A Prospective, Randomized, Double-blind, Placebo Controlled Single Centre Trial to Assess the Efficacy and Safety of rESWT Combined With a Specific Rehabilitation Program for Acute Hamstring Muscle Complex Injury Type 3b in Athletes
Phase: NA
Conditions: Athletic Injuries
Sponsor: Kinef Kinesiología Deportiva

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A prospective, randomized, double-blind, placebo 
controlled single centre trial to assess the efficacy and 
safety of radial extracorporeal shock wave therapy 
combined with a specific rehabilitation program for acute 
hamstring muscle complex injury Type 3b in athletes 
 
 
 
 
 
 
 

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INVESTIGATORS 
ROLE 
Javier Crupnik, PT 
Physiotherapist.  
KinEf Kinesiología Deportiva 
Av. Cabildo 808 5°M. 1426. CABA, Argentina 
Phone: +54-911-51483899 
E-mail: jcrupnik@ondasdechoque.com.ar 
Principal Investigator 
Santiago Silveti, PT 
KinEf Kinesiología Deportiva 
Av. Cabildo 808 5°M. 1426. CABA, Argentina 
Phone: +54-9-341-3998899 
E-mail: santiagosilveti@gmail.com 
Co-Author 
Natalia Wajnstein, MD 
Especialist in Sports Medicine and Ultrasonography 
Av. Cabildo 808 5°M. 1426. CABA, Argentina 
Phone: +54-911-63544478 
E-mail: dranataliaw@gmail.com 
Co-Author 
Peter Stiller, MD 
Specialist in General Medicine and Emergency Medicine 
Team doctor for FC Augsburg 1907 (German “Bundesliga” (First 
League) professional soccer club) 
Allgemeinmedizin Lechhausen 
22 Brentanostr. 
Augsburg 86167 
Germany 
Phone: +49-821-6509790 
Fax: +49-821-65097922 
E-mail: peter.stiller@gmx.net  
Co-Author 
Alisa Vollhardt 
Extracorporeal Shock Wave Research Unit 
Department of Anatomy II 
Ludwig-Maximilians-University 
11 Pettenkoferstr. 
Munich, 80336 
Germany 
Phone: +49-89-2180-72620 
Fax: +49-89-2180-72683 
E-mail: alisa_vh@gmx.de 
Co-Author 
Dr. Christoph Schmitz, MD 
Extracorporeal Shock Wave Research Unit 
Department of Anatomy II 
Ludwig-Maximilians-University 
11 Pettenkoferstr. 
Munich, 80336 
Germany 
Phone: +49-89-2180-72620 
Fax: +49-89-2180-72683 
E-mail: christoph_schmitz@med.uni-muenchen.de 
Co-Author 
 

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1. Background 
 
Epidemiology of acute hamstring muscle complex injury in sports 
Acute injuries of the hamstring muscle complex (HMC) are frequently observed in various 
sports disciplines both in elite and recreational sport (Müller-Wohlfahrt et al., 2013; 
Fiorentino and Blemker, 2014; Kellermann et al., 2017), and are the most common injury in 
soccer (e.g., Petersen et al., 2014; Lohrer et al., 2016). Despite intensive research into 
prevention and management of acute HMC injury during the last decade epidemiological 
data show no decline in injury and re-injury rates (Valle et al., 2015). In this regard Petersen 
et al. (2010) prospectively observed 374 Danish elite soccer players during a 12-month 
period and registered 46 first-time and eight recurrent HMC injuries (incidence rates: 12.3% 
[first-time injuries] and 2% [recurrent injuries]). Statistically significantly more players 
experienced a first-time acute HMC injury during a match than during training. Moreover, 
among 32 players who suffered from acute HMC injury in a period of 12 months before the 
study, eight players incurred an injury that fulfilled the criteria for a recurrent injury 
(incidence: 25%). Approximately two thirds of the first-time injuries were categorized as 
moderate, with time to return to play between 8 to 28 days (Petersen et al., 2010). 
 
Anatomy and pathophysiology 
Anatomical and functional aspects of the HMC predispose it to injury, including the fact that 
the muscles cross two joints (Fig. 1) and undergo eccentric contraction during the gait and 
running cycle (Linklater et al., 2010).  
 
Figure 1. The hamstring muscle complex (shown from dorsal). 1, 
semimembranous muscle; 2, semitendinous muscle; 3, long head of the biceps 
femoris muscle; 4, short head of the biceps femoris muscle (picture generated 
with Essential Anatomy 3 registered to C.S.). 
 
 
 
 
 
 
Acute HMC injury typically occurs through an eccentric mechanism at the terminal stages of 
the swing phase of running (Hoskins and Pollard, 2005) (Fig. 2).  
 

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Figure 2. Running cycle. 1, initial contact; 2, take off; 3, initial swing; 4 and 5, mid-swing; 6, 
terminal swing. The flash symbol in 6 indicates the most vulnerable phase of the running cycle for 
incurring 
an 
acute 
HMC 
injury 
(modified 
from 
https://www.physio-
pedia.com/Running_Biomechanics).  
 
The long head of the biceps femoris (LHBF) muscle is most commonly affected, and within 
the LHBF muscle, the proximal myotendinous junction and proximal locations are most 
commonly affected (Crema et al., 2016). 
 
Clinical presentation and diagnosis 
The diagnosis of acute HMC injury is based on the presence of acute-onset pain in the 
posterior thigh, and presence of the triad of pain on contraction, stretching and palpation 
(Reurink et al., 2014b). Imaging has a role in confirming the site of injury and characterizing 
its extent, providing some prognostic information and helping plan treatment (Linklater et al., 
2010). In this regard both magnetic resonance imaging (MRI) and ultrasonography (US) 
have been shown to be effective for identification of hamstring strains and tendinopathy 
(e.g., Kolouris and Connell, 2005; Petersen et al., 2014; Chu and Rho, 2016). Both MRI and 
US provide detailed information about the HMC with respect to localization and 
characterization of injury (Kolouris and Connell, 2005). In a systematic review Fournier-
Farley et al. (2016) established several clinical, MRI and US determinants that are 
associated with a longer recovery time in nonoperative management of acute HMC injury 
(summarized in Table 1). However, it is important to realize that for an individual HMC injury 
none of these MRI and US determinants show a direct correlation with the time to return to 
play (Petersen et al., 2014; Chu and Rho, 2016). Accordingly, the prognosis of HMC injuries 
should not be guided by imaging findings alone (Petersen et al., 2014). 
 

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Table 1. Determinants having an effect on the time to return to play after hamstring muscle complex 
injury in athletes (according to Fournier-Farley et al., 2016). MRI, magnetic resonance imaging; US, 
ultrasonography. 
Clinical determinants 
MRI determinants 
US determinants 
• Stretching-type injuries 
• Positive findings 
• Large cross-sectional area 
• Recreational-level sports 
• Higher grade of injury 
• Injury outside the 
musculotendinous junction 
• Structural versus functional 
injuries 
• Muscle involvement >75% 
• Hematoma 
• Greater range of motion 
deficit with the hip flexed at 
90° 
• Complete transection 
• Structural injury 
• Time to first consultation >1 
week 
• Retraction 
• Injury involving the biceps 
femoris 
• Increased pain on the visual 
analog scale 
• Central tendon disruption of 
the biceps femoris 
 
• >1 day to be able to walk 
painfree after the injury 
• Proximal tendon involvement  
 
• Shorter distance to the ischial 
tuberosity 
 
 
• Length of the hamstring 
injury 
 
 
• Depth, volume, and large 
cross-sectional area 
 
 
 
Pathological classification 
According to Müller-Wohlfahrt et al. (2013) muscle injuries in sports (including acute HMC 
injuries) should be classified as shown in Figure 3. This classification has important 
implications for treatment and prognosis (i.e., time to return to play) of acute HMC injury, as 
outlined in detail below. The anatomical difference between a Type 3a injury (minor partial 
muscle tear ≤ 5 mm; intrafascicle/bundle-tear) and a Type 3b injury (moderate partial muscle 
tear > 5 mm; interfascicle/bundle-tear) is shown in Figure 4. 
 
 
 
Figure removed because of copyright reasons 
 
 
Figure 3. Classification of muscle injuries in sports (taken from Müller-Wohlfahrt et al., 2013) 
 
 
 
 

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Figure removed because of copyright reasons 
 
 
Figure 4. (A) Microscopic anatomy of a skeletal muscle. (B) Schematic illustration of 
minor/intrafascicle (Type 3a) and moderate/interfascicle (Type 3b) partial muscle tears (taken from 
Müller-Wohlfahrt et al., 2013). 
 
