Exercise Into Pain in Chronic Rotator Cuff Related Shoulder Pain: a Prospective Single-Group Feasibility Study
Phase: NA
Conditions: Shoulder Impingement Syndrome
Sponsor: Universiteit Antwerpen

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Title (clinicaltrial.gov): Exercise Into Pain in Chronic Rotator Cuff Related 
Shoulder Pain: a Prospective Single-Group Feasibility Study 
 
NCT number: NCT04154345 
 
Article of reference: Cavaggion C, Juul-Kristensen B, Luque-Suarez A, et al “Exercise into pain in chronic 
rotator cuff related shoulder pain: a prospective single-group feasibility study” BMJ Open 
2023;13:e070698. doi: 10.1136/bmjopen-2022-070698  
 
Date of document uploaded in clinicaltrial.gov: 9/10/2024 
 
Description of this document:  
This research proposal was approved on 6/11/2020 by the expert panel on Medical Sciences from the 
Flemish Research Council (FWO). It is described in pages 2-14 of this document.  
Afterwards a progress report was submitted on 11/5/2022 to FWO and then positively re-evaluated. 
It is described in pages 15-18.  
Ethical approval for the original protocol had been already obtained from the Ethical Committee of the 
University Hospital of Antwerp (ref:B300201837376) on 10/09/2018 and four subsequent 
amendments have been approved during the PhD project.  
 
 

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PHD FELLOWSHIP FUNDAMENTAL RESEARCH - FWO 
 
Rationale And Positioning With Regard To The State-Of-The-Art  
 
Shoulder pain is the third most common musculoskeletal disorder, with lifetime prevalence ranging 
from 10% to 67% 1,2 and high reoccurrence rate of 41% after 1 year from the initial presentation 3. The 
socio-economic burden of shoulder pain is mainly due to sick leave, representing 84% of the total cost 
per patient in a Swedish cost-of-illness study. On the other hand, the mean healthcare cost is 326 euros 
per patient with physiotherapy accounting for 60%4. Currently, non-operative management in form of 
physiotherapist-led exercises is the primary choice of treatment 5 and subacromial shoulder pain (SSP) 
is the most commonly diagnosed shoulder complaint 6. However, it is not clear which are the best types 
of exercise, and in particular if pain should be elicited or avoided during exercise 7,8. In the current 
framework of the concept “hurt not equalling harm” 9, we propose that the therapeutic modality of 
“exercising into discomfort” has strong benefit in the treatment of SSP. Numerous studies have been 
conducted on SSP but none has investigated the specific role of exercising into discomfort on shoulder 
pain and functionality. Therefore, the main aim of the current proposal is to investigate the 
effectiveness of exercising into discomfort in order to achieve faster and superior benefits in pain and 
function. Patients and physiotherapists will be the first beneficiaries of this project: reconceptualising 
the role of pain in exercise therapy will improve the conservative treatment in SSP, leading to postpone 
or even avoid surgery and reducing the high recurrence rate and healthcare costs. If successful, this 
can be proposed in the future for the management of other chronic tendinopathies. 
Previous studies have clearly shown that shoulder exercises are the preferred first choice of treatment 
for patients with SSP 5,10-13. National guidelines recommend active rehabilitation strategies for at least 
three months and limited use of glucocorticoid injection 14,15. Numerous systematic reviews have been 
conducted on different modalities of exercise therapy in terms on specific muscle-activation (scapular-
focused approach 16), type of contractions (eccentric exercises 17) or training modalities (such as 
stabilization or proprioception 18), but no strong recommendations on the superiority of one approach 
to another can be drawn18. A review of systematic reviews suggested that loaded exercises and higher 
doses could provide superior benefits 19. Another recent systematic review 9 advocated that exercising 
into discomfort in general musculoskeletal chronic pain could facilitate the reconceptualization of pain 
by addressing fear avoidance, self-efficacy and catastrophizing beliefs within a framework of “hurt not 
equalling harm” 9. The rationale behind this approach lies on the analgesic effect of exercise as a form 
of endogenous pain modulation, which increases the pain threshold and reduces the pain intensity 
ratings through endogenous opioids and endocannabinoid mechanisms, occurring at peripheral, spinal 
and/or central sites 20. Moreover, exercising a de-conditioned tissue allows the central nervous system 
(CNS) to reprocess the perceived painful stimuli into a new positive perception so the painful 
movement can be reintroduced progressively 21,22.  
The experience of discomfort during training is already well-documented in the rehabilitation of lower 
limb tendinopathies: significant improvements were reported in RCTs where the progression and load 
of exercises were individually prescribed using the pain monitoring system (through the Visual 
Analogue Scale, VAS or Numeric Pain Rating Scale NPRS) for both patellofemoral pain 23 and Achilles 
tendinopathies 24. Similarly, in shoulder rehabilitation research, promising results were found in an RCT 
comparing specific (loaded) exercises versus non-specific exercises in patients with subacromial 
impingement syndrome 25. The authors reported a reduced need for surgery at 1 and 5 years of follow-
up 25,26, and a significantly greater improvement of pain and shoulder function in the specific exercise 
group, in whom the pain monitoring model was used to score the individual resistance for each patient. 
However, in all previous studies pain during exercises was never exceeding 5/10 on VAS scale23-25,27, 
even in studies which claim to test a painful strategy versus a non-painful one 28. Hence, the role played 
by pain during exercise is not clear and since different exercises are equally clinically successful, it is 
more important to give individualized loaded exercises instead of one-size fits all programs, whatever 
the concept is (motor control, eccentric exercises, scapular exercises). Despite the potential of 

