Conditions: Apophysitis; Juvenile
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 45
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to determine if there is a difference in time to meet return to sport criteria for Pediatric patients with apophysitis of the knee who receive iontophoresis with Dexamethasone Sodium Phosphate (DSP) and Physical Therapy (PT) as those who receive iontophoresis with placebo and PT or PT alone.

Approximately 147 patients will be enrolled in this study.

Detailed description:
Iontophoresis is a treatment that allows medication to be delivered across your skin to the painful area without having to have an injection into your muscle or soft tissue, through a vein in your arm, or taking a pill. Instead, liquid medication is placed on a patch (like a large Band-Aid) and then placed on your knee over the location where it hurts. A plastic device, like a battery, is then attached to the patch for three minutes. During this time, this device begins to deliver the medication through your skin and into the area that hurts, and also charges the patch so it can continue to deliver the medication for two hours once the device is removed. The medication is delivered by a mild electrical current. The most common drug used with iontophoresis for pain caused by such things as apophysitis of the knee is dexamethasone sodium phosphate (dexamethasone).

This is an investigational study. Dexamethasone is a steroid medication that has been approved by the U.S Food and Drug Administration (FDA) to treat many types of problems (such as joint problems, skin and allergy problems, eye, stomach, and lung problems), but has not been approved to treat apophysitis of the knee using iontophoresis. In this study, it is an experimental drug.

Participants will be randomized to one of three treatment groups:

* Physical therapy with iontophoresis using Dexamethasone
* Physical therapy with iontophoresis using an inactive drug called a placebo
* Physical therapy alone

Participants will be asked to attend study visits twice/week for up to 8 weeks or until they are able to pass the Return To Sport Checklist, whichever is sooner. Participants will the receive a 30-Day Follow Up phone call and complete a survey at the 90-Day mark, making each participant's study duration approximately five (5) months.

Arms:
arm 1: Iontophoresis is a non-invasive delivery mechanism for transmitting a medication to a local area of the body. The I-Bresis™ System and I-Bresis™ Patch will be the delivery system used for this study. The I-Bresis™ Patch is an adhesive patch. 1.5 ml of the dexamethasone sodium phosphate (4ml/1mL) will be placed on one side and 1.5 ml of 0.9% sodium chloride (saline) solution will be placed on the other. Duration of exposure: 123 minutes. Frequency of exposure: twice per week for a total of 12 sessions over a maximum of 8 weeks or until Return to Sport Criteria are met, whichever is sooner. Participants will also receive the standard PT protocol for apophysitis of the knee. This will involve up to 20 visits. arm 2: Iontophoresis is a non-invasive delivery mechanism for transmitting a medication to a local area of the body. The I-Bresis™ System and I-Bresis™ Patch will be the delivery system used for this study. The I-Bresis™ Patch is an adhesive patch. 1.5 ml of 0.9% sodium chloride (saline) solution will be placed on one side and 1.5 ml of 0.9% saline solution will be placed on the other. Duration of exposure: 123 minutes. Frequency of exposure: twice per week for a total of 12 sessions over a maximum of 8 weeks or until Return to Sport Criteria are met, whichever is sooner. Participants will also receive the standard PT protocol for apophysitis of the knee. This will involve up to 20 visits. arm 3: Participants will only receive the standard PT protocol for apophysitis of the knee. This will involve up to 20 visits.

Interventions: intervention 1: Dexamethasone Sodium Phosphate intervention 2: Iontophoresis intervention 3: Physical Therapy
Intervention descriptions: intervention 1: Dexamethasone sodium phosphate administered via iontophoresis intervention 2: Iontophoresis on affected knee intervention 3: Physical therapy of affected knee

Protocol document:
Prot_SAP_000.pdf: 
 
Iontophoresis with Dexamethasone in Combination 
With Physical Therapy for the Treatment of Pediatric 
Patients Diagnosed with Apophysitis of the Knee: A 
Randomized, Double-Blind, Placebo-Controlled Trial  
IND # - 140701 
Principal Investigator: Dana Reesman, PT, DPT 
 Sponsor: Children’s Hospital of the King’s Daughters Sports Medicine 
Department 
Funded In Part By: Children’s Health Foundation 
CHKDSM-001 Version Number:  v 6.0 
20 May 2020 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
4.1 
Removed reference to no planned interim analysis.  
9.4.7 
Added Interim Analyses 
 