Treatment 
Acute HMC injuries Type 4 (i.e., subtotal or complete muscle tear or tendinous avulsion 
according to Müller-Wohlfahrt et al., 2013; Fig. 3) require early surgical repair (e.g., Brucker 
and Imhoff, 2005; Folsom and Larson, 2008; Barnett et al., 2015). However, acute HMC 
injuries Type IV are rare (Reurink et al., 2014b). 
The treatment of choice of acute HMC injuries Type 3a and 3b (Figs 3 and 4) is a 
progressive physiotherapeutic exercise programme (e.g., Robinson and Hamilton, 2014; 
Reurink et al., 2014b; Hamilton et al., 2015). Besides this, there is currently only insufficient 
scientific evidence to support other treatment methods, including local infiltrations as 
recommended by Müller-Wohlfahrt et al. (2013) (Reurink et al., 2012; 2014b). In particular, 
injections of platelet-rich-plasma (PRP) showed no effect when compared to control (e.g., 
Pas et al., 2015; Zanon et al., 2016; Manduca and Straub, 2017). Results from a very 
prominent study by Reurink et al. (2014a) on injections of PRP in acute HMC injury Type 3b 
published in The New England Journal of Medicine are shown in Fig. 5.  
It is of note that another study that was published very recently in the The New England 
Journal of Medicine demonstrated the negative clinical consequences of protracted 
immobilization after an acute muscle injury Type 3b in recreational sports. Starting 
rehabilitation two days after injury rather than waiting for nine days shortened the interval 
from injury to pain-free recovery and the time to return to play by approximately three weeks 
without any significant increase in the risk of reinjury (Bayer et al., 2017). The authors of this 
study concluded that the observed difference supports the importance of early loading of 
injured musculotendinous tissue. 
According to Müller-Wohlfahrt et al. (2013) acute muscle injuries Type 3a and 3b have 
different time frames for recovery and return to play, with optimal treatment between 10 and 
14 days in case of Type 3a and on average approximately six weeks in case of Type 3b (see 
also Figs 5 and 6). However, particularly in case of acute HMC injury Type 3b there is 
considerable interindividual variability in the time frame for return to play (Figs 5 and 6). 
 
Most importantly, particularly the high reinjury rate of acute HMC injury suggests 

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that commonly utilized rehabilitation programs may be inadequate at resolving 
possible muscular weakness, reduced tissue extensibility, and/or altered movement 
patterns associated with the injury (Heiderscheit et al., 2010). Accordingly, there is 
need for developing innovative treatment options particularly for acute HMC injury 
Type 3b. 
 
 
 
Figure removed because of copyright reasons 
 
 
Figure 5. Kaplan-Meier curves for the cumulative probability of resumptions of sports activity after 
treating acute HMC injury Type 3b with injections of platelet-rich-plasma or placebo in a study by 
Reurink et al. (2014a) published in The New England Journal of Medicine (modified from Reurink et 
al., 2014a). Each patient in the PRP+ group received two 3-ml injections of PRP. The first injection 
was administered within five days after the injury and was followed five to seven days later by the 
second injection. Patients in the PRP- group received two 3-ml injections of saline (placebo). Besides 
this, patients in both groups performed an identical, daily, progressively phased, criteria-based 
rehabilitation program that was based on the best available evidence (Sherry and Best, 2004; Mason et 
al., 2005; Heiderscheid et al., 2010). The vertical red lines indicate the times to return to play with 
optimal treatment after acute muscle injury Type 3a (between 10 and 14 days) and Type 3b 
(approximately 6 weeks) established by Müller-Wohlfahrt et al. (2013). Note the considerable 
interindividual variability in the time frame to return to play in this study by Reurink et al. (2014a) 
(range, 14 to 105 days; green line). 
 
 
 
Figure removed because of copyright reasons 
 
 
Figure 6. Kaplan-Meier curves for the cumulative probability of resumptions of sports activity after 
treating acute HMC injury Type 3b (in approximately 60% of the patients) or acute calf muscle injury 
Type 3b (in approximately 40%) with a standardized four-stage therapy regimen (daily repeated static 
stretching (week 1), daily isometric loading with increasing load (weeks 2 to 4), dynamic loading with 
increasing resistance three times per week (weeks 5 to 8) and functional exercises combined with 
heavy strength training three times per week (weeks 9 to 12) in a study by Bayer et al. (2017) 
published in The New England Journal of Medicine (modified from Bayer et al., 2017). The therapy 
started either on day 2 after injury (early-therapy group) or on day 9 after injury (delayed-therapy 
group), respectively. The vertical red lines indicate the median times to return to play for the two 

8 
 
groups (62.5 days in case of the early-therapy group and 83 days in case of the delayed-therapy 
group). 
 
 
Novel treatment options for acute HMC injury Type 3b 
Very recently it was demonstrated that extracorporeal shock wave therapy (ESWT) may 
accelerate regeneration after acute skeletal muscle injury (Zissler et al., 2017; 
Mattyasovszky et al., 2017). The use of extracorporeal shock waves in medicine was first 
reported over 30 years ago as a treatment for kidney stones (Chaussy et al., 1980), and is 
commonly referred to as ‘extracorporeal shock wave lithotripsy’, or ‘ESWL’ (Rassweiler et 
al., 2011). Extracorporeal shock waves are also used as a treatment for musculoskeletal 
conditions such as plantar heel pain (reviewed in, e.g., Speed, 2014; Schmitz et al., 2015) 
and boney non-union (Biedermann et al., 2003; Cacchio et al., 2009), and is commonly 
referred to as ‘extracorporeal shock wave therapy’ (ESWT) to differentiate from ESWL 
(Speed, 2014).  
With respect to regeneration after acute skeletal muscle injury Zissler et al. (2017) 
divided adult Sprague-Dawley rats into four experimental groups (2 ESWT+ groups and 2 
ESWT- groups) as well as an uninjured control group (n ≥ 6 in each group). An acute 
cardiotoxin-induced injury was set into the quadriceps femoris muscle of the rats in the 
experimental groups. Then, a single session of focused extracorporeal shock wave therapy 
(fESWT; outlined in detail below) was administered to injured muscles of the rats in the 
fESWT+ groups one day after injury, whereas the rats in the fESWT- groups received no 
treatment. At four and seven days after injury, one rat each of the fESWT+ and fESWT- 
groups was euthanized. Regenerating lesions were excised and analyzed by 
histomorphometry and immunohistochemistry to assess fiber size, myonuclear content, and 
recruitment of satellite cells. Zissler et al. (2017) found that the size and myonuclear content 
of regenerating fibers in fESWT+ muscles were statistically significantly increased compared 
with fESWT- muscle fibers at both four and seven days after injury. Similarly, at both time 
points, fESWT+ muscles exhibited statistically significantly higher contents of paired box 
protein 7 (pax7)-positive satellite cells, mitotically active H3P+ cells, and of cells expressing 
the myogenic regulatory factors, myoD and myogenin. These data indicate enhanced 
proliferation and differentiation rates of satellite cells after fESWT. Mitotic activity at four days 
after injury was doubled in fESWT+ compared with fESWT- muscles. Zissler et al. (2017) 
concluded that fESWT may stimulate regeneration of skeletal muscle tissue and accelerate 
repair processes. 
Mattyasovszky et al. (2017) (with one of us [C.S.] serving as co-author) isolated cells 
from muscle specimens taken from adult patients undergoing spine surgery. Muscle cells 

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were exposed to radial extracorporeal shock wave therapy (rESWT) in vitro with different 
energy flux densities. Cell viability and gene expression of Pax7, neural cell adhesion 
molecule (NCAM) and myogenic factor 5 (Myf5) as muscle cell markers were compared to 
non-exposed muscle cells that served as controls. The authors found that isolated muscle 
cells were positive for the hallmark protein of satellite cells, Pax7, NCAM and Myf5. 
Exposure to rESWT at low energy densities enhanced cell viability whereas higher energy 
densities had no significant impact on cell viability. Gene expression of Pax7 was up-
regulated after exposure to higher energy densities, whereas Pax7, NCAM and Myf5 gene 
expression was down-regulated after exposure to even higher energy densities. 
Mattyasovszky et al. (2017) concluded that rESWT has the potential to modulate the 
biological function of human skeletal muscle cells. 
 
There are three different types of extracorporeal shock waves that could be used in 
ESWT for acute HMC injury Type 3b, focused, defocused and radial (Fig. 7), and several 
modes of operation of focused, defocused and radial extracorporeal shock wave generators 
(Fig. 8). 
 
