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SHOCK WAVE THERAPY, ASSOCIATED TO ECCENTRIC

STRENGTHENING VERSUS ISOLATED ECCENTRIC

STRENGTHENING FOR ACHILLES INSERTIONAL

TENDINOPATHY TREATMENT: A DOUBLE BLINDED

RANDOMIZED CLINICAL TRIAL

Journal: BMJ Open

Manuscript ID bmjopen-2016-013332

Article Type: Protocol

Date Submitted by the Author: 13-Jul-2016

Complete List of Authors: Mansur, Nacime; Universidade Federal de Sao Paulo, Orthopaedics Faloppa, Flavio; Federal University of São Paulo (UNIFESP/EPM), Orthopedics and Traumatology - Division of Hand Surgery and Upper Limb Belloti, João ; Federal University of São Paulo (UNIFESP/EPM), Orthopedics and Traumatology - Division of Hand Surgery and Upper Limb Ingham, Sheila; Universidade Federal de Sao Paulo, Orthopaedics Matsunaga, Fabio; Federal University of São Paulo (UNIFESP/EPM), Orthopedics and Traumatology - Division of Hand Surgery and Upper Limb Santos, Paulo; Universidade Federal de Sao Paulo, Orthopaedics Santos, Bruno; Universidade Federal de Sao Paulo, Orthopaedics Carrazzone, Oreste; Universidade Federal de Sao Paulo, Orthopaedics Peixoto, Gabriel; Universidade Federal de Sao Paulo, Orthopaedics Ayoama, Bruno; Universidade Federal de Sao Paulo, Orthopaedics Tamaoki, Marcel Jun; Universidade Federal de Sao Paulo, Orthopaedics

<b>Primary Subject Heading</b>:

Evidence based practice

Secondary Subject Heading: Sports and exercise medicine, Research methods, Rehabilitation medicine, Public health, Occupational and environmental medicine

Keywords: achilles, tendinopathy, insertional, shock wave, Foot & ankle < ORTHOPAEDIC & TRAUMA SURGERY, eccentric

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NACIME SALOMÃO BARBACHAN MANSUR

SHOCK WAVE THERAPHY, ASSOCIATED TO ECCENTRIC STRENGTHENING VERSUS ISOLATED ECCENTRIC STRENGTHENING FOR ACHILLES INSERTIONAL TENDINOPATHY TREATMENT: A DOUBLE BLINDED RANDOMIZED CLINICAL TRIAL.

Nacime Salomão Barbachan Mansur

Flávio Faloppa

João Carlos Belloti

Sheila J. McNeill Ingham

Fabio Teruo Matsunaga

Paulo Roberto Dias dos Santos

Bruno Schiefer dos Santos

Oreste Lemos Carrazzone

Gabriel Peixoto

Bruno Takeshi Aoyama

Marcel Jun Sugawara Tamaoki

Project submitted to government funding [CNPq (Conselho Nacional de Pesquisa – National Research Council under the protocol number 8094833648737701)].

Registered in the Clinical Trials database under the protocol number 8094833648737701 (NCT02757664) on 05/02/2016.

Study being conducted in São Paulo Federal University (UNIFESP), São Paulo – SP, Brazil.

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SHOCK WAVE THERAPHY, ASSOCIATED TO ECCENTRIC STRENGTHENING VERSUS ISOLATED ECCENTRIC STRENGTHENING FOR ACHILLES INSERTIONAL TENDINOPATHY TREATMENT: A DOUBLE BLINDED RANDOMIZED CLINICAL TRIAL.

Abstract

Introduction: There is no consensus regarding the treatment of Achilles insertional tendinopathies. Eccentric

training remains the choice in the conservative treatment of this illness; however, the good results in the

management of non-insertional tendinopathy were not replicated in the insertional disease. Shock wave therapy

has been described as an alternative to these patients.

Hypothesis: Shock wave therapy, adjunctive to eccentric strengthening protocol, will improve measures of pain

and function.

Design: Double blind, placebo-controlled, parallel groups, randomized clinical trial.

Methods and Analysis: Nine-three patients, referred from health care services, will be assessed and enrolled in

this study. They will be divided in two groups (randomized by sequentially numbered identical envelopes), one

containing the combination of shock wave and eccentric exercises as treatment, and the other comprehending

the exercises and the placebo treatment (apparatus placed in the therapeutic head). The assessments will occur in

2, 4, 6, 12 and 24 weeks. Patients will be evaluated primarily by the Victorian Institute of Sport Assessment-

Achilles questionnaire (VISA-A) and secondarily by the Visual Analogue Scale (VAS), Algometry, the

American Orthopedic Foot and Ankle Society (AOFAS) scale and the 12 Item Short Form Health Survey (SF-

12). We will use Comparison of Two Proportions via relative frequency analysis, the Pearson Correlation the

Chi-Square test and the ANOVA for statistical analyses.

Discussion: This study intends to demonstrate if the association of the eccentric exercise program with the

shock wave therapy can produce good results. In an attempt to prevent the high costs and complications

associated with surgery, we will try to prove this combination as a viable therapeutic option in the management

of this disease. The strengths of the study are the design and the combination of methods.

Ethics and Dissemination: The study is registered in the Clinical Trials database and approved by the

University Ethics Committe.

The study is registered in the Clinical Trials database (protocol number: 8094833648737701) and approved by the University Ethics Committee (number: 1373481).

1. Introduction

Calcaneus tendinopathy can be classified according to its anatomic site, as insertional and non-

insertional tendinopathy. It is characterized by intratendinous degenerations, secondary to low grade

inflammatory signs and erratic biological healing (Hartog 2009, Irwin 2010, Magnan et al 2014). The insertional

tendinopathy occurs in the Achilles attachment to the tuberosity of the calcaneus bone and up to 2 cm proximal

to the tuberosity. It is generally associated with a traction enthesophyte (upper spur), Haglund deformity (pump

bump) and with pre- and retro-achilles bursitis. The diagnosis is made based on clinical evaluation; ancillary

tests, such as X-Ray and Ultra Sound, are done only to confirm the lesion and to exclude differential diagnoses

(stress fractures, tumours). The clinical diagnosis consists of checking the level of pain via palpation of the

tendinous insertion region in the calcaneus bone (and up to 2cm around this region). The occurrence of volume

increase and mild hyperemia also supports the diagnosis (Hartog 2009, Irwin 2010, Magnan et al 2014, Kearney

et al 2010).

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Historically, the disease´s initial treatment is based on eccentric strengthening of the tendon. Results for

non-insertional tendinopathy are encouraging, with an 82% success rate when analysing return to previous

activities. However, evidence indicates that eccentric strengthening for insertional tendinopathy produced a rate

of improvement ranging between 32 and 67% of the patients (Irwin 2010, Magnan et al 2014, Kearney et al

2010). Within this context, shock wave therapy has been proposed as a viable option, in case of failure of the

conservative treatment and prior to referral to surgery (Al-Abbad et al). Over the last 30 years, extracorporeal

shock waves have been safely and efficiently used in the treatment of various pathological conditions.

Extracorporeal shock wave lithotripsy (ESWL), for example, is a well-established treatment for urological

pathologies. More recently, shock waves therapy is being used in the treatment of pseudo-arthrosis and several

types of tendinopathy with prominent results (Wang et al 2002, Hsu et al 2004, Wang et al 2003, Chen et al

2003).

Accumulating evidence indicates that the use of shock waves induces neovascularisation and release of

angiogenic markers by the recruitment of mesenchymal stem cells. The molecular mechanism explaining how

the shock wave produces this consequences is yet to be determined (Chen 2004, Wang 2011).

Neovascularisation improves blood irrigation, which, in its turn, contributes to tissue regeneration in the tendon-

bone junction. Separate lines of inquiry suggested that shock wave therapy, relative to placebo therapies,

induces a higher increase of mechanical resistance and concentration of markers of collagen synthesis (i.e.

hydroxiproline and pyridinoline), which are important components of the healing process (Wang et al 2002, Hsu

et al 2004, Wang et al 2003).

Clinically, few complications are associated to shock waves. The most frequently reported is a regional

transitory hyperaemia (Al-Abbad et all 2013). Few patients (5%) report having pain after shock wave

application, which normally ceases at the end of the treatment. (Furia et al 2006). Tendon rupture was described

in the literature in only one study (Costa et al 2005), that showed 2 cases of older patients in a population of 49

cases. The authors couldn’t find a true relation between the therapy and the events. Rasmussem et al (2008) has

done a randomized clinical trial with 48 patients and 12 months of follow-up, comparing the use of shock wave

therapy in patients after 4 weeks of conservative treatment, including stretching and strengthening , with the

placebo. Superior results regarding pain and function were shown in the group that received the intervention.