3 
 
resistance training, it remains uncertain what dose of resistance should be given and whether the 
patient will benefit from having some discomfort/pain during the training or not. 7 Therefore, the 
first objective of this project is to test the effectiveness of exercising into discomfort in a strength 
training program on pain and function.  
The uncertainty in the best-evidence practice is also due to the multifactorial aetiology of SSP. The 
major hypothesis is that a reduction of the space between the acromion and the glenohumeral joint, 
the so-called subacromial space, causes an encroachment of the soft tissues during arm elevation, 
often referred to as “shoulder impingement” 6,15,29. The subacromial tissues mainly involved are the 
rotator cuff (RC) tendons, 29 encountering degeneration and inflammation 6,30. However, this 
anatomical “impingement” theory does not sufficiently explain the pathophysiology 15, which in fact 
displays a multifactorial aetiology31,32. Both intrinsic and extrinsic mechanisms are involved in SSP; the 
former in terms of degeneration of the tendon itself 31, the latter in terms of compression of the RC 
tendons. Intrinsic factors are linked to tendon degeneration, due to the natural process of aging, 
altered biology, genetic predisposition and tendon mechanical properties 31,32. Extrinsic factors 
originate externally from the RC tendons and include anatomical variants of the acromion, alterations 
of humeral or scapular kinematics (named scapular dyskinesis), muscle imbalance, postural deviations 
and soft tissue tightness. In particular, scapular dyskinesis is a key component in the production of 
symptoms in SSP, in association with muscle imbalance or inadequate activation patterns (i.e. 
decreased activity of the serratus anterior and lower trapezius, and overactivation of the upper 
trapezius) 33. However, the presence of scapular dyskinesis is not always associated with changes in 
shoulder symptoms and function during and after the rehabilitation. Therefore, the second objective 
is to investigate whether improvements in shoulder pain, function and quality of life is positively 
related with reduced presence of scapular dyskinesis.  
In this context, ultrasound (US) imaging has the potential to quantify the changes in the subacromial 
space and in the tendon structures during the rehabilitation process. US is able to characterize tissue 
using high-frequency sound waves, which is typically between 5 and 12 MHz in the musculoskeletal 
field 34. It has numerous advantages: it is non-invasive and non-radiating compared to radiography or 
computed tomography (CT) scan, cheaper and with higher image resolution than Magnetic Resonance 
Imaging (MRI), and available also as portable device 34,35. On the other hand, it is highly operator-
dependent and artifacts on the US image, such as anisotropy in tendon examination, can easily be 
encountered 36. Nevertheless, a standardized procedure and a thorough training can minimize these 
pitfalls 37,38. The subacromial space can be measured by US imaging as the articular distance between 
the acromion and the humeral head, called the acromiohumeral distance (AHD) 37-39. This 
measurement has shown to be reliable and sensitive 30,37,40. US can also detect tendon thickening, 
which is a sign of tendinopathy37. Numerous studies have specifically analysed the supraspinatus 
tendon thickness (STT), as this is the RC tendon mostly involved in SSP 40,41. Although contrasting results 
have been found regarding differences in the STT between symptomatic and asymptomatic 
participants 37,38,41,42, it is possible that thicker tendons are more apparent in early stages of SSP and 
thinner in later stages 31. In contrast, a systematic review concluded that RC abnormalities, such as 
degeneration or thinning, occur equally in symptomatic and asymptomatic populations, suggesting 
that these changes are part of the normal aging process 43. Moreover, the interplay between STT and 
subacromial space was recently described as an occupation ratio, which represents the proportion of 
the subacromial space occupied by STT 41. This ratio was higher in patients with SSP, showing that STT 
occupied a greater percentage of the subacromial space. However, until present the mechanistic role 
of the subacromial space and its relationship with RC tendons thickness has not been studied in 
relation to the recovery process of SSP. This could however provide useful knowledge on the working 
mechanisms of SSP therapy. Therefore, the third objective is to examine the effects of exercising into 
discomfort on changes in subacromial space (quantified as acromiohumeral distance –AHD-) and 
tendon structures measured by US imaging in SSP patients. As such, unravelling the factors 
contributing to the SSP recovery process will help clinicians to better steer their therapy and adapt 
therapeutic parameters during physiotherapy.  

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The relationship between clinical symptoms and tendon structural changes/subacromial space is a 
matter of great debate. Contrasting results are present in the literature regarding the relationship 
between subacromial space (measured as AHD) and functional improvement, with some studies 
showing a strong correlation 30 and others suggesting the opposite 44. However, the relationships 
between AHD and functional improvements during and after treatment has not been largely explored 
and it warrants further investigations 45. Concerning the association between STT and clinical 
outcomes, increased STT has been linked to decreased muscle strength and palpable tenderness 42, 
making it a reproducible parameter of tendon state during the rehabilitation process. In daily general 
practice, combining clinical information with US findings could aid the prescription of tailored exercises 
for SSP patients, leading to improved patient outcomes. Therefore, in the fourth objective this study 
will elucidate the relationship between US findings and clinical symptoms during and after 
‘exercising into discomfort’. 
In summary, although physiotherapy offers promising results in the recovery of SSP, it is still not clear 
which type of exercise provides the best outcome and whether the patient should feel discomfort 
during the performance of an exercise, or pain should be avoided. This project aims to provide clinical 
evidence for the ‘exercise into discomfort’ approach, which can influence the entire concept of the 
management of SSP, contributing to the development of the best evidence-based practice in 
physiotherapy and reducing the relative healthcare costs of SSP. If this concept is proven to be 
successful, it confirms how the body’s analgesic system is able to tackle its own pain similarly to other 
chronic pathologies such as patellofemoral pain or low back pain. This project will rely on both clinical 
outcomes (pain, function, scapular dyskinesis) and objective measures of subacromial space and RC 
tendon changes acquired with US. In this way, we will be able to track the evolution of subjective and 
objective changes happening during and after the rehabilitation process and how the presence of 
pain/discomfort during exercise influences them.  
Scientific Research Objectives 
The primary aim of this project is to provide proof-of-concept for the clinical effectiveness of the 
“exercising into discomfort” approach in patients with SSP. In the first three objectives, the focus will 
be on its effect on shoulder pain and functionality (patient-reported outcomes, objective 1), on 
scapular dyskinesis (objective 2), subacromial space, and the tendon structures (objective 3) during 
and after 3 months of exercise therapy in patients with SSP. In the fourth objective, the relationship 
between patient reported outcomes and the US measurements during the treatment course will be 
explored.  Two groups will be compared in a randomized controlled trial (RCT): an intervention group 
“exercising into discomfort” (G1) and a control group “exercising without discomfort” (G2). The time 
points of assessment will be prior to the treatment at baseline (T0), at 6 weeks during treatment (T1), 
end of treatment at 12 weeks (T2), and follow up at 26 weeks (T3).  
OBJECTIVE 1  
 
