A Prospective, Randomized, Controlled, Single Centre Trial to Assess the Efficacy and Safety of Radial Extracorporeal Shock Wave Therapy in Patients With Chronic Non-specific Low Back Pain
Phase: NA
Conditions: Low Back Pain
Sponsor: First Affiliated Hospital of Zhejiang University

1 
A prospective, randomized, controlled, single centre trial to 
assess the efficacy and safety of radial extracorporeal shock 
wave therapy in patients with chronic non-specific low back 
pain 
NCT03337607
October 20，2017

2 
INVESTIGATORS 
ROLE 
Prof. (Ms.) Zyiying FENG, MD 
Department of Pain Medicine  
First Affiliated Hospital of Zhejiang University 
79  Qingchun Road 
Hangzhou 
Zhejiang Province 
China, 310003 
E-mail: 13989881666@163.com
Principal Investigator 
Prof. 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 

3 
1. Background
Non-specific low back pain is defined as low back pain not attributable to a recognizable, known 
specific pathology (e.g., infection, tumour, osteoporosis, fracture, structural deformity, 
inflammatory disorder, radicular syndrome, or cauda equina syndrome) (Balagué et al., 2012). 
Non-specific low back pain is common and affects people of all ages (e.g., Carraggee, 2005; 
Bhangle et al., 2009; Maher et al., 2017). It is second only to the common cold as the most 
common affliction of mankind and is among the leading complaints bringing patients to 
physicians’ offices (e.g., Bhangle et al., 2009; Maher et al., 2017). The reported point 
prevalence of  non-specific low back pain is as high as 33 percent (e.g., Skovron et al., 1994; 
Maher et al., 2017), its one-year prevalence as high as 73 percent (e.g., Cassidy et al., 1998; 
Maher et al., 2017) and its lifetime prevalence exceeds 70% in most industrialized countries 
(Balagué et al., 2012), with an annual incidence of 15% to 20% in the United States of America 
(Bhangle et al., 2009). In physically active adults not seeking medical attention, the annual 
incidence of clinically significant non-specific low back pain (pain level, 4 or more on a 10-point 
scale) with functional impairment is approximately 10 to 15 percent (Carragee et al., 2005). In 
China, non-specific low back pain has become one of the leading causes of disability-adjusted 
life-years (DALYs) in 2010, next to cardiovascular diseases (stroke and ischaemic heart 
disease), cancers (lung and liver cancer) and depression (Yang et al., 2013). Zhang et al. 
(2015) reported the prevalence of non-specific low back pain as 41% in Chinese adolescents, 
and a close relationship between non-specific low back pain and self-reported academic 
pressure.  
An alarming increase in the prevalence of chronic non-specific low back pain has been 
observed in industrialized countries over the last years. For instance, in North Carolina (USA) 
the prevalence of chronic, impairing non-specific low back pain increased from 3.9 percent in 
1992 to 10.2 percent in 2006 (Freburger et al., 2009). Increases were seen in both men and 
women, and across all ages and racial and ethnic groups. In China, the years lived with 
disability (YLDs) showed a 44% increase from 1990 to 2010 (Yang et al., 2013). (Note that 
different definitions of chronicity of non-specific low back pain were proposed in the literature, 
mainly characterized by the duration of symptoms (c.f. Cedraschi et al., 1999), e.g.: (i) more 
than seven weeks (Spitzer et al., 1987); (ii) more than three months (Nachemson and Bigos, 
1984; Frymoyer, 1988; Frank, 1993); and (iii) at least half the days in a 12-month period in a 
single or in multiple episodes (Von Korff, 1994). In the proposed study chronicity will be defined 
as duration of symptoms of more than three months). 

4 
 
The social and economic impact of non-specific low back pain is substantial. It is the most 
frequent cause of disability for people under age 45. In 2005, the mean age- and sex-adjusted 
medical expenditure in the USA among respondents with spine problems was US$ 6,096 vs 
US$ 3,516 in those without spine problems, and it had increased by 65% (adjusted for inflation) 
from 1997 to 2005 (Martin et al., 2008). 
Management for patients with non-specific low back pain is challenged by the problems that 
most back pain has no recognizable cause (>85%), an underlying systemic disease is rare, and 
most episodes of back pain are unpreventable (e.g., Carraggee, 2005; Bhangle et al., 2009; 
Maher et al., 2017). 
Acute non-specific low back pain (lasting three to six weeks) usually resolves in several 
weeks, although recurrences are common and low-grade symptoms are often present years 
after an initial episode. Risk factors for the development of disabling chronic or persistent non-
specific low back pain (variously defined as lasting more than three months or more than six 
months) include preexisting psychological distress, disputed compensation issues, other types 
of chronic pain, and job dissatisfaction (Carragee et al., 2005; Hoy et al., 2010; Stubbs et al., 
2016). 
The goals of management for patients with non-specific low back pain are to (i) decrease 
the pain, (ii) restore mobility, (iii) hasten recovery so the patient can resume normal daily 
activities as soon as possible, (iv) prevent development of a chronic recurrent condition, and (v) 
restore and preserve physical and financial independence and comfort (Bhangle et al., 2009).  
In February 2017 the American College of Physicians issued a novel guideline for treating 
nonradicular low back pain (Qaseem et al., 2017), as follows (quoted from Qaseem et al., 
2017): 
 
Recommendation 1: given that most patients with acute or subacute low back pain improve 
over time regardless of treatment, clinicians and patients should select nonpharmacologic 
treatment with superficial heat (moderate-quality evidence), massage, acupuncture, or 
spinal manipulation (low-quality evidence). If pharmacologic treatment is desired, clinicians 
and patients should select nonsteroidal anti-inflammatory drugs or skeletal muscle relaxants 
(moderate-quality evidence). (Grade: strong recommendation). 
 
Recommendation 2: for patients with chronic low back pain, clinicians and patients should 
initially select nonpharmacologic treatment with exercise, multidisciplinary rehabilitation, 
acupuncture, mindfulness-based stress reduction (moderate-quality evidence), tai chi, yoga, 
motor control exercise, progressive relaxation, electromyography biofeedback, low-level 

5 
laser therapy, operant therapy, cognitive behavioral therapy, or spinal manipulation (low-
quality evidence). (Grade: strong recommendation). 

Recommendation 3: in patients with chronic low back pain who have had an inadequate
response to nonpharmacologic therapy, clinicians and patients should consider
pharmacologic treatment with nonsteroidal anti-inflammatory drugs as first-line therapy, or
tramadol or duloxetine as second-line therapy. Clinicians should only consider opioids as an
option in patients who have failed the aforementioned treatments and only if the potential
benefits outweigh the risks for individual patients and after a discussion of known risks and
realistic benefits with patients. (Grade: weak recommendation, moderate-quality evidence).
Unfortunately, few if any treatments have been proven effective for non-specific low back pain in 
meta-analyses, including limited bed rest (Dahm et al., 2010), physical activity and exercise 
(Geneen et al., 2017), back schools (Poquet et al., 2016), traction (Wegner et al., 2013), 
massage (Furlan et al., 2015), chiropractic (Rubinstein et al., 2011; 2012), radiofrequency 
denervation (Mass et al., 2015), paracetamol (Saragiotto et al., 2016), opioids (Chaparro et al., 
2013) and, ultimately, surgery (in cases of cauda equina syndrome, infections, tumors and 
fractures compressing the spinal cord, mechanical instability of the back, and, perhaps, 
intractable pain with a positive straight-leg-raising test and no response to conservative therapy) 
(Lawrence et al., 2008; Globe et al., 2008; Bhangle et al., 2009; Machado et al., 2009). Earlier 
studies demonstrated that muscle relaxants are effective in the management of non-specific low 
back pain, but the adverse effects require that they be used with caution (van Tulder et al., 
2003). Accordingly, the aforementioned guideline by the American College of Physicians is only 
based on low- and moderate-quality evidence (see also Chou et al., 2016). 
This highly unsatisfying situation is also reflected by the randomized controlled clinical trials 
on non-specific low back pain listed in the Physiotherapy Evidence Database (PEDro; 
https://www.pedro.org.au/simplified-chinese/ or https://www.pedro.org.au/traditional-chinese/) 
(as of May 09, 2017). The PEDro database is a freely available database of over 36,000 
randomized controlled trials (RCTs), systematic reviews and clinical practice guidelines in 
physical and rehabilitation medicine. For each RCT, review or guideline, the PEDro database 
provides the citation details, the abstract, and a link to the full text, where possible. All RCTs 
listed in the PEDro database are independently assessed for quality (the assessment criteria 
are summarized in Table 1). All but two of the PEDro scale items are based on the Delphi list 
(Verhagen et al., 1998). PEDro is currently the largest independent database on topics related 
to physical and rehabilitation medicine, and is often used by investigators in Norway, Australia, 
and New Zealand; less so by other European and North American investigators. Non-specific 

