Pilot Investigation to Evaluate Effectiveness of Shockwave Therapy, a Combination of Shockwave Therapy and Photobiomodulation and Physical Therapy in the Management of Non-insertional Achilles Tendinopathy: A Randomized Control Trial With Elective Cross-Over Design
Phase: NA
Conditions: Achilles Tendinopathy
Sponsor: Spaulding Rehabilitation Hospital

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Pilot Investigation to Evaluate Effectiveness of Shockwave Therapy, Photobiomodulation and 
Physical Therapy in the Management of Non-insertional Achilles Tendinopathy 
 
NCT04725513 
 
Date of document: January 17, 2024 
 
 
 

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I. 
BACKGROUND AND SIGNIFICANCE 
 
Non-insertional Achilles Tendinopathy (AT) is a common overuse injury in adults who are both 
athletes and nonactive.2 Tendinopathy occurs when there is either a failed healing response or the 
failure of normal turnover or remodeling response.3 AT can result in pain and limited movement 
due to the injury.  
 
In the last few decades there has been an increased prevalence of people running to maintain a 
healthier lifestyle.1 With an increase in running, there has been an increase in running-related 
injuries. Of these running-related injuries, AT contributes to between 6.2% and 9.5% .1 It’s been 
estimated in some studies that burden of AT may reach 52% lifetime prevalence in runners.9  
 
The most common treatment of choice for AT now are exercise loading programs.2 Eccentric 
strengthening (ECC), although the current most prominent treatment, may only improve 
symptoms in approximately 60% of AT patients.2  
 
Laser-induced photobiomodulation (PBM) has been shown to increase cell proliferation and 
metabolism, which may aid in the repair and remodeling process.3,4 Photobiomodulation therapy 
(PBMT) has been shown to be effective in a variety of clinical settings depending on wavelength 
and paraments used.4 In a meta-analysis and systematic review on plantar fasciitis, it was found 
that PBMT is effective with exercise and without exercise.4 Tumilty et al. found that PBMT was 
effective in the treatment of AT, but it was more effective when paired with exercise sessions, 
however other studies have shown mixed results.3  
 
Extracorporeal shockwave therapy (ESWT) is a process in which energy is delivered to the 
muscles or tendons to relieve aches and pains.6 Like PBMT, ESWT is used to treat a variety of 
musculoskeletal conditions, however it is more expensive and therefore used less often.5 A 
recent network meta-analysis showed that in the long term when ECC was combined with ESWT 
it was effective in treating AT, however there is limited data available on the impacts of ESWT 
in short term recovery.2 Notably PBMT was not able to be compared in the analysis due to no 
published studies meeting criteria for inclusion. There is also limited information available on 
the best energy settings to be used in treating AT,2 and therefore more research needs to be done 
into the impact of ESWT on treating AT. 
 
PBMT and ESWT are effective treatments, and a study on the treatment of other tendons in the 
body - lateral epicondylitis (tennis elbow) - showed improvement in both the PBMT and the 
ESWT arms, with ESWT showing a significant difference in increasing handgrip strength.5 
Studies such as this are promising that ESWT and PBMT will be effective in treating other 
tendon injuries such as AT. This promising result combined with the previous unclarity in the 
best treatment for AT justifies the need for more research. The sub-section of AT amongst 
runners has had very limited research and given the high prevalence, is something that should be 
addressed. Therefore, our study will compare three different treatment arms utilizing SWT, 
PBMT and traditional physical therapy, and using both questionnaires and measured outcomes 
we will assess the most effective treatment for AT.  
 
 

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II. 
SPECIFIC AIMS 
 
The primary aim of this pilot study is to evaluate the effects of standard physical therapy 
compared to treatment with SWT, and a combination of SWT and PBMT (each combined with 
physical therapy) in the management of Achilles tendinopathy. We hypothesize runners in each 
treatment allocation will see improvement in functional outcomes, pain and measures of Achilles 
tendon structure compared to baseline measures. As SWT and PBMT may change structural 
properties and modulate pain in tendinopathy, we anticipate greater measures in running 
function for participants assigned to SWT and PBMT in treatment over physical therapy as sole 
treatment.  
The secondary outcome will be to evaluate cross-over response. After the initial 3-month 
randomized control trial, subjects who are not satisfied with results, will be able to select a different 
treatment arm for the remaining 3 months of the study. 
 