  
 
ii 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 4 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 5 
2 
INTRODUCTION ............................................................................................................................................ 6 
2.1 
Study Rationale .................................................................................................................................... 6 
2.2 
Background........................................................................................................................................... 6 
2.3 
Risk/Benefit Assessment .................................................................................................................... 7 
2.3.1 
Known Potential Risks ..................................................................................................... 7 
2.3.2 
Known Potential Benefits .............................................................................................. 11 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 12 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 12 
4 
STUDY DESIGN ........................................................................................................................................... 14 
4.1 
Overall Design .................................................................................................................................... 14 
4.2 
Scientific Rationale for Study Design.............................................................................................. 15 
4.3 
Justification for Dose ......................................................................................................................... 15 
4.4 
End of Study Definition ..................................................................................................................... 15 
5 
STUDY POPULATION ................................................................................................................................ 15 
5.1 
Inclusion Criteria ................................................................................................................................ 15 
5.2 
Exclusion Criteria ............................................................................................................................... 16 
5.3 
Lifestyle Considerations .................................................................................................................... 16 
5.4 
Screen Failures .................................................................................................................................. 17 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 17 
6 
STUDY INTERVENTION ............................................................................................................................ 17 
6.1 
Study Intervention(s) Administration ............................................................................................... 17 
6.1.1 
Study Intervention Description ..................................................................................... 17 
6.1.2 
Dosing and Administration ............................................................................................ 18 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 19 
6.2.1 
Acquisition and accountability ...................................................................................... 19 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 19 
6.2.3 
Product Storage and Stability ....................................................................................... 19 
6.2.4 
Preparation ...................................................................................................................... 20 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 20 
6.4 
Study Intervention Compliance ........................................................................................................ 21 
6.5 
Concomitant Therapy ........................................................................................................................ 21 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 22 
7.1 
Discontinuation of Study Intervention ............................................................................................. 22 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 22 
7.3 
Lost to Follow-Up ............................................................................................................................... 23 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 23 
8.1 
Efficacy Assessments ....................................................................................................................... 23 
8.2 
Safety and Other Assessments ....................................................................................................... 25 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 26 
8.3.1 
Definition of Adverse Events  and suspected adverse reaction .............................. 26 


  
 
iii 
8.3.2 
Definition of Serious Adverse Events (SAE) or serious suspected adverse 
reaction 
26 
8.3.3 
Classification of an Adverse Event .............................................................................. 26 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 27 
8.3.5 
Adverse Event Reporting .............................................................................................. 28 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 30 
8.3.7 
Reporting Events to Participants ................................................................................. 30 
8.4 
Unanticipated Problems .................................................................................................................... 31 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 31 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 31 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 32 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 32 
9.1 
Statistical Hypotheses ....................................................................................................................... 32 
9.2 
Sample Size Determination .............................................................................................................. 33 
9.3 
Populations for Analyses .................................................................................................................. 33 
9.4 
Statistical Analyses............................................................................................................................ 33 
9.4.1 
General Approach .......................................................................................................... 33 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 33 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 34 
9.4.4 
Safety Analyses .............................................................................................................. 34 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 34 
9.4.6 
Sub-Group Analyses ..................................................................................................... 34 
9.4.7 
Interim Analyses ............................................................................................................. 34 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 35 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 35 
10.1.1 
Informed Consent Process ........................................................................................... 35 
10.1.2 
Study Discontinuation and Closure ............................................................................. 36 
10.1.3 
Confidentiality and Privacy ........................................................................................... 36 
10.1.4 
Key Roles and Study Governance .............................................................................. 37 
10.1.5 
Safety Oversight ............................................................................................................. 38 
10.1.6 
Clinical Monitoring .......................................................................................................... 38 
10.1.7 
Quality Assurance and Quality Control ....................................................................... 38 
10.1.8 
Data Handling and Record Keeping ............................................................................ 39 
10.1.9 
Protocol Deviations ........................................................................................................ 40 
10.1.10 
Publication and Data Sharing Policy ........................................................................... 40 
10.1.11 
Conflict of Interest Policy .............................................................................................. 40 
10.2 
Abbreviations ...................................................................................................................................... 40 
10.3 
Protocol Amendment History ........................................................................................................... 42 
11 
REFERENCES ............................................................................................................................................. 43 
12 
APPENDICES ............................................................................................................................................... 45 
12.1 
Lower Extremity Functional Scale (LEFS) ..................................................................................... 45 
12.2 
Wong Baker FACES Pain Scale ..................................................................................................... 46 
12.3 
Return To Sport Checklist ................................................................................................................ 47 
12.4 
Godin Leisure-Time Exercise Questionnaire ................................................................................. 48 
12.5 
30-Day Phone Follow Up .................................................................................................................. 49 
12.6 
90-DAY FOLLOW UP (ELECTRONIC SURVEY) .............................................................. 50 
 