6 
 
low back pain was addressed in more than 1800 RCTs listed in the PEDro database. Table 2 
summarized those RCTs listed in the PEDro database that received 10 or 9 points on the 
PEDro quality scale (as of May 09, 2017). It becomes obvious that these studies do not provide 
the basis for a conclusive recommendation how to treat non-specific low back pain. 
Table 1. Assessment criteria of the PEDro database (modified from www.pedro.org.au). 
Part 1: criteria for inclusion of clinical trials in PEDro (all criteria must be fulfilled) 
 The trial must involve comparison of at least two interventions. One of these interventions could be a no treatment control, or a sham 
treatment. 
 At least one of the interventions being evaluated must be currently part of physiotherapy practice or could become part of 
physiotherapy practice. However, the study need not be carried out by physiotherapists.  
 The interventions should be applied to subjects who are representative (or who are intended to be representative) of those to whom 
the intervention might be applied in the course of physiotherapy practice. 
 The trial should involve random allocation or intended-to-be-random allocation of subjects to interventions.  
 The paper must be a full paper (not an abstract) in a peer-reviewed journal. 
Part 2: assessment criteria of clinical trials included in PEDro 
No. 
Assessment criterion 
1* 
Eligibility criteria were specified. 
2 
Subjects were randomly allocated to groups. 
3 
Allocation was concealed. 
4 
The groups were similar at baseline regarding the most important prognostic indicators. 
5 
There was blinding of all subjects. 
6 
There was blinding of all therapists who administered the therapy. 
7 
There was blinding of all assessors who measured at least one key outcome. 
8 
Measures of at least one key outcome were obtained from more than 85% of the subjects initially allocated to groups. 
9 
All subjects for whom outcome measures were available received the treatment or control condition as allocated or, where this 
was not the case, data for at least one key outcome was analysed by “intention to treat”. 
10 
The results of between-group statistical comparisons are reported for at least one key outcome. 
11 
The study provides both point measures and measures of variability for at least one key outcome. 
* This criterion influences external validity, but not the internal or statistical validity of the trial. It has been included in the PEDro scale so that 
all items of the Delphi scale9 are represented on the PEDro scale. This item is not used to calculate the PEDro score. 
 

7 
 
Table 2. All randomized controlled trials on non-specific low back pain listed in the PEDro database 
(www.pedro.org.au) (as of May 09, 2017) that received 10 or 9 points on the PEDro quality scale shown 
in Table 1. 
P 
Study 
T 
O 
Main outcome 
10 
Glazov et al. (2014) 
C 
-- 
Infrared laser acupuncture not superior to placebo treatment 
10 
Konstantinovic et al. (2010) 
A 
+ 
Nimesulide 200 mg/day and low-level laser therapy superior to nimesulide 200 
mg/day and placebo LLLT or nimesulide alone 
9 
Arguisuelas et al. (2016) 
C 
++ 
Myofascial Release protocol (MFR) superior to sham MFR 
9 
Corrêa et al. (2016) 
C 
-- 
Interferential current (IFC) not superior to placebo IFC 
9 
Panagopoulos et al. (2015) 
* 
- 
Standard physiotherapy plus visceral manipulation not superior to standard 
physiotherapy alone 
9 
Hsieh et al. (2014) 
C 
- 
Hotpack plus short-term 890-nm light therapy not superior to hotpack plus 
placebo light therapy 
9 
Parreira et al. (2014) 
C 
-- 
Kinesio taping with 10 to 15% tension applied in flexion to create skin 
convolutions in neutral not superior to kinesio taping without tension 
9 
Vas et al. (2014) 
C 
++ 
True auriculopressure superior to placebo auriculopressure 
9 
Licciardone et al. (2013a) 
C 
++ 
Osteopathic manual treatment (OMT) superior to sham OMT 
9 
Pach et al. (2013) 
C 
- 
Individualized acupuncture not superior to standardized acupuncture 
9 
Licciardone et al. (2013b) 
C 
- 
Osteopathic manual treatment not superior to ultrasound therapy 
9 
Sharpe et al. (2012) 
A+C 
++ 
Attention bias modification (ABM) superior to sham ABM 
9 
Castro-Sánchez et al. (2012) 
C 
-- 
Kinesio taping over the lumbar spine not superior to sham taping 
 
Chen et al. (2012) 
C 
++ 
Functional fascial taping superior to placebo taping 
9 
Wang et al. (2012) 
C 
+ 
Core stability training superior to conventional exercise 
9 
Buchmuller et al. (2012) 
C 
-- 
TENS not superior to sham TENS 
9 
Costa et al. (2009) 
C 
-- 
Motor control exercise not superior to placebo (detuned ultrasound therapy and 
detuned short-wave therapy) 
9 
Glazov et al. (2009) 
C 
-- 
Infrared laser acupuncture not superior to placebo treatment 
9 
Koopman et al. (2009) 
C 
-- 
Microcurrent therapy not superior to placebo 
9 
Hancock et al. (2008) 
A 
- 
Spinal manipulative therapy (SMT) plus paracetamol plus advice not superior 
to sham SMT plus paracetamol plus advice 
9 
Kennedy et al. (2008) 
A 
-- 
Acupuncture not superior to placebo 
9 
Hancock et al. (2007) 
A 
-- 
Diclofenac 50 mg twice daily (D) and spinal manipulative therapy (SMT) not 
superior to D plus placebo SMT, placebo D and SMT or double placebo 
9 
Pengel et al. (2007) 
SA 
++ 
Physiotherapist-directed exercise and advice superior to placebo 
9 
Brinkhaus et al. (2006) 
C 
++ 
Acupuncture superior to placebo 
9 
Santilli et al. (2006) 
A 
++ 
Active manipulations superior to simulated manipulations 
9 
Brizzi et al. (2004) 
C 
++ 
Hydrofor applications of a mixture containing both NSAIDs and muscle 
relaxants superior to Hydrofor applications of a drug-free solution 
9 
Kovacs et al. (2003) 
C 
+ 
Medium-firm mattresses superior to firm mattresses 
9 
Beurskens et al. (1997) 
C 
-- 
Traction not superior to placebo 
9 
Hadler et al. (1987) 
A 
+ 
Spinal manipulation superior to spinal mobilization without the rotational 
forces and leverage required to move facet joints. 
P, points on the PEDro quality scale; T, type of study; A, acute non-specific low back pain; SA, subacute non-specific low back pain; C, chronic 
non-specific low back pain; *, new episode of non-specific low back pain (defined as an episode which was preceded by a period of at least one 
month without non-specific low back pain); O, outcome; ++ investigated therapy statistically significantly (p<0.05) superior to placebo treatment; 
+, investigated therapy superior to alternative therapy (p<0.05); -, investigated therapy not superior to alternative therapy (p<0.05); --, 
investigated therapy not superior to placebo treatment (p<0.05). 
 