Kearney et al (2010) did a systematic review of the literature, looking for evidences concerning the calcaneus

insertional tendinopathy treatment. They found only one paper (Furia 2005) with the utilization of the therapy,

and, nevertheless, the work was criticized by the small sample and the methodology inconsistencies.

Shock wave therapy has been progressively more studied. Recent evidence has indicated that this

technique is a promising option for the management of chronic insertional tendinopathy; however, the evidence

is still insufficient to inform a consensus regarding the indication of this treatment in this very frequent disease.

Herein, our objective is to evaluate the effectiveness of shock wave therapy associated to an eccentric

strengthening protocol, and compare it to eccentric strengthening associated to placebo, using the function by

Victorian Institute of Sports Assessment-Achilles (VISA-A). The primary hypothesis is that adjunctive shock

wave therapy will mitigate pain and improve function as compared to placebo.

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2. Material and Method

2.1 Design, setting and recruitment

This will be a double blind, placebo-controlled, parallel groups, randomized clinical trial., The study

will be conducted at Hospital São Paulo, a tertiary, teaching hospital fully affiliated with the Universidade

Federal de São Paulo (UNIFESP), in the Orthopedics and Traumatology Department (DOT) at the Centre of

Tissue Research and Regeneration (CPRT).

Particpiants will be enrolled at the CPRT, which provide assessment and treatment to approximately

XYZ new patients with chronic insertional tendinopathy per week . Parctipiants will be referred by local

orthopaedist doctors or health professionals. The information to these physicians will be delivered by e-mail

addressed directly to them, as well as via posters exhibited in places containing orthopaedic medical care

(outpatient clinic, emergency room).

2.2 Inclusion Criteria

• Individuals must be older than 18 and younger than 65 years of age, both genders;

• Participants must be experiencing pain symptoms in the calcaneus tendon insertion region over the last

three months;

• Clinical diagnosis of chronic insertional tendinopathy, defined as presence of pain at palpation of the

tendinous insertion region in the calcaneus bone (and up to 2cm around this region); and the

occurrence of increased regional volume, associated to findings of tendinopathy in the ultrasound.

2.3 Exclusion Criteria

• Previous surgery involving the affected foot or ankle;

• History or documented evidence of autoimmune or peripheral vascular diseases;

• History or documented evidence of peripheral neuropathy (nervous compression syndrome, tarsal

tunnel syndrome) or systemic inflammatory disease a (rheumatoid arthritis, spondylitis, Reiter

Syndrome, etc.);

• Non-Insertional or mixed tendinopathy (insertional and non-insertional);

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• Previous infiltration in the affected tendon over the six months preceding the initial assessment;

• Beginning of the present pain, due to a trauma;

• Pregnancy;

• Any condition that represents a contraindication of the proposed therapies;

• Impossibility or incapacity to sign the informed Consent Form;

• History or documented evidence of blood coagulation disorders (including treatment with anti-

coagulants, but excluding aspirin);

• Use of heart pacemaker;

• Presence of infectious process (superficial on skin and cellular tissue, or deep in the bone) in the region

to be treated;

2.4 Sampling

The sampling calculation is based on the studies of Rompe et al 2008 and Sayana et al 2007; and

considers an estimated effect size of 3.3, a standard deviation of 16.2 and (sampling error of 5%). It was

calculated considering 93 patients divided in two groups in a randomized way, estimating that 41 evaluable

subjects per treatment arm will have better than 80% power to detect a difference in results between the shock-

wave and the placebo subjects at a level of 5% significance As we expected a 10% loss in the follow-up, based

in other clinical studies, we plan to include an extra 10% of participants, totalizing 51 patients per group.

2.5 Procedures

A written, signed and dated informed consent will be obtained from the subject before any study-

related procedures are performed. The patients will have to fill out an initial questionnaire in order to be enrolled

(Attachment 1). After that, the assistant doctor will do the physical diagnostic examination. Then, Ultrasound

and X-rays procedures will take place, in order to complete the diagnostic assessment. The patient will be

included in the protocol and duly randomized after the diagnostic confirmation is done via anamnesis and

physical examination, and also after completion of supplementary tests, and fulfilment of all the inclusion

criteria and non-adequacy to the exclusion criteria.

The randomization sequence will be generated via computing software

(http://www.randomizer.org/form.htm), producing a list from 1 – x, and each number will be related to a sole

treatment method. We will do a randomization with interchanged blocks, with the same number of patients in

each group.

Each non-transparent, opaque, sealed envelope, numbered from 1 to 104, will contain either a paper

with the word “physiotherapy” or with the words “physiotherapy and shock wave”. Each treatment method will

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have the same number of envelopes. The patients will be initially assessed individually, being randomized and

allocated in the same way. The intervention procedures will be the same, with the same positioning and

preparations, but differing regarding the existence of a support at the applicator head of the shock wave

apparatus in the group of patients without shock wave.

Neither the patient nor the evaluator doctor will have access to the protocol test applied to each patient,

and the shock wave (or the placebo) will be conducted by a different physician. The patients in the placebo

group will receive an apparatus´ therapeutic head with the support that impedes the shock wave propagation

directly on the appliance field. This will prevent the insertional region to receive any healing stimulus. Patients

will still be able to hear the equipment shock wave noise and feel the tremble provoked by machine in contact

with the heel.

2.6 Intervention

2.6.1 Utilization of shock waves

1) Period from diagnosis to intervention: up to 1 week.

2) Patient will be lying on the stretcher in the supine position; barefooted, with ear muffs, the feet towards

the shock wave apparatus.

3) The procedure region will be marked with ink (tendon insertion: the point with highest local bulging or

the penultimate transversal crease of the skin in the region.)

4) US gel will be applied on the region that will receive the shock wave;

5) Radial shock waves will be applied with a BLT600 equipment (BTL Medical Technologies - Canada),

the intensity being 2000 to 3000 pulses, 7 to 10Hz of frequency, and 1,5 a 2,5Bar of intensity per

application.

6) Shock waves will be applied on the first day of treatment (D0) as described above, then repeated on the

second week after the first intervention (2nd week) and four weeks after the first intervention (4th

week).

2.6.2 Group without Shock wave


2) Patient lying on the stretcher in the supine position; barefooted, with ear muffs, the feet towards the

shock wave apparatus.

3) Localization of the procedure region, marking it with ink (tendon insertion: the point with highest local

bulging or the second last transversal crease of the skin in the region.)

4) Appliance of US gel on the region that will receive the shock wave;

5) Placing of the apparatus´ therapeutic head with the support that impedes the shock wave propagation

directly on the appliance field.

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6) Appliance of radial shock waves with the BLT600 equipment (BTL Medical Technologies - Canada),


application.

7) Appliance on the first day of treatment (D0) as described above, repeated on the second week after the

first intervention (2nd week) and four weeks after the first intervention (4th week).

2.6.3 Eccentric Exercises

The groups will be submitted to the Alfredson eccentric strengthening protocol (Alfredson et al 2001)

for 12 weeks, starting on the same day of the first appliance. The exercises will be shown to the patients by the

assistant doctor, and a booklet (Attachment 2) will be handed out, with detailed explanation concerning the

protocol to be followed. The patient will practice the exercises standing on a step, 20cm high. Participants will

do exercises of passive ankle extension (dorsiflexion), three series of 15 repetitions, with the knee stretched, and

three series of 15 repetitions with the knee flexed by 20 degrees. The eccentric stage (downwards) of the

movement will be done slowly, only with the affected member, until it reaches its maximum non painful stretch

(including the negative stage). The concentric stage (upwards) will be done only with the non-affected member.

In case the pathology involves the two members, the patient will use the upper members to help the practice in

the concentric stage. The patients will be encouraged to increase the load with 5kg load weights placed in a

backpack which the patient will wear to practice the exercise. The load increase is done as long as the exercise

gets painless to the patient. The objective´s fulfilment and the quality of the exercise are indicated by the

discomfort felt on that region after the performance of the series.

The patients cannot perform their base sports activities during the first eight weeks of training. After

the fourth week they will be free to run on a flat incline, to do biking and water activities that do not generate

painful symptoms. After the eighth week they will be permitted to gradually re-start the sports activities that

they used to perform previously, as long as they are not feeling any pain. The strengthening execution, the

intensification process, as well as the engagement in the treatment will be checked during the return to repeat the

appliances; and during the follow-up with the doctor. To increase adhesion to intervention protocol, hand-outs

with tables containing dates to be indicated concerning the days the patient executes the protocol´s exercises;

also with blank spaces for notes about the use of medication or occurred complications.

2.6.4 Adjuvant therapies

Both groups will be submitted to the same post intervention care program, and they will be advised to

use the following adjuvant therapies according to the intensity of their symptoms:

Cryotherapy

Every patient will be oriented to perform cold compresses on the tendon insertional region three times a

day, during 20 minutes, with at least two hours of interval between them.