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STATEMENT OF COMPLIANCE 
This study will be conducted in compliance with the protocol, United States Code of Federal Regulations 
(CFR) 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and applicable state, local, and 
federal regulatory requirements. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form will be obtained before any participant is enrolled.  Any amendment to 
the protocol will be reviewed and approved by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination by the IRB will 
be made regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form. 
 
All personnel involved in the conduct of this study have completed Collaborative Institutional Training 
Initiative (CITI) Training in Human Subjects Research.  
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Iontophoresis with Dexamethasone in Combination With Physical Therapy 
(PT) for the Treatment of Pediatric Patients Diagnosed with Apophysitis of 
the Knee: A Randomized, Double-Blind, Placebo-Controlled Trial  
Study Description: 
This trial is a three-arm, randomized, double-blind, placebo-controlled 
comparison study looking at the functional and patient reported outcomes 
of iontophoresis (with dexamethasone sodium phosphate (DSP)) or 0.9% 
sodium chloride (placebo) in conjunction with PT  versus PT alone to treat 
pediatric patients diagnosed with apophysitis of the knee.   
 
The null and alternative hypotheses for the primary endpoint are: 
Null Hypothesis: Time to achieve Return To Sport (RTS) criteria for 
Pediatric patients with apophysitis of the knee who receive iontophoresis 
with DSP and PT is the same as those who receive iontophoresis with 
placebo and PT or PT alone.   
 
Alternative Hypothesis: Time to achieve RTS criteria for Pediatric patients 
with apophysitis of the knee who receive iontophoresis with DSP and PT 
will be different from those who receive iontophoresis with placebo and 
PT or PT alone.  
 
The null and alternative hypotheses for the secondary endpoints are: 
Secondary Endpoint (Efficacy) - Patient reported outcomes: 
Null Hypothesis: There is not any significant difference in patient reported 
outcomes (Lower Extremity Function Scale (LEFS), Godin Leisure-Time 
Exercise, and FACES pain scale) between pediatric patients with 
apophysitis of the knee who receive iontophoresis with DSP and PT and 


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those who receive iontophoresis with placebo and PT or PT alone.  
 
Alternative Hypothesis: Patient reported outcomes (LEFS, Godin Leisure-
Time Exercise, and FACES pain scale) of pediatric patients with apophysitis 
of the knee who receive iontophoresis with DSP and PT will be different 
from those who receive iontophoresis with placebo and PT or PT alone.  
 
Secondary Endpoint (Safety) : Frequency and intensity of adverse events 
Null Hypothesis: There is not any significant difference in frequency and 
intensity of adverse events between pediatric patients with apophysitis of 
the knee who receive iontophoresis with DSP and PT and those who 
receive iontophoresis with placebo and PT or PT alone.  
 
Alternative Hypothesis: Frequency and intensity of adverse events among 
pediatric patients with apophysitis of the knee who receive iontophoresis 
with DSP and PT will be different from those who receive iontophoresis 
with placebo or PT alone.   
Objectives: 
 
Primary Objective:   
- 
To compare the functional outcomes of iontophoresis with DSP in 
combination with PT versus iontophoresis with placebo in 
combination with PT versus PT alone in pediatric patients diagnosed 
with apophysitis of the knee. 
Secondary Objectives:  
- 
To compare the patient reported outcomes of iontophoresis with DSP 
in combination with PT versus iontophoresis with placebo in 
combination with PT versus PT alone in pediatric patients diagnosed 
with apophysitis of the knee. 
- 
To compare the safety of iontophoresis with DSP in combination with 
PT versus iontophoresis with placebo in combination with PT versus 
PT treatment alone in pediatric patients diagnosed with apophysitis of 
the knee.   
Endpoints: 
Primary Endpoint:  
- 
Length of time to meet RTS criteria as measured in days 
Secondary Endpoints:  
- 
Percent difficulty with activities as measured by the LEFS 
- 
Patient reported activity as measured by the Godin Leisure-Time 
Activity Questionnaire 
- 
Patient reported pain as measured by the FACES Pain Scale 
- 
Safety as measured by number and intensity of iontophoresis or DSP-
related adverse events 
 