III. 
SUBJECT SELECTION 
a. Inclusion/Exclusion Criteria 
Inclusion Criteria 
Patients will be eligible if they meet the following criteria: 
• Patients aged between 18-65 years old with a diagnosis of mid-portion Achilles 
tendinopathy (including both unilateral and bilateral)  
• Running is the pre-injury primary form of physical activity and pre-injury would complete 
on average 10 miles per week or more of running 
• VISA-A <80 at baseline to be eligible 
 
Exclusion Criteria 
Exclusion criteria includes: 
• Less than 3 months of symptoms 
• Primary insertional Achilles tendinopathy 
• Diagnosis of rheumatological disease/connective tissue condition, symptomatic arthritis 
of foot and ankle, a primary running related injury outside Achilles tendinopathy, other 
contraindications to PBMT or SWT 
• Have received SWT within the past 3 months to their Achilles 
• Prior injection within 3 months 
• Currently enrolled in PT for more than 4 weeks for their condition 
• Women who are pregnant or those who are planning to become pregnant. This is due 
to the fact that pregnancy will reduce participants activity after the treatment and the safety 
concerns related to shockwave treatment.  
• Patients with neuropathy affecting sensation to pain  
• Patients with a known underlying cardiac disease that could be affected by shockwave 
therapy  
• Patients with known history of Achilles tendon rupture 
• Patient currently taking oral steroids or fluoroquinolone antibiotics 
 
IV. 
SUBJECT ENROLLMENT 
a. Recruitment Procedure 

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We hope to enroll 60 runners into three treatment arms (n=20 in each arm). We will be using a 
multi-pronged approach to recruit patients: 
• Running Clinics 
o Referral from Dr. Tenforde 
o Referrals from other physicians at MGB and Harvard affiliated hospitals 
§ A letter and flyer will be provided to other practitioners in the MGB network 
to ask them to refer our study information to their patients. 
• Social Media 
• Email Lists 
o Flyers to be sent to different email lists of running clubs  
• Hospital advertising 
o Flyers 
o Rally 
o Research Patient Data Registry (RPDR) 
 
b. Procedure for obtaining informed consent 
A member of the research study staff will introduce the study to the patient and if they express 
interest in the study, then they can have the informed consent explained to them. Patients will 
have as much time as necessary to consult with their family or their physicians before enrolling 
in the study. If the patient understands and accepts the document, it will be signed, and the 
subject will be enrolled. No treatment or data collection will be done without informed consent.  
Consent can be obtained by any member of the study staff who has been trained in Good Clinical 
Practice (GCP). If a potential study subject is a patient of the PI, Dr. Adam Tenforde, then 
consent will be obtained by a different trained study staff member to avoid any concern for 
coercion. Consent may be gained in person or using the MGB online database – REDCap. 
 
V. 
STUDY PROCEDURE 
a. Overall Research Design and Methods 
This study has been split into two parts. Part 1 is the initial randomized control trial, and Part 
2 is when the participants can select the treatment they want to receive if they are not 
satisfied with their initial treatment. In Part 1 patients will not be blinded to the treatment arm 
that they receive due to the obvious differences in the treatments. 
Participants will also be asked to log their return to running at home using the University of 
Delaware Return to Sport protocol.8 
 
Part 1 
Study participants will be randomly assigned to one of three treatment groups, using a block 
randomization generator that is implemented into REDCap. There will be 20 patients per 
treatment group, no power calculation as this is a feasibility study. The three treatment arms are: 
physical therapy only, SWT and physical therapy, and a combination of SWT, PBMT and 
physical therapy. All runners, regardless of treatment group, will be asked to enroll in physical 
therapy at a location that is convenient to them (and accepts their insurance if applicable) and 
complete a standard physical therapy program addressing individual strength deficits in both 
proximal (spine and hip girdle) along with distal (thigh, leg and foot/ankle) muscle groups. To 
standardize loading program, we will provide all runners with an at-home exercise program 
designed by Dr. Karin Silbernagel for progressive Achilles tendon loading. This will be 

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completed alongside the physical therapy they are receiving. Activities including running will be 
allowed as tolerated following published guidelines by Dr. Silbernagel.8 
In subjects who have bilateral AT, the leg with the most severe symptoms (determined by the 
VISA-A) will be chosen as the primary data for the study, however both legs will be treated 
consistent with the treatment group the subject was randomized into. Outcomes will be obtained 
for each Achilles tendon, regardless of treatment, using VISA-A at each data collection point. 
Participants will also be asked to complete a weekly log of running and completing PT exercises. 
 