Pain Killers

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Level 1:

• Dipyrone 1g every 6 hours, in case of pain, or

• Paracetamol 750mg every 6 hours

Level 2 (in case the pain does not diminish with level 1):

• Tramadol 50mg every 6 hours, in case of pain, or

• Codeine 30mg every 6 hours, in case of pain.

The patient must present, at each visit to the doctor, the daily annotation concerning the used sedative

medication In case the pain increases right after any of the established treatments, the patient will be permitted

to take analgesics (group 1) during a period of 5 days. The medication will be supplied to the patient after the

intervention, with the respective orientation concerning its use. After the period of five days of sedation, in case

the pain persists, the patient will be reassessed, to check the necessity of changing the medication (group 2). If

after the second assessment (with six weeks) the pain is stronger than in the initial painful stage (previous to the

treatment) the patient will have the option of either changing the treatment or being excluded from the study.

2.7 Primary outcome

• Visa-A Score

Significant increase of the studied group´s score in comparison to the pre-intervention scores.

2.8 Secondary outcome

• EVA

• AOFAS

• SF-12

• Algometry (pain threshold and VAS with 3kg)

2.9 Subject Discontinuation

Subjects may be discontinued from the study participation at any time. Reasons for discontinuation

include:

1. Voluntary discontinuation by the subject without prejudice to further treatment.

2. Development of Complex Regional Pain Syndrome or any huge inflammatory response. Achilles tendon

rupture (all of them are going to be considered failure).

3. Pain and function severe impairment.

2.9 Statistical Analysis:

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Primary analysis will be performed on the intention-to-treat population (all subjects with at least one

study intervention and one post-baseline efficacy assessment). The primary point for analyses of efficacy will be

week 24. The Mixed-Model for Repeated Measures method will be used to impute missing data for subjects

who discontinue during the study. The primary efficacy measure will be change from baseline to study endpoint

on the Visa-A Score, which will be analysed with a repeated measures t-test. Subsequently, repeated measures

MANCOVA will be administered to test for co-variations and main effects. The significance level will be set at

a p-value < 0.05.

Discussion

Insertional Achilles tendinopathy is a common disease, affecting both athletes and the sedentary

population. Its etiology is related to a poor biological body response after micro lesions to the tendon (occurring

during training or in a daily usual activity). Degenerative changes and a low inflammatory reaction are the

characteristics of these tissues, revealing a low healing response to injury. This illness normally induces patients

to look for medical care due pain, function impairment and decrease in athletic performance. Approximately

16% of the active individuals end up abandoning their sports activities in consequence of this disorder.

The traditional initial treatment of choice is non-surgical, comprehending modalities such as physical

therapy and exercises. Yet, this approach has not produced encouraging results over the last years and currently

there is still no standard conservative treatment for Achilles insertional tendinopathy. Whereas the eccentric

strengthening program is one of the clinicians preferred modalities of treatment, it has not lead to the same good

results as in other tendon locations. This scenario contributed to the increase in the number of surgeries

performed for this illness in the past decades. Procedures that are not excused from high costs and possible

complications, such as wound dehiscence, infection, nerve damage and tendon rupture.

Several alternatives to the classical treatment (e.g. infiltration, electro-stimulation, sclerotherapy,

among others) have been considered, in order to stimulate healing stimulus to the degenerated tendon. The low

success rates have provided the impetus to explore practical and cheaper ways to induce the adequate reparation

of these tissues. Evidence indicates that shock wave therapy is an excellent option to treat recalcitrant tendinous

diseases. By stimulus of soft tissue healing in behalf of angiogenesis enhancing and diffusion of cytokine

molecules, this treatment has become a reliable option in the approach of this illness.

While isolated shock wave treatment has shown encouraging results during the past years, they were

not definitive. Adjuvant administration of the Alfredson protocol proved to be a trustworthy combination in the

non-insertional presentation of this disorder in a recent study. The technical composition of shock wave and

tendon´s eccentric strengthening can be the answer to patient´s improvement in the Achilles insertional

tendinopathy, with the additional benefit of avoiding the complications and high costs associated with the

surgical treatment.

Contributorship statement

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Nacime Salomão Barbachan Mansur: main researcher.

Literature revision, writing, paper submissions, patient recruiting, study design and data collecting.

[email protected]

+5511994500853

Ambulatório de Ondas de Choque da UNIFESP - Centro de Traumatologia do Esporte

Rua Estado de Israel 636, Vila Clementino, São Paulo – SP

Flávio Faloppa: co-orientation and study design.

João Carlos Belloti: co-orientation and study design.

Sheila J. McNeill Ingham: co-orientation, writing and study design.

Fabio Teruo Matsunaga: co-orientation, writing and data collecting.

Paulo Roberto Dias dos Santos: shock-wave application and implementation.

Bruno Schiefer dos Santos: shock-wave application and implementation.

Oreste Lemos Carrazzone: literature revision, writing.

Gabriel Peixoto: Visa-A translation to Portuguese and implementation.

Bruno Takeshi Aoyama: medical student enrolled in the project. Implementation and data collecting.

Marcel Jun Sugawara Tamaoki: main orientation. Literature revision, writing, study design and paper

submissions.

All authors contributed to refinement of the study protocol and approved the final manuscript.


Orthopedic and Traumatology Department

783 Borges Lagoa St, 5th Floor, Vila Clementino, São Paulo – SP

Tel.: (+5511) 5576.4848 | VOIP – 3009/ 1434/2910/2887/2909

Competing Interests

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and

declare: no support from any organisation for the submitted work; no financial relationships with any

organisations that might have an interest in the submitted work in the previous three years; no other

relationships or activities that could appear to have influenced the submitted work.

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14. Saxena A, Ramdath S Jr, O'Halloran P, Gerdesmeyer L, Gollwitzer H. Extra-corporeal pulsed-activated

therapy ("EPAT" sound wave) for Achilles tendinopathy: a prospective study. J Foot Ankle Surg. 2011

May-Jun;50(3):315-9. doi: 10.1053/j.jfas.2011.01.003.

15. Wilson M, Stacy J. Shock wave therapy for Achilles tendinopathy. Curr Rev Musculoskelet Med. 2010 Nov

26;4(1):6-10. doi: 10.1007/s12178-010-9067-2.

16. Hart L. Shock-wave treatment was more effective than eccentric training for chronic insertional achilles

tendinopathy. Clin J Sport Med. 2009 Mar;19(2):152-3. doi: 10.1097/01.jsm.0000347357.41069.27.

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17. Rompe JD, Furia J, Maffulli N. Eccentric loading versus eccentric loading plus shock-wave treatment for

midportion achilles tendinopathy: a randomized controlled trial. Am J Sports Med. 2009 Mar;37(3):463-70.

doi:1177/0363546508326983.

18. Rasmussen S, Christensen M, Mathiesen I, Simonson O. Shock wave therapy for chronic Achilles

tendinopathy: a double-blind, randomized clinical trial of efficacy. Acta Orthop. 2008 Apr;79(2):249-56.

doi: 10.1080/17453670710015058.

19. Rompe JD, Furia J, Maffulli N. Eccentric loading compared with shock wave treatment for chronic

insertional achilles tendinopathy. A randomized, controlled trial. J Bone Joint Surg Am. 2008 Jan;90(1):52-

61. doi: 10.2106/JBJS.F.01494.

20. Furia JP. High-energy extracorporeal shock wave therapy as a treatment for chronic noninsertional Achilles

tendinopathy. Am J Sports Med. 2008 Mar;36(3):502-8. Epub 2007 Nov 15.

21. Rompe JD, Nafe B, Furia JP, Maffulli N. Eccentric loading, shock-wave treatment, or a wait-and-see policy

for tendinopathy of the main body of tendo Achillis: a randomized controlled trial. Am J Sports Med. 2007

Mar;35(3):374-83. Epub 2007 Jan 23. Erratum in: Am J Sports Med. 2007 Jul;35(7):1216

22. Furia JP. High-energy extracorporeal shock wave therapy as a treatment for insertional Achilles

tendinopathy. Am J Sports Med. 2006 May;34(5):733-40.

23. Costa ML, Shepstone L, Donell ST, Thomas TL. Shock wave therapy for chronic Achilles tendon pain: a

randomized placebo-controlled trial. Clin Orthop Relat Res. 2005 Nov;440:199-204.

24. Furia JP. [Extracorporeal shock wave therapy in the treatment of chronic insertional Achilles tendinopathy].

Orthopade. 2005 Jun;34(6):571-8. German.