Study Population: 
147 pediatric patients referred by the Children’s Hospital of the King’s 
Daughters (CHKD) Primary Care Sports Medicine Physicians and 
Orthopedic Physicians to the CHKD Sports Medicine PT Department, with a 
diagnosis of apophysitis of the knee.   
Phase: 
II  
Description of 
Participants will be screened, enrolled, and treated at six (6) CHKD Sports 


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Sites/Facilities Enrolling 
Participants: 
Medicine PT Clinics across the Hampton Roads area.   
 
Description of Study 
Intervention: 
The study intervention is iontophoresis therapy using 4mg/ml DSP in 
conjunction with standard PT. This will be compared to iontophoresis 
therapy using placebo with standard PT and standard PT alone.  
Iontophoresis is a non-invasive delivery mechanism for transmitting a 
medication to a local area of the body. DSP is a synthetic adrenocortical 
steroid approved for the use in endocrine, rheumatic, collagen, 
dermatologic, allergic, ophthalmic, gastrointestinal, respiratory, 
hematologic, neoplastic, and edematous disorders.  DSP is approved by 
the Food and Drug Administration (FDA) for intravenous, intramuscular, 
intra-articular, or intralesional administration but not via iontophoresis. 
Study Duration: 
Study enrollment is estimated to last 40 months, followed by six (6) 
months of data analysis, for total study duration of 46 months.   
Participant Duration: 
Each participant’s study duration will be approximately five (5) months.   
 
 
 


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1.2 
SCHEMA 
 
Timeline 
 
 
Within 90 Days of 
MD Referral  
(Day -90 – Day 0) 
 
 
 
Initial PT Evaluation*- 
Standard of Care 
 
 
 
 
 
 
 
 
 
Day 1 
 
 
 
 
 
Enrollment/  
Randomization/  
Study Intervention  
Treatment 1* 
Iontophoresis w/ DSP + PT n = 49 
 
Iontophoresis w/ Placebo + PT n = 49 
 
 
PT Alone n = 49 
 
Weeks 1 – 8  
or when RTS 
Criteria Met 
 
Maintenance – Study 
Treatment  
 
 
 
 
 
 
Weeks 1 –   
 
 
 
 
Maintenance - Standard of 
Care PT Treatment 
 
 
 
 
 
30-Day Post  
RTS Criteria Met 
 
 
 
 
Follow Up  
(Via Phone) 
 
 
 
 
 
90-Day Post  
RTS Criteria Met 
 
 
 
 
Follow Up  
(Via Electronic Survey) 
 
 
 
 
*-Initial PT Evaluation and Enrollment/ Randomization/ Study Intervention Treatment 1 Visits may be 
combined and completed on the same day. 
 


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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
 
Clinic Visits 
 
Follow-Up 
 
Study Treatment Visits 
Clinic  
Check 
Early 
Stop 
Visit 
 
Procedures ( Time to 
Complete) 
 
Initial 
Evaluation* 
 
# 1* 
 
# 2 - # 4 # 5 # 6 – # 11 
 
# 12 or 
Week 8, 
or when 
Return 
To Sport 
Criteria  
Met 
30 –Day 
By 
Phone 
90-Day 
By 
Survey 
Standard PT Treatment 
X 
 
 
 
 
 
 
 
 
 
Standard PT Treatment  
 
    
X -------------------------------------------------------------X  
 
 
 
Inclusion/ Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
Informed Consent  
 
X 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
FACES Pain Scale  
 
X 
X 
X 
X 
X 
X 
X 
 
 
Brief Physical Exam of the 
Targeted Knee  
 
X 
X 
X 
X 
X 
X 
X 
 
 
Medication Review  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lower Extremity Functional 
Scale (LEFS)  
 