Part 2 
At the 3-month follow-up, participants who are not satisfied with their outcome will be given the 
option to choose one of the remaining treatment arms. Regardless of what treatment a patient 
chooses, if any, there will be one final visit conducted at 6 months for final data collection. 
 
Physical Therapy Only Arm 
After enrollment, participants will be assigned the home exercise program from Dr. Silbernagel 
and physical therapy with a therapist of their choice, instructions will include addressing any 
other lower extremity impairments known to contribute to Achilles tendinopathy including 
proximal strengthening program.10,11 The treatment protocol from Silbernagel et al. (2017)7 is 
described below: 
 
Phase 1: Week 1 – 2 (perform exercises every day) 
• Pain-monitoring model information and advice on exercise activity 
• Circulation exercises (moving foot up/down) 
• 2-legged toe raises standing on the floor (3 sets × 10-15 repetitions/set) 
• 1-legged toe raises standing on the floor (3 × 10)  
• Sitting toe raises (3 × 10) 
• Eccentric toe raises standing on the floor (3 × 10)  
Phase 2: Week 3 – 5 (Perform exercises every day) 
• 2-legged toe raises standing on edge of stair (3 × 15)  
• 1-legged toe raises standing on edge of stair (3 × 15)  
• Sitting toe raises (3 × 15) 
• Eccentric toe raises standing on edge of stair (3 × 15)  
• Quick-rebounding toe raises (3 × 20)  
 
Phase 3: Week 3 – 12 (Perform exercises every day and with heavier load 2-3 times/week) 
• 1-legged toe raises standing on edge of stair with added weight (3 × 15)  
• Sitting toe raises (3 × 15) 
• Eccentric toe raises standing on edge of stair with added weight (3 × 15) 
• Quick-rebounding toe raises (3 × 20)  
• Plyometric training  
 
Phase 4: Week 12 – 6 months (Perform exercises 2-3 times/week) 
• 1-legged toe raises standing on edge of stair with added weight (3 × 15)  
• Eccentric toe raises standing on edge of stair with added weight (3 × 15)  
• Quick-rebounding toe raises (3 × 20)  
Patients when working with their physical therapist, may be at different stages in their 
rehabilitation, continued physical activity/sport may be performed without a negative effect on 
recovery if the guidance on pain level and perceived exertion scale laid out by Dr. Silbernagel is 

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followed. Patients do not need to stop their activities as long as the activity is modified according 
to the pain monitoring model, and recovery days are adjusted accordingly.  
 
Shockwave (SWT) Arm: 
The shockwave arm will receive shockwave treatment in addition to the physical therapy 
program from Dr. Silbernagel. They will receive one treatment a week and one telephone check-
in a week for three weeks. Dr. Tenforde, the PI, will perform the SWT on all study participants, 
using the OrthoPlus Ultra 100/radial D-Actor. This Extracorporeal Pressure Activation 
Treatment (EPAT) device will be used at a radial shockwave of 3000 counts treatment settings of 
15 Hz minimum 2 bars with a focus applicator head at mid-portion of Achilles using clinical 
focusing technique, and 3000 counts at 15 Hz minimum 2.5 bars using broad oscillator to 
myotendinous region and over symptomatic areas of gastrocnemius and soleus.  Maximal 
settings will be 4 bars and initial treatment will start at 500 strikes at 1.5 bars for each treatment 
head to allow participant to be comfortable as we start shockwave sessions. The research 
coordinator will conduct the telephone calls to check-in on physical therapy exercise compliance 
and response to each treatment.  
 