25. Perlick L, Schiffmann R, Kraft CN, Wallny T, Diedrich O. [Extracorporal shock wave treatment of the

achilles tendinitis: Experimental and preliminary clinical results]. Z Orthop Ihre Grenzgeb. 2002 May-

Jun;140(3):275-80.

26. Wang, C. J., Chen, C. E., et al. Treatment of nonunions of long bone fractures with shock waves. Clin

Orthop 2001, 387: 95-101.

27. Wang, C. J., Huang, H. Y,, Chen, H. H., et l. Effect of shock wave therapy on acute fractures of the tibia. A

study in a dog model. Clin Orthop 2001, 387:112-118.

28. Giusti, G.; Penteado, F. T.; Santos, J. B.G.; Alves, M. T. S.; Faloppa, F.. Effect of shock wave in the growth

plate of rabbits (Efeito de ondas de choque na placa de crescimento de coelhos). Acta Ortop Bras 2005,

13(1):31-4

29. Meirer, R., Kamelger, F. S., Huemer, G., Wanner, S., Piza-Katzer, H. Extracorporeal shock wave may

enhance skin flap survival in an animal model. British Journal of Plastic Surgery 2005, v.58 ; pp 53-57

30. Sayana MK, Maffulli N. Eccentric calf muscle training in non-athletic patients with Achilles tendinopathy.

J Sci Med Sport. 2007 Feb;10(1):52-8

31. Mafi N, Lorentzon R, Alfredson H. Superior short-term results with eccentric calf muscle training

compared to concentric training in a randomized prospective multicenter study on patients with chronic

Achilles tendinosis. Knee Surg Sports Traumatol Arthrosc. 2001;9(1):42-7.

32. Fahlström M, Jonsson P, Lorentzon R, Alfredson H. Chronic Achilles tendon pain treated with eccentric

calf-muscle training. Knee Surg Sports Traumatol Arthrosc. 2003 Sep;11(5):327-33. Epub 2003 Aug 26.

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33. Ohberg L, Alfredson H. Effects on neovascularisation behind the good results with eccentric training in

chronic mid-portion Achilles tendinosis? Knee Surg Sports Traumatol Arthrosc. 2004 Sep;12(5):465-70.

Epub 2004 Apr 2.

Ethics and Means of Dissemination

The Project is registered in the Clinical Trials database under the protocol number 8094833648737701

(NCT02757664) on 05/02/2016. Study approved by the University Ethics Committee under the number

1373481.

SCHEDULE

August 2015 November

2015

Marc

h

2016

May 2016 August

2016

Nove

mber

2016

Febru

ary

2017

May

2017

August 2017

Literature

consultation

Project

Development

Ethics

Committee

Submission

Starting

Patient

Recruiting

Data

Colle

ction

Data

collection

Registration

at Clinical

Trials

Database

Data

Collection

BMJ Open

Acess

Protocol

Publication

Protocol

Submissio

n for

Publication

in BMJ

Open

Acess

Journal

(IMPACT

FACTOR

2,27)

Data

collec

tion

Data

collec

tion

Data

collecti

on

Analysis of

Results

Reports

Dissertation

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Drawing:

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CONSORT 2010 checklist Page 1

CONSORT 2010 checklist of information to include when reporting a randomised trial*

Section/Topic Item No Checklist item

Reported on page No

Title and abstract

1a Identification as a randomised trial in the title 1

1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) 2

Introduction

Background and

objectives

2a Scientific background and explanation of rationale 2,3

2b Specific objectives or hypotheses 3

Methods

Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 4

3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons 4,5

Participants 4a Eligibility criteria for participants 4,5

4b Settings and locations where the data were collected 4

Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were

actually administered

6

Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they

were assessed

8

6b Any changes to trial outcomes after the trial commenced, with reasons 8

Sample size 7a How sample size was determined 5

7b When applicable, explanation of any interim analyses and stopping guidelines 8

Randomisation:

Sequence

generation

8a Method used to generate the random allocation sequence 5

8b Type of randomisation; details of any restriction (such as blocking and block size) 5

Allocation

concealment

mechanism

9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers),

describing any steps taken to conceal the sequence until interventions were assigned

5,6

Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to

interventions

6

Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those 6

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CONSORT 2010 checklist Page 2

assessing outcomes) and how

11b If relevant, description of the similarity of interventions 6

Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 8

12b Methods for additional analyses, such as subgroup analyses and adjusted analyses 8

Results

Participant flow (a

diagram is strongly

recommended)

13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and

were analysed for the primary outcome

x

13b For each group, losses and exclusions after randomisation, together with reasons x

Recruitment 14a Dates defining the periods of recruitment and follow-up x

14b Why the trial ended or was stopped x

Baseline data 15 A table showing baseline demographic and clinical characteristics for each group x

Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was

by original assigned groups

x

Outcomes and

estimation

17a For each primary and secondary outcome, results for each group, and the estimated effect size and its

precision (such as 95% confidence interval)

x

17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended x

Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing

pre-specified from exploratory

x

Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) X

Discussion

Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 9

Generalisability 21 Generalisability (external validity, applicability) of the trial findings 9

Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence x

Other information

Registration 23 Registration number and name of trial registry 11

Protocol 24 Where the full trial protocol can be accessed, if available 11

Funding 25 Sources of funding and other support (such as supply of drugs), role of funders 1

*We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also

recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials.

Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.

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RANDOMIZED CLINICAL TRIAL

Journal: BMJ Open

Manuscript ID bmjopen-2016-013332.R1


Date Submitted by the Author: 19-Oct-2016









jopen.bmj.com

/B

MJ O


ownloaded from




SHOCK WAVE THERAPHY, ASSOCIATED TO ECCENTRIC STRENGTHENING VERSUS ISOLATED ECCENTRIC STRENGTHENING FOR ACHILLES INSERTIONAL TENDINOPATHY TREATMENT: A DOUBLE BLINDED RANDOMIZED CLINICAL TRIAL PROTOCOL.


Flávio Faloppa







Gabriel Peixoto






Version: ENG_Insertional Shock Wave Protocol_14_Oct16_REVIEWED

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Abstract

Background: There is no consensus regarding the treatment of Achilles insertional tendinopathies. Eccentric training remains the main choice in the conservative treatment of this illness; however, the good results in the management of non-insertional Achilles tendinopathy were not replicated in the insertional disease. Low energy shock wave therapy has been described as an alternative to these patients,

but has yet to be empirically tested.

Hypothesis: Shock wave therapy, adjunctive to eccentric strengthening protocol, will improve measures of pain and function.


Materials and Methods: Nine-three patients with a diagnosis of chronic insertional tendinopathy, referred from primary or secondary health care services, will be assessed and enrolled in this study. They will be divided in two groups (randomized by sequentially numbered identical envelopes, which will be administered serially to participants), one containing the combination of low energy shock wave and eccentric exercises, as treatment, and the other comprehending the exercises and the placebo treatment (an apparatus placed in the therapeutic head). The assessments will occur in 2, 4, 6, 12 and 24 weeks. Patients will be evaluated primarily by the Victorian Institute of Sport Assessment-Achilles questionnaire (VISA-A) and secondarily by the Visual Analogue Scale (VAS), Algometry, the American Orthopedic Foot and Ankle Society (AOFAS) scale, the Foot and Ankle Outcome Score (FAOS) and the 12 Item Short Form Health Survey (SF-12). We will use Comparison of Two Proportions via relative frequency analysis, the Pearson Correlation the Chi-Square test and the ANOVA for statistical analyses.

Discussion: This study intends to demonstrate if the association of the eccentric exercise program with the shock wave therapy can produce good results regarding the treatment of the Achilles insertional tendinopathy. In an attempt to prevent the high costs and complications associated with the surgical

intervention, we will try to prove this combination as a viable therapeutic option in the conservative management of this prevalent disease.

The strengths of the study are the design and the novelty of the combination of methods. The main limitation is the short follow-up course.


1. Introduction



inflammatory signs and erratic biological healing (Hartog 2009, Irwin 2010, Magnan et al 2014). The insertional

tendinopathy occurs in the Achilles attachment to the tuberosity of the calcaneus bone and up to 2 cm proximal

to the tuberosity. It is generally associated with a traction enthesophyte (upper spur), Haglund deformity (pump

bump) and with pre- and retro-achilles bursitis. The diagnosis is made based on clinical evaluation; ancillary

tests, such as X-Ray and Ultra Sound, are done only to confirm the lesion and to exclude differential diagnoses

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(stress fractures, tumours). The clinical diagnosis consists of checking the level of pain via palpation of the

tendinous insertion region in the calcaneus bone (and up to 2cm around this region). The occurrence of volume

increase and mild hyperemia also supports the diagnosis (Hartog 2009, Irwin 2010, Magnan et al 2014, Kearney

et al 2010).