X 
 
X 
 
X 
 
X 
X 
 
Return to Sport Criteria 
(RTS) Checklist  
 
X 
X 
X 
X 
X 
X 
 
 
 
Godin Leisure-Time Exercise 
Questionnaire  
 
X 
 
 
 
 
 
 
X 
X 
Compliance Check to Home 
Exercise Program, Patch 
Wear Time, Ice Application, 
Bracing, and Activity 
Restrictions 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Iontophoresis Treatment 
(Groups A and B only)  
 
X---------------------------------------------X 
 
 
 
 
Complete Case Report 
Forms 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Apophysitis refers to pain and inflammation at the apophysis, or secondary ossification center, thought 
to occur secondary to repetitive tensile stress at the tendinous attachment to the bone.1 Apophysitis of 
the tibial tubercle was first described in 1903 separately by Osgood and Schlatter.2   Osgood Schlatter 
Disease (OSD)was described as the painful separation of the epiphysis of the tibial tuberosity occurring 
in children and adolescents undergoing rapid growth, placing stress on the developing tibial tubercle 
through patellar tendon force.3  It is theorized that traction apophysitis and traumatic avulsion of the 
secondary ossification center occurs during the apophyseal stage of maturation of the tibial apophysis.2  
Males commonly become symptomatic between the ages of 12 and 15 years old and females develop 
pain between the ages of 8 and 12 years old.2  OSD affects 21% of athletic adolescents and 4.5% of aged 
matched nonathletic controls.4 Sinding-Larsen-Johansson (SLJ) Syndrome is similar to OSD in that it is 
due to traction apophysitis from the extensor mechanism except in SLJ the traction occurs at the inferior 
pole of the patella at the patellar tendon insertion.  It occurs most commonly in boys age 11-13 years 
old.   
Individual’s history and physical exam are typically sufficient to make a diagnosis. Patients usually 
present with a vague history of a gradual onset of pain and mild swelling overlying the tibial tuberosity.  
In both cases, pain is exacerbated after activities involving running and jumping as well as those with 
direct contact over the tibial tuberosity or patella such as kneeling.3   
In OSD, plain radiographs often show irregularity of the apophysis with separation from the tibial 
tuberosity in early stages and fragmentation of the apophysis in later stages. In SLJ, radiographs may 
show irregular ossification or fragmentation of the inferior pole of the patella which ultimately will fuse 
to the patella during growth. 
 
There are no prospective randomized controlled interventional studies evaluating the treatment of OSD 
or SLJ.  Both are self-limited diseases and generally cease with skeletal maturity.3 All data and evidence 
regarding treatment are from retrospective studies.  Initial management is non-operative and consists of 
rest, ice, oral anti-inflammatory medications, protective knee padding and PT.1 Patients with mild pain 
often continue their normal sports and activities while those with more severe pain benefit from rest or 
change to low impact sports and activities.  OSD and SLJ often result in pain with activities of daily living, 
decreased participation in sports and physical education, and decrease activity, fitness and socialization. 
 
 
2.2 
BACKGROUND  
The purpose of this double-blind placebo-controlled study is to evaluate the effects of treatment with 
DSP iontophoresis as an adjunct therapy with PT in pediatric patients with apophysitis of the knee.  
Patients diagnosed with OSD or SLJ will be randomized to one of three treatment groups: treatment DSP 
iontophoresis and PT, iontophoresis with placebo and PT, or PT alone.  This study will compare the 
functional and patient reported outcomes of each group. 