 
Recently extracorporeal shock wave therapy (ESWT) was introduced into the management of 
non-specific low back pain (Nedelka et al., 2014; Lee et al., 2014; Han et al., 2015; Moon et al., 
2016). The use of extracorporeal shock waves (ESWs) 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 

8 
 
shock waves are also used as a treatment for various musculoskeletal conditions such as 
calcifying tendinopathy of the shoulder, eoicondylitis, Achilles tendinopathy and plantar 
fasciopathy (e.g., Speed, 2014; Schmitz et al., 2015), and is commonly referred to as 
‘extracorporeal shock wave therapy’, or ‘ESWT’ to differentiate from ESWL (Speed, 2014). By 
means of a systematic review of data derived from the PEDro database Schmitz et al. (2015) 
demonstrated that ESWT is effective and safe, and for the aforementioned conditions RCTs on 
ESWT were the predominant type of RCT listed in the PEDro database and/or obtained the 
highest PEDro scores among all investigated treatment modalities.  
There are three different types of ESWs used in ESWT for musculoskeletal conditions, 
focused, defocused and radial (Fig. 1 below), and several modes of operation of focused, 
defocused and radial extracorporeal shock wave generators (Fig. 2 below). Focused, defocused 
and radial ESWs are single acoustic impulses with an initial high positive peak pressure 
between 10 and 100 megapascals (MPa) reached in less than one microsecond (µs) (Rompe et 
al., 2007). The positive pressure amplitude is followed by a low tensile amplitude of a few 
microseconds duration that can generate cavitation (Chitnis and Cleveland, 2005; Schmitz et 
al., 2013; Angstman et al., 2015; Császár et al., 2015). They are further characterized by a short 
life cycle of approximately 10-20 µs and a broad frequency spectrum. Focused ESWs differ from 
radial ESWs in the penetration depth into the tissue, some physical characteristics, and the 
technique for generating them (Ogden et al., 2001; Schmitz et al., 2013; Császár et al., 2015). 
However, without going into detail, there is no scientific evidence in favor of either radial ESWT 
(rESWT) or focused ESWT (fESWT) with respect to treatment outcome, and no scientific 
evidence that a certain fESWT technology is superior to the other technologies (Schmitz et al., 
2015). 
Several molecular and cellular mechanisms were reported on how ESWs might mediate 
their pain-relieving action. Specifically, exposure of the distal femur of rabbits to focused ESWs 
decreased the amount of Substance P (SP) in the periosteum (Maier et al., 2003) and 
diminished the number of neurons immunoreactive for substance P in dorsal root ganglia L5 
(Hausdorf et al., 2008). Furthermore, application of shock waves to rat skin decreased calcitonin 
gene-related peptide (CGRP) immunoreactivity in dorsal root ganglion neurons (Takahashi et 
al., 2003). Substance P is concentrated in unmyelinated C-fibers (responsible for throbbing, 
chronic pain; Kandel et al., 2000) and a subpopulation of slowly conducting, lightly myelinated 
A- nerve fibers, and is released at central and peripheral terminals of sensory nociceptive 
neurons after stimulation (Keen et al., 1982; Malcangio and Bowery, 1999; Snijdelaar et al., 
2000). CGRP is a marker of sensory neurons typically involved with pain perception and was 

9 
 
immunohistochemically co-localized with substance P in capsaicin-sensitive axons (Gibbins et 
al., 1985). Activation of peripheral small diameter sensory neurons by local depolarization, 
axonal reflexes, or dorsal root reflexes releases substance P and CGRP. Both substances then 
act on target cells in the periphery such as mast cells, immune cells and vascular smooth 
muscle cells, thus producing inflammation. This phenomenon is called neurogenic inflammation, 
and is an inflammatory symptom that results from the release of substances from primary 
sensory nerve terminals (Holzer, 1988; Richardson and Vasko, 2002). Evidence has emerged 
that chronic inflammation contributes to the etiology of pain in insertion tendinopathies such as 
tennis elbow and chronic plantar fasciitis (LeMelle et al., 1990; Schepsis et al., 1991; Roetert et 
al., 1995). Furthermore, Uchio et al. (2002) found that SP (as well as interleukin 1 alpha and 
transforming growth factor beta-1) are involved in the pathogenesis of tennis elbow, without 
apparent infiltration of inflammatory cells. Moreover, depletion of substance P was repeatedly 
shown to reduce experimentally induced inflammation of paws and joints in laboratory animals 
(Lam and Ferrell, 1991; Cruwys et al., 1995; Garrett et al., 1997). It is therefore reasonable to 
hypothesize that reduction of SP and CGRP in the target tissue (Maier et al., 2003; Takahashi 
et al., 2003) in conjunction with reduced synthesis of this molecule in dorsal root ganglia cells 
(Hausdorf et al., 2008) plays an important role in ESWT-mediated long-term analgesia in the 
treatment of musculosceletal conditions.  
With respect to non-specific low back pain it is important to note that in rats, the presence of 
SP and CGRP immunoreactive nerve fibers was demonstrated in the lumber facet joints (Ohtori 
et al., 2000). Furthermore, SP immunoreactive fibers were found more extensively in lumbar 
intervertebral discs from patients with discogenic low back pain than in normal control discs, 
together with the formation of a zone of vascularized granulation tissue from the nucleus 
pulposus to the outer part of the annulus fibrosus along the edges of the fissures (Peng et al., 
2005). These findings suggested that the zone of granulation tissue with extensive innervation 
along the tears in the posterior part of the painful disc may be responsible for causing the pain 
of discography and of discogenic low back pain (Peng et al., 2005). Accordingly, ESWT could 
be of great significance in the treatment of persistent non-specific low back pain. 
It is critical to note that the energy signature of ESWT devices fundamentally differs from the 
energy signature of certain “mechanical shockwave devices” utilized for spinal manipulative 
therapy (Liebscher et al., 2014). Furthermore, ESWT must not be confused with treatments that 
apply vibration at a low frequency (10, 50, 100, or 250 Hz), causing an oscillatory pressure 
(described as shock wave therapy by Seco et al., 2011). Seco et al’s (2011) statement that, 
strictly speaking, both shock waves and ultrasound could be referred to as “vibrotherapy”, 

10 
 
because both use vibration with a therapeutic goal, does not consider fundamental differences 
between the energy signatur of ESWT devices and the energy signature of vibrating massage 
devices, as shown by Angstman et al. (2014).  
 
Fig. 1 (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. 2). 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 skin. The 
projectile generates stress waves in the applicator that transmit pressure waves into tissue. The point of 
highest pressure is found at the 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 flux 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). 
 
 

11 
 
 
Fig. 2 (modified from Schmitz et al., 2015). Schematic representation of the mode of operation of focused 
(A-C), defocused (D) and radial I 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 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 

12 
 
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). I 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). 
 
 
The studies on ESWT for non-specific low back pain performed so far (summarized in Table 3) 
have  only established very limited evidence of efficacy and safety of ESWT for non-specific low 
back pain. This is due to low sample size, lack of power analyses, lack of reporting critical 
information such as the follow-up interval, and the fact that only one RCT on this indication was 
performed so far. 
 

13 
 
Table 3. Details of all studies on ESWT for non-specific low back pain listed in PubMed as of May 09, 
2017. 
Study 
Nedelka et al. (2014) 
Lee et al. (2014) 
Han et al. (2015) 
Moon et al. (2016) 
Diagnosis 
Unilateral chronic 
lumbar facet pain 
Chronic low back pain 
Chronic low back pain 
Sacroiliac joint pain 
Type of study 
Pilot retrospective 
study 
Cohort study (no 
randomization) 
Cohort study (no 
randomization) 
Randomized 
controlled trial 
Power analysis 
Not reported 
Not reported 
Not reported 
Not reported 
ESWT: 
 
 
 
 
No. of patients 
21 
13 
15 
15 
Device 
Duolith, radial part 
(Storz Medical, 
Tägerwillen, 
Switzerland) 
JEST-2000 (Joeun 
Medical, Daejeon, 
Korea 
VITERA (Comed, 
Korea) 
Unknown 
Type of ESWT 
Radial 
Radial 
Focused, 
electrohydraulic 
 
Applicator 
15-mm titanium DPI 
applicator 
17-mm head 
17 mm head 
 
No. of ESWT sessions 
5 
12 
12 
1 
Interval between ESWT sessions 
[days] 
7 
3.5 (two sessions per 
week) 
3.5 (two sessions per 
week) 
N/a 
No. of shock waves per ESWT 
session 
3000 
2000 
1000 
2000 
Bar / EFD of shock waves 
3.5 /0.12 mJ/mm2 
0.10 mJ/mm2 
0.01-0.16 mJ/mm2 
Unknown 
Frequency of shock waves [Hz] 
Not provided 
7 
7 
Unknown 
Additional treatment 
N/a 
Exercise program 
N/a 
N/a 
Alternative treatment 1 
 
 
 