To investigate the effectiveness of exercising into discomfort during a strength 
training program in the treatment of SSP on self-reported shoulder pain and 
function 
Methods 
Double Blind Randomized Controlled Trial comparing 2 groups (G1 versus G2), with 
SPADI (Shoulder Pain and Disability Index, a valid and reliable patient-reported 
outcome measure of pain and disability 46) as primary outcome. A “high pain 
monitoring model” will be used to monitor pain during and 1 hour after every 
exercise in G1 (see “intervention” in methodology).  
Hypothesis 
In G1 SPADI will be reduced more than in G2.  
Novelty/ 
Relevance 
If successful, the results of this study will lead to a reconceptualization of exercises 
in SSP, allowing pain (defined as discomfort sensation) to be an essential component 
and not a barrier in the physiotherapy treatment. 
 

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OBJECTIVE 2 
 
To investigate whether improvements in shoulder pain, function and quality of life 
is positively related with reduced presence of scapular dyskinesis 
Methods  
Scapular dyskinesis will be registered by visual observation at rest and during 
movements (abduction and flexion) and its effects on pain will be tested by scapular 
assistance test and scapular retraction test 
Hypothesis  
Scapular dyskinesis will decrease more in G1, in relation to the increase in strength 
and coordination of the scapulothoracic and scapulohumeral muscles.  
Novelty/ 
relevance 
Although the scapular control will be integrated in the exercises in both groups from 
the first session, we expect a greater improvement in G1 thanks to both increased 
muscle strength and regained self-efficacy in movement performance. Therefore, it 
is relevant to register how scapular dyskinesis is evolving during treatment in order 
to understand when and in which subgroups of patients it is contributing to 
symptoms of SSP. 
 
OBJECTIVE 3 
 
To investigate the effects of exercising into discomfort on changes in subacromial 
space (quantified as acromiohumeral distance AHD) and tendon structures 
measured by US imaging in SSP patients 
Methods 
Analysis of the secondary outcomes (subacromial space and tendon structure 
changes measured by US imaging) of the RCT conducted in objective 1 
Hypothesis 
In both groups there will be an increase in the subacromial space and decrease in 
STT. These changes will be more evident in G1  
Novelty/ 
Relevance 
The lack of understanding of tendon structural changes in “exercising into 
discomfort” in patients with SSP contributes to the inadequate management of this 
pathology. Information on such parameters will provide insights into the 
mechanisms behind this modality of exercise therapy during and after the end of 
the treatment. Moreover, this study aims to clarify the role of the subacromial space 
as a valuable indicator of SSP recovery. To the best of our knowledge, this is the first 
time that tendon structures are monitored during the treatment other than before 
and after rehabilitation (assessment at T2). 
 
OBJECTIVE 4 
 
To examine whether improvement in shoulder pain, function and quality of life is 
associated with changes in the subacromial space and tendon structures as 
measured by US imaging 
Methods 
Analysis of possible association between parameters measured by US (subacromial 
space, RC tendon thickness) and clinical symptoms (self-reported shoulder pain, 
questionnaires on functionality and quality of life) at T0, T1, T2, T3 in the RCT 
Hypothesis 
There will be a significant correlation between US imaging parameters and clinical 
symptoms  
Novelty/ 
Relevance 
There is contrasting evidence in the literature regarding the association between 
subacromial space and clinical symptoms. This study will elucidate this question and 
further enhance the knowledge regarding other significant tendon changes (i.e. 
combining AHD and RC thickness in the occupational ratio) during and after 
exercising into discomfort, laying the groundwork for future prognostic studies.  
 
This project proposal is organized as a collaboration with other partner universities, relying on different 
expertise: Prof. Filip Struyf (University of Antwerp, Belgium) will be the main promotor of the PhD 
student 
and 
he 
is 
currently 
the 
world 
leading 
expert 
on 
shoulder 
pain 
(http://expertscape.com/ex/shoulder+pain); Prof. Luque-Suarez Alejandro (University of Malaga, 
Spain) will give guidance in the US training together with Santiago Navarro-Ledesma, who obtained a 
joint PhD degree (Malaga – Antwerp) on the use of US in rehabilitation for shoulder pain; Prof. Juul-

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Kirstensen Birgit (University of Southern Denmark), expert on exercise therapy in shoulder pain and 
Dr. Lennard Voogt (University College Rotterdam) expert on assessment and management of chronic 
musculoskeletal pain. They wrote the initial project for the grant at the University of Antwerp together 
and they gave and will give continuous assistance during all the phases of the project (definition of the 
intervention, feasibility study, reliability study on US measures, RCT). 
 
Research methodology and work plan 
 
WP1: Preparation of the trial 
In the previous academic year 2018/2019 the PhD student focused on the preparation of the trial, 
which included different tasks reported in the work plan in Table 1 (page 10).  
 