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Iontophoresis has been used clinically for over 50 years to deliver drugs transdermally to localized areas 
of inflammation.  Iontophoresis uses a mild electrical current to “push” ionic compounds through the 
skin and usually increases the rate and extent of absorption compared with passive treatments like the 
applications of creams, gels or ointments.5 The most common drug used clinically for musculoskeletal 
pain delivered by iontophoresis is DSP. DSP is a phosphate ester prodrug of DSP that transforms the 
highly lipophilic DSP into a water-soluable molecule suitable for injection.  The water solubility and two 
ionizable groups of DSP make it an ideal candidate for transdermal iontophoresis.  Iontophoresis delivers 
significantly more DSP solution across in vivo human skin compared to passive delivery.5 
While iontophoresis of DSP is widespread and has been used for decades in musculoskeletal conditions, 
studies evaluating its benefits in musculoskeletal conditions have been mixed.  Some studies have 
shown improved outcomes in pain and function in a number of musculoskeletal conditions, whereas 
other studies have shown no benefits.5 There have been no studies evaluating its use in the treatment of 
OSD or SLJ. 
Epicondylitis or “tennis elbow” is the musculoskeletal condition DSP iontophoresis has been evaluated 
with most.  One high quality randomized control trial of DSP iontophoresis for epicondylitis showed 
significant short-term improvement in pain and global function compared to placebo when treatment 
concluded, although benefit did not persist at one month follow up.6 Another high quality randomized 
control trial of DSP iontophoresis use in epicondylitis showed no short or long term improvement in pain 
or strength compared to placebo.7   A high quality randomized controlled trial in mild to moderate 
carpal tunnel syndrome comparing DSP iontophoresis to iontophoresis with distilled water showed no 
significant improvement in patient reported outcome scores or on nerve conduction studies.8  When 
used as a treatment for acute Achilles tendonitis in a double-blind study, DSP iontophoresis showed 
positive effects compared to iontophoresis with saline, but the study was underpowered and 
inconclusive.9 
While DSP iontophoresis has been used to treat musculoskeletal conditions for decades, there are few 
high quality studies evaluating its use in this manner.  Data supporting its use has been at best mixed.  
No studies on DSP iontophoresis use in OSD or SLJ exist, but it is commonly used for these indications.  
Our study will be the first to evaluate DSP iontophoresis for these conditions.  The limited studies done 
on the use of DSP iontophoresis for musculoskeletal conditions demonstrates the importance of 
performing a high quality trial. 
 
 
2.3 
RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS  
 
 
2.3.1.1 Iontophoresis 
 
 
May cause mild tingling, prickling and/or warm sensation – this is normal and should be 
anticipated by the participant 
 
Redness underneath the application site  used for iontophoresis 
 
Dryness or rough skin in area where the iontophoresis was administered 
 
Skin discoloration or hyperpigmentation 


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 
On rare occasions, iontophoresis therapy can result in transient skin reactions such as rash, 
inflammation, irritation or burns (blistering).  These skin reactions may be the result of: 
o individual sensitivity to the ionic solution used  
o the condition of the skin at the onset of treatment  
o reaction to the materials in the electrodes  
o a poor connection between the electrode and the patient’s skin.  
 
Participants will be instructed that if the treatment becomes painful, or if they experience a burning 
sensation, or an excessive sensation, they should remove the Patch and notify their Treating 
Therapist.   
 
 
2.3.1.2 DSP  
 
DSP is an adrenocortical steroid anti-inflammatory drug commonly used with iontophoresis in physical 
therapy.10  DSP, used in this research study, is approved by the FDA for intravenous, intramuscular, 
intra-articular, or intralesional use.11  The contraindications, warnings, and precautions associated with 
intravenous, intramuscular, intra-articular, or intralesional use are well outlined in the drug package 
insert.  However, for this study, and in line with standard practice, DSP will be administered via 
iontophoresis, a route of administration not approved by the FDA.   
 
Literature shows delivering medication via iontophoresis requires a smaller dose of medication than by 
other routes of administration, is non-invasive, and delivers the medication locally versus systemically, 
minimizing the risks of adverse drug reactions.10  There is no published data on the systemic effects of 
DSP administered via iontophoresis.   
 
Although not expecting systemic side effects, in the absence of published data, below are listed possible 
side effects, warnings, and precautions when DSP is given for intravenous, intramuscular, intra-articular, 
or intralesional use.   
 
When given for intravenous, intramuscular, intra-articular, or intralesional use: 
Known systemic side effects:  
  
 
 
Fluid and electrolyte disturbances:  
o Sodium retention 
o Fluid retention 
o Congestive heart failure in susceptible patients 
o Potassium loss 
o Hypokalemic alkalosis 
 
Musculoskeletal  
o Muscle weakness 
o Steroid myopathy 
o Loss of muscle mass 
o Osteoporosis 
o Vertebral compression fractures 
o Aseptic necrosis of femoral and humeral heads 


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When given for intravenous, intramuscular, intra-articular, or intralesional use: 
o Pathologic fracture of long bones 
o Tendon rupture 
 