 
Figure 7 (modified from Schmitz et al., 2015). Working principle of focused (on the left), defocused 
(in the middle) and radial (on the right) extracorporeal shock wave technology. In case of focused 
shock waves, single acoustic pulses are generated either with a spark-gap (electrohydraulic 
principle), a technology similar to a loudspeaker (electromagnetic principle), or piezocrystals 
(piezoelectric principle) (black bars represent shock wave generators; details are provided in Fig. 8 
below). By means of reflectors of certain shape and/or the use of acoustic lenses the acoustic pulses 
are converted into a focused acoustic pressure wave/shock wave with a point of highest pressure (red 
arrow) at the desired target (green dot) within pathological tissue. By changing the shape of the 
reflector (and/or the acoustic lens) the acoustic waves emitted from a focused shock wave generator 
can be converted into a slightly convergent, parallel, or even divergent acoustic pressure wave/shock 
wave (“defocused shock wave”). In case of radial shock waves a projectile is fired within a guiding 
tube that strikes a metal applicator placed on the patient’s skin. The projectile generates stress waves 
in the applicator that transmit pressure waves into tissue. The point of highest pressure is found at the 

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tip of the applicator. It is of note that any disturbance in the pathway of the acoustic pulses between a 
focused shock wave source and the target within tissue (such as bone, calcifications, etc.; red dots in 
the figures) may result in some parts of the acoustic pulse not reaching the target and, thus, 
weakening the shock wave energy (i.e. the energy density) at the target. The same disturbances would 
not impact the energy of radial shock waves at the target (for defocused shock waves it is unknown to 
what extent they are weakened by disturbance in the pathway of the acoustic pulses between the shock 
wave source and the target within tissue). This is most probably the reason why in muscle tissue, the 
energy of focused shock waves was found to be decreased by >50% compared to measurements in 
water, whereas for radial shock waves measurements in muscle tissue and water were consistent 
(Kearney et al., 2010). 
 
 
 
Figure 8 (modified from Schmitz et al., 2015). Schematic representation of the mode of operation of 
focused (A-C), defocused (D) and radial (E) extracorporeal shock wave generators. (A) 
Electrohydraulic principle (fESWT): a high voltage discharges rapidly across two electrode tips 
(spark-gap) (1) that are positioned in water. The spark-gap serves as the first focal point (1). The heat 
generated by this process vaporizes the surrounding water. This generates a gas bubble centered on 
the first focal point, with the gas bubble being filled with water vapor and plasma. The result of the 
very rapid expansion of this bubble is a sonic pulse, and the subsequent implosion of this bubble 
causes a reverse pulse, manifesting a shock wave. By means of reflectors of certain shape (2), this 
shock wave can be converted into a convergent/focused acoustic pressure wave/shock wave with a 
point of highest pressure at the second focal point (3). (B) Electromagnetic principle (fESWT): a 
strong, variable magnetic field is generated by passing a high electric current through a coil (4). This 

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causes a high current in an opposed metal membrane (5), which causes an adjacent membrane (6) 
with surrounding liquid to be forced rapidly away. Because the adjacent membrane is highly 
conductive, it is forced away so rapidly that the compression of the surrounding liquid generates a 
shock wave within the liquid. By means of an acoustic lens (7) of certain shape, this shock wave can 
be converted into a convergent/focused acoustic pressure wave/shock wave with a point of highest 
pressure at a focal point (8). (C) Piezoelectric principle (fESWT): a large number of piezocrystals (9) 
are mounted in a bowl-shaped device (10); the number of piezocrystals can vary from a few to several 
thousands (typically between 1,000 and 2,000). When applying a rapid electrical discharge, the 
piezocrystals react with a deformation (contraction and expansion), which is known as the 
piezoelectric effect. This induces an acoustic pressure puls in the surrounding water that can steep 
into a shock wave. Because of the design of the bowl-shaped device an acoustic pressure wave/shock 
wave can emerge with a point of highest pressure at a focal point (11). (D) Defocused principle 
(shown here for the electrohydraulic principle). By changing the shape of the reflector (12) the shock 
wave emitted from the first focal point is converted into a slightly convergent, parallel, or even 
divergent acoustic pressure wave/shock wave (“defocused shock wave”) (13). (E) Ballistic principle 
(rESWT): compressed air (pneumatic principle; 14) or a magnetic field (not shown) is used to fire a 
projectile (15) within a guiding tube (16) that strikes a metal applicator (17) placed on the patient’s 
skin. The projectile generates stress waves in the applicator that transmit pressure waves into tissue 
(18). 
 
 
To our knowledge randomized controlled trials (RCTs) testing efficacy and safety of 
rESWT for acute HMC injury Type 3b have not yet been published. In contrast, rESWT has 
become an established treatment modality for various musculoskeletal conditions such as 
calcifying tendonitis of the shoulder, tennis elbow and plantar fasciopathy, to mention only a 
few (details can be found in Schmitz et al., 2015). Among the 44 RCTs on rESWT currently 
listed in the PEDro database (status of September 09, 2017), 29 (66%) were performed with 
the rESWT device Swiss DolorClast (Electro Medical Systems, Nyon, Switzerland).  
All of us (J.C., P.S. and C.S.) have extensive practical experience with rESWT for 
various musculoskeletal conditions using the Swiss DolorClast. Most importantly, all of us 
have already gained practical experience with rESWT for acute HMC injury Type 3b in 
athletes. One of our (P.S. and C.S.) most prominent patients was a professional soccer 
player at a European top club (regularly playing in the UEFA Champions League) who 
incurred a HMC injury Type 3b and returned to play (full 90-min match with his national 
team) 35 days later. In the aforementioned studies by Reurink et al. (2014a) (outlined in 
detail in Fig. 5 above) and Bayer et al. (2017) (outlined in Fig. 6 above) the cumulative 
probability of resumptions of sports activity on day 35 after acute HMC injury Type 3b in 

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professional soccer players (Reurink et al., 2014a) or recreational athletes (Bayer et al., 
2017) was only respectively 20% (Reurink et al., 2014a) or 5% (Bayer et al., 2017) after 
treatment with a rehabilitation program (Fig. 9). 
 
 
 
Figure removed because of copyright reasons 
 
 
Figure 9. Cumulative probability of resumptions of sports activity after treating acute HMC injury 
Type 3b in studies by Reurink et al. (2014a) (A) and Bayer et al. (2017) (B) published in The New 
England Journal of Medicine. The red lines indicate the cumulative probability of resumptions of 
sports activity on day 35 after injury after treatment with a rehabilitation program (placebo group in 
the study of Reurink et al. (2014a) and early-therapy group in the study by Bayer et al. (2017)).. 
 
 
Considering the limited evidence of efficacy and safety of rESWT for acute HMC injury Type 
3b, further research is needed to support the use of rESWT for this condition. Taking into 
account the proven efficacy and safety of rESWT using the Swiss DolorClast for treating 
musculoskeletal conditions (Schmitz et al., 2015), the widespread use of the Swiss 
DolorClast based on its proven efficacy and safety, and our own very promising pilot data of 
rESWT using the Swiss DolorClast for treating acute HMC injury Type 3b in athletes it is 
reasonable to hypothesize that (i) the combination of rESWT and a specific rehabilitation 
program is effective and safe in treatment of acute HMC injury Type 3b, (ii) this combination 
therapy is statistically significantly more effective than the same specific rehabilitation 
program alone, and (iii) this combination therapy will gain widespread acceptance as soon 
as effectiveness and safety will be demonstrated in a randomized controlled trial. This is the 
main purpose of the proposed study.  
 

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2. Hypothesis 
• 
Based on the results of the systematic literature search outlined above it is hypothesized 
here that the combination of radial extracorporeal shock wave therapy performed 
with the Swiss DolorClast device (Electro Medical Systems, Nyon, Switzerland) 
and a specific rehabilitation program (thereafter, "rESWT + RP") is effective and 
safe in treatment of acute HMC injury Type 3b, and is statistically significantly more 
effective than the combination of sham-rESWT and RP (thereafter, "sham-rESWT + 
RP"). 
 
3. Study Objectives 
3.1. General Objective 
1) To determine the efficacy and safety of rESWT + RP (compared with sham-rESWT + 
RP) in treatment of acute HMC injury Type 3b. 
 
3.2. Specific Objectives 
1) To determine the individual and mean time to return to play after treating acute HMC 
injury Type 3b with respectively rESWT + RP or sham-rESWT + RP.  
2) To determine the incidence of re-injury during a period of six months after return to play 
following treatment of acute HMC injury Type 3b with respectively rESWT + RP or sham-
rESWT + RP. 
3) To evaluate patient’s pain score during respectively rESWT or sham-rESWT for acute 
HMC injury Type 3b using the Visual Analogue Scale (VAS) score. 
4) To evaluate patient’s satisfaction at six months after the end of treatment. 
 