Literature review and survey on current physiotherapy practice 
The first task was to develop an intervention protocol for the modality “exercise into discomfort”.  In 
order to achieve this goal, a literature review on exercise therapy in SSP is being conducted. The PhD 
student collaborated also in a survey on current physiotherapy practice in Belgium and the 
Netherlands, which has been recently published in peer-reviewed journal (Task 1.1, work package 
WP1,Table 1). With this background information, the PhD student together with the research team 
designed the intervention (Task 1.2, WP1) during the academic year 2018/2019. After ethical approval, 
the successful recruitment of physiotherapists for the feasibility study started.  
 
Feasibility study  
In the recruited private practice, the feasibility study is now ongoing (Task 1.3, WP1). It includes 12 
patients, which will allow to test 80% of compliance rate, ranging between 0.78 and 0.84 within a 95% 
of confidence interval. This number was obtained with the “Score method incorporating continuity 
correction” reported by Newcombe et al. 47 
The feasibility study aims to: 1) test a high-pain monitoring model (which is the intervention applied in 
G1 -“exercise into discomfort”-) and the rate of adherence to this modality, 2) test the rate of 
recruitment at this private practice, 3) verify adverse effects 4) test the practicability of delivering 
clinical questionnaires via online survey Qualtrics, 5) provide an indication of the time needed to collect 
the data.   
The high pain monitoring model is based on the pain monitoring model which has been previously 
used in many studies23,24,48,49. The difference is that the pain during exercise is higher than in the 
previous studies until the 9th week, with certain caveats: 1) during the exercises, the patient should 
feel discomfort/pain exceeding the pain at rest, ranging between 4 and 7 on NPRS (Numeric Pain Rating 
Scale). During the last set of 10/15 repetitions pain should not exceed 7; 2) Discomfort/pain should 
return to baseline level after 1 hour; 3) Discomfort/pain should not increase from day to day. In the 
last phase of the treatment (between 9th and 12th week) the pain during exercise ranges between 0 
and 2 on NPRS, in order to allow the patient to focus on more proprioceptive and sport/work related 
tasks. A preliminary analysis of the data on 6 patients at the 6-week follow-up showed that all the 
subjects attended at least 4/6 physiotherapy sessions and they were all adherent to the home exercise 
(at least 10/11 home exercises completed) except one patient. Two patients experienced a slight 
increase (1 point on NPRS) in the level of pain after the physiotherapy or home exercise in the first 
three weeks. Discussing with both physiotherapists and patients, this was related to an increased level 
of sport in the same period or due to additional treatment of the posterior capsule, which can provoke 
initially some pain. The physiotherapist adapted the exercise and from the 4th week onwards the pain 
decreased to initial levels after 1 hour of exercise. Moreover, it emerged that a measurement of the 
pain after 1day was necessary to evaluate the evolution of the pain after painful exercises.  This will 
be added in the design of the RCT and it is also in line with the recent recommendation for evaluating 
pain during and after exercises50. 

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The rate of recruitment at this private practice was 5 patients per month, which means we will be able 
to recruit 60 patients for the RCT at this practice in 1 year (WP2), thereby minimizing the recruitment 
risk inherent to RCTs. Two physiotherapists conducted an initial screening at the first visit based on the 
history taking, which allowed to exclude 37 patients. If considered eligible, the patients underwent to 
a second screening phase led by the PhD student: only 3 patients were excluded at this time point. The 
estimated time for the screening is 30 minutes while 1 hour is necessary for the rest of the 
measurements. Qualtrics proofed to be a practical modality of taking clinical questionnaires because 
no data were lost, and the patients who did not filled in the questionnaire within 2 days were sent a 
reminder.  
Ultrasound measures 
In May 2019 the US machine was bought with the budget of the doctoral grant. In August 2019 the 
PhD student followed a training on US imaging during a research stay of 4 days under the supervision 
of the US expert Santiago Navarro Ledesma at the partner University of Malaga (Task 1.4, WP1). In 
February 2020 this researcher came to Antwerp for a 2-week period to conduct an inter-reliability 
study on the US parameters previously decided and discussed during the research stay. This part of 
the project is currently in the phase of data analysis. This will allow to validate the skills of the PhD 
student as novice sonographer and to decide which US measures are valid and reliable to be part of 
the second phase (RCT, WP2). The US measures are described in WP2, under “Outcomes measures”. 
 
Ethical approval and fine-tune protocol  
Ethical approval for the original protocol has been already obtained from the Ethical Committee of the 
University of Antwerp. The reliability study and feasibility study have been added and approved by 
submitting two amendments. The whole protocol will be analysed and modified based on the feedback 
of the physiotherapists and the patients. A revision of the protocol after the feasibility study will be 
critically analysed together with the rest of the research team in April 2020 during one or more Skype 
meetings and, if necessary, also submitted as 
amendment to the Ethical Committee. 
 
WP2: Randomized controlled trial  
Design 
This 
study 
will 
be 
conducted 
as 
an 
experimental randomized, controlled, double-
blind trial (RCT) in one physiotherapy practice 
in Belgium. The patients with SSP will be 
randomized into one of 2 groups (concealed, 
permuted block randomization of 2,4,6 size 
using 
randomisation.com), 
being 
either 
exercising into discomfort (G1) or exercising 
with slight/no discomfort (G2).  
All training sessions will be applied for 12 
weeks, three times weekly. The time points of 
assessment will be: before the start of the 
treatment (T0), at 6 weeks (T1), 12 weeks (T2), 
26 weeks (T3). All participating patients will 
follow the flowchart illustrated in Figure 1.   
Sample size 
The sample size calculation was made using 
the Edland method, R package longpower 1.0-
1151, based on the following data: 8% points as smallest clinically important difference in SPADI 52, 15% 
of estimated drop-out (as mean of dropout rates from previous studies 53-55) and 30% for adjustment 
26 weeks follow-up (T3) 
26 weeks follow-up (T3) 
Informed consent + 
 baseline assessment (T0) 
Second screening for eligibility (PhD student) 
First screening for eligibility (physiotherapist) 
Exclusion: decline to participate, not 
meeting the initial inclusion criteria  
Exclusion: decline to participate, not 
meeting the inclusion criteria  
Exercise into discomfort  
G1 (n=27) 
Exercise slight/no 
discomfort G2 (n=27) 
6 weeks follow-up (T1) 
6 weeks follow-up (T1) 
12 weeks follow-up  
12 weeks follow-up  
12 weeks: end of 
intervention G1 
12 weeks: end of 
intervention G2 
Drop-out: protocol deviations, 
lost at follow up 
Drop-out: protocol 
deviations, lost at follow-up 
Randomization 
(n=54) 
Figure 1 Flow chart 