Historically, the disease´s initial treatment is based on eccentric strengthening of the tendon. Results for

non-insertional tendinopathy are encouraging, with an 82% success rate when analysing return to previous

activities. However, evidence indicates that eccentric strengthening for insertional tendinopathy produced a rate

of improvement ranging between 32 and 67% of the patients (Irwin 2010, Magnan et al 2014, Kearney et al

2010). Within this context, shock wave therapy has been proposed as a viable option, in case of failure of the

conservative treatment and prior to referral to surgery (Al-Abbad 2013 et al). Over the last 30 years,

extracorporeal shock waves have been safely and efficiently used in the treatment of various pathological

conditions. Extracorporeal shock wave lithotripsy (ESWL), for example, is a well-established treatment for

urological pathologies. More recently, low (Wang et al 2002, Wang et al 2003) and high (Hsu et al 2004, Chen

et al 2003) energy shock waves therapies are being used in the treatment of pseudo-arthrosis and several types

of tendinopathy with prominent results.


angiogenic markers by the recruitment of mesenchymal stem cells. The molecular mechanism explaining how

the shock wave produces these consequences is yet to be determined (Chen 2004, Wang 2011).

Neovascularisation improves blood irrigation, which, in its turn, contributes to tissue regeneration in the tendon-

bone junction. Separate lines of inquiry suggested that shock wave therapy, relative to placebo therapies,

induces a higher increase of mechanical resistance and concentration of markers of collagen synthesis (i.e.

hydroxiproline and pyridinoline), which are important components of the healing process (Wang et al 2002, Hsu

et al 2004, Wang et al 2003).


transitory hyperaemia (Al-Abbad et all 2013). Few patients (5%) report having pain after high energy shock

wave application, which normally ceases at the end of the treatment. (Furia et al 2006). Tendon rupture was

described in the literature in only one study (Costa et al 2005), that showed 2 cases of older patients in a

population of 49 cases. The authors couldn’t find a true relation between the therapy and the events. Rasmussem

et al (2008) has done a randomized clinical trial with 48 patients and 12 months of follow-up, comparing the use

of radial shock wave therapy in patients after 4 weeks of conservative treatment, including stretching and

strengthening , with the placebo. Superior results regarding pain and function were shown in the group that

received the intervention. Kearney et al (2010) did a systematic review of the literature, looking for evidences

concerning the calcaneus insertional tendinopathy treatment. They found only one paper (Furia 2006) with the

utilization of the high energy therapy, and, nevertheless, the work was criticized by the small sample and the

methodology inconsistencies.



is still insufficient to inform a consensus regarding the indication of this treatment in this very frequent disease.

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Herein, our objective is to evaluate the effectiveness of low energy shock wave therapy associated to an

eccentric strengthening protocol, and compare it to eccentric strengthening associated to placebo, using the

function by Victorian Institute of Sports Assessment-Achilles (VISA-A). The primary hypothesis is that

adjunctive shock wave therapy will mitigate pain and improve function as compared to placebo.


2.1 Design, setting and recruitment

This will be a double blind, placebo-controlled, parallel groups, randomized clinical trial. The study




Participants will be enrolled at the CPRT, which provide assessment and treatment to approximately 10

(ten) new patients with chronic insertional tendinopathy per week. They will be referred by local orthopaedist

doctors or health professionals. The information to these physicians will be delivered by e-mail addressed

directly to them, as well as via posters exhibited in places containing orthopaedic medical care (outpatient clinic,

emergency room).




three months;


tendinous insertion region in the calcaneus bone (and up to 2cm around this region); and the occurrence

of increased regional volume, associated to findings of tendinopathy in the ultrasound.




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Syndrome, etc.);




• Pregnancy;






• Presence of infectious process (superficial on skin and cellular tissue, or deep in the bone) in the

region to be treated;

2.4 Sampling

The sampling calculation is based on the studies of Rompe et al 2008 and Sayana et al 2007; and

considers an estimated effect size of 3.3, a standard deviation of 16.2 and (sampling error of 5%). It was

calculated considering 93 patients divided in two groups in a randomized way, estimating that 41 evaluable

subjects per treatment arm will have better than 80% power to detect a difference in results between the shock-

wave and the placebo subjects at a level of 5% significance As we expected a 10% loss in the follow-up, based

in other clinical studies, we plan to include an extra 10% of participants, totalizing 51 patients per group.

2.5 Procedures










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each group.












with the heel.

2.6 Intervention










application.



week).








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application.




The groups will be submitted to the Alfredson eccentric strengthening protocol (Alfredson et al 2001)

for 12 weeks, starting on the same day of the first appliance. The exercises will be shown to the patients by the

assistant doctor, and a booklet (Attachment 2) will be handed out, with detailed explanation concerning the

protocol to be followed. The patient will practice the exercises standing on ground level, starting from a flexed

ankle position (tiptoes). Participants will do exercises of passive ankle extension (dorsiflexion), three series of

15 repetitions, with the knee stretched, and three series of 15 repetitions with the knee flexed by 20 degrees. The

eccentric stage (downwards) of the movement will be done slowly, only with the affected member, until it

reaches its maximum non painful stretch (including the negative stage). The concentric stage (upwards) will be

done only with the non-affected member. In case the pathology involves the two members, the patient will use

the upper members to help the practice in the concentric stage. The patients will be encouraged to increase the

load with 5kg load weights placed in a backpack which the patient will wear to practice the exercise. The load

increase is done as long as the exercise gets painless to the patient. The objective´s fulfilment and the quality of

the exercise are indicated by the discomfort felt on that region after the performance of the series.












Cryotherapy



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Pain Killers

Level 1:













2.7 Primary outcome

• Visa-A Score



• EVA

• AOFAS

• FAOS

• SF-12




include:





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2.10 Strategies to Increase Adhesion to Intervention Protocols

Hand-outs with tables containing dates to be indicated concerning the days the patient executes the

protocol´s exercises and also holding blank spaces for notes about the use of medication or occurred

complications.








a p-value < 0.05.

Discussion

Insertional Achilles tendinopathy is a common disease, affecting both athletes and the sedentary
















of these tissues. Evidence indicates that shock wave therapy is an excellent option to treat recalcitrant tendinous

diseases. By stimulus of soft tissue healing in behalf of angiogenesis enhancing and diffusion of cytokine


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surgical treatment.

Contributorship statement Nacime Salomão Barbachan Mansur: main researcher.


[email protected]

+5511994500853













submissions.



Orthopedic and Traumatology Department.

783 Borges Lagoa St, 5th Floor, Vila Clementino, São Paulo – SP. Tel.: (+5511) 5576.4848 | VOIP – 3009/

1434/2910/2887/2909

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Competing Interests


declare no support from any organization for the submitted work; no financial relationships with any

organizations that might have an interest in the submitted work in the previous three years; no other


References

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Dec;14(4):639-50. doi: 10.1016/j.fcl.2009.08.005.

2. Irwin TA. Current concepts review: insertional achilles tendinopathy. Foot Ankle Int. 2010 Oct;31(10):933-

9. doi: 10.3113/FAI.2010.0933.

3. Magnan B, Bondi M, Pierantoni S, Samaila E. The pathogenesis of Achilles tendinopathy: a systematic

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2010 Aug;31(8):689-94. doi: 10.3113/FAI.2010.0689.


neovascularization at the tendon-bone junction. A study in rabbits. J Orthop Res. 2003 Nov;21(6):984-9.

6. Chen YJ, Wang CJ, Yang KD, Kuo YR, Huang HC, Huang YT, Sun YC, Wang FS. Extracorporeal shock

waves promote healing of collagenase-induced Achilles tendinitis and increase TGF-beta1 and IGF-I

expression. J Orthop Res. 2004 Jul;22(4):854-61.

7. Chen YJ, Kuo YR, Yang KD, Wang CJ, Huang HC, Wang FS. Shock wave application enhances pertussis

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9. Wang CJ, Huang HY, Pai CH. Shock wave-enhanced neovascularization at the tendon-bone junction: an


10. Wang CJ, Chen HS, Chen CE, Yang KD. Treatment of nonunions of long bone fractures with shock waves.

Clin Orthop Relat Res. 2001 Jun;(387):95-101.

11. Wang CJ, Huang HY, Chen HH, Pai CH, Yang KD. Effect of shock wave therapy on acute fractures of the

tibia: a study in a dog model. Clin Orthop Relat Res. 2001 Jun;(387):112-8.



2014 Apr 8;10:46-51. eCollection 2014 Sep.



10.1177/0363546514531911. Epub 2014 May 9.

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10.1186/1757-1146-5-15.


tissue. Muscles Ligaments Tendons J. 2012 Jun 17;2(1):33-7. Print 2012 Jan.