4. Study protocol 
4.1. Introduction 
An advanced study design of a clinical trial is ways more than just to decide how many 
patients will be treated with treatment X and how many patients with treatment Y, and how 
treatments X and Y should be performed. Actually an advanced study design of a RCT has 
to consider everything that will be checked later in assessments of the methodological 
quality of a RCT of health care interventions. There are at least six different assessments 
available: 
1. Jadad et al. (1996) – This is a very basic assessment, attributing to each RCT a quality 
score out of a maximum of six points: (1) Was the generation of randomization sequence 
described? (2) Was the method of allocation concealment described? (3) Was an 

14 
 
intention to treat analysis used? (4) What number of patients was lost to follow-up? (5) 
Was the outcome assessment blind? and (6) Was the patient blind to treatment 
allocation? The design of the proposed study on rESWT + RP for acute HMC injury Type 
3b considers all these aspects. 
2. The DELPHI list (Verhagen et al., 1998) – The DELPHI list consists of the following 
questions: (1) Was a method of randomization performed? (2) Was the treatment 
allocation concealed? (3) Were the groups similar at baseline regarding the most 
important prognostic indicators? (4) Were the eligibility criteria specified? (5) Was the 
outcome assessor blinded? (6) Was the care provider blinded? (7)  Was the patient 
blinded? (8) Were point estimates and measures of variability presented for the primary 
outcome measures? (9) Did the analysis include an intention-to-treat analysis? The 
design of the proposed study on rESWT + RP for acute HMC injury Type 3b considers all 
these aspects, except of the fact that the care providers will not be blinded. 
3. The PEDro scale (Physiotherapy Evidence Database; www.pedro.org.au; Blobaum, 
2006) - This scale is a development of the DELPHI list and consists of a total of 10 scale 
items, including random allocation, concealment of allocation, comparability of groups at 
baseline, blinding of patients, therapists and assessors, analysis by intention to treat and 
adequacy of follow-up, between-group statistical comparisons, and reports of both point 
estimates and measures of variability. The design of the proposed study on rESWT + RP 
for acute HMC injury Type 3b considers all these aspects, except of the fact that the 
therapists will not be blinded. 
4. Chalmers et al. (1981) – This assessment consists of two evaluation forms that include 
29 individually scored items, allowing a maximum score of 100. 
5. Downs and Black (1998) –This assessment includes 27 individually scored items, 
allowing a maximum score of 32. 
6. The CONSORT statement (Schulz et al., 2010) – The CONSORT statement is intended 
to improve the reporting of RCTs, enabling readers to understand a trial's design, 
conduct, analysis and interpretation, and to assess the validity of its results. 
The assessments of Chalmers et al. (1981), Downs and Black (1998) and Schulz et al. 
(2000) are very similar. However, Downs and Black (1998) provide the most specific 
questions. Accordingly, the design of the proposed study on rESWT + RP for acute HMC 
injury Type 3b was developed according to the criteria set out by Downs and Black (1998). 
The proposed study on rESWT + RP for acute HMC injury Type 3b will achieve a very high 
rating on the assessment by Downs and Black (1998). 
 

15 
 
4.2. Study design  
• 
Main study: randomized controlled trial (RCT) on rESWT + RP vs. sham-rESWT + RP, 
with blinding of patients and evaluators/assessors, but without blinding of therapists 
applying the treatments (the rationale for this is provided in Section 4.11. “Blinding of 
therapists and assessors” below). 
 
4.3. Inclusion criteria 
• 
Adults (both male and female) with clinical and ultrasonographic diagnosis of acute HMC 
injury Type 3b. 
• 
Age range: between 18 and 35 years. 
• 
Physical conditions for rehabilitation (i.e., no surgery required) 
• 
Willingness of the patient to participate in the study, and written informed consent signed 
and personally dated by the patient. 
• 
No contraindications for rESWT. 
 
4.4. Exclusion criteria 
• 
Children and teenagers below the age of 18.  
• 
Adults aged >35 years old. 
• 
Patients with clinical and ultrasonographic diagnosis of acute HMC injury Type 3b who 
got injured more than seven days before potential enrollment into this study. 
• 
Patients with clinical and ultrasonographic diagnosis of acute HMC injury Type 3A or 
Type 4. 
• 
Bilateral acute HMC injury (Types 3A, 3B or 4). 
• 
Proven or suspected HMC injury (Types 3A, 3B or 4) of the same lower limb in the time 
period of six months before potential enrollment into this study. 
• 
Muscle injury caused by external impact on the back of the affected thigh (Category B 
according to Müller-Wohlfahrt et al., 2013). 
• 
Surgery on the affected lower limb in the time period of one year before potential 
enrollment into this study. 
• 
Acute or chronic lumbar pathology (because some cases of thigh pain may relate to 
spinal pathology; c.f. Linklater et al., 2010). 
• 
No willingness of the patient to participate in this study, and/or written informed consent 
not signed and not personally dated by the patient. 
• 
Contraindications of rESWT: 
o treatment of pregnant patients, 
o treatment of patients with blood-clotting disorders (including local thrombosis), 

16 
 
o treatment of patients treated with oral anticoagulants, 
o treatment of patients with local bacterial and/or viral infections/inflammations, 
o treatment of patients with local tumors, and 
o treatment of patients treated with local corticosteroid applications in the time period of 
six weeks before the first rESWT session (if applicable). 
 
4.5. Groups and treatments 
All subjects will perform a specific rehabilitation program (RP) that will last for eight weeks, 
independent of the individual time interval to return to play (in line with Bayer et al., 2017). 
This RP was developed based on recommendations in the literature (Mendiguchia and 
Brughelli, 2011; Askling et al., 2014; Mendiguchia et al., 2017). The key objective of this RP 
is that after injury, the subject will develop functional, neuromuscular and biomechanical 
skills according to the demands of the sport she/he performs, while minimizing the risk of re-
injury. Therefore, the proposed RP will take the subject through a combination of low-risk 
and high-demand movements, based on a systematic process. This process will consist of 
an orderly sequence of steps or phases – acute phase, subacute/regeneration phase, and 
functional phase). Each phase will depend on the outcome of the previous phase and will 
use the individualized response as criterion of progression. The RP will be controlled by the 
same physiotherapist who will not participate in the inclusion/exclusion process or any 
subsequent evaluation of the subject.  
 
Acute phase 
The goals of the acute phase include:  
• 
prevent re-rupture at the injured site, 
• 
prevent excessive inflammation and formation of scar tissue, 
• 
increase tensile strength, adhesion and elasticity of new granulation tissue, 
• 
reduce build-up of interstitial fluid, and 
• 
detect and treat any lumbo-pelvic dysfunction. 
Once a subject will be included in the proposed study she/he will be instructed to avoid the 
use of medication and apply the RICE principle (rest, ice, compression and elevation) three 
times per day in order to stop the injury-induced bleeding into the muscle tissue and thereby 
minimize the extent of the injury (see, e.g., Jarvinen et al., 2007).  
With regard to the optimum time interval for starting active rehabilitation after acute HMC 
injury Type 3b Jarvinen et al. (2007) recommended immobilization for three to five days, 
followed by active mobilization. Bayer et al. (2017) pointed out that starting rehabilitation two 
days after injury rather than waiting for nine days shortened the interval from injury to pain-

17 
 
free recovery and the time to return to play by approximately three weeks without any 
significant increase in the risk of reinjury. However, it is not known whether starting 
rehabilitation already two days after injury has any benefit over starting rehabilitation five 
days after injury. We will therefore follow the recommendation by Jarvinen et al. (2017) and 
progress to the sub-acute phase after five days.  
The criterion for progression to the subacute/regeneration phase will be 
• 
absence of pain five days after injury.  
If the symptoms caused by the injured muscle persist for more than five days we will 
reconsider the existence of more extensive tissue damage and/or intramuscular hematoma 
that might require special attention and treatment by an orthopedic surgeon. 
 