8 
 
for non-linearity of the data (since there is usually a higher decrease in SPADI in the first 3 months 
compared to 6 months). Considering a mixed regression model for repeated measures and using a 
moderate effect size (corresponding to 8% as smallest clinically relevant difference), confidence level 
at 5%, and power at 90%, the required total sample size is 54 subjects, taking into account 15% drop-
out rate. The variance of the residuals cannot be estimated from previous studies, but it has a very 
limited effect on the sample size. It does not change the result of the power calculation, and therefore 
it is not included in this analysis.  
Physiotherapist and patient recruitment  
The physiotherapists participating in the feasibility study agreed in taking part to the second phase of 
the project (Task 2.1, WP2). They will perform a standardized initial screening of all patients referred 
with SSP diagnosis. The rate of recruitment estimated in feasibility study will allow us to recruit 54 
patients in 1 year time, between April 2020 and April 2021. The last measurement of the last patient 
should be in October 2021 (6 months follow-up, Task 2.3, WP2). Following the successful procedure 
developed in the feasibility study, the patient will be screened in two phases: first by the 
physiotherapist and, if they are willing to participate, secondly by the PhD student at a separate visit.    
The inclusion criteria are: 1) patients aged 18-65 years old; 2) referred to non-operative physiotherapy 
treatment due to shoulder pain; 3) shoulder pain for at least three months’ duration prior to 
enrolment; 4) at least three of the following positive provocative shoulder tests: Neer test, Hawkins-
Kennedy test, Jobe test, painful arc, external rotation resistance test 56.  
The exclusion criteria are: 1) resting pain more than 2/10 on VAS scale; 2) bilateral shoulder pain; 3) 
history of shoulder surgery, fracture or dislocation; 4) clinically (positive drop-arm test, external or 
internal rotation lag test) and/or previous ultrasonography examination confirming the presence of 
full-thickness rotator cuff tear or calcifications larger than 5mm 57; 5) evidence of adhesive capsulitis; 
6) corticoid injections 6 weeks prior to the study. Further exclusion criteria are: history of cervical or 
thoracic spine surgery, primary complaint of spinal pain or signs of CNS involvement or signs of cervical 
nerve root involvement; presence of competing pathologies (inflammatory arthritis, neurological 
disorders, fibromyalgia, malignancy, psychiatric illness, etc.); primary diagnosis of acromioclavicular 
pathology, shoulder instability. Furthermore, patients will be excluded if they have a radiologically 
confirmed fracture, pregnancy or inability to understand spoken and written Dutch.  
Intervention  
It corresponds to “Task 2.2”, WP2 in Table 1 (page 10). Every physiotherapy session lasts 30 minutes 
and it includes 20 minutes of exercise therapy based on 4 strengthening exercises and 10 minutes of 
manual therapy (focusing on the release of posterior capsule). The manual therapy will be applied to 
all the patients without distinction to the two groups. The exercise therapy will be the distinct element 
between the two groups: group 1 (G1, exercising into discomfort) will execute exercises with pain 
intensity from 4/10 to maximum 7/10 on a NPRS scale, while group 2 (G2, exercising with slight/no 
discomfort) will execute not/slightly-painful exercises with pain intensity inferior to 2/10. These limits 
are set in order to ensure a clear difference in pain intensity between the two groups and a preliminary 
analysis of the feasibility study showed it was possible for the patient in G1 to train between 4 and 
7/10 following the high-pain monitoring model. The pain level in G1 will decrease to 0-2 at 9th week so 
the patients can focus on more proprioceptive or sport/work related tasks. The exercises are 
individually prescribed and each patient will have 4 personalized strengthening exercises, with one 
focusing on the painful direction (which is usually abduction, flexion or external rotation) and the rest 
of exercises will elicit pain but not in the painful direction (for example, closed kinetic chain exercises 
or exercises with elastic bands). The aim in both groups is to gain strength in both scapulothoracic and 
scapulohumeral muscles, re-balancing the force couples in the shoulder joint during specific 
movements (i.e. re-train arm elevation in which a lower activity of serratus anterior and overactivation 
of the upper trapezius is present), without isolating one muscle during the exercise. Scapula 
stabilization exercises will be integrated with rotator cuff strengthening in one exercise (i.e. closed 
kinetic chain as push-up) from the first session, since recent studies showed that the order of exercise 