 
No. of patients 
20 
15 
15 
15 
Procedure 
C: single injection of 6 
ml 1% trimecaine and 
7 mg of 
betamethazone 
CPT: Conservative 
physical therapy, 
comprising 
hyperthermia using 
hot packs, ultrasound 
and TENS (details not 
provided) 
CPT: Conservative 
physical therapy, 
comprising 
hyperthermia using 
hot packs (20 min), 
ultrasound (5 min) and 
TENS (15 min) 
Sham ESWT 
Alternative treatment 2 
 
N/a 
N/a 
N/a 
No. of patients 
20 
 
 
 
Procedure 
RMBN: 
Radiofrequency 
Medial Branch 
Neurotomy  
 
 
 
Follow-up interval 
M2, M6 and M12 
Not provided 
Not provided 
W1 and W4 
Investigated variables 
Pain (VAS score), 
Oswestry Disability 
Index 
Pain (VAS score), 
dynamic balance 
ability 
Pain (VAS score), 
Oswestry Disability 
Index, Beck 
depression index 
Pain (VAS score), 
Oswestry Disability 
Index, 
Definition of treatment success 
Not provided 
Not provided 
Not provided 
Not provided 
VAS at baseline (ESWT) 
Not provided 
7.2 ± 0.8 (SD? SEM?) 
7.0 ± 0.76 (SD? 
SEM?) 
6.42 ± ? 
VAS at follow-up (ESWT) 
Not provided 
4.5 ± 1.1 (SD? SEM?) 
3.6 ± 1.1 (SD? SEM?) 
3.64 ± ? 
Outcome 
RMBN > rESWT > C 
ESWT > CPT 
ESWT > CPT 
ESWT > Sham ESWT 
EFD, energy flux density; M, month, W, week. 
 
 
Accordingly, further research is needed to support the use of ESWT for non-specific low back 
pain. Taking into account (i) the well-known molecular and cellular mechanisms of action of 
ESWT in pain relief (outlined in detail above), (ii) the proven efficacy and safety of rESWT for 
treating musculoskeletal conditions (Schmitz et al., 2015), and (iii) the fact that the rESWT 

14 
 
device Swiss DolorClast (Electro Medical Systems, Nyon, Switzerland) has become by far the 
best investigated ESWT technology in the field of Evidence Based Medicine (Table 4), it is 
reasonable to hypothesize that treatment of non-specific low back pain with the Swiss 
DolorClast is not only effective and safe but will get widespread acceptance and clinical use as 
soon as effectiveness and safety will be demonstrated in a randomized controlled trial. This is 
the purpose of the proposed project.  
 
Table 4. Devices used in all studies on ESWT listed in the PEDro database as of January 01, 2017 (note 
that in some studies the name of the used device was not mentioned). 
Device 
T 
Manufacturer 
No. of studies 
DolorClast 
R 
Electro Medical Systems (Nyon, Switzerland) 
25 
Epos Ultra 
F-EH 
Dornier MedTech (Wessling, Germany) 
11 
Sonocur 
F-EM 
Siemens (Erlangen, Germany) 
11 
Minilith SL 1 
F-EM 
Storz Medical (Tägerwillen, Switzerland) 
10 
Modulith SLK 
F-EM 
Storz Medical 
9 
Ossatron 
F-EH 
HMT (Kreuzlingen, Switzerland) 
7 
Osteostar 
F-EM 
Siemens 
7 
Duolith SD1 focused 
F-EM 
Storz Medical 
5 
Orthospec 
F-EH 
Medispec (Yehud, Israel) 
4 
Physio SW Therapy 
R 
Pagani (Paderno Dugnano, Italy) 
3 
BTL-5000 
R 
BTL (Prague, Chech Republic) 
2 
EvoTron 
F-EH 
HMT 
2 
JEST-2000 
R 
Joeunmedical (Daejeon, Korea) 
2 
Masterpuls MP 100 
R 
Storz Medical 
2 
Orthima 
F-EM 
Direx (Petah Tikva, Israel) 
2 
Piezoson 100 
F-PE 
Richard Wolf (Knittlingen, Germany) 
2 
Piezoson 300 
F-PE 
Richard Wolf 
2 
Piezowave 
F-PE 
Richard Wolf 
2 
Stonelith V5 
 
PCK (Ankara, Turkey) 
2 
Compact 
F-EM 
Dornier 
1 
Duolith SD1 radial 
R 
Storz Medical 
1 
Lithostar 
F-EM 
Siemens 
1 
MedTech Epos 
F-EM 
Dornier 
1 
MFL 5000 
F-EH 
Phillips (Eindhoven, Netherlands) 
1 
Masterpuls MP 200 
R 
Storz Medical 
1 
Orthowave 
F-EH 
MTS 
1 
Piezolith 2501 
F-PE 
Richard Wolf 
1 
ShockMaster 
R 
Gymna (Bilzen, Belgium) 
1 
R, radial; F-EH, focused-electrohydraulic; F-EM, focused-electromagnetic; F-PE, focused-piezoelectric. 
 
 
 

15 
 
2. Hypothesis 
Based on the results of the systematic literature search outlined above it is hypothesized here 
that rESWT using the Swiss DolorClast is effective and safe in treatment of non-specific low 
back pain. 
Because the majority of patients with non-specific low back pain presenting to the Department 
of Pain Medicine at the First Affiliated Hospital of Zhejiang University, Hangzhou are suffering 
from chronic non-specific low back pain, the proposed project will be restricted to the treatment 
of chronic non-specific low back pain. 
The standard therapy of chronic non-specific low back pain at the Department of Pain 
Medicine at the First Affiliated Hospital of Zhejiang University consists of the non-steroidal anti-
inflammatory drug Celecoxib (200 mg per day) and the antispasmodic drug Eperisome (50 mg  
per day) (henceforth abbreviated to as C-E drug therapy). Considering the established evidence 
of superiority of combination therapies of rESWT performed with the Swiss DolorClast and other 
treatment modalities (such as the combination of rESWT and plantar fascia-specific stretching in 
case of chronic plantar fasciopathy; Rompe et al., 2015; and the combination of rESWT and 
eccentric loading in case of chronic midportion Achilles tendinopathy; Rompe et al., 2009) the 
proposed study will specifically test the hypothesis that rESWT performed with the Swiss 
DolorClast in combination with C-E drug therapy is statistically significantly more effective than 
either rESWT or C-E drug therapy alone in the treatment of chronic non-specific low back pain. 
 
3. Study Objectives 
3.1. General Objective 
1) To determine the efficacy and safety of rESWT in combination with C-E drug therapy in 
treatment of chronic non-specific low back pain. 
 
3.2. Specific Objectives 
1) To determine the efficacy of combined rESWT /C-E drug therapy, rESWT alone and C-E 
drug therapy alone in treatment of chronic non-specific low back pain. 
2) To evaluate patient’s pain score, Oswestry Disability Index score, Clinical Global Impression 
score, and anxiety and depression score (including GAD-7, PHQ-9, PHQ-15 and pain 
disaster score) at baseline and at two weeks, four weeks, 12 weeks and 24 weeks after 
baseline. 

16 
 
3) To evaluate patient’s lumbar curvature using lateral X-ray radiographs at baseline and at 12 
weeks after baseline. 
4) To evaluate patient’s cross-sectional area of the paravertebrate muscles using MRI at 
baseline and at 12 weeks after baseline. 
5) To evaluate safety of rESWT in treatment of chronic non-specific low back pain. 
 
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 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 for chronic soft tissue wounds 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 
for chronic soft tissue wounds considers all these aspects, except of the fact that the care 
providers will not be blinded. 
3. The PEDro scale (Blobaum, 2006) (outlined in detail in Section 1 above) - 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, 

17 
 
between-group statistical comparisons, and reports of both point estimates and measures of 
variability.  The design of the proposed study on rESWT for chronic non-specific low back 
pain considers all these aspects, except of the fact that patients and therapists will not be 
blinded (which is in principle not possible when comparing combined ESWT /C-E drug 
therapy with ESWT alone and C-E drug therapy alone). 
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 for chronic non-specific low back pain 
was developed according to the criteria set out by Downs and Black (1998). The proposed study 
on rESWT for chronic non-specific low back pain will achieve a very high rating on the 
assessment by Downs and Black (1998). 
 