Subacute/Regeneration Phase 
The goals of the subacute/regeneration phase include: 
• 
improve overall core stability, 
• 
improve strength and symmetry,  
• 
reduce pain during prone isometric, isolated hamstring contractions at 15° knee flexion, 
• 
improve hamstring flexibility of both legs, 
• 
improve hip flexor flexibility of both legs, and 
• 
improve neuromuscular control. 
During the subacute/regeneration phase the subject will work on both legs daily during a 
single session. Exercises will be conducted to correct the different risk factors and 
mechanisms related to the lesion of the hamstring musculature. The exercises will be 
divided into four groups: 
• 
core stability and lumbopelvic control, 
• 
flexibility and neural mobilization, 
• 
hamstring and gluteal strength, and 
• 
running technique 
(see also 
http://wolterskluwer.http.internapcdn.net/wolterskluwer_vitalstream_com/MP4s/permalink/ms
s/a/mss_2017_02_28_mendiguchia_msse-d-16-00910r4_sdc1.mp4). 
In addition, basic aerobic conditioning will start when the subject will be able to perform 
at least three sessions of the running technique without any discomfort or pain. Three 
running sessions per week will be performed at the clinic of the Principal Investigator and will 
include four sets of five minutes at a low to moderate intensity (individually rated by the 
subject). Suspension of running sessions will be permitted in the event of discomfort or pain. 
The criteria for progression to the functional phase will be:  

18 
 
• 
no pain in prone position with knee flexed to 15°, 
• 
no pain during slump test, 
• 
< 10% asymmetry when in prone position with knee flexed to 15°, 
• 
< 10% asymmetry during active knee extension test, and 
• 
< 5° asymmetry in the modified Thomas Test.  
 
Functional phase  
The goals of the functional phase include:  
• 
increase the optimum length of the hamstrings, 
• 
decrease leg asymmetries in optimum length, 
• 
decrease leg asymmetries in concentric hip extension, 
• 
decrease leg asymmetries in horizontal force production during running, and 
• 
improve torsional capabilities. 
The functional phase will comprise daily exercises, with three sessions per week at the clinic 
of the Principal Investigator (every other day) and the remaining sessions at the club or at 
home. The exercises will comprise the following: 
• 
core stability and lumbopelvic control, 
• 
flexibility and neural mobilization, 
• 
hamstring and gluteal strength, 
• 
plyometric training, and  
• 
running technique. 
During the Functional Phase, the running session will consist of two sets of ten minutes at 
moderate to high intensity (individually rated by the subject). Suspension of running sessions 
will be permitted in the event of discomfort or pain. 
The criteria for return to play will be (according to van der Horst et al., 2016): 
• 
absence of pain on palpation, 
• 
absence of pain during flexibility testing (active knee extension test and passive straight 
leg raise test), 
• 
absence of pain during strength testing (isometric force test), 
• 
absence of pain during and after functional testing (repeated sprint ability test and single 
leg bridge), 
• 
similar hamstring flexibility, 
• 
psychological readiness / athlete confidence, and 
• 
clearance by the medical staff. 
The quantity and quality of the supervised rehabilitation sessions at home or the sports club 
will be documented. 

19 
 
 
Patients in the rESWT group will receive the below:  
• 
Specific rehabilitation program as outlined above. 
• 
In addition: rESWT as follows: 
o nine rESWT sessions; 
o three sessions per week (interval between sessions: two or three days); 
o rESWT device: Swiss DolorClast (Electro Medical Systems, Nyon Switzerland), 
EvoBlue handpiece, 15 mm applicator; 
o 2500 rESWs per session, with energy density between 0.12 and 0.16 mJ/mm2 
(achieved by operating the Swiss DolorClast at air pressure between three and four 
bar), depending on what the patient tolerates; 
o rESWs applied at 15 Hz (i.e., 15 rESWs per second), resulting in treatment time 
between three and five minutes per session; 
o application of rESWs in prone position, with the patient lying on an examination table; 
o exact location of the application of rESWs determined by clinical and 
ultrasonographic examinations; 
o treatment of both the side of injury and the entire affected muscle (from distal to 
proximal in order to relax the affected muscle); 
o application of rESWs in sagittal (dorsal →ventral) direction; and 
o no use of local anesthesia. 
 
Patients in the sham-rESWT group will receive the below:  
• 
Specific rehabilitation program as outlined above. 
• 
In addition: sham-rESWT as outlined above, with a specially designed placebo EvoBlue 
handpiece that looks and sounds like the EvoBlue handpiece of the Swiss DolorClast, 
but does not generate radial shock waves. This is achieved by blocking the projectile 
[“13” in Fig. 2] shortly before it strikes the metal applicator [“15” in Fig. 2]). The placebo 
EvoBlue handpiece will not emit any radial shock wave energy. 
 
4.6. Recruitment of patients 
• 
Patients in the rESWT group and the sham-rESWT group will be recruited from the Club 
Deportivo UAI Urquiza (Villa Lynch, Province Buenos Aires, Argentina) and will be 
recruited over the same period of time (approximately 12 months).  
• 
Recruitment of patients will start immediately after approval of the study by the Ethics 
Committee of the Universidad Abierta Interamericana (Buenos Aires, Argentina). 

20 
 
• 
Officials of the Club Deportivo UAI Urquiza will be instructed that athletes who 
experience sudden, sharp pain in the posterior aspect of the thigh during training or 
competition shall immediately stop activity. These athletes will then be evaluated 
regarding the presence of the inclusion criteria of this study on the day of injury. 
• 
All potential patients that fulfill the inclusion criteria and do not fulfill any of the exclusion 
criteria outlined above will be offered to participate in this study until the total number of 
patients (rESWT group: n=20; sham-rESWT group: n=20) will be recruited. Accordingly, 
the patients that will be prepared to participate in this study will be representative of the 
entire population from which they were recruited. We will report the proportion of those 
asked who agreed. 
• 
The intervention will be undertaken in a specialist centre that is representative of the 
clinics most of the source population would attend if seeking treatment of acute 
HMCinjury Type 3b. 
 
4.7. Informed Consent Process 
Should patients agree to be part of this study, they will be guided through the informed 
consent process first, as described here. The Informed Consent Process will be done at the 
clinic of the Principal Investigator of this study (Javier Crupnik, Av. Cabildo 808, 5º M, 
Buenos Aires, Argentina). A copy of the Participant Information Sheet will be given to them. 
The patient will be given sufficient time to read and understand everything written on the 
document. The Principal Investigator will be there to explain and answer any queries that 
may arise. The patient will sign the Informed Consent Form if agreeable thereafter. 
 
4.8. Randomization and blinding of patients 
• 
Patients that fulfill the inclusion criteria and do not fulfill any of the exclusion criteria will 
be randomly allocated to either rESWT + RP (n=20) or sham-rESWT + RP (n=20).  
• 
Randomization will be performed as described by Rompe et al. (2008) in a randomized, 
controlled study on rESWT for Achilles tendinopathy. Specifically, a computerized 
random-number generator will be used to formulate an allocation schedule. Patients will 
be randomized to either treatment (rESWT + RP or sham-rESWT + RP), with use of the 
method of randomly permuted blocks. The randomization scheme will be generated with 
the use of the website, www.randomization.com. Fifty patients will be randomized into 
five blocks. A medical assistant at the clinic of the Principal Investigator will allocate 
interventions by means of opaque sealed envelopes that will be marked according to the 
allocation schedule. The medical assistant will be unaware of the size of the blocks. 

21 
 
• 
The randomized intervention assignment as outlined above will be concealed from both 
patients and health care staff until recruitment will be complete and irrevocable. 
• 
Patients will be blinded in this study. 
• 
The assessor will be blinded in this study. The assessor is the person who will assess 
the outcome of treatment during follow up. In this study, the assessor will be a medical 
assistant at the clinic of the Principal Investigator. 
• 
The therapist will not be blinded in this study. The therapist is the person who will 
administer either rESWT or sham-rESWT to the patient. In this study, the therapist will 
be the Principal Investigator (J.C.). 
 
4.9. Study treatment and visits 
As outlined in Section 4.5 “Groups and treatments” above all subjects will perform RP that 
will last for eight weeks, independent of the individual time interval to return to play. 
• 
The RP will start with a first visit to the clinic of the Principal Investigator during which 
clinical and ultrasonographic diagnosis will be performed. This first visit may take place 
on the day of injury (D0) or the first day (D1) or second day (D2) after injury (the sooner 
the better). 
• 
After the first visit an individual number of days will follow until the fifth day after injury 
(D5) will be reached (acute phase). During this time the subject will apply the RICE 
principle (rest, ice, compression and elevation). Visits to the clinic of the Principal 
Investigator may be scheduled during this time but are not mandatory. 
• 
On D5 the subacute/regeneration phase of the RP will start, with three visits per week to 
the clinic of the Principal Investigator (outlined in detail in Section 4.5 “Groups and 
treatments” above). The exact time for progression from the subacute/regeneration 
phase to the functional phase of the RP will be individually determined, depending on 
whether the criteria for progression will be fulfilled. During the functional phase there will 
also be three visits per week to the clinic of the Principal Investigator. 
• 
Study treatments (rESWT or sham-rESWT) will start on D5. Each subject will be treated 
with nine sessions of rESWT or sham-rESWT, with three sessions per week. 
Accordingly, study treatments may take place at D5, D7, D9, D12, D14, D16, D19, D21 
and D23. 
• 
Six months after inclusion into the study there will be a separate visit for evaluating 
patient’s satisfaction with the treatment outcome. 
 
The time interval necessary for reaching return to play will be as follows: 

22 
 
• 
Based on our experience we expect that approximately 75% of the subjects treated with 
rESWT + RP will reach return to play within five weeks after D0.  
• 
Furthermore, we expect that only approximately 25% of the patients treated with sham-
rESWT + RP will reach return to play within five weeks after D0.  
 
The Principal Investigator will perform the following procedures at the first visit: 
• 
check eligibility 
• 
obtain informed consent 
• 
perform randomization 
• 
collect patient’s demographics & medical history 
 
Furthermore, the Principal Investigator will perform the following procedures at all visits: 
• 
record any concomitant medication 
• 
perform clinical examination 
• 
perform physical examination of the injured muscle 
• 
dispense study treatment 
• 
perform efficacy assessment 
• 
report adverse events (AE) and serious adverse events (SAE) 
• 
complete relevant section of case report form (CRF) 
 
4.10. Outcome of Interest 
4.10.1. Primary clinical outcome and definition of treatment success  
• 
Primary clinical outcome will be the individual time (days) necessary to return to play.  
• 
Individual treatment success is defined as the possibility to return to play with the 
following criteria fulfilled (according to van der Horst et al., 2016): 
o absence of pain on palpation, 
o absence of pain during flexibility testing (active knee extension test and passive 
straight leg raise test), 
o absence of pain during strength testing (isometric force test), 
o absence of pain during and after functional testing (repeated sprint ability test and 
single leg bridge), 
o similar hamstring flexibility, 
o psychological readiness / athlete confidence, and 
o Medical Staff clearance. 
 

23 
 
4.10.2. Secondary clinical outcomes 
Secondary clinical outcomes will be: 
• 
individual patient’s satisfaction at six months after inclusion into the study (using a scale 
ranging from 0 [maximum dissatisfaction] to 10 [maximum satisfaction]), and 
• 
presence or absence of re-injury during a time period of six months after inclusion into 
the study (defined as sudden, sharp pain in the posterior aspect of the thigh that was 
initially injured, accompanied by the same objective criteria initially used for the diagnosis 
of acute HMC injury Type 3b).   
 
4.10.3. Additional evaluations 
In addition to primary and secondary clinical outcomes the following parameters will be 
evaluated and reported: 
• 
Patient’s sex, age, weight, height, and body mass index. 
• 
Interval between injury and the first treatment (in days). 
• 
Patient’s individual training load (number of training sessions per week; duration of 
training sessions). 
 
4.11. Blinding of therapists and assessors  
• 
Therapists applying the treatments will not be blinded. This will be done because even 
when using coded “active” and “placebo” handpieces in a study on rESWT, blinding of 
therapists can only be achieved when another person prepares the device before rESWT 
or sham-rESWT. This, however, is almost impracticable and has not been done in any of 
the more than 100 studies on radial and focused ESWT listed in the PEDro database 
(Schmitz et al., 2015). The solution to this issue is a strict, standardized way of 
interaction between the therapist and the patients, irrespective of treatment allocation (as 
mentioned in a study by Buchbinder et al., 2002). This approach will also be applied in 
the present study.  
• 
All assessments before the first treatment (baseline) and during the follow-up period will 
be performed by assessors blind to the intervention. 
 
5. Follow-up and statistical analysis 
• 
Follow-up will be the same for all study patients (outlined in detail in Section 4.10. 
above). 
• 
The design of this study guarantees that there will be full compliance with the allocated 
treatment and, thus, no contamination of one group. 

24 
 
• 
The patient’s age, gender, body mass index, sport that practices, position in the field, 
sporting gesture that caused the injuriy are potential confounding factors when treating 
acute HMC injury Type 3b with rESWT. Normal distribution of these data will be tested 
using the D'Agostino-Pearson omnibus test. In case of passing the normality test we will 
report mean and standard error of the mean of these variables; otherwise we will report 
inter-quartile ranges of these variables. Comparison between groups will be performed 
with Student’s t test in case of passing the normality test or the nonparametric Mann-
Whitney test in case of not passing the normality test. 
• 
As outlined in Section 4.11.1. “Primary clinical outcome and definition of treatment 
success” above, the primary clinical outcome will be the individual time (days) necessary 
to return to play. The primary clinical outcome will return a single data point (number of 
days) for each patient. Time of return to play is not normally distributed data. 
Accordingly, we will report inter-quartile ranges of this variable. Comparison between 
groups will be performed using the nonparametric Mann-Whithney test.  
• 
As outlined in Section 4.11.2. “Secondary clinical outcomes“ above, one secondary 
clinical outcome will be assessment of patient’s satisfaction at six months after inclusion 
into this study (using a scale ranging from 0 [maximum dissatisfaction] to 10 [maximum 
satisfaction]). This secondary clinical outcome will return a single data point (on a scale 
ranging from 0 zo 10) for each patient, which is not normally distributed data. 
Accordingly, we will report inter-quartile ranges of this variable. Comparison between 
groups will be performed using the nonparametric Mann-Whithney test.  
• 
As also outlined in Section 4.11.2. “Secondary clinical outcomes“ above, another 
secondary clinical outcome will be presence or absence of re-injury during a time period 
of six months after inclusion into the study. This secondary clinical outcome will return a 
single data point (“yes” or “no”) for each patient, which is not normally distributed data. 
Accordingly, we will report absolute and relative numbers of “yes” and “no” of this 
variable. Comparison between groups will be performed using Fisher’s exact test.  
• 
The probability value of less than 0.05 (p-value < 0.05) will be considered as statistically 
significant (Lang &Secic, 2006). 
• 
All calculations will be performed using GraphPad Prism (version 5.00 for Windows, 
GraphPad Software, San Diego, CA, USA). 
• 
All main conclusions of the study will be based on analyses of intention to treat rather 
than anaylses of treatment. Note that there are various available methods for handling 
missing data in clinical trials (European Medicines Agency, 2010). In case of missing 
data (i.e., in case a patient will withdraw or will be lost during the treatment or the follow-
up periods) we will determine together with the statistics experts at the Institute for 

25 
 
Medical Informatics, Biometry and Epidemiology (IBE) at the Ludwig-Maximilians-
University of Munich (Munich, Germany) the most appropriate method for performing 
analyses of intention to treat. After randomization and the first rESWT or placebo 
treatment, no patient will be replaced.  
• 
All efforts will be made to keep the proportion of patients lost to follow-up too small to 
affect the main findings of this study. 
• 
Patient-centered care throughout this study will ensure that no patients will be lost to 
follow-up, or the number of patients lost to follow-up will be so small that findings would 
be unaffected by their inclusion.    
• 
We will report actual probability values for all outcomes except where probability values 
less than 0.001 are found. 
• 
We will avoid any retrospective unplanned subgroup analysis and, thus, “data dredging”. 
 
5.1. Power analysis 
In the aforementioned studies by Reurink et al. (2014a) (outlined in detail in Fig. 5 above) 
and Bayer et al. (2017) (outlined in Fig. 6 above) the cumulative probability of resumptions of 
sports activity on day 35 after acute HMC injury Type 3b in professional soccer players 
(Reurink et al., 2014a) or recreational athletes (Bayer et al., 2017) was only respectively 
20% (Reurink et al., 2014a) or 5% (Bayer et al., 2017) after treatment with a rehabilitation 
program (Fig. 9). 
On this basis we performed a Power analysis for a percentage of 25% as well as (ii) for 
various other percentages (ranging between 10% and 99.9%) of patients with treatment 
success when treated with sham-rESWT + RP (n=20), accounting for a two sided-
confidence interval of 95% (and, thus, a type-1 error rate of 5%) and a percentage of 
patients with treatment success when treated with rESWT + RP (n=20) of 75%. Calculations 
were performed using the software, Open Source Epidemiologic Statistics for Public Health 
(www.openepi.com). The results are summarized in Table 3 (on the next page). 
Furthermore, we calculated the minimum sample size in both groups (rESWT + RP, 
sham-rESWT + RP) that would be necessary for detecting a difference in treatment success 
between the patients treated with rESWT + RP and the patients treated with sham-rESWT + 
RP accounting for a two sided-confidence interval of 95% and a power of 0.8. Calculations 
were also performed using the software, Open Source Epidemiologic Statistics for Public 
Health (www.openepi.com). The results are summarized in Table 4 (also on the next page). 
 

26 
 
Table 3. Power for the proposed RCT on rESWT + RP for acute HMC injury Type 3b, accounting for 
a two sided-confidence interval of 95% and a percentage of patients with treatment success when 
treated with rESWT + RP of 75%. *, calculated from data reported by Reurink et al. (2014a) and 
Bayer et al. (2017). 
Percent of patients treated 
with sham-rESWT + RP with 
treatment success [%] 
Power 
based 
on 
Normal 
approximation [%] 
Power 
based 
on 
Normal 
approximation 
with 
continuity correction [%] 
99.9 
67.4 
44.8 
90 
23.4 
10.3 
80 
5.3 
5.3 
70 
5.0 
5.0 
60 
16.9 
8.0 
50 
36.8 
23.6 
40 
61.7 
47.1 
30 
84.1 
73.2 
25* 
91.8 
84.2 
20 
96.6 
92.3 
10 
99.8 
99.3 
0 
100 
100 
 
Table 7. Sample size in the proposed RCT on rESWT + RP for acute HMC injury Type 3b, 
accounting for a two sided-confidence interval of 95% and a power of 0.8. The percentage of patients 
with treatment success when treated with rESWT + RP was set at 75 based on own experience 
(unpublished data). *, calculated from data reported by Reurink et al. (2014a) and Bayer et al. (2017). 
 
Sample size of both groups (rESWT + RP, sham-rESWT + RP) 
according to… 
Percent of patients 
with treatment 
success when treated 
with sham-rESWT + 
RP [%] 
Kelsey et al. (1996) 
Fleiss et al. (2003) 
Fleiss et al. (2003) 
with continuity 
correction 
99.9 
28 
27 
35 
90 
99 
98 
111 
80 
1095 
1094 
1134 
70 
1221 
1220 
1259 
60 
154 
152 
165 
50 
59 
58 
66 
40 
32 
31 
36 
30 
20 
19 
23 
25* 
16 
15 
19 
20 
13 
12 
16 
10 
10 
8 
11 
 
In summary, the proposed study would have a power of less than 0.8 in finding a 
difference in treatment success (possibility to return to play with criteria defined by van der 
Horst et al. [2016] fulfilled) between rESWT + RP and sham-rESWT + RP for treating acute 
HMC injury Type 3b if the percentage of patients with treatment success when treated with 

27 
 
sham-rESWT + RP would be higher than 30%. This, however, is not to be expected 
considering the aforementioned data by Reurink et al. (2014a) and Bayer et al. (2017) (c.f. 
Fig. 9). This reinforces the validity of the protocol of this study for testing efficacy and safety 
of rESWT + RP using the Swiss DolorClast for acute HMC injury Type 3b.  
 
6. Patient protection procedures 
6.1. Procedures in the event of Adverse Events 
• 
Potential unwanted side effects of rESWT may be petechial bruises of the skin at the 
location of application of rESWs and temporary numbness. These unwanted side effects 
normally vanish within one or two days. 
• 
Should any unwanted side effects persist for longer than usual, the investigators will treat 
these patients according to usual standard of care of the institution. 
 
6.2. Procedures in the event of Emergency 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to cope with medical emergencies during the study.  
 
6.3. Procedures in the event of Pregnancy 
A patient must be instructed to inform the Principal Investigator if she becomes pregnant 
during the study. As pregnancy is a contraindication for treatment with rEWST, the patient 
will be terminated from the study. The investigator will follow up the pregnancy until the 
outcome is known. 
 
6.4. Patient data protection 
Patients' anonymity will be maintained and confidentiality of records and documents that 
could identify patients will be protected. Patients will only be identified by their assigned 
identification number on all CRFs and other records and documents. The Principal 
Investigator will keep a Patient Identification List with complete identification information 
(name, address, contact number) on each patient. Documents not for submission to the 
Ethics Committee of the Universidad Abierta Interamericana (Buenos Aires, Argentina), such 
as patient’s written informed consent form, will be maintained by the Principal Investigator in 
strict confidence. 
Monitors and auditors from the Argentinean National Administration of Drugs, Food and 
Medical Technology (Administración Nacional de Medicamentos, Alimentos y Tecnología 
Médica (ANMAT), Avenida de Mayo 869 (C1084AAD), Ciudad Autónoma de Buenos Aires, 
Argentina) or other regulatory agencies, will be granted direct access to patients' medical 

28 
 
records and other study documents for verification of study procedures and data without 
violating the confidentiality of the patient. The patient should be informed that by signing a 
written informed consent form, the patient is authorizing such access. All electronic data 
processed at ANMAT will be identified by patient numbers only, thereby ensuring that 
patients' identity remains unknown to ANMAT. 
 
6.5. Insurance 
With respect to any liability directly or indirectly caused by the investigational products in 
connection with this study, the Principal Investigator assumes liability by law for possible 
injury to the patients. Every effort will be made to achieve that (i) the Principal Investigator 
and his staff will follow the instructions of the manufacturers of the Swiss DolorClast device 
in accordance with this protocol and any amendments thereto, and (ii) the Principal 
Investigator and his staff will in general performe this study in accordance with scientific 
practice and currently acceptable techniques and know how. 
 
6.6. Rescue medication/procedure 
rESWT and RP themselves do not require specific rescue medication / procedures.  
 
7. Study Termination/Suspension 
The Principal Investigator holds the right to suspend or terminate patient’s participation in 
this study in the event of deterioration of clinical condition at the discretion of the Principal 
Investigator.  
 
7.1 Patient Withdrawal & Drop-out 
Patients are free to withdraw from this study at any time for any reason. 
Patients may also be withdrawn from this study at any time at the discretion of 
the Principal Investigator. Should a patient withdraw or is withdrawn, every effort will be 
made to complete and report the observations as thoroughly as possible. Possible reasons 
for withdrawal will be documented. For e.g.:  
• 
adverse event(s), 
• 
abnormal laboratory values, 
• 
improvement of patient’s condition such that he/she no longer requires study treatment, 
• 
insufficient therapeutic effect, 
• 
protocol violation (eg. incorrectly enrolled or randomised), 
• 
patient requires use of unacceptable concomitant medication, 
• 
patient not compliant with protocol procedures, 

29 
 
• 
patient develops a condition during the study that violates the inclusion/exclusion criteria, 
• 
lost to follow-up, 
• 
death, and 
• 
any other reason, in the Principal Investigator's opinion, that would impede the patient’s 
participation in the study. 
 
7.2. Procedures for handling withdrawal 
Patients who withdraw or are withdrawn from this study will have the below information 
recorded: 
• 
The reason(s) for their withdrawal 
• 
Presence of any AEs and if so will be followed up by regular scheduled visits, telephone 
contact and correspondence until satisfactory clinical resolution of AEs is achieved. 
• 
At least one follow-up contact (scheduled visit, telephone contact, correspondence) for 
safety evaluation during the 30 days following the last session of study treatment. 
• 
In the event of pregnancy, the patient should be monitored until conclusion of the 
pregnancy and the outcome of pregnancy reported. 
 
7.3. Patient replacement policy 
After randomization and either the first rESWT treatment or the first sham-rESWT treatment, 
respectively, no patient will be replaced. 
 
7.4. Medications permitted or not permitted during this study 
No other adjunct specific treatment for acute HMC injury Type 3b is allowed during the 
duration of the study. Other medications not permitted are as explained in the Exclusion 
Criteria. Medications permitted are those not mentioned in the Exclusion Criteria. 
 
8. Ethical Consideration 
The researchers have conssidered the ethical issues that may arise with the conduct of this 
study. This trial will only be conducted after seeking approval from the Ethics Committee of 
the Universidad Abierta Interamericana (Buenos Aires, Argentina). 
 

30 
 
9. Patient Withdrawal & Compensation 
Participation in this study is completely voluntary. The participants will not be paid for joining 
this study nor will they be expected to pay to join this study. Participants are able to withdraw 
themselves from this study at any time without any reason and consequences to their follow-
up treatments. Standard routine care will still be provided to them. The researchers hold the 
right to use any data collected until a participant would withdraw from this study.  
 