 
SHW and PBMT Arm 
This treatment arm will receive both SWT and PBMT in addition to the physical therapy 
program from Dr. Silbernagel. The SWT will be performed by PI, Dr. Tenforde, and the PBMT 
will be performed by either the PI or a trained member of the study staff. Training for the PBMT 
will be conducted by a local LightForce representative. They will receive PBMT using the 
LightForce® XPi 25W device with the Smart Hand Piece technology, which has a built-in 
accelerometer in the hand piece that controls the speed of light delivery to the treatment area. 
The therapy is delivered through a flexible optical fiber threaded through the hand piece, which 
contains a rolling glass massage ball. PBMT will be delivered at 10 J/cm2 and applied in a 
serpentine pattern to the calf from the fold in the back of the knee to the bottom of the foot and 
the sole of the foot including the arch. A member of the study team will calculate the treatment 
area according to a standard protocol (appendix I), and calculate the treatment time.  
Patients will receive PBMT twice a week for three weeks, and SWT will be combine once a 
week for three weeks. 
 
  
b. Visit Details  
 
After consent has been obtained, patients will be randomly allocated to one of the three treatment 
arms. The expectations for the visits for the different study arms are outlined below: 
 
Table 1: Outlined visits from three different study arms 
 
Physical Therapy only  
Shockwave 
PBMT & Shockwave 
T0: Baseline 
Subject screening & enrollment* 
Part 1 
Subject to be randomly assigned a treatment arm  

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T1: week 1 visit 1 
VISA-A, ProMIS-29, 
UWRI, patient goals 
Ultrasound, heel raises & 
hopping test 
Treatment 1 
VISA-A, ProMIS-29, 
UWRI, patient goals 
Ultrasound, heel raises & 
hopping test 
PBMT & SW treatment 
VISA-A, ProMIS-29, 
UWRI, patient goals 
Ultrasound, heel raises & 
hopping test 
T2: week 1 visit 2 
telephone check-in 
telephone check-in 
PBMT treatment only 
T3: week 2 visit 1 
telephone check-in 
Treatment 2 
PBMT & SW treatment 
T4: week 2 visit 2 
telephone check-in 
Telephone check-in 
PBMT treatment only 
T5: week 3 visit 1 
telephone check-in 
Treatment 3 
PBMT & SW treatment 
T6: week 3 visit 2 
telephone check-in 
VISA-A, ProMIS-29, 
UWRI 
telephone check-in 
VISA-A, ProMIS-29, 
UWRI 
PBMT treatment only 
VISA-A, ProMIS-29, 
UWRI 
T7: 6 week follow up 
telephone check-in 
VISA-A, ProMIS-29 & 
UWRI 
telephone check-in 
VISA-A, ProMIS029 & 
UWRI 
telephone check-in 
VISA-A, ProMIS-29 & 
UWRI 
T8: 3 month follow up 
VISA-A, ProMIS-29, 
UWRI, patient goals, 
patient satisfaction, new 
treatment selection 
Ultrasound, heel raise & 
hopping test 
VISA-A, ProMIS-29, 
UWRI, patient goals, 
patient satisfaction, new 
treatment selection 
Ultrasound, heel raise & 
hopping test 
VISA-A, ProMIS-29, 
UWRI, patient goals, 
patient satisfaction, new 
treatment selection 
Ultrasound, heel raise & 
hopping test  
Part 2 
Participants to choose treatment and follow visit schedule as listed above  
T9: 6 month follow up 
Patient satisfaction, 
ultrasound, heel raises & 
hopping test 
Patient satisfaction, 
ultrasound, heel raises & 
hopping test 
Patient satisfaction, 
ultrasound, heel raises & 
hopping test 
*At baseline subjects will be screened for their eligibility using the inclusion and exclusion 
criteria described on page 2 of this document. To determine pregnancy female patients will be 
asked if they are pregnant, planning to become pregnant, or not pregnant. MGB guidelines 
state that when using non-iodizing radiation if a woman states she is not pregnant, no pregnancy 
test is required.  
Due to the nature of COVID-19, in-person visits, check-ins, and questionnaires, can be 
rescheduled +/- 14 days within each of the outlined study timepoints.  
 
Physical Therapy 
In part 1 the physical therapy only arm will only have to complete 2 in-person visits, baseline 
and the 3 month follow up, but they will receive two calls a week for the first three weeks to 
ensure consistency with the other treatment arms, and the virtual 6 week follow-up. The number 
of visits they will have to complete in part 2 will depend on which treatment arm the subject 
selects, but they will be required to come in at least once to complete the 6 month follow-up. The 
study will start when they enroll in the study and start the Dr. Silbernagel’s protocol. 
 