Gastrointestinal  
o Peptic ulcer with possible subsequent perforation and hemorrhage 
o Perforation of the small and large bowel, particularly in patients with 
inflammatory bowel disease 
o Pancreatitis 
o Abdominal distention 
o Ulcerative esophagitis 
 
Dermatologic  
o Impaired wound healing 
o Thin fragile skin 
o Petechiae and ecchymoses 
o Erythema 
o Acne 
o Increased sweating 
o May suppress reactions to skin tests 
o Burning or tingling, especially in the perineal area (after I.V. injection) 
o Other cutaneous reactions, such as allergic dermatitis, urticaria, angioneurotic 
edema 
 
Neurologic  
o Convulsions 
o Increased intracranial pressure with papilledema (pseudotumor cerebri) usually 
after treatment 
o Vertigo 
o Headache 
o Psychic disturbances 
 
Endocrine  
o Menstrual irregularities 
o Development of cushingoid state 
o Suppression of growth in children 
o Secondary adrenocortical and pituitary unresponsiveness, particularly in times 
of stress, as in trauma, surgery, or illness 
o Decreased carbohydrate tolerance 
o Manifestations of latent diabetes mellitus 
o Increased requirements for insulin or oral hypoglycemic agents in diabetics 
o Hirsutism 
 
Ophthalmic  
o Posterior subcapsular cataracts 
o Increased intraocular pressure 
o Glaucoma 
o Exophthalmos 
 
Metabolic  
o Negative nitrogen balance due to protein catabolism 
 
Cardiovascular  
o Myocardial rupture following recent myocardial infarction  


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When given for intravenous, intramuscular, intra-articular, or intralesional use: 
o Hypertension 
o Cardiac dysrhythmia 
 
Other  
o Anaphylactoid or hypersensitivity reactions 
o Thromboembolism 
o Weight gain 
o Increased appetite 
o Nausea 
o Malaise 
o Hiccups 
o Immunosuppression 
 
The following warnings/precautions listed in the drug package insert will not be 
included in the consent form as they are associated with long-term use and the design 
of this study is for short-term use of DSP: 
 
Warnings/Precautions associated with DSP (when given for intravenous, 
intramuscular, intra-articular, or intralesional use): 
 
Related to adverse effects: 
 
Adrenal suppression – may cause hypercortisolism or suppression of hypothalamic-
pituitary-adrenal (HPA) axis), particularly in younger children or in patients receiving 
high doses for prolonged periods. HPA axis suppression may lead to adrenal crisis 
 
Immunosuppression – prolonged use of corticosteroids may increase the incidence of 
secondary infection, cause activation of latent infections, mask acute infection, prolong 
or exacerbate viral infections, or limit response to killed or inactivated vaccines 
 
Kaposi sarcoma – prolonged treatment with corticosteroids has been associated with 
the development of Kaposi sarcoma in case reports; if noted, discontinuation of therapy 
should be considered 
 
Disease-related concerns: 
 
Cardiovascular disease – use caution in patients with heart failure, acute MI and/or 
hypertension 
 
Diabetes – use caution in patients with diabetes mellitus; may alter glucose 
production/regulation leading to hyperglycemia 
 
Gastrointestinal disease – use caution in patients with GI diseases (diverticulitis, fresh 
intestinal anastomoses, active or latent peptic ulcer, ulcerative colitis, abscess or other 
pyogenic infection) due to perforation risk 
 
Hepatic impairment – use caution in patients with hepatic impairment, including 
cirrhosis; long-term use has been associated with fluid retention 
 
Myasthenia gravis – use caution in patients with myasthenia gravis; exacerbation of 
symptoms has occurred especially during initial treatment with corticosteroids 
 
Ocular disease – use caution in patients with cataracts and/or glaucoma; increased 
intraocular pressure, open-angle glaucoma, and cataracts have occurred with 
prolonged use. Use with caution in patients with a history of ocular herpes simplex; 
corneal perforation has occurred; do not use in active ocular herpes simplex. Not 


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When given for intravenous, intramuscular, intra-articular, or intralesional use: 
recommended for the treatment of optic neuritis; may increase frequency of new 
episodes 
 
Osteoporosis – use caution in patients with osteoporosis; high doses and/or long-term 
use of corticosteroids have been associated with increased bone loss and osteoporotic 
fractures 
 
Renal impairment – use caution in patients with renal impairment; fluid retention may 
occur 
 
Seizure disorders – use caution in patients with a history of seizure disorder; seizures 
have been reported with adrenal crisis 
 
Thyroid disease - Changes in thyroid status may necessitate dosage adjustments; 
metabolic clearance of corticosteroids increases in hyperthyroid patients and decreases 
in hypothyroid one 
Other: 
Pediatrics: May affect growth velocity; growth should be routinely monitored in pediatric 
patients 
 
Participants will be instructed to call 9-1-1 or seek medical treatment at their nearest emergency 
department if they experience a severe reaction.  
 