18. Saxena A, Ramdath S Jr, O'Halloran P, Gerdesmeyer L, Gollwitzer H. Extra-corporeal pulsed-activated

therapy ("EPAT" sound wave) for Achilles tendinopathy: a prospective study. J Foot Ankle Surg. 2011

May-Jun;50(3):315-9. doi: 10.1053/j.jfas.2011.01.003. Epub 2011 Mar 15.

19. Wilson M, Stacy J. Shock wave therapy for Achilles tendinopathy. Curr Rev Musculoskelet Med. 2010 Nov

26;4(1):6-10. doi: 10.1007/s12178-010-9067-2.





doi: 10.1177/0363546508326983. Epub 2008 Dec 15.

22. Rasmussen S, Christensen M, Mathiesen I, Simonson O. Shockwave therapy for chronic Achilles


doi: 10.1080/17453670710015058.



61. doi: 10.2106/JBJS.F.01494.

24. Furia JP. High-energy extracorporeal shock wave therapy as a treatment for chronic noninsertional Achilles

tendinopathy. Am J Sports Med. 2008 Mar;36(3):502-8. Epub 2007 Nov 15.



Mar;35(3):374-83. Epub 2007 Jan 23. Erratum in: Am J Sports Med. 2007 Jul;35(7):1216.





28. Furia JP. [Extracorporeal shockwave therapy in the treatment of chronic insertional Achilles tendinopathy].


29. Perlick L, Schiffmann R, Kraft CN, Wallny T, Diedrich O. [Extracorporal shock wave treatment of the

achilles tendinitis: Experimental and preliminary clinical results]. Z Orthop Ihre Grenzgeb. 2002 May-

Jun;140(3):275-80. German.

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30. Giusti Guilherme, Penteado Fernando Travaglini, Santos João Baptista Gomes dos, Alves Maria Tereza de

Seixas, Faloppa Flávio. Efeito de ondas de choque na placa de crescimento de coelhos. Acta ortop.

bras. [Internet]. 2005 [cited 2016 Oct 17]; 13(1):31-34. Available from:

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S141378522005000100008&lng=en.

31. Meirer R, Kamelger FS, Huemer GM, Wanner S, Piza-Katzer H. Extracorporal shock wave may enhance

skin flap survival in an animal model. Br J Plast Surg. 2005 Jan;58(1):53-7.


J Sci Med Sport. 2007 Feb;10(1):52-8. Epub 2006 Jul 7.








Epub 2004 Apr 2.




1373481.

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SCHEDULE


2015

Marc

h

2016

May 2016 August

2016

Nove

mber

2016

Febru

ary

2017

May

2017

August 2017

Literature

consultation

Project

Development

Ethics

Committee

Submission

Starting

Patient

Recruiting

Data

Colle

ction

Data

collection

Registration

at Clinical

Trials

Database

Data

Collection

BMJ Open

Acess

Protocol

Publication

Protocol

Submissio

n for

Publication

in BMJ

Open

Acess

Journal

(IMPACT

FACTOR

2,27)

Data

collec

tion

Data

collec

tion

Data

collecti

on

Analysis of

Results

Reports

Dissertation

Drawing:

Fig1

Flow_Achilles

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Fig1_FlowAchilles

Study Flowchart

190x221mm (96 x 96 DPI)

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1

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym _____________

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry _____________

2b All items from the World Health Organization Trial Registration Data Set _____________

Protocol version 3 Date and version identifier _____________

Funding 4 Sources and types of financial, material, and other support _____________

Roles and responsibilities

5a Names, affiliations, and roles of protocol contributors _____________

5b Name and contact information for the trial sponsor _____________

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities

_____________

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee)

_____________

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2

Introduction

Background and rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention

_____________

6b Explanation for choice of comparators _____________

Objectives 7 Specific objectives or hypotheses _____________

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

_____________

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained

_____________

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists)

_____________

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be administered

_____________

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease)

_____________

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests)

_____________

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _____________

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended

_____________

Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure)

_____________

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3

Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations

_____________

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size _____________

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions

_____________

Allocation concealment mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

_____________

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions

_____________

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how

_____________

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s allocated intervention during the trial

_____________

Methods: Data collection, management, and analysis

Data collection methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol

_____________

18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols

_____________

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4

Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol

_____________

Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol

_____________

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) _____________

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation)

_____________

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed

_____________

21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial

_____________

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct

_____________

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor

_____________

Ethics and dissemination

Research ethics approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval _____________

Protocol amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators)

_____________

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5

Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how (see Item 32)

_____________

26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable

_____________

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial

_____________

Declaration of interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site _____________

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that limit such access for investigators

_____________

Ancillary and post-trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation

_____________

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing arrangements), including any publication restrictions

_____________

31b Authorship eligibility guidelines and any intended use of professional writers _____________

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code _____________

Appendices

Informed consent materials

32 Model consent form and other related documentation given to participants and authorised surrogates _____________

Biological specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable

_____________

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items. Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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http://www.creativecommons.org/licenses/by-nc-nd/3.0/







RANDOMIZED CLINICAL TRIAL PROTOCOL

Journal: BMJ Open



Date Submitted by the Author: 01-Dec-2016









jopen.bmj.com

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ownloaded from






Flávio Faloppa







Gabriel Peixoto






Version: ENG_Insertional Shock Wave Protocol_18_Nov16_REVIEWED_2

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Abstract

Background: There is no consensus regarding the treatment of Achilles insertional tendinopathies. Eccentric training remains the main choice in the conservative treatment of this illness; however, the good results in the management of non-insertional Achilles tendinopathy were not replicated in the insertional conditon. Low energy shock wave therapy has been described as an alternative to these

patients, but has yet to be empirically tested.



Materials and Methods: Nine-three patients with a diagnosis of chronic insertional tendinopathy, referred from primary or secondary health care services, will be assessed and enrolled in this study. They will be divided in two groups (randomized by sequentially numbered identical envelopes, which will be administered serially to participants), one containing the combination of low energy shock wave and eccentric exercises, as treatment, and the other comprehending the exercises and the placebo treatment (an apparatus placed in the therapeutic head). The assessments will occur in 2, 4, 6, 12 and 24 weeks. Patients will be evaluated primarily by the Victorian Institute of Sport Assessment-Achilles questionnaire (VISA-A) and secondarily by the Visual Analogue Scale (VAS), Algometry, the American Orthopedic Foot and Ankle Society (AOFAS) scale, the Foot and Ankle Outcome Score (FAOS) and the 12 Item Short Form Health Survey (SF-12). We will use Comparison of Two Proportions via relative frequency analysis, the Pearson Correlation the Chi-Square test and the ANOVA for statistical analyses.

Discussion: This study intends to demonstrate if the association of the eccentric exercise program with the shock wave therapy can produce good results regarding the treatment of the Achilles insertional tendinopathy. In an attempt to prevent the high costs and complications associated with the surgical

intervention, we will try to prove this combination as a viable therapeutic option in the conservative management of this prevalent condition.

The strengths of the study are the design and the novelty of the combination of methods. The main limitation is the short follow-up course.


1. Introduction



inflammatory signs and erratic biological healing.1-3

The insertional tendinopathy occurs in the Achilles

attachment to the tuberosity of the calcaneus bone and up to 2 cm proximal to the tuberosity. It is generally

associated with a traction enthesophyte (upper spur), Haglund deformity (pump bump) and with pre- and retro-

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achilles bursitis. The diagnosis is made based on clinical evaluation; ancillary tests, such as X-Ray and Ultra

Sound, are done only to confirm the lesion and to exclude differential diagnoses (stress fractures, tumours). The

clinical diagnosis consists of checking the level of pain via palpation of the tendinous insertion region in the

calcaneus bone (and up to 2cm around this region). The occurrence of volume increase and mild hyperemia also

supports the diagnosis. 1-4

Historically, the condition´s initial treatment is based on eccentric strengthening of the tendon. Results

for non-insertional tendinopathy are encouraging, with an 82% success rate when analysing return to previous

activities. 5,6 However, evidence indicates that eccentric strengthening for insertional tendinopathy produced a

rate of improvement ranging between 32 and 67% of the patients. 2-4 Within this context, shock wave therapy

has been proposed as a viable option, in case of failure of the conservative treatment and prior to referral to

surgery. 7-9 Over the last 30 years, extracorporeal shock waves have been safely and efficiently used in the

treatment of various pathological conditions.10,11

Extracorporeal shock wave lithotripsy (ESWL), for example, is

a well-established treatment for urological pathologies. More recently, low 12-14

and high 14,15

energy shock

waves therapies are being used in the treatment of pseudo-arthrosis 16,17 and several types of tendinopathy with

prominent results. 18-21


angiogenic markers by the recruitment of mesenchymal stem cells. 12,13,22

The molecular mechanism explaining

how the shock wave produces these consequences is yet to be determined. 15,17

Neovascularisation improves

blood irrigation, which, in its turn, contributes to tissue regeneration in the tendon-bone junction. Separate lines

of inquiry suggested that shock wave therapy, relative to placebo therapies, induces a higher increase of

mechanical resistance and concentration of markers of collagen synthesis (i.e. hydroxiproline and pyridinoline),

which are important components of the healing process. 12,14,16


transitory hyperaemia. 7 Few patients (5%) report having pain after high energy shock wave application, which

normally ceases at the end of the treatment. 8 Tendon rupture was described in the literature in only one study