10. Adverse Events  
10.1. Definitions 
 
Adverse event (AE) 
Any untoward medical occurrence in a patient administered an investigational product and 
which does not necessarily have a causal relationship with treatment. An AE can therefore 
be any unfavourable and unintended sign, symptom, laboratory observation or disease 
temporarily associated with the use of the investigational products, whether or not related to 
the investigational products. 
The following should be reported as AE: 
• 
Treatment emergent symptoms which include: 
o medical conditions or signs or symptoms that were absent before starting study 
treatments, and 
o medical conditions or signs or symptoms present before starting study treatments 
and worsen (increase severity or frequency) after starting study treatments. 
• 
Abnormal laboratory values or tests that induce clinical signs or symptoms or require 
therapy. 
• 
Any adverse experience even if no rESWs have been administered. 
Any doubtful event should be treated as an AE. 
 
Unexpected adverse event 
Any adverse event not reported in the safety section of the Investigator's Brochure or if the 
event is of greater frequency, specificity or severity. 
 
Serious adverse event (SAE) 
Any adverse event occurring that: 
• 
results in death, or 
• 
is a life threatening adverse experience defined as any adverse event that places the 
patient, in the view of the Principal Investigator, at immediate risk of death from the 

31 
 
reaction as it occurred (note that this does not include a reaction that, in case it would 
have occurred in a more severe form, would have caused death, and/or 
• 
results in patient hospitalisation or prolongation of existing hospitalisation. 
 
The following hospitalisations are not considered to be SAEs: 
• 
those planned before entry into the study, 
• 
elective treatment for a condition unrelated to study indication or study treatment, 
• 
those that occur on an emergency outpatient basis and do not result in admission 
(unless fulfilling other criteria in SAE definition), and 
• 
parts of normal treatment or monitoring of this study indication and are not associated 
with any deterioration in condition. 
 
Furthermore, the following events are not considered to be SAEs: 
• 
those that result in a significant or persistent disability or incapacity defined as any event 
that results in a substantial and/or permanent disruption of the patient’s ability to carry 
out normal life functions, 
• 
those that are a congenital anomaly or birth defect, 
• 
those that are any instance of overdose, either accidental or intentional (suspected or 
confirmed), and 
• 
any other important medical event, based upon appropriate medical judgement, that may 
jeopardise the patient or may require medical or surgical intervention to prevent or avert 
one of the outcomes listed above. 
 
10.2. Detecting and documenting AE 
Information about all AEs, whether volunteered by the patient, discovered by investigator 
questioning or detected through physical examination, laboratory test or other means, will be 
recorded on the Adverse Event Page of the CRF and followed up as appropriate. 
 
Each AE will be described by: 
 
a) Nature of AE 
This will be documented in terms of a medical diagnosis(es). When this is not possible, the 
AE will be documented in terms of signs and/or symptoms observed by the Principal 
Investigator or reported by the patient. 
 

32 
 
b) Duration of AE 
Start and end dates will be documented. 
 
c) Assessment of causality 
The Principal Investigator will attempt to explain each AE and assess its relationship, if any, 
to the study treatments. Causality should be assessed using the following definitions: 
 
• Very likely 
− 
The AE follows a reasonable temporal sequence from study treatments 
administration, 
− 
abates upon discontinuation of study treatments, and 
− 
reappears on repeated exposure (re-challenge). 
 
• Probable 
− 
The AE follows a reasonable temporal sequence from study treatments 
administration, 
− 
abates upon discontinuation of study treatment, and 
− 
cannot reasonably be explained by known characteristics of the patient’s clinical 
state. 
 
• Possible 
− 
The AE follows a reasonable temporal sequence from study treatments 
administration, 
− 
but could have been produced by the patient’s clinical state or other mode of therapy 
administered to the patient. 
 
• Doubtful 
− 
The temporal association between study treatments and AE is such that the study 
treatments are not likely to have any reasonable association with the observed event. 
 
• Very unlikely 
− 
The AE is definitely produced by the patient’s clinical state or other mode of therapy 
administered to the patient. 
 

33 
 
The degree of certainty with which an AE is attributed to study treatments or alternative 
cause like natural history of disease or concomitant treatment will be guided by the following 
considerations: 
• 
time relationship between treatment and occurrence of AE, 
• 
de-challenge and re-challenge information, if applicable, 
• 
dose response relationships, 
• 
lack of alternative explanations, i.e. no concomitant drug used and no other inter-current 
disease, 
• 
reaction of similar nature being previously observed with the study treatments, and  
• 
reaction having often been reported in the literature for the study treatments. 
 
d) Severity of AE 
• 
Mild: awareness of signs or symptoms, but they are easily tolerated. 
• 
Moderate: enough discomfort to cause interference with usual activity. 
• 
Severe: incapacitating, with inability to work or do usual activity. 
 
10.3. Reporting of SAE 
Information about all SAE will be recorded on the Serious Adverse Event Section of the 
CRF. All events documented in the SAE Form must be reported within 24 hours to ANMAT  
Any death or congenital abnormality, if brought to the attention of the Principal 
Investigator within six months after cessation of study treatments, whether considered 
treatment related or not, should be reported to ANMAT 
 
10.4. Treatment and follow up of AE 
Treatment of any AE is at the sole discretion of the Principal Investigator. Patients with AE 
will be followed up until the event has resolved or until the condition has stabilized. 
Otherwise appropriate medical care will be arranged for the patient. Abnormal tests will be 
repeated until they return to baseline levels or an adequate explanation of the abnormality 
has been found. 
 
In the Event of Pregnancy 
A female patient must be stopped from the treatments and immediately inform the Principal 
Investigator if she becomes pregnant during this study. The medical monitor will be 
contacted immediately to break the blind. The Principal Investigator will counsel the patient 
and discuss the risks of continuing with the pregnancy and the possible effects on the foetus. 
Monitoring of the patient will continue until conclusion of the pregnancy.  

34 
 
Pregnancies will be formally reported as SAEs. 
 
10.5. Safety update 
Electro Medical Systems will notify investigators of all AEs that are serious or unexpected 
and very likely, probably or possibly related to the investigational products. The Principal 
Investigator must retain such notice with the Investigator's Brochure and immediately submit 
a copy of this information to the Ethics Committee of the Universidad Abierta Interamericana 
(Buenos Aires, Argentina).. The Ethics Committee of the Universidad Abierta Interamericana 
(Buenos Aires, Argentina).will determine if the informed consent requires revision. The 
Principal Investigator should also comply with the procedures of the Ethics Committee of the 
Universidad Abierta Interamericana (Buenos Aires, Argentina). for reporting any other safety 
information. 
 
10.6. Potential unwanted side effects 
Potential unwanted side effects of rESWT may be petechial bruises of the skin at the 
location of application of rESWs and temporary numbness. These unwanted side effects 
normally vanish within one or two days. In case of petechial bruises of the skin at the 
location of application of rESWs they will be photographed and documented in the patient’s 
record. Temporary numbness will also be documented in the patient’s record. In the 
exceptional case that these unwanted side effects would really persist for longer than one or 
two days, (i) the corresponding patient would no longer be treated with rESWT or sham-
rESWT but would be kept in the study for follow-up analysis, (ii) petechial bruises would be 
treated with, e.g., ice until they disappear, and (iii) patients with persistent numbness would 
be presented to a neurologist.  
 
11. Statement on Confidentiality  
All data collected from participants will not have any personal identifiers. They will instead be 
given a specific research ID to respect the privacy and confidentiality of participants. The 
Principal Investigator will keep a separate Patient Identification List with complete 
identification information (name, address, contact number) and randomization number on 
each patient. All data collected will be stored in a computer that is protected by a password 
at the clinic of the Principal Investigator. Only investigators and study team members will 
have access to the study data. This limits the access to study data to the minimum number 
of individuals necessary for quality control, audit and analysis. Participants will not be given 
access to any personal information and study data collected during this study. 
 

35 
 
12. Data Protection 
All data collected will be stored in a computer that is protected by a password at the clinic of 
the Principal Investigator. Only investigators and study team members will have access to 
the study data. Study data will be stored for a duration of five years after completion of this 
study. All data will be destroyed thereafter. 
 
13. Publication Policy 
The investigators shall have the right to publish or permit the publication of any information 
or material relating to or arising from this study. All study data will be reported in a collective 
manner without any personal identifiers to protect the confidentiality of the participants.  
 
14. Conflict of Interest 
The rESWT equipment to be used in this study (Swiss DolorClast) is purchased from Electro 
Medical Systems (Nyon, Switzerland). 
Dr. Christoph Schmitz serves as paid consultant for and receives benefits from Electro 
Medical Systems. However, Electro Medical Systems will have no any role in patient 
recruitment, treatment of patients, data collection and analysis, decision to publish, or 
preparation of corresponding manuscripts. Furthermore, Dr. Christoph Schmitz will have no 
any role in patient recruitment, treatment of patients and data collection. 
No other potential conflicts of interest relevant to this study have been reported. 
 
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