4.2. Study design  
 
Randomized controlled trial (RCT), no blinding of patients and therapists applying the 
treatments (the rationale for this is provided in Section Blinding of therapists and assessors 
below, there will be blinding of evaluators/assessors. 
 

18 
 
4.3. Schematic diagram of study design: 
 
 
 
 
4.4. Inclusion criteria 
 
Adults (both male and female) with non-specific low back pain for more than three months. 
 
Age range: between 18 and 80 years. 
 
Willingness of the patient to participate in the study, and written informed consent signed 
and personally dated by the patient. 
 
Chronic non-specific low back pain clinically diagnosed as repeated lumbar sourness and 
swelling pain or a chronic progressive process, accompanied by (i) X-ray examination to 
exclude lumbar vertebrate fractures, spondylolysis, spondylolisthesis and severe 
osteoporosis, and/or (ii) MRI with normal signal or low nucleus pulposus signal. 
 
No contraindications for rESWT. 
 
4.5. Exclusion criteria 
 
Children and teenagers below the age of 18.  

19 
 
 
Elderly aged >80 years old 
 
No willingness of the patient to participate in the study, and/or written informed consent not 
signed and not personally dated by the patient. 
 
Previous spinal fracture or spinal surgery. 
 
Protrusion of a lumbar intervertebral disk, ankylosing spondylitis, scoliosis, lumbar 
spondylolisthesis and lumbar spondylolysis. 
 
Systemic disorders and psychiatric disorders. 
 
Contraindications of C-E drug treatment, including: 
o treatment of patients allergy to celecoxib, eprisome or sulfonamides, 
o patients with gastrointestinal bleeding or bleeding history, 
o patients with renal dysfunction, 
o patients with severe heart failure, and 
o lactating women. 
 
Contraindications of rESWT: 
o treatment of pregnant patients, 
o treatment of patients with blood-clotting disorders (including local thrombosis), 
o treatment of patients treated with oral anticoagulations, 
o treatment of patients with local tumors,  
o treatment of patients with local bacterial and/or viral infections (including lumbar 
vertebral tuberculosis), and 
o treatment of patients treated with local corticosteroid applications in the time period of six 
weeks before the first rESWT session (if applicable). 
 
Participation in any other clinical trial in the time period of 12 weeks before potential 
inclusion in the proposed study. 
 
4.6. Groups and treatments 
Patients in the rESWT plus C-E drugs group will receive the below:  
 
Celecoxib  (1  200 mg per day for moderate pain [NRS 4-6; c.f. Section 4.11.2 below] or 2 
 200 mg per day [NRS 7-10]) for four weeks. 
 
Eperisome (3  50 mg per day) for four weeks. 
 
Four rESWT sessions with the Swiss Dolorclast and the EvoBlue handpiece, as follows: 
o One rESWT session per week. 

20 
 
o 4 × 1000 rESWs per session (1000 rESWs each applied to the left and the right 
paravertebrate muscles above L3 to S1 using the 36-mm applicator, plus 1000 rESWs 
each applied to the left and the right sacroiliacal joint using the 15-mm convex 
applicator, in prone position of the patient. 
o rESWs applied at 15 Hz 
o Air pressure of the Swiss DolorClast (and, thus, the energy flux density of the applied 
rESWs) gradually increased during the first 200 rESWs each until the maximum 
dyscomfort the patient can tolerate will be reached, followed by 800 rESWs at this air 
pressure / energy flux density. 
o No application of local anaesthetics (Rompe et al., 2005; Schmitz et al., 2013; 2015). 
 
Patients in the rESWT group will receive the below:  
 
Four rESWT sessions with the Swiss Dolorclast and the EvoBlue handpiece as described 
above for the rESWT plus C-E drugs group. 
 
Patients in the C-E drugs group will receive the below:  
 
Celecoxib and Eperisome as described above for the rESWT plus C-E drugs group. 
 
In addition, all patients will be advised to perform simplified, safe core stability training and 
flexion relaxation training at home, which is mainly based on the contraction of the lumbar 
muscles, under the guidance of a unified rehabilitation training video (two training sessions per 
week; each training session lasting for approximately 20 minutes; training for 24 weeks). 
 
4.7. Recruitment of patients 
 
Patients in the rESWT plus C-E drugs group, the rESWT group and the C-E drugs group will 
be selected from the same hospital (Department of Pain Medicine at the First Affiliated 
Hospital of Zhejiang University), and will be recruited over the same period of time.  
 
Recruitment of patients will start immediately after approval of the study by the Medical 
Research and Ethics Committee of the First Affiliated Hospital of Zhejiang University. 
 
Patients will be recruited during regular visits to the Department of Pain Medicine at the First 
Affiliated Hospital of Zhejiang University. 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 
the proposed study until the total number of patients (rESWT plus C-E drugs group: n=50; 
rESWT group: n=50; C-E drugs group: n=50) will be recruited. Accordingly, the subjects that 

21 
 
will be prepared to participate in the proposed 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 
hospitals in China most of the source population would attend if seeking treatment of chronic 
non-specific low back pain. 
 
4.8. Informed Consent Process 
Should patients agree to be part of the proposed study, they will be guided through the informed 
consent process first, as described here. The Informed Consent Process will be done at the 
Department of Pain Medicine at the First Affiliated Hospital of Zhejiang University. 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. 
 
4.9. 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 plus C-E drugs (n=50), rESWT alone (n=50) or C-E 
drugs alone (n=50), respectively (sample size is addressed in Section 5.1. Power analysis 
below). 
 
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. Subjects will be 
randomized to either treatment (rESWT plus C-E drugs, rESWT alone or C-E drugs alone), 
with use of the method of randomly permuted blocks. The randomization scheme will be 
generated with the use of the website www.randomization.com. One hundred and fifty 
patients will be randomized into five blocks. A medical assistant at the Department of Pain 
Medicine at the First Affiliated Hospital of Zhejiang University 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. 
 
The randomized intervention assignment as outlined above will be concealed from both 
patients and health care staff until recruitment will be complete and irrevocable. 

22 
 
 
Neither patients nor therapists will be blinded in the proposed study. The therapist will be the 
person who will administer rEWST to the patient. 
 
The assessor will be blinded in the proposed study. The assessor is the person who will 
assess treatment success during follow up.  
 
4.10. Study treatment and visits 
Study visits of patients in the rESWT plus C-E drugs group and the rESWT group will take place 
at 0, 1, 2 and 3 weeks for administering rESWT. A single study visit of patients in theC-E drugs 
group will take place at 0 weeks.  
In addition,  
 
at two weeks (i.e., after two rESWT sessions and immediately before the third rESWT 
session in case of patients in the rESWT plus C-E drugs group and the rESWT group),  
 
four weeks (i.e., one week after the last rESWT session in case of patients in the rESWT 
plus C-E drugs group and the rESWT group)  
 
12 weeks and  
 
24 weeks after baseline 
treatment outcome will be evaluated (separate visits at four weeks, 12 weeks and 24 weeks 
after baseline in case of patients in the rESWT plus C-E drugs group and the rESWT group, as 
well as separate visits at two weeks, four weeks, 12 weeks and 24 weeks after baseline in case 
of patients in the rESWT group). 
 
The investigator will perform the following procedures at the first visit: 
 
check eligibility, 
 
obtain informed consent, 
 
perform randomization, and 
 
collect patient’s demographics & medical history. 
 
Furthermore, the investigator will perform the following procedures at all visits: 
 
record any concomitant medication, 
 
perform clinical examination, 
 
report adverse events (AE) and serious adverse events (SAE), and 
 
complete relevant section of case report form (CRF) 
 

23 
 
Study visits and procedures are summarized in Tables 5 and 6 below. 
 