23 ,

that showed 2 cases of older patients in a population of 49 cases. The authors couldn’t find a true relation

between the therapy and the events. Rasmussem et al 24 has done a randomized clinical trial with 48 patients and

12 months of follow-up, comparing the use of radial shock wave therapy in patients after 4 weeks of

conservative treatment, including stretching and strengthening, with the placebo. Superior results regarding pain

and function were shown in the group that received the intervention. Kearney et al 4 did a systematic review of

the literature, looking for evidences concerning the calcaneus insertional tendinopathy treatment. They found

only one paper 8 with the utilization of the high energy therapy, and, nevertheless, the work was criticized by the

small sample and the methodology inconsistencies.



is still insufficient to inform a consensus regarding the indication of this treatment in this very frequent

condition.9,19,25

Herein, our objective is to evaluate the effectiveness of low energy shock wave therapy

associated to an eccentric strengthening protocol, and compare it to eccentric strengthening associated to

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placebo, using the function by Victorian Institute of Sports Assessment-Achilles (VISA-A). The primary

hypothesis is that adjunctive shock wave therapy will mitigate pain and improve function as compared to

placebo.


2.1 Design, setting and recruitment (Fig1_Flow_Achilles)









emergency room).




three months;









Syndrome, etc.);


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• Pregnancy;








2.4 Sampling

The sampling calculation is based on the studies of Rompe et al 21 and Sayana et al

6; and considers an

estimated effect size of 3.3, a standard deviation of 16.2 and (sampling error of 5%). It was calculated

considering 93 patients divided in two groups in a randomized way, estimating that 41 evaluable subjects per

treatment arm will have better than 80% power to detect a difference in results between the shock-wave and the

placebo subjects at a level of 5% significance As we expected a 10% loss in the follow-up, based in other

clinical studies, we plan to include an extra 10% of participants, totalizing 51 patients per group.

2.5 Procedures











each group.

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with the heel.

2.6 Intervention










application.



week).










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application.




The groups will be submitted to the Alfredson eccentric strengthening protocol 26-28

for 12 weeks,

starting on the same day of the first appliance. The exercises will be shown to the patients by the assistant

doctor, and a booklet (Attachment 2) will be handed out, with detailed explanation concerning the protocol to be

followed. The patient will practice the exercises standing on ground level, starting from a flexed ankle position

(tiptoes). Participants will do exercises of passive ankle extension (dorsiflexion), three series of 15 repetitions,

with the knee stretched, and three series of 15 repetitions with the knee flexed by 20 degrees. The eccentric

stage (downwards) of the movement will be done slowly, while the patient contracts the muscles and increases

the distance between attachment and insertion points. This must be performed only with the affected member,

until its heel reaches the terrain level. The concentric stage (upwards) will be done only with the non-affected

member. In case the pathology involves the two members, the patient will use the upper members to help the

practice in the concentric stage. The patients will be encouraged to increase the load with 5kg load weights

placed in a backpack which the patient will wear to practice the exercise. The load increase is done as long as

the exercise gets painless to the patient. The objective´s fulfilment and the quality of the exercise are indicated

by the discomfort felt on that region after the performance of the series.












Cryotherapy



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Pain Killers

Level 1:













2.7 Primary outcome

• Visa-A Score



• EVA

• AOFAS

• FAOS

• SF-12




include:


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complications.








a p-value < 0.05.

Discussion

Insertional Achilles tendinopathy is a common condition, affecting both athletes and the sedentary













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conditions. By stimulus of soft tissue healing in behalf of angiogenesis enhancing and diffusion of cytokine







surgical treatment.



[email protected]

+5511994500853













submissions.


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783 Borges Lagoa St, 5th Floor, Vila Clementino, São Paulo – SP.

Tel.: (+5511) 5576.4848 | VOIP – 3009/ 1434/2910/2887/2909

(Table1)

Competing Interests


declare no support from any organization for the submitted work; no financial relationships with any

organizations that might have an interest in the submitted work in the previous three years; no other


References


Dec;14(4):639-50. doi: 10.1016/j.fcl.2009.08.005.


9. doi: 10.3113/FAI.2010.0933.




2010 Aug;31(8):689-94. doi: 10.3113/FAI.2010.0689.



10.1186/1757-1146-5-15.









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Dec;18(12):2169-79.





10.1177/0363546514531911. Epub 2014 May 9.








doi: 10.1177/0363546508326983. Epub 2008 Dec 15.







doi: 10.1080/17453670710015058.

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61. doi: 10.2106/JBJS.F.01494.








Epub 2004 Apr 2.




1373481.

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SCHEDULE (Table1)


2015

Marc

h

2016

May 2016 August

2016

Nove

mber

2016

Febru

ary

2017

May

2017

August 2017

Literature

consultation

Project

Development

Ethics

Committee

Submission

Starting

Patient

Recruiting

Data

Colle

ction

Data

collection

Registration

at Clinical

Trials

Database

Data

Collection

BMJ Open

Acess

Protocol

Publication

Protocol

Submissio

n for

Publication

in BMJ

Open

Acess

Journal

(IMPACT

FACTOR

2,27)

Data

collec

tion

Data

collec

tion

Data

collecti

on

Analysis of

Results

Reports

Dissertation

Drawing:

Fig1

Flow_Achilles

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Fig1_FlowAchilles

Study Flowchart

190x221mm (96 x 96 DPI)

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1














_____________


_____________

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2

Introduction



_____________




_____________



_____________


_____________


_____________


_____________


_____________



_____________


_____________

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3


_____________



Allocation:

Sequence generation


_____________



_____________


_____________


_____________


_____________




_____________


_____________

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4


_____________


_____________



_____________

Methods: Monitoring


_____________


_____________


_____________


_____________




Protocol amendments


_____________

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5


_____________


_____________


_____________




_____________



_____________


_____________



Appendices





_____________


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RANDOMIZED CLINICAL TRIAL PROTOCOL

Journal: BMJ Open



Date Submitted by the Author: 14-Dec-2016









jopen.bmj.com

/B

MJ O


ownloaded from






Flávio Faloppa







Gabriel Peixoto






Version: ENG_Insertional Shock Wave Protocol_14_Dez16_REVIEWED_3

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Abstract

Background: There is no consensus regarding the treatment of Achilles insertional tendinopathies.

Eccentric training remains the main choice in the conservative treatment of this illness; however, the good results in the management of non-insertional Achilles tendinopathy were not replicated in the insertional condition. Low energy shock wave therapy has been described as an alternative to these patients, but has yet to be empirically tested.



Materials and Methods: Nine-three patients with a diagnosis of chronic insertional tendinopathy, referred from primary or secondary health care services, will be assessed and enrolled in this study. They will be divided in two groups (randomized by sequentially numbered identical envelopes, which will be

administered serially to participants), one containing the combination of low energy shock wave and eccentric exercises, as treatment, and the other comprehending the exercises and the placebo treatment (an apparatus placed in the therapeutic head). The assessments will occur in 2, 4, 6, 12 and 24 weeks. Patients will be evaluated primarily by the Victorian Institute of Sport Assessment-Achilles questionnaire (VISA-A) and secondarily by the Visual Analogue Scale (VAS), Algometry, the American Orthopedic

Foot and Ankle Society (AOFAS) scale, the Foot and Ankle Outcome Score (FAOS) and the 12 Item Short Form Health Survey (SF-12). We will use Comparison of Two Proportions via relative frequency analysis, the Pearson Correlation the Chi-Square test and the ANOVA for statistical analyses.

Discussion: This study intends to demonstrate if the association of the eccentric exercise program with the shock wave therapy can produce good results regarding the treatment of the Achilles insertional tendinopathy. In an attempt to prevent the high costs and complications associated with the surgical intervention, we will try to prove this combination as a viable therapeutic option in the conservative management of this prevalent condition. The strengths of the study are the design and the novelty of the combination of methods. The main limitation is the short follow-up course.

Ethics and Dissemination: The study is registered in the Clinical Trials database (protocol number: 8094833648737701) and was approved by the University Ethics Committee (number: 1373481).