9 
 
(scapular and then RC exercises or vice versa) was not affecting significantly the clinical outcomes58. 
Our hypothesis is that a painful shoulder program focusing on strengthening exercises, with certain 
caveats, will load the shoulder muscles allowing a better and possibly faster recovery.   
The choice of the research team to not choose a particular and specific sets of exercises was motivated 
by two main reasons: 1) allow the physiotherapist to prescribe individualized exercises and 2) let the 
physiotherapist progress the exercise based on patient’s needs (sport, work-related activities) and to 
adapt it on the load provoking pain. In both groups, lifestyle advice, ergonomics corrections, pain 
education regarding the subacromial shoulder pain will be provided, in line with current physiotherapy 
practice in Belgium59. We believe that this approach of “exercising into discomfort” can give a different 
insight in the treatment of SSP but it will remain well-integrated in the current physiotherapy practice. 
Outcome measures 
All outcomes will be measured at baseline (T0) and 6 (T1), 12 (T2), 26 (T3) weeks and the assessors will 
be blinded to group allocation. The primary outcome is the difference in mean change between 
groups from T0 to T1, T2 (12 weeks, end of the treatment), and T3 (26 weeks, follow-up) in the patient 
self-reported outcome score Shoulder Pain and Disability Index (SPADI). This questionnaire is a 
patient-reported outcome measure (PROM) with high test–retest reliability and construct validity 46 
and is available and validated in Dutch 46.  
Secondary outcomes are registered for each patient at the same time points as the primary outcome, 
except for the Global Perceived Effect Score, which will be assessed after 1st treatment and then at 6 
and 12 weeks. The secondary outcomes are:   
Scapular dyskinesis: The procedure we will use is based on the procedures described by Tate et al. 60 
and Struyf et al. 61. Scapular position will be observed at rest and during active loaded and unloaded 
humeral motion in a frontal and sagittal plane. The effect of scapular correction will be tested by means 
of the modified scapular assistance test and scapular retraction test 61,62. Reduction of pain during 
these tests compared with non-assistance during the same tests confirms scapular involvement in the 
shoulder complaints.  
Subacromial space: Acromiohumeral distance (AHD) is a US measurement used to quantify the 
subacromial space. It is defined as the shortest linear distance between the most inferior aspect of the 
acromion and the humeral head 30. AHD is measured at 0 and 60 degrees of active shoulder elevation 
in the scapular plane, following the procedure of measurement indicated by Navarro-Ledesma et al 39. 
It has already been used to evaluate different populations, such as healthy volunteers 39 and patients 
with shoulder pain 30,37.  
Tendon changes: Tendon structural changes (limited to RC thickness and long biceps) will be evaluated 
using US device and following international guidelines 37,41,44,63. STT will be also computed as 
percentage of subacromial space, known as the occupation ratio (using the formula [(STT/AHD)*100] 
41. 
Shoulder strength and Range of Motion (ROM): Shoulder strength is measured as isometric strength 
measurements with handheld dynamometer (IsoForce Dynometer EVO2; Medical Device Solutions 
AG) in abduction external rotation and scapular plane elevation. ROM in active and passive abduction 
and external/internal rotation will be determined with a goniometer (HALO digital goniometer; HALO, 
Medical Devices). These devices are already available at the University of Antwerp. 
Shoulder related Quality of Life: Health-related Quality of Life index and Health-related Quality of Life 
VAS, measured with the EQ-5D-5L 64. 
Adherence: The pain and the amount of exercise performed will be recorded in an exercise and pain 
diary. The participants will be asked to complete a pain diary, reporting pain on the VAS scale before 
and 1 hour and 1 day after each training session as well as the home training. Adherence will be 
analysed in terms of compliance with self-reported exercise diary: good compliance is defined by 
attendance of 6/9 supervised sessions and 80% of 27 home exercises. 

10 
 
Fear of pain questionnaire-9 and Fear-Avoidance Beliefs Questionnaire (FABQ): these outcomes 
allow qualitative analysis of which patient characteristics (i.e. high level of anxiety and fear associated 
with pain) undermine compliance in case low adherence is observed. These questionnaires are both 
psychometrically sound and validated in Dutch  65-67.  
Other relevant outcomes: Patients fill out the global perceived effectiveness (GPE) rating (1-much 
worse, 2-slightly worse, 3-no change, 4-slightly better, 5-much better) after the first session, at 6 and 
12 weeks 68.  
WP3: Data analysis  
Statistical analyses will be performed using JMP ®Pro 14.0.0 (SAS Institute Inc., Cary, NC, USA) . Level 
of significance is set at p= 0.05. Appropriate descriptive statistics will be performed.  
OBJECTIVE 1,2,3: A mixed regression model for repeated measures will be used to assess both the 
evolution of SPADI (pain and function), strength, ROM and US parameters within persons from baseline 
(T0) over time (T1, T2, T3) and the differences in evolution between subjects. Potential confounders 
are: age, gender, BMI, previous corticosteroid injections, severity of initial symptoms. They will be 
measured during the history taking at the first assessment and added into the mixed regression model 
as co-variants. If for a certain variable the percentage of missingness will be more than 15%, multiple 
imputation for missed observation will be used. There are three assumptions for the mixed regression 
model: change over time, a sensible measure for time (multiple time points of measure), normality of 
residuals (it will be checked using a Shapiro-Wilk test). If these residuals are not normally distributed, 
an appropriate transformation will be performed first. Therefore, this model best fits the longitudinal 
design of the RCT. OBJECTIVE 4:  correlation analysis between tendon structures and clinical symptoms 
using the correlation for pairs of continuous variables in JMP.  
Work Plan  
Table 1 shows the overall timeline of this four-year project, including the following four work packages 
(WP): the preparation of the trial (WP1), the RCT (WP2), data analysis (WP3), finalizing PhD (WP4). The 
main 4 milestones are: fine-tune protocol after feasibility study (M1), end of patients recruitment (M2), 
end of data analysis (M3), submission and correction of relevant publications (M4). 
Year 
2019 
2020 
2021 
2022 
2023 
Quarter 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
WP1: preparation of the trial 
 
 
 
 
Task 1.1 
Systematic review in exercise in SSP, survey on 
physiotherapy practice in SSP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Task 1.2 
Development of intervention protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Task 1.3 
Feasibility study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Task 1.4 
US training, US reliability study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Task 1.5 
Fine-tune protocol, ethical approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WP2: RCT 
 
 
 
 
Task 2.1 
Baseline measurements T0 (0w) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Task 2.2  
Intervention – T1(6w), T2 (12w) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Task 2.3 
Follow up – T3 (26w) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WP3: Data analysis 
 
 
 
 
Task 2.1 
Data analysis for Objectives 1,2,3,4 (T0,T1,T2)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Task 2.2 
Data analysis for Objectives 1,2,3,4 (T3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WP4: Finalising PhD 
 
 
 
 
Task 4.1  
Writing articles (systematic review, feasibility study, 
protocol RCT, RCT) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Task 4.2 
writing PhD thesis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Task 4.3 
Submission and defence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Milestones 
M1 
M2 
M3 
M4 
 
Table 1 Timeline of 4-year project. WP=Work packages, T0=baseline, T1=6weeks, T2=12weeks, T3=26weeks 
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15 
 
PROJECT OUTLINE – renewal 11/5/2022 
 
Specify the progress of your PhD project. 
If you deviate from the approved application please describe and motivate. 
  