2.3.2 KNOWN POTENTIAL BENEFITS  
The iontophoresis system allows for the delivery of dexamethasone at a controlled rate to ensure 
therapeutic efficacy. Due to its continuous medication delivery at a pre-programmed rate, the risk of 
over or under dosing with iontophoresis is effectively eliminated. As a transdermal drug delivery system, 
benefits include the avoidance of “first-pass” metabolism, drug-food interactions, gastrointestinal 
absorption, and enzymatic activity, all of which may be a factor in oral drug administration. In contrast 
to injections, iontophoresis is a noninvasive method for delivering medication. While it does utilize a 
direct electrical current, it is typically well-tolerated with minimal discomfort.12 Iontophoresis using the 
I-Bresis™ system is a convenient method of dexamethasone delivery, with easy application, performed 
in clinic by trained therapists.  
While there is no specific research regarding the use of iontophoresis with DSP for knee apophysitis, 
there is literature indicating that it is useful for treatment of pain, resulting in reduction of disability 
associated with other musculoskeletal disorders.6,9,13,14,15,16,17 Current literature on Osgood-Schlatter 
disease describes common use of nonsteroidal anti-inflammatory drugs for a short period of time for 
decreased prostaglandin synthesis, pain-relief, and anti-inflammatory effects.3,18 Iontophoresis allows 
administration of DSP, an anti-inflammatory corticosteroid, without the risks involved with oral 
ingestion.  
While knee apophysitis is described in the literature as a self-limiting condition, it typically results in 
immediate functional limitations. Individuals with knee apophysitis are often prescribed rest or activity 
limitations as part of the current recommendations for conservative treatment. This results in limited 
participation in sports, physical education class, and recreational activities, thereby reducing physical 
activity, fitness, and socialization with peers. If iontophoresis with DSP is shown to facilitate expedited 


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recovery of knee apophysitis, it would result in both physical and psychosocial benefits for affected 
individuals. 
 
2.3.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
The systemic administration of steroids such as dexamethasone is associated with side effects that can 
affect multiple organ systems in the body including the muscular system, skeletal system, immune 
system, renal system, digestive system, integumentary system, nervous system, endocrine system, and 
circulatory system. Since dexamethasone will be administered transdermally in this study and for a short 
duration of time, we do not expect to see the systemic side effects of the medication. We have 
minimized the risk to the participants by administering DSP transdermally. The side effects of most 
concern would be local cutaneous reactions or hypersensitivity reactions.  
 
The benefits of facilitating a quicker recovery from knee apophysitis to allow both the physical and 
psychosocial benefits previously described far outweigh any small mostly theoretical risk. Any local 
reaction that could occur is self-limited in time and morbidity. In our almost 20 years in clinical 
experience of using iontophoresis with DSP we have never seen any significant adverse reaction. 
However, we have seen thousands of patients improve quickly with the addition of iontophoresis with 
DSP. From 2009 (the year data collection started) to 2018, the CHKD Sports Medicine PT program has 
administered over 23,000 iontophoresis with DSP treatments and none have resulted in a significant 
adverse reaction.  Currently there are no published studies documenting this perceived clinical benefit 
and it is imperative to determine if it is better than the current home regimen. Outside of the benefits to 
the individual patient there are also benefits to the parent/ guardian of the minor child by minimizing 
their time lost from work. This in turn will have societal benefits (psychosocially and economically). 
 
3 
OBJECTIVES AND ENDPOINTS 
PRIMARY OBJECTIVE:  
To compare the functional outcomes of iontophoresis with DSP in combination with PT versus 
iontophoresis with placebo in combination with PT versus PT alone in pediatric patients diagnosed with 
apophysitis of the knