible cause of midportion Achilles tendinopathy is plantaris friction syndrome (PFS). In this subset of patients, the pain is located to the postero-medial aspect of the Achilles tendon. The plantaris tendon is a small vestigial tendon originating from the lateral femoral condyle, crossing obliquely to the medial side of the Achilles tendon and inserting into the medial side of the calcaneum. The anatomy at the insertion is highly variable. Over 80% of plantaris tendons insert separately to the Achilles tendon \[Daseler\]. Biomechanical evidence suggests that the plantaris tendon is stiffer and stronger than the Achilles tendon \[Lintz\]. Under load therefore, differential movement between the tendons may occur. Subsequently the plantaris tendon can become tendinopathic and thickened. Adhesions may develop between it and the adjacent Achilles tendon \[Bedi\], initiating medial midportion Achilles tendinopathy. Sensitization of the nerve endings in the fat layer between the Achilles and plantaris has also been demonstrated. The optimal treatment of PFS is currently unclear. Treatments include physiotherapy, injection and surgical excision \[Bedi\]\[Pearce\]\[Weinberg\]\[Calder-2014\]\[Alfredson-2011\].

Sodium Hyaluronate One potential treatment is injection with sodium hyaluronate which is a viscosupplement solution. It has primarily been used for joint lubrication in arthropathy, but can also be used for tendinopathy \[Lynen\]. Ostenil Tendon is a sodium hyaluronate solution that potentially acts in several ways to reduce pain. One mode is to act as a lubricant between tendons or between the tendon and its sheath \[Akasaka 2005\]\[Akasaka 2006\]\[Nishida\]\[Kumar\]\[St Onge\]. It may also promote tendon healing \[Chen\]\[Yagishta\]. According to unpublished work, Ostenil Tendon significantly reduced pain at 6 weeks for peroneal and also midportion Achilles tendinopathy \[Company literature\]. It may also act as a medium to allow free passage of nutrients to the tendon \[Hagberg\]. Sodium hyaluronate injection placed in the interval between the plantaris tendon and Achilles tendon could potentially reduce friction and subsequently pain. Although the effect of sodium hyaluronate injections have been reported in the hip and knee, no previous studies have reported its efficacy for PFS. The primary aim of the current study is to assess the impact of sodium hyaluronate injections in patients with PFS.

Ultrasound tissue characterization Methods of assessing the Achilles tendon for tendinopathy continue to be debated. Common methods include ultrasound and magnetic resonance imaging \[Khan\]\[Astrom\]. A novel assessment tool is ultrasound tissue characterization (UTC) which uses ultrasound to quantify tendon structure \[van Schie\]\[Docking-2015\]\[Docking-2016\]\[Rosengarten\]\[Bedi\].

Structural integrity of the tendon matrix is categorized in four echo types (1-green, 2-blue, 3-red, 4-black). Echo types 1 and 2 reflect aligned fibrillar structure, whereas types 3 and 4 indicate disorganised tissue \[Bedi\]. The entire length of the tendon can be analyzed with a minimum detectable difference in structure to be 1% \[Docking-2015\]. Bedi et al showed significant improvement in UTC following excision of plantaris for midportion Achilles tendinopathy \[Bedi\]. However this study was limited because UTC images were not performed at a uniform time pre- and post- surgery \[Bedi\]. Masci et al found improvement in UTC echo-structure at 6 month follow-up post plantaris excision combined with improvement in VISA-A scores \[Masci\]. It is debated as to whether fibrillar integrity and matrix organisation correlate with symptoms. For example, a study in elite Australian football players showed that UTC changed following pre-season training, but all players remained asymptomatic at the start and end of the study \[Rosengarten\]. Ultrasound studies have also questioned the relationship of tendon structure in tendinopathy and patient function \[Khan\]\[McAuliffe\]. In a study of gymnasts, clinical assessment has only moderate correlation with ultrasound and MR appearances \[Emerson\].

Given the novelty of UTC for the Achilles tendon, the secondary aim of this study is to assess whether UTC changes following treatment for PFS and to correlate any changes with functional outcome scores.

Aims summary

1. To determine changes in Achilles tendon matrix structure using UTC before and after treatment (6 month follow up)
2. To assess medium term (2 years) effectiveness of a sodium hyaluronate injection in the space between the plantaris and Achilles tendons for midportion Achilles tendinopathy which is associated with PFS.
3. To correlate UTC changes with functional scores

Hypothesis The alternate hypotheses are that sodium hyaluronate injection improves both 1) function and 2) structure of the Achilles tendon for PFS.

Outcome measures

* Ultrasonographic tissue characterisation (UTC)
* Functional scores - Victorian Institute of Sports Assessment-Achilles (VISA-A) \[Robinson\] and Foot and Ankle Outcome scores (FAOS)

Methods This will be a single centre prospective case series of patients in whom PFS has been diagnosed based upon clinical examination by a Consultant foot \& ankle surgeon, physiotherapist and imaging. Patients will be prospectively followed up with pre and post intervention patient reported outcome scores.

Sample Population 33 patients diagnosed with PFS will be identified and invited to participate in the study once the decision has been made to treat with sodium hyaluronate.