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Shockwave 
The shockwave group will have 3 in-person visits and 3 virtual visits in part 1, and then at least 
one visit in Part 2 for the 6 month follow up. The number of visits required in part 2 will depend 
on what treatment the subject chooses at the 3 month check in.  
 
Shockwave + Photobiomodulation therapy 
The PBMT and SWT treatment arm requires 6 in person visits in part 1 (3 for PBMT alone and 3 
for PBMT & SWT), 1 virtual visit (6 week follow up) and at least 1 visit in part 2. The number 
of visits in part 2 will depend on which treatment the subject chooses at T8 (see table 1). 
 
 
Study Visits for all treatment arms: 
An overview of the questionnaires and measurements that will be taken at various time points, 
regardless of treatment arm, are described in table 2. 
 
 
 
Table 2: Overview of questionnaires and measurements required regardless of treatment arm 
 
 
 
VI. 
BIOSTATISTICAL ANALYSIS 
a. Specific data variables being collected 
Questionnaires: 
• Symptoms severity specific to Achilles will be VISA-A 
 
Questionnaires 
Measurements 
Visit 
VISA-
A 
ProMIS-
29 
UWRI Patient 
goals 
Treatment 
preference 
Patient 
satisfaction 
Return  
to sports 
worksheet 
collection 
Ultrasound Heel 
raise & 
hopping 
test 
Baseline 
x 
x 
x 
x 
x 
 
 
x 
x 
3-week 
follow-
up 
x 
x 
x 
 
 
 
x 
 
 
6-week 
follow 
up 
x 
x 
x 
 
 
 
x 
 
 
3-month 
follow-
up 
x 
x 
x 
x 
x 
x 
x 
x 
x 
6-month 
follow 
up  
x 
x 
x 
x 
x 
x 
x 
x 
x 

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o The VISA-A is currently the only valid and reliable measure to assess function and 
pain in AT (validity, P<0.01; test-re-test reliability, r = 0.98) (2*) 
• ProMIS-29 will be used to capture other aspects of non-disease specific measures of health-
related domains (physical, mental and social health).  
• The University of Wisconsin Running Injury and Recovery Index (UWRI) will measure 
aspects unique to the running population.  
• Visual analog scale of pain 
• To quantify patient choice and motivation for treatment, an unvalidated survey will be 
obtained to determine patient goals of enrollment in study and reason for selecting a 
different intervention.  
• Patient satisfaction with treatment 
• Participant demographics 
o Age at enrollment 
o Gender 
o Fitzpatrick skin type 
o Self-identified race and/or ethnicity 
o Marital status 
o Military status 
o Exclusion Criteria 
o BMI calculated from height and weight 
o Achilles tendon surgical history 
• Expected AE interview forms 
o Achilles specific (one for each limb at week 1 check in, week 2 check in, 3 week 
follow-up, 6 week follow-up, 3 month follow-up, and 6 month follow-up) 
 
Ultrasound: Ultrasound measures will be assessed at baseline, 3 months and 6 months. Measures 
of interest include cross-sectional area, degree of thickening within the tendon at site of maximal 
circumference and maximal pain, and presence and number of neovessels on color flow doppler. 
Function: Quantitative function in heel raises to fatigue will be measured at baseline, 3 months 
and 6 months on both affected and unaffected limb. We will also ask the participants to complete 
20 hops and rate their pain using a visual analog scale (0 to 10).  
Return to running: We will be asking participants to record their return to running, following 
Drs. Silbernagel & Crossley8 protocol. In order to log this, they will track the date, exercise and 
pain level using the University of Delaware training diary.8  
 
b. Study Endpoints 
Objective Endpoints 
• Ultrasound endpoints 
• Calf raises 
 
Subjective Endpoints 
• Questionnaires 
 
c. Statistical methods 
For the statistical analysis of both the primary outcome, VISA-A, and secondary outcomes, 
PROMIS-29, UWRI, VAS, ultrasound measurements, and functional tests, we will use the 

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Shapiro-Wilk test to for normality in the data. For the continuous data we will use the t-test and 
ANOVA test if the data is normally distributed, and we will use the Mann-Whitney U test and 
Kruskal-Wallis analyze the data that is not normally distributed. For the binary data we will use 
the chi2 or Fishers test to compare the data.  
In the first phase of the study, the randomized control trial, we will use a multivariable linear 
regression, controlling for: sex, BMI, age, medical condition (thyroid disease and diabetes) and 
prior oral steroid and/or fluoroquinolone use. In phase 2 after the elective cross-over, we will use 
the models described above as repeated measure models.  
Interim analysis will be performed after 30 participants are enrolled to review for safety and 
tolerance to treatment. 
 
VII. 
RISKS AND DISCOMFORTS 
 
Physical Therapy 
There are no expected risks or discomforts associated with the physical therapy, however physical 
therapy involves exercises designed to address causes of movement impairment, similar response 
to exercising muscles such as soreness and pain may be experienced. This is minimized by 
supervision by trained physical therapy using best practices to guide treatment. 
 
 
Shockwave  
The OrthoPlus Ultra 100 is a Class I FDA approved device with minimal risk. It is a low energy 
device and no severe events have been reported. 
Reported discomforts of shockwave include bruising, swelling and rarely, tissue damage. Pain 
response is expected due to device treatment over sites of injury and use of process of clinical 
focusing; we will monitor each patient and adjust treatment settings to ensure pain is tolerable 
during the treatment. 
 
 
Photobiomodulation  
The risks associated with PBMT are minimal. Mild discomfort may be experienced during the 
treatment, the treatment should not be “hot”, but participants should notify the study team member 
if they feel any uncomfortable warming. Individuals with neuropathies or difficulty distinguishing 
changes in skin temperature are at higher risk. Protective eyewear will be provided and must be 
worn by the participant and study team member during operation of the laser to protect your eyes 
from accidental laser exposure. No serious adverse events have been reported using this treatment.  
 
VIII. POTENTIAL BENEFITS 
 
a. Potential benefits to the subjects 
Medical/Physical benefits 
The aim of this study is to improve recovery of AT, it is expected that all treatment arms will 
help AT recovery, some treatments potentially quicker that other, more traditional treatment 
options. 
Compensation 

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All patients will be eligible to receive PBMT or SWT without cost. The cost of medical 
assessment or prescribed physical therapy will be paid by patient through traditional health 
insurance.  
Patients will be able to receive checks up to $150 in renumeration for completing the study. They 
will receive their payment at the end of the study, if they withdraw early, they will be 
compensated for the visits that they did complete as broken down below: 
• Enrollment and completion of 6-week follow-up: $50 
• 3-month follow-up: $50 
• 6-month follow-up: $50 
 
b. Potential benefits to society 
Taking part in this study will include a sense of contributing to the benefit of other through 
participating in medical research. 
 
IX. 
MONITORING AND QUALITY ASSURANCE 
 
a. Data and safety monitoring 
The principal investigator (PI) will be responsible for the protocol safety monitoring. The PI will 
make study documents (e.g., consent forms, data pulls) and pertinent hospital or clinical records 
readily available for inspection by the local IRB and over sight staff for confirmation of the study 
data. All those responsible for data collection and storage will be aware of and comply with all 
regulatory requirements related to Adverse Events (AE). If a person becomes ill or is injured as a 
direct result of study, medical care will be made available. All adverse events (and device events) 
will be followed to resolution and reported to the MGB IRB. Documentation of the presence of 
any side-effect, adverse event and unexpected device events will be completed at every visit and 
will be reported in accordance with AE reporting guidelines of the MGB IRB. Persons will be 
encouraged to contact the investigator or a member of his staff at any time between visits 
concerning adverse events or worsening of symptoms. An event that is deemed serious by the 
principal investigator will be recorded in the person’s study binder and will be handled in an 
expeditious manner. If at any time during the study, the PI judges that the risk to subjects 
outweighs the potential benefits, the PI shall have the discretion and responsibility to recommend 
that the study be terminated. 
Data will be shared with the Geneva Foundation via REDCap. This data will include de-
identified common demographic variables, including: biological sex, marital status, year of birth, 
self-identified race and/or ethnicity, Fitzpatrick skin type, military status (civilian vs other 
aspects of prior or current military service), and injury location.  
 
 
b. Plan for review of adverse events 
An Adverse Event (AE) is any untoward medical occurrence in a subject that does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign, symptom, or disease temporally associated with the use of an investigational 
product, whether or not related to the investigational product.  
All AEs that occur after the subject signs the consent form will be documented as an AE. The 
Investigator will ensure that all events that occur during the study period are recorded. All AEs 
will be followed until resolution or until, in the Investigator’s judgement, that are chronic and 

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stable. In an emergency situation appropriate medical measures will be taken to stabilize the 
subject.  
 