Strengths and Limitations

The strengths of the study:

• Study design is ideal for treatment recommendations.

• Combination of methods novelty.

• Previous sample size calculation.

• Double blinded design minimizing benchmarking bias.

• Trial registration.

• Previous protocol publication minimizing publication bias.

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The main limitations:

• Short follow-up course limiting the crosscheck of long-term effects and complications.

• Single centre study decreasing external validation.

1. Introduction



inflammatory signs and erratic biological healing.1-3

The insertional tendinopathy occurs in the Achilles

attachment to the tuberosity of the calcaneus bone and up to 2 cm proximal to the tuberosity. It is generally

associated with a traction enthesophyte (upper spur), Haglund deformity (pump bump) and with pre- and retro-

achilles bursitis. The diagnosis is made based on clinical evaluation; ancillary tests, such as X-Ray and Ultra

Sound, are done only to confirm the lesion and to exclude differential diagnoses (stress fractures, tumours). The

clinical diagnosis consists of checking the level of pain via palpation of the tendinous insertion region in the

calcaneus bone (and up to 2cm around this region). The occurrence of volume increase and mild hyperemia also

supports the diagnosis. 1-4

Historically, the condition´s initial treatment is based on eccentric strengthening of the tendon. Results

for non-insertional tendinopathy are encouraging, with an 82% success rate when analysing return to previous

activities. 5,6 However, evidence indicates that eccentric strengthening for insertional tendinopathy produced a

rate of improvement ranging between 32 and 67% of the patients. 2-4 Within this context, shock wave therapy

has been proposed as a viable option, in case of failure of the conservative treatment and prior to referral to

surgery. 7-9 Over the last 30 years, extracorporeal shock waves have been safely and efficiently used in the

treatment of various pathological conditions.10,11

Extracorporeal shock wave lithotripsy (ESWL), for example, is

a well-established treatment for urological pathologies. More recently, low 12-14 and high 14,15 energy shock

waves therapies are being used in the treatment of pseudo-arthrosis 16,17

and several types of tendinopathy with

prominent results. 18-21


angiogenic markers by the recruitment of mesenchymal stem cells. 12,13,22

The molecular mechanism explaining

how the shock wave produces these consequences is yet to be determined. 15,17 Neovascularisation improves

blood irrigation, which, in its turn, contributes to tissue regeneration in the tendon-bone junction. Separate lines

of inquiry suggested that shock wave therapy, relative to placebo therapies, induces a higher increase of

mechanical resistance and concentration of markers of collagen synthesis (i.e. hydroxiproline and pyridinoline),

which are important components of the healing process. 12,14,16


transitory hyperaemia. 7 Few patients (5%) report having pain after high energy shock wave application, which

normally ceases at the end of the treatment. 8 Tendon rupture was described in the literature in only one study

23 ,

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that showed 2 cases of older patients in a population of 49 cases. The authors couldn’t find a true relation

between the therapy and the events. Rasmussem et al 24 has done a randomized clinical trial with 48 patients and

12 months of follow-up, comparing the use of radial shock wave therapy in patients after 4 weeks of

conservative treatment, including stretching and strengthening, with the placebo. Superior results regarding pain

and function were shown in the group that received the intervention. Kearney et al 4 did a systematic review of

the literature, looking for evidences concerning the calcaneus insertional tendinopathy treatment. They found

only one paper 8 with the utilization of the high energy therapy, and, nevertheless, the work was criticized by the

small sample and the methodology inconsistencies.



is still insufficient to inform a consensus regarding the indication of this treatment in this very frequent

condition.9,19,25

Herein, our objective is to evaluate the effectiveness of low energy shock wave therapy

associated to an eccentric strengthening protocol, and compare it to eccentric strengthening associated to

placebo, using the function by Victorian Institute of Sports Assessment-Achilles (VISA-A). The primary

hypothesis is that adjunctive shock wave therapy will mitigate pain and improve function as compared to

placebo.


2.1 Design, setting and recruitment (Fig1_Flow_Achilles)









emergency room).




three months;

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Syndrome, etc.);




• Pregnancy;








2.4 Sampling

The sampling calculation is based on the studies of Rompe et al 21 and Sayana et al

6; and considers an

estimated effect size of 3.3, a standard deviation of 16.2 and (sampling error of 5%). It was calculated

considering 93 patients divided in two groups in a randomized way, estimating that 41 evaluable subjects per

treatment arm will have better than 80% power to detect a difference in results between the shock-wave and the

placebo subjects at a level of 5% significance As we expected a 10% loss in the follow-up, based in other

clinical studies, we plan to include an extra 10% of participants, totalizing 51 patients per group.

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2.5 Procedures











each group.












with the heel.

2.6 Intervention










application.

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week).












application.




The groups will be submitted to the Alfredson eccentric strengthening protocol 26-28

for 12 weeks,

starting on the same day of the first appliance. The exercises will be shown to the patients by the assistant

doctor, and a booklet (Attachment 2) will be handed out, with detailed explanation concerning the protocol to be

followed. The patient will practice the exercises standing on ground level, starting from a flexed ankle position

(tiptoes). Participants will do exercises of passive ankle extension (dorsiflexion), three series of 15 repetitions,

with the knee stretched, and three series of 15 repetitions with the knee flexed by 20 degrees. The eccentric

stage (downwards) of the movement will be done slowly, while the patient contracts the muscles and increases

the distance between attachment and insertion points. This must be performed only with the affected member,

until its heel reaches the terrain level. The concentric stage (upwards) will be done only with the non-affected

member. In case the pathology involves the two members, the patient will use the upper members to help the

practice in the concentric stage. The patients will be encouraged to increase the load with 5kg load weights

placed in a backpack which the patient will wear to practice the exercise. The load increase is done as long as

the exercise gets painless to the patient. The objective´s fulfilment and the quality of the exercise are indicated

by the discomfort felt on that region after the performance of the series.





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Cryotherapy



Pain Killers

Level 1:













2.7 Primary outcome

• Visa-A Score



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• EVA

• AOFAS

• FAOS

• SF-12




include:








complications.








a p-value < 0.05.

Discussion

Insertional Achilles tendinopathy is a common condition, affecting both athletes and the sedentary


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conditions. By stimulus of soft tissue healing in behalf of angiogenesis enhancing and diffusion of cytokine







surgical treatment.



[email protected]

+5511994500853






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submissions.




783 Borges Lagoa St, 5th Floor, Vila Clementino, São Paulo – SP.

Tel.: (+5511) 5576.4848 | VOIP – 3009/ 1434/2910/2887/2909

(Table1)

Competing Interests

All authors have completed the ICMJE uniform disclosure form

at www.icmje.org/coi_disclosure.pdf and declare no support from any organization for the submitted work; no

financial relationships with any organizations that might have an interest in the submitted work in the previous

three years; no other relationships or activities that could appear to have influenced the submitted work.

References


Dec;14(4):639-50. doi: 10.1016/j.fcl.2009.08.005.


9. doi: 10.3113/FAI.2010.0933.




2010 Aug;31(8):689-94. doi: 10.3113/FAI.2010.0689.

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10.1186/1757-1146-5-15.



























Dec;18(12):2169-79.





10.1177/0363546514531911. Epub 2014 May 9.






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doi: 10.1177/0363546508326983. Epub 2008 Dec 15.







doi: 10.1080/17453670710015058.



61. doi: 10.2106/JBJS.F.01494.








Epub 2004 Apr 2.




1373481.

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SCHEDULE (Table1)


2015

Marc

h

2016

May 2016 August

2016

Nove

mber

2016

Febru

ary

2017

May

2017

August 2017

Literature

consultation

Project

Development

Ethics

Committee

Submission

Starting

Patient

Recruiting

Data

Colle

ction

Data

collection

Registration

at Clinical

Trials

Database

Data

Collection

BMJ Open

Acess

Protocol

Publication

Protocol

Submissio

n for

Publication

in BMJ

Open

Acess

Journal

(IMPACT

FACTOR

2,27)

Data

collec

tion

Data

collec

tion

Data

collecti

on

Analysis of

Results

Reports

Dissertation

Drawing:

Fig1

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Flow_Achilles

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Fig1_FlowAchilles

Study Flowchart

190x221mm (96 x 96 DPI)

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1














_____________


_____________

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2

Introduction



_____________




_____________



_____________


_____________


_____________


_____________


_____________



_____________


_____________

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3


_____________



Allocation:

Sequence generation


_____________



_____________


_____________


_____________


_____________




_____________


_____________

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4


_____________


_____________



_____________

Methods: Monitoring


_____________


_____________


_____________


_____________




Protocol amendments


_____________

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5


_____________


_____________


_____________




_____________



_____________


_____________



Appendices





_____________


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