Inclusion Criteria Patients aged 18-75 years Able to provide informed consent Diagnosis of PFS requiring sodium hyaluronate injection Able to follow physiotherapy instructions Exclusion Criteria Previous Achilles tendon surgery Previous injection therapy for Achilles midportion tendinopathy Age \< 18 \>75 years Active local infection Active bleeding disorder or anticoagulant therapy Allergies to lignocaine or sodium hyaluronate Active deep vein thrombosis

Patient Recruitment and Consent All patients will be given the information sheet regarding the study and will be consented by the CI or the Fortius foot and ankle fellow. All be patients will be recruited and treated at the Fortius Clinic.

Proposed treatment will include one or two sodium hyaluronate (Ostenil Tendon) injections. Physiotherapy is a routine part of current treatment, usually provided off site.

Injection protocol All injections will be carried out by a Consultant Radiologist at the Fortius Clinic. Approximately 3-5mm of 1% lignocaine will be injected to create a plane between Plantaris and the medial Achilles tendon. Subsequently, 2-3ml of Ostenil Tendon (sodium hyaluronate) will be injected into the space between the Achilles and plantaris tendons.

UTC assessment UTC assessment at 6 and 12 weeks is a routine part of our current treatment protocol for PFS and allows guidance of treatment. Patients will have pre and post treatment UTC assessment of the Achilles tendon. For the purposes of the study, an extra UTC assessment will be performed at 6 months, during part of their routine clinical follow up appointment. This final UTC assessment will be provided free to the patients. All UTC assessments will be conducted by the same experienced physiotherapist.

Follow up Patient reported outcome scores will be completed prior to treatment and at 6 weeks, 3 months,6 months, 1 and 2 years. Outcome scores at 1 and 2 years will be performed online via an automated email system.

UTC will be conducted at 6 weeks, 3 months and 6 months.

Ethical Issues:

Patients will be free to choose to participate or not in the study. If they choose not to participate it will not affect their treatment in any way.

No patient or volunteer will take part in the study without giving written informed consent and we will exclude those patients who are unable to give this consent.

Legal Issues:

There are no legal issues identified that will affect this study.

Management issues:

This study will take place at the Fortius Clinic, which is a private clinic. The patients included would be receiving one or two sodium hyaluronate injections, and two UTC assessments as part of the routine treatment of PFS. They will be charged for this as normal. There will be no additional charge for the final UTC assessment at 6 months.

Risks:

Patients agreeing to take part in the study will be receiving the routine treatment for PFS that they would be receiving even if the study was not taking place. There are therefore no additional risks to the patient.

Data collection All data collection will be done within the premises of the Fortius clinic by members of the clinical team, which includes a physiotherapist who works on site for the Tendon Performance Clinic. In addition to the outcome score and UTC data information regarding patient demographics, medical history and treatment will also be collected.

Data confidentiality Data will be stored in Fortius/Tendon Performance Clinic computers which are password protected and comply with information governance guidelines. No one outside the clinical team will have access to the data.

Any information that leaves the clinic will have patient identifiable information removed. All of the results will be analysed and published using anonymous data only. Details about patient's involvement in the study will also be recorded in patients' medical records held by the Fortius Clinic/Tendon Performance Clinic.

Power analysis In 18 asymptomatic elite Australian football players, UTC demonstrated improvement in Achilles tendon structure over a 5 month period following pre-season training \[Docking-2016\]. Bedi et al reported UTC changes following Plantaris excision and ventral paratendinous Achilles tendon scraping in athletes. In 11 patients, the fibrillar structure of the Achilles tendon improved from 90 to 96%, SD 8% p=.04. Mean VISA-A scores improved from 51 to 95, SD 12, p=.0001. Regarding sodium hyaluronate injection, only one study was found assessing its use for midportion Achilles tendinopathy \[Lynen\]. Lynen et al compared two paratendinous injections with three ESWT treatments given at weekly intervals in 62 patients. No previous studies have assessed its use for PFS.

Considering the limited evidence available, we estimate the sample size required to demonstrate improvements in UTC (assuming change in type 1 and 2 echo types from 90% to 96%, SD 8%) to be at least 28 patients. With an expected drop out rate of 15%, we plan to recruit 33 patients to the study.

Statistical analysis Analyses will be conducted using a statistical package. A paired t test will be used to compare pre and post treatment VISA-A scores. UTC results will be compared using Wilcoxon signed rank test (non parametric data). A p value of 0.05 will be defined as statistically significant.

Eligibility criteria: Inclusion Criteria:

* Patients aged 18-75 years
* Able to provide informed consent
* Diagnosis of PFS requiring sodium hyaluronate injection
* Able to follow physiotherapy instructions

Exclusion Criteria:

* Previous Achilles tendon surgery
* Previous injection therapy for Achilles midportion tendinopathy
* Age \< 18 \>75 years
* Active local infection
* Active bleeding disorder or anticoagulant therapy
* Allergies to lignocaine or sodium hyaluronate
* Active deep vein thrombosis

Primary outcomes:
measure: Ultrasound Tissue Characterisation (UTC)
timeFrame: up to 6 months post intervention
Secondary outcomes:
measure: Foot and Ankle Outcome Score (FAOS) Functional outcome
timeFrame: up to 2 years post intervention
measure: Victorian Institute of Sports Assessment-Achilles (VISA-A)
timeFrame: up to 2 years post intervention
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Fortius Clinic
city: London
country: United Kingdom
facility: Fortius Clinic
Study officials:
affiliation: Fortius Clinic, London
name: James Calder, MD FRCS
role: PRINCIPAL_INVESTIGATOR
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