Table 5. Study visits and procedures planned for the rESWT plus C-E drugs group and the rESWT group 
 
Screening, 
baseline assessment, 
randomization and 
first treatment 
Additional study visits 
and follow-up 
examinations 
Additional 
follow-up 
examinations 
End 
Visit 
1 
2 
3 
4 
5 
6 
7 
Timeline 
0 
1  wk 
2 
wks 
3  
wks 
4 wks 
12 
wks 
24wks 
Procedures 
 
 
 
 
 
 
 
Check eligibility 
X 
 
 
 
 
 
 
Obtain informed consent 
X 
 
 
 
 
 
 
Perform randomization 
X 
 
 
 
 
 
 
Collect patient’s demographics & medical history 
X 
 
 
 
 
 
 
Record any concomitant medication 
X 
X 
X 
X 
X 
X 
X 
Perform clinical examination 
X 
X 
X 
X 
X 
X 
X 
Dispense rESWT 
X 
X 
X 
X 
 
 
 
Perform efficacy assessment 
 
 
X 
 
X 
X 
X 
Report AE and SAE 
X 
X 
X 
X 
X 
X 
X 
Complete relevant section of CRF 
X 
X 
X 
X 
X 
X 
X 
 
 
Table 6. Study visits and procedures planned for theC-E drugs group  
 
Screening, 
baseline assessment, 
randomization and 
first treatment 
Follow-up examinations 
End 
Visit 
1 
2 
3 
4 
5 
Timeline 
0 
2 wks 
4 wks 
12 wks 
24wks 
Procedures 
 
 
 
 
 
Check eligibility 
X 
 
 
 
 
Obtain informed consent 
X 
 
 
 
 
Perform randomization 
X 
 
 
 
 
Collect patient’s demographics & medical history 
X 
 
 
 
 
Record any concomitant medication 
X 
X 
X 
X 
X 
Perform clinical examination 
X 
X 
X 
X 
X 
Perform efficacy assessment 
 
X 
X 
X 
X 
Report AE and SAE 
X 
X 
X 
X 
X 
Complete relevant section of CRF 
X 
X 
X 
X 
X 
 
 
4.11. Outcome of Interest 
4.11.1. Primary clinical outcome and definition of treatment success  
 
Primary clinical outcome will be the Pain Self-Efficacy Questionnaire (PSEQ) score 
(Nicholas, 1989).  
o Patients will be asked to rate how confident they are at the time of examination despite 
the presence of their pain in performing the following activities, listed by selecting a 
number on a 7 point scale where 0 equals ‘‘not at all confident’’ and 6 equals 
‘‘completely confident’’: 
 
I can enjoy things, despite the pain. 

24 
 
 
I can do most of the household chores (e.g. tidying-up, washing dishes, etc.), despite 
the pain. 
 
I can socialize with my friends or family members as often as I used to do, despite 
the pain. 
 
I can cope with my pain in most situations. 
 
I can do some form of work, despite the pain (“work” includes housework, paid and 
unpaid work). 
 
I can still do many of the things I enjoy doing, such as hobbies or leisure activitiy, 
despite the pain. 
 
I can cope with my pain without additional medication (next to rESWT plus C-E 
drugs, rESWT alone or C-E drugs alone, respectively). 
 
I can still accomplish most of my goals in life, despite the pain. 
 
I can live a normal lifestyle, despite the pain. 
 
I can gradually become more active, despite the pain. 
o Scores on the PSEQ may range from 0 to 60, with higher scores indicating stronger 
selfefficacy beliefs. 
o A point score change of 11 points for the PSEQ score corresponds to the minimal 
clinically important difference (MCID), defined as the smallest difference that patients 
and clinicians perceive to be worthwhile when treating chronic non-specific low back 
pain (Maughan and Lewis, 2010).  
o According to Maughan and Lewis (2010) the PSEQ score is responsive to clinically 
important change over time. 
o The PSEG score will be collected at baseline and at all follow-up examinations, i.e., two 
weeks, four weeks, 12 weeks and 24 weeks after baseline. 
o In the present study treatment success is defined as individual improvement of the 
PSEG score by more than 20 points at 12 weeks after baseline. 
 
4.11.2. Secondary clinical outcomes 
Secondary clinical outcomes will be: 
 
Numerical Rating Scale (NRS) score - The NRS will ask patients to rate their pain intensity 
on an 11-point scale where 0 indicates no pain and 10 indicates worst imaginable pain. The 
NRS score will be collected at baseline and at all follow-up examinations, i.e., two weeks, 
four weeks, 12 weeks and 24 weeks after baseline. A point score change of 4 points for the 
NRS score corresponds to the MCID (Maughan and Lewis, 2010). Note that according to 

25 
 
Maughan and Lewis (2010) the NRS score is least responsive in measuring clinically 
meaningful change in a chronic non-specific low back pain population. 
 
Oswestry Low Back Pain Disability Questionnaire (OLDPDQ) score (Fairbank and Pynsent, 
2000; Davidson and Keating, 2001) – The OLDPDQ score is considered the ‘gold standard’ 
of low back functional outcome tools. The questionnaire is composed of ten sections 
(addressing pain intensity, personal care, lifting, walking, sitting, standing, sleeping, sex life, 
social life and travelling); for each section the possible score is 5 and, thus, the total 
possible score is 50. The final score is calculated as [(sum of individual scores) / 50] *100 
(%), and is interpreted as minimal disability (0% to 20%), moderate disability (21% to 40%), 
severe disability (41% to 60%), crippled (61% to 80%) or patients are either bed-bound or 
exaggerating their symptoms (81% to 100%). The OLDPDQ score will be collected at 
baseline and at all follow-up examinations, i.e., two weeks, four weeks, 12 weeks and 24 
weeks after baseline. A point score change of 8 points for the OLDPDQ score corresponds 
to the MCID (Maughan and Lewis, 2010). 
 
Patient Health Questionnaire 9 (PHQ-9) score (Kroenke et al., 2001) – The PHQ-9 will be 
used to assess depression. Patients will be asked how often, over the last two weeks, they 
had been bothered by the following problems: (i) little interest or pleasure in doing things; (ii) 
feeling down, depressed or hopeless; (iii) trouble falling or staying asleep, or sleeping too 
much; (iv) feeling tired or having little energy; (v) poor appetite or overeating; (vi) feeling bad 
about themselves, or that they are a failure or have let themselves or their family down; (vii) 
trouble concentrating on things, such as reading the newspaper or watching television; (viii) 
moving or speaking so slowly that other people could have noticed? Or the opposite – being 
so fidgety or restless that they have been movin around a lot more than usual; and (ix) 
thoughs that they would be better of dead or of hurting themselves in some way. For each 
potential problem the PHQ-9 score uses a 4-point scale where 0 = not at all, 1 = several 
days, 2 = more than half the days and 3 = nearly every day. The PHQ-9 score will be 
collected at baseline and at 12 weeks and 24 weeks after baseline. 
 
Lumbar curvature measurements performed on lateral lumbosacral spine radiographs – 
Chun et al. (2017) found a strong relationship between non-specific low back pain and 
decreased lumbar lordotic curvature in a recent meta-analysis based on 13 studies 
consisting of 796 patients suffering from non-specific low back pain and 927 healthy 
controls. Lateral X-rays of the lumbar spine will be taken in the standing position according 
to standard protocols in the literature (e.g., Chernukha et al., 1976; Marks et al., 2009; Been 
and Kalichman, 2014) and analyzed using Cobb’s angle, vertebral body and intervertebral 

26 
 
disc wedging, and facet joint angle (Fig. 3) (e.g., Been and Kalichman, 2014). Lumbar 
curvature measurements will be performed at baseline and at 12 weeks after baseline. 
 
Fig. 3 (taken from Been and Kalichman, 2014). Measurements of lumbar 
lordosis Cobb’s angle (LA), vertebral body (B) and intervertebral disc 
(D) wedging, and facet joint angle (F). 
 
 
 
 
 
 
 
 
4.12. 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 ESWT, blinding of ESWT 
therapists can only be achieved when another person prepares the device before rESWT or 
sham treatment.  This, however, is almost impracticable and has not been done in any of 
the more than 100 studies on rESWT and and fESWT listed in the PEDro database (Schmitz 
et al., 2015). The solution to this issue is a strict, standardized way of interaction between 
the ESWT 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 proposed study.  
 
All assessments before the first treatment (baseline) and during the follow-up period will be 
performed by assessors blind to the intervention. 
 

27 
 
5. Follow-up and statistical analysis 
 
Follow-up will be the same for all study patients. 
 
The design of the proposed study guarantees that there will be full compliance with the 
allocated treatment and, thus, no contamination of one group. 
 
The patient’s age, gender, body mass index, job occupation and duration of non-specific low 
back pain are potential confounding factors when treating chronic non-specific low back pain 
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 ANOVA followed by Bonferroni post 
tests for pairwise comparisons in case of passing the normality test, or the nonparametric 
Kruskall-Wallis test followed by Dunns tests for pairwise comparisons in case of not passing 
the initial normality test. 
 
As outlined in Section “Primary clinical outcome and definition of treatment success” above, 
the primary clinical outcome will the PSEQ score at 12 weeks after baseline. Treatment 
success (i.e., number of patients with individual improvement of PSEQ score by more than 
20% at 12 weeks after baseline) will be tested with Fisher’s exact test.  
 
As outlined in Section “Secondary clinical outcomes” above, the secondary clinical 
outcomes will be the NRS score, OLDPDQ score, PHQ-9 score, Cobb’s angle, vertebral 
body and intervertebral disc wedging and facet joint angles. Each secondary clinical 
outcome will return a single data point at each time of follow-up examination. The NRS 
score, OLDPDQ score and PHQ-9 score are not normally distributed data. Accordingly, we 
will report inter-quartile ranges of these variables. Comparison between groups will be 
performed using the nonparametric Kruskall-Wallis test followed by Dunns tests for pairwise 
comparisons. Normal distribution of the Cobb’s angle, vertebral body and intervertebral disc 
wedging and facet joint angles will be tested using the D'Agostino-Pearson omnibus test. 
Comparison between groups will be performed with ANOVA followed by Bonferroni post 
tests for pairwise comparisons in case of passing the normality test, or the nonparametric 
Kruskall-Wallis test followed by Dunns tests for pairwise comparisons in case of not passing 
the initial normality test. 
 
The probability value of less than 0.05 (p-value < 0.05) will be considered as statistically 
significant (Lang &Secic, 2006). 

28 
 
 
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 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 treatment with respectively rESWT plus C-E drugs, rESWT alone 
or C-E drugs alone, 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 the proposed study. 
 
Patient-centered care throughout the proposed 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 none of the studies on ESWT for non-specific low back pain performed so far (Nedelka et al., 
2014; Lee et al., 2014; Han et al., 2014; Moon et al., 2016) a definition of treatment success 
was defined, a Power analysis was reported and the PSEQ score was used to assess clinical 
outcome. Accordingly, these studies are only of very limited use for the purpose of performing a 
Power analysis of the proposed study. 
Based on anecdotal evidence from several therapists in Europe and Latin America who 
have been using rESWT for non-specific low back pain for more than a decade we hypothesize 
that treatment of chronic non-specific low back pain with rESWT alone as described above will 
result in a success rate of approximately 70%, and the combination of rESWT andC-E drugs in 
a success rate of approximately 85%. Furthermore, based on our own experience we 
hypothesize that treatment of chronic non-specific low back pain withC-E drugs alone as 
described above will result in a success rate of only approximately 35%     

29 
 
On this basis we performed a Power analysis, both for a percentage of 35% as well as for 
various other percentages (ranging between 10% and 99.9%) of patients with treatment 
success when treated withC-E drugs alone, accounting for a two sided-confidence interval of 
95% (and, thus, a type-1 error rate of 5%). Calculations were performed using the software 
Open Source Epidemiologic Statistics for Public Health (www.openepi.com). The results are 
summarized in Tables 7 and 8. 
 
Table 7. Power for the proposed RCT on rESWT plus C-E drugs or rESWT alone for chronic non-
specific low back pain, accounting for a two sided-confidence interval of 95% and a percentage of 
patients with treatment success of 40% when treated with C-E drugs alone (assuming n=50 patients per 
group). 
Percent of patients treated with rESWT 
plus C-E drugs or C-E drugs alone with 
treatment success [%] 
Power based on Normal approximation 
[%] 
Power based on Normal approximation 
with continuity correction [%] 
99.9 
100 
100 
90 
100 
100 
85 
100 
100 
80 
99.8 
99.6 
70 
95.0 
92.4 
60 
71.3 
63.5 
50 
32.7 
25.2 
40 
7.2 
3.5 
35 
1.1 
0 
 
 
Table 8. Power for the proposed RCT on rESWT plus C-E drugs for chronic non-specific low back pain, 
accounting for a two sided-confidence interval of 95% and a percentage of patients with treatment success 
of 70% when treated with rESWT alone (assuming n=50 patients per group). 
Percent of patients treated with rESWT 
plus C-E drugs or C-E drugs alone with 
treatment success [%] 
Power based on Normal approximation 
[%] 
Power based on Normal approximation 
with continuity correction [%] 
99.9 
99.3 
98.3 
90 
71.2 
61.2 
85 
43.4 
33.4 
80 
20.9 
14.2 
70 
1.1 
0 
 
 
Furthermore, we calculated the minimum sample size in both groups (rESWT, control) that 
would be necessary for detecting a difference in treatment success between  
 
the patients treated with rESWT plus C-E drugs and the patients treated with C-E drugs 
alone,  
 
the patients treated with rESWT alone and the patients treated with C-E drugs alone, and  

30 
 
 
the patients treated with rESWT plus C-E drugs and the patients treated with C-E drugs 
alone,  
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 Tables 9 and 10. 
 
Table 9. Sample size in the proposed RCT on rESWT plus C-E drugs or rESWT alone for chronic non-
specific low back pain, 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 C-E drugs alone was set at 40%. 
 
Sample size of both groups (rESWT, placebo) according to… 
Percent of patients with 
treatment success when 
treated with rESWT plus C-E 
drugs or rESWT alone [%] 
Kelsey et al. (1996) 
Fleiss et al. (2003) 
Fleiss et al. (2003) with 
continuity correction 
99.9 
10 
8 
11 
90 
15 
14 
17 
85 
19 
17 
22 
80 
24 
23 
28 
70 
44 
42 
49 
60 
99 
97 
107 
50 
389 
388 
408 
 
 45 
1502 
1501 
1540 
 
 
Table 10. Sample size in the proposed RCT on rESWT plus C-E drugs for chronic non-specific low back 
pain, 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 alone was set at 70%. 
 
Sample size of both groups (rESWT, placebo) according to… 
Percent of patients with 
treatment success when 
treated with rESWT plus C-E 
drugs or rESWT alone [%] 
Kelsey et al. (1996) 
Fleiss et al. (2003) 
Fleiss et al. (2003) with 
continuity correction 
99.9 
23 
22 
28 
90 
63 
62 
72 
85 
122 
121 
134 
80 
297 
296 
316 
75 
1221 
1220 
1259 
 
 
In summary, the proposed study has a power of more than 0.8 in finding a difference in 
treatment success (individual improvement of the PSEG score by more than 20 points at 12 
weeks after baseline) between rESWT plus C-E drugs and C-E drugs alone, as well as between 
rESWT alone and C-E drugs alone, for treating chronic non-specific low back pain when 
randomizing at least 49 patients into each group.  

31 
 
On the other hand, the proposed study does not have a power of more than 0.8 in finding a 
difference in treatment success (individual improvement of the PSEG score by more than 20 
points at 12 weeks after baseline) between rESWT plus C-E drugs and rESWT alone, for 
treating chronic non-specific low back pain when randomizing less than 134 patients into each 
group.  
In summary, the proposed study can test the following hypotheses in the treatment of 
chronic non-specific low back pain:(i) rESWT plus C-E drugs is superior to C-E drugs alone, and 
(ii) rESWT alone is superior to C-E drugs alone. Furthermore, the proposed study can retrieve 
important pilot data for designing a follow-up study testing the hypothesis that  rESWT plus C-E 
drugs is superior to rESWT alone in the treatment of chronic non-specific low back pain.  
Collectively, the results of the Power analysis reinforce the validity of the proposed study 
protocol for testing efficacy and safety of rESWT using the Swiss DolorClast for chronic non-
specific low back pain. 
 
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 
treatment side and temporary numbness. These unwanted side effects normally vanish 
within one or two days.  
 
Potential unwanted side effects of celecoxib and Eperisome are increasing the risk of 
cardiovascular events and gastrointestinal events, exhaustion, dizziness. 
 
Should any unwanted side effects persists for longer than usual, the investigators will treat 
these patients according to usual standard of care of the First Affiliated Hospital of Zhejiang 
University. 
 
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 
The subject must be instructed to inform the investigator if she becomes pregnant during the 
study. As pregnancy is a contraindication for treatment with rEWST, the patient will be 

32 
 
terminated from the study. The investigator will follow up the pregnancy until the outcome is 
known. 
 
6.4. Patient data protection 
Subjects' anonymity will be maintained. In order to guarantee confidentiality of records and 
documents that could identify subjects, subjects will only be identified by their assigned 
identification number on all case report forms (CRFs) and other records and documents. The 
investigator will keep a Patient Identification List with complete identification information 
(identification number, name, address, contact number) on each subject. Documents not for 
submission to the Medical Research and Ethics Committee of the First Affiliated Hospital of 
Zhejiang University and/or the Chinese Clinical Trial Register such as subject's written informed 
consent form will be maintained by the investigator in strict confidence. 
 
6.5. Insurance 
With respect to any liability directly or indirectly caused by the investigational products in 
connection with the proposed study, the principal investigator and the Department of Pain 
Medicine at the First Affiliated Hospital of Zhejiang University assumes liability by law for 
possible injury to the subject. The investigator and his/her staff will strictly follow the instructions 
of the manufacturer of the rESWT device Swiss DolorClast (Electro Medical Systems; Nyon, 
Switzerland) in accordance with the proposed protocol and any amendments thereto. 
Furthermore, the investigator and his/her staff will in general perform the proposed study in 
accordance with scientific practice and currently acceptable techniques and know how. 
 
6.6. Rescue medication/procedure 
rESWT itself does not require specific rescue medication / procedures.  
 
7. Study Termination/Suspension 
The principal investigator holds the right to suspend or terminate patient’s participation in the 
proposed study in the event of deterioration of clinical condition at the discretion of the 
investigator.  
 
7.1 Subject Withdrawal & Drop-out 
Subjects are free to withdraw from the study at any time for any reason. 

33 
 
Subjects may also be withdrawn from the study at any time at the discretion of 
the investigator. Should a subject 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 subject's condition such that he/she no longer requires study treatment 
 
insufficient therapeutic effect 
 
protocol violation (eg. incorrectly enrolled or randomised) 
 
subject requires use of unacceptable concomitant medication 
 
subject not compliant with protocol procedures 
 
subject develops a condition during the study that violates the inclusion/exclusion criteria 
 
lost to follow-up 
 
death 
 
any other reason, in the investigator's opinion, that would impede the subject's participation 
in the study 
 
7.2. Procedures for handling withdrawal 
Subjects who withdraw or are withdrawn from the study will have the below information 
recorded: 
 
the reason(s) for their withdrawal, 
 
presence of any adverse events and if so will be followed up by regular scheduled visits, 
telephone contact and correspondence until satisfactory clinical resolution of adverse events 
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, and 
 
in the event of pregnancy, the subject should be monitored until conclusion of the pregnancy 
and the outcome of pregnancy reported. 
 
7.3. Subject replacement policy 
After randomization and the first rESWT plus C-E drugs, rESWT alone or C-E drugs alone 
treatment, no patient will be replaced. 
 

34 
 
7.4. Medications permitted or not permitted during the study. 
No other adjunct pharmacological treatment for non-specific low back pain 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 considered the ethical issues that may arise with the conduct of the 
proposed study. The proposed study will only be conducted after seeking approval from the 
Medical Research and Ethics Committee of the First Affiliated Hospital of Zhejiang University. 
 
9. Subject Withdrawal & Compensation 
Participation in the proposed study is completely voluntary. The participants will not be paid for 
joining the proposed study nor will they be expected to pay to join the proposed study. 
Participants are able to withdraw themselves from the proposed study at any time without any 
reason and consequences to their follow-up treatment. 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 the proposed study.  
 
10. Adverse Events  
10.1. Definitions 
 
Adverse event (AE) 
Any untoward medical occurrence in a subject 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 temporally 
associated with the use of the investigational product, whether or not related to the 
investigational product. 
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 
treatment, and 

35 
 
o medical conditions or signs or symptoms present before starting study treatment and 
worsen (increase severity or frequency) after starting study treatment; 
 
abnormal laboratory values or tests that induce clinical signs or symptoms or require 
therapy; 
 
any adverse experience even if no drug has been administered, for example during run in or 
wash out phase of the study; and 
 
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 
subject, in the view of the investigator, at immediate risk of death from the reaction as it 
occurred. Note that this does not include a reaction that had it occurred in a more severe 
form, it would have caused death, and/or 
 
results in subject hospitalization or prolongation of existing hospitalization. 
 
The following hospitalizations 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), 
 
parts of normal treatment or monitoring of the study indication and are not associated with 
any deterioration in condition, 
 
results in a significant or persistent disability or incapacity defined as any event that results 
in a substantial and/or permanent disruption of the subject's ability to carry out normal life 
functions, 
 
is a congenital anomaly or birth defect, 
 
is any instance of overdose, either accidental or intentional (suspected or confirmed), and/or 

36 
 
 
is any other important medical event, based upon appropriate medical judgement, that may 
jeopardize the subject 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, would 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 investigator or reported 
by the subject. 
 
b) Duration 
Start and end dates 
 
c) Assessment of causality 
The investigator will attempt to explain each AE and assess its relationship, if any, to the study 
treatment. Causality should be assessed using the following definitions: 
 
• Very likely 
 
The AE follows a reasonable temporal sequence from study treatment administration, 
 
abates upon discontinuation of study treatment, and 
 
reappears on repeated exposure (re-challenge). 
 
• Probable 
 
The AE follows a reasonable temporal sequence from study treatment administration, 
 
abates upon discontinuation of study treatment, and 
 
cannot reasonably be explained by known characteristics of the subject's clinical state. 
 
• Possible 

37 
 
 
The AE follows a reasonable temporal sequence from study treatment administration, 
 
but could have been produced by the subject's clinical state or other mode of therapy 
administered to the subject. 
 
• Doubtful 
 
The temporal association between study treatment and AE is such that the study 
treatment is not likely to have any reasonable association with the observed event. 
 
• Very unlikely 
 
The AE is definitely produced by the subject's clinical state or other mode of therapy 
administered to the subject. 
 
The degree of certainty with which an AE is attributed to study treatment 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 rESWT device Swiss 
DolorClast, and/or 
 
reaction having often been reported in literature for similar devices. 
 
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 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 the Medical Research 
and Ethics Committee of the First Affiliated Hospital of Zhejiang University. 

38 
 
Any death or congenital abnormality, if brought to the attention of the investigator within 6 
months after cessation of study treatment, whether considered treatment related or not, should 
be reported to the Medical Research and Ethics Committee of the First Affiliated Hospital of 
Zhejiang University. 
 
10.4. Treatment and follow up of AE 
Treatment of any AE is at the sole discretion of the investigator. Subjects with AE will be 
followed up until the event has resolved or 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 subject must be stopped from the treatment and immediately inform the 
investigator if she becomes pregnant during the study. The medical monitor will be contacted 
immediately to break the blind. The investigator will counsel the subject and discuss the risks of 
continuing with the pregnancy and the possible effects on the foetus. Monitoring of the subject 
will continue until conclusion of the pregnancy.  
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 product. The investigator must 
retain such notice with the Investigator's Brochure and immediately submit a copy of this 
information to the Medical Research and Ethics Committee of the First Affiliated Hospital of 
Zhejiang University. The Medical Research and Ethics Committee of the First Affiliated Hospital 
of Zhejiang University will then determine if the informed consent requires revision. The 
investigator should also comply with the procedures of the Medical Research and Ethics 
Committee of the First Affiliated Hospital of Zhejiang University 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 and temporary 
numbness at the side of treatment. These unwanted side effects normally vanish within one or 

39 
 
two days. In case of petechial bruises of the skin they will be photographed and documented in 
the patient’s record. Temorary 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 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 (identification number, name, address, contact number) and randomization number 
on each subject. All data collected will be stored in a computer that is protected by a password 
at the Department of Pain Medicine at the First Affiliated Hospital of Zhejiang University. 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 the proposed study. 
 
12. Data Protection 
All collected data will be stored in a computer that is protected by a password at the Department 
of Pain Medicine at the First Affiliated Hospital of Zhejiang University. Only investigators and 
study team members will have access to the study data. Study data will be stored for a duration 
of five (5) years after completion of the 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 the proposed 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 

40 
 
The rESWT equipment to be used in the proposed 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 the proposed study were reported. 
 
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