Serious Adverse Event (SAE) is any untoward medical occurrence that: 
• Results in death 
• Is life-threatening 
• Requires in subject hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly/birth defect  
• Is another medically important condition. 
 
Adverse Event Severity Assessments 
The guidelines outlined in CTCAE v4 will be used for severity assessments. (Note – the term 
“severe” is a measure of intensity and that a severe AE is not necessarily serious). 
AE Severity Grading Scale 
Severity Grade 
Description 
Mild (1) 
Awareness of sign, symptom, or event, but easily 
tolerated; does not interfere with usual daily 
activities or tasks. 
Moderate (2) 
Discomfort enough to cause interference with 
usual daily activity. It may warrant therapeutic 
intervention. 
Severe (3) 
Incapacitating; inability to perform usual 
activities and daily tasks; significantly affects 
clinical status; requires therapeutic intervention. 
Life-threatening 
(4) 
Emergency treatment required life-threatening, 
death. 
Each AE will be categorized as “serious” or “not serious” based on the definition of an 
SAE.  
Adverse Event Causality Assessments  
Adverse events will be assigned a relationship (causality) to the treatments.  The PI will be 
responsible for determining the relationship between the treatment and the AE. The type of event 
will help assess the likelihood that an AE is related to the treatment.  Relationship of AEs to 
study products will be classified as follows: 
• Not Related: No relationship exists between the AE and the treatment. The event is 
attributed to a pre-existing medical condition or an intercurrent event unrelated to the 
study device and procedures. 
• Possibly Related:  Follows the treatment, but may have been developed as a result of an 
underlying clinical condition or treatments/interventions unrelated to the study. 
• Probably Related:  Follows the treatment, but is unlikely to have developed as a result 
of the subject’s underlying clinical condition or other treatment or other interventions. 

13 
 
• Definitely Related:  Follows the treatment and the physical evidence shows a convincing 
relationship to the treatment. 
• Unknown:  Follows the treatment, but unable to determine the relationship to the 
treatment. 
Serious injury is defined to be an injury or illness that results in permanent impairment of a body 
function or permanent damage to a body structure, or necessitates medical or surgical 
intervention to preclude permanent impairment of a body function or permanent damage to a 
body structure that occurs during the course of the trial beginning after informed consent has 
been executed and extending until 30 days after the final study visit. 
Partners IRB must be notified within 5 working days/ 7 business days of SAE discovery. 
The Investigator is responsible for maintaining documentation in the study file that indicates the 
IRB has been properly notified. 
 
 

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X. 
REFERENCES 
 
1. Lopez, A. D., et al. What are the Main Running Related Musculoskeletal Injuries? A 
Systematic Review. Sports Medicine 42, 891-905 (2012) 
2. Rhim, H. C., et al. Comparative Efficacy and tolerability of Nonsurgical Therapies for 
the Treatment of Midportion Achilles Tendinopathy: A Systematic Review With 
Network Meta-Analysis. The Orthopaedic Journal of Sports Medicine 8 (7), 1-8 (2020) 
3. Tumilty, S., et. al. Photobiomodulation and eccentric exercise for Achilles tendinopathy: 
a randomized control trial. Lasers in Medical Science 31, 127-135 (2016).  
4. Do Santos, S. A., et al. Parameters and Effects of Photobiomodulation in Plantar 
Fasciitis: A Meta-Analysis and Systematic Review. Photobiomodulation, Photomedicine, 
and Laser Surgery 37 (6), 327-335 (2019) 
5. Celik, D., et al. Photobiomodulation Therapy Versus Extracorporeal Shock Wave 
Therapy in the Treatment of Lateral Epincondylitis. Photobiomodulation, Photomedicine, 
and Laser Surgery 37 (5), 269-275 (2019) 
6. CuraMedix, OrthoPulseTM Ultra Operations Manual Part No. 23300.0100, 
www.curamedix.com  
7. Silbernagel, K. G., et al. Continued Sports Activity, Using a Pain-Monitoring Model, 
During Rehabilitation in Patients with Achilles Tendinopathy: A Randomized Control 
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