Table 1 shows the overall timeline, including the following five work packages (WP): the preparation 
of the trial (WP1), the RCT (WP2), data analysis (WP3), writing articles and finalizing PhD (WP5). The 
main 4 milestones are: fine-tune protocol after feasibility study (M1), end of patient’s recruitment 
(M2), end of data analysis for RCT (M3), writing PhD dissertation (M4). The project was financed by 
the University of Antwerp from 1/10/2018 to 30/10/2020 and by the FWO from 1/11/2020 to 
31/10/2022. The timeline has been adapted and it is based on recruitment rate for the RCT of the 
last two years, impacted by the Covid-19 pandemic. Changes compared to the initial FWO project 
are described in detail below.  
 
Table 1 Timeline. The years in orange indicate the funding from DOCPRO (University of Antwerp) and the years in green 
indicate the funding from FWO. Abbreviations: M=Milestone, PT=physiotherapy, RCT=Randomized Controlled Trial, 
SSP=Subacromial Shoulder Pain, T0=baseline, T1=9weeks, T2=12weeks, T3=26weeks, US=Ultrasound, WP=Work package. 
The initial timeline proposed in the FWO project is in light blue, adaptations to the timeline are indicated in dark blue.  
WP1: Preparation of the trial 
Development of the intervention for the RCT (WP1: 1.1, 1,2): Aim: develop the intervention protocol 
for the RCT based on the most recent literature about exercises in subacromial shoulder pain. The 
intervention protocol was developed by October 2019. Moreover, a survey on current 
physiotherapy practice in Belgium and the Netherlands was published to serve as a starting point 
for the intervention (co-authorship, see Publication list). Status: completed according to the plan. 
US training and US reliability study (WP1: 1.4): Aim: validate the skills of the PhD student as novice 
sonographer. In August 2019 the PhD student followed a US training during a 4-days research stay 
supervised by the US expert Santiago Navarro Ledesma. In February 2020 the US expert came to 
Antwerp for a 2-week period to conduct an inter-reliability study on the US parameters previously 
decided and discussed during the research stay. Status: completed according to the plan.  

16 
 
The research stay proposed in the first FWO project in Denmark in September 2020 on the use of 
the sonoelastography, which is an US feature detecting differences in the elasticity of the soft 
tissues, was not conducted. It was not possible to measure this feature with the available US 
machine and the PhD student acquired the necessary US skills already in the reliability study phase 
performed in February 2020 for the relevant measures for the RCT.   
Feasibility study and fine-tune the protocol (WP1, 1.3 1.5): Aim: a feasibility study on exercise into 
discomfort was performed from November 2019 to May 2020. Status: completed (start delayed 
compared to FWO initial project, from Q3-2019 to Q4-2019). A critical revision of the protocol for 
the RCT was performed after the feasibility study, as mentioned in the FWO application. Some 
changes were necessary to the protocol. 1) Changes to the intervention in the RCT: the 
intervention in the RCT changed from 4 exercises into discomfort between 4-7 on a Numeric Pain 
Rating Scale (NPRS, scale 0-10) proposed in the initial FWO application to 1 exercise into discomfort 
and the 3 remaining exercises performed with no/minimal pain. This modification was necessary 
after a thorough analysis of the feasibility study and discussion with the physiotherapists and the 
research team. If this single painful exercise was not provocative anymore (4-7 on NPRS) before 9 
weeks, a rate of perceived exertion (Borg Scale) was used instead of the NPRS. In this way, the 
exercises could be between 4 (somewhat hard) and 7 (very hard) representing more the subjective 
effort during the exercise than the pain provoked during the exercises. Although this modification 
could potentially change the comparison between a painful vs. non-painful exercise program, this 
final decision was taken together with the research team in order to compensate possible 
deviations from the protocol in the future RCT. 2) Impact of Covid-19 on feasibility study: patients 
stopped to go to the physiotherapists from March to May 2020 but they continued to exercise at 
home. Questionnaire were sent online via Qualtrics, therefore subjective data were not lost. 
Objective measures (i.e. strength and US measures) were lost for 7 patients at follow-up of 6 and/or 
12 weeks but available data for patients who went at least 7 out of 9 sessions to the 
physiotherapists were analysed in order to adjust the protocol for the RCT. Milestone 1 (ethical 
approval on amendments to the protocol and fine-tune the protocol for the RCT): completed 
according to the plan. 
WP2: RCT 
The RCT started in July 2020 and is still on going. In the initial FWO application the aim was to start 
the recruitment in April 2020 and to complete it by April 2021, with the final follow up in October 
2021 (6 month after baseline assessment). A change to the timeline and sample size was necessary 
because of the low recruitment rate during the pandemic of Covid-19. The recruitment rate during 
the feasibility study before the pandemic (November 2019-February 2020) was 4-5patients/month. 
The recruitment rate during the RCT was: 2.6 patients/month during the first year (July 2020-July 
2021) and then 1.2 patient/month in the following 6 months (August 2021-January 2022). Fifty-four 
patients were included in the initial sample size calculation, estimating 15% of drop-out, 
power=90% and minimal clinically important difference (MCID)=8 points on the primary outcome 
SPADI. We planned to recruit patients until May 2022, aiming to 44 patients, with the last follow up 
measure in November 2022. Forty-four patients will still allow to have a well-powered study (85%) 
with MCID=10 points, which is considered in the range 8-13 points of the MCID in SPADI (Roy JS, 
MacDermid JC, Woodhouse LJ. Measuring shoulder function: a systematic review of four 
questionnaires. Arthritis Rheum. 2009;61(5):623-32). The extended time for data analysis in 2023 
will allow the PhD student to conduct a thorough data analysis of objective and subjective data (see 
“Data analysis for 2nd term”). Status: 42 patients were recruited by the end of April 2022.  
 
 

17 
 
WP3: Data analysis  
Data analysis 1st,2nd US articles (WP3, 3.1 and 3.2): 
Status: data analysis completed. The time necessary 
for data analysis for the US measures was added to 
the timeline. Main results: inter-rater reliability was 
calculated in the reliability study performed in 
February 2020 with the US expert Santiago Navarro 
Ledesma. Inter-rater reliability varied largely from 
poor to good between two examiners with different 
US experience (novice VS expert examiner). 
However, since the only US examiner for the RCT is 
the PhD student, the data for the intra-rater 
reliability of the PhD student were considered 
relevant in order to proceed to the US measures in 
the RCT. The intra-rater reliability of the PhD 
student can be found in Table 2. The ICC values for the PhD student are ranging from good to 
excellent (0.85-0.97). The measures with weights (AHD60w and CHD60w) were excluded in the final 
protocol in the RCT because of time limitations in the measurement protocol and also because the 
patients could not hold the weight assigned for the whole testing period.  
The first manuscript resulting from this reliability phase was: “Subacromial space measured by 
ultrasound imaging in asymptomatic subjects and patients with subacromial shoulder pain: an 
inter-rater reliability study”; authors: Claudia Cavaggion, Santiago Navarro-Ledesma, Alejandro 
Luque-Suarez, Birgit Juul-Kristensen, Lennard Voogt, Filip Struyf; journal: Physiotherapy Theory and 
Practice (IF2020=2.28, Q3 Rehabilitation), Manuscript 1. The data analysis for the second 
manuscript has been completed and the manuscript will be submitted by June 2022 (see 
Manuscript 2).  
Data analysis of feasibility study (WP3, 3.3): Status: data analysis completed. The time necessary 
for data analysis for the feasibility study was added to the timeline. The manuscript has been 
recently submitted (see Manuscript 3). 
Updated research approach and work plan for the 2nd term.  
Update, elaborate and motivate the planned course of activities for the 2nd term. You might use a table or 
graphic representation (timing work packages, milestones, critical path). 
 
WP2 RCT: End of patient recruitment and data collection 
As previously mentioned, we changed the timeline compared to the initial FWO proposal, based on 
the current recruitment rate impacted by the Covid-19 pandemic. The end of patient recruitment 
will be in May 2022 (Milestone 2) and the last follow up will be in November 2022. The adaptations 
are indicated in dark blue in Table 1. Status: data collection. 
WP3: Data analysis 
Data analysis of the RCT (WP3, 3.4 and 3.5): demographics and other objective measures (strength, 
range of motion, scapular dyskinesis, data from the US machine) will be processed already from 
June 2022, but the data concerning the randomization process of two groups will be unblinded only 
at the end of the trial in November 2022. Related manuscripts: see Manuscript 4 and 5. The end of 
the data analysis will be Milestone 3. Status: Milestone 3 has been delayed from Q2 2022 (initial 
FWO project) to Q4 2023. This delay is due to a decrease in patient recruitment caused by the 
pandemic of Covid-19. However, thanks to the extension of the FWO scholarship, there will be 
sufficient time to recruit all patients and to conduct a thorough data analysis for both objective and 
subjective measures.  
US measure 
Intra-rater reliability, ICC (95%CI) 
AHD  
0.97 (0.93-0.99) 
SSP 
0.87 (0.71-0.94) 
AHD60 
0.85 (0.69-0.93) 
AHD60w 
0.77 (0.52-0.90) 
CHD0 
0.93 (0.86; 0.97) 
LHB 
0.90 (0.78; 0.96) 
SCP 
0.92 (0.83; 0.97) 
CHD60 
0.91 (0.81; 0.96) 
CHD60w 
0.88 (0.76; 0.95) 
Table 2 - US measures. ICC: 2-way mixed model, absolute 
agreement (average measures). Abbreviations: AHD= 
Acromiohumeral Distance, AHD60= Acromiohumeral 
Distance at 60°; AHD60w= Acromiohumeral Distance at 
60° with free weight; CHD= Coracohumeral Distance, 
CHD60= Coracohumeral Distance at 60°; CHD60w= 
Coracohumeral Distance at 60° with free weight; LHB= 
Long Head of Biceps tendon; SCP= Subscapularis tendon, 
SSP= Supraspinatus tendon. 

18 
 
WP4: Articles, PhD thesis  
• 
Manuscript 2: “Reliability of coracohumeral distance and subcoracoid tendons in 
subacromial pain syndrome” Claudia Cavaggion, Santiago Navarro-Ledesma, Birgit Juul-
Kristensen, Alejandro Luque-Suarez, Lennard Voogt, Filip Struyf.  
• 
Manuscript 3: “Exercise into pain in chronic rotator cuff related shoulder pain: a feasibility 
trial”  
• 
Manuscript 4: “The effect of exercise into pain in chronic rotator cuff related shoulder pain: 
a randomized controlled trial” 
• 
Manuscript 5: “The effect of exercise into pain in subacromial shoulder pain on subacromial 
and subcoracoid spaces” 
PhD Thesis (Milestone 4): “The effect of exercise into discomfort on clinical outcomes and 
ultrasound imaging parameters in patients with subacromial shoulder pain”. The submission will be 
4 months before the defence, and the defence will be within the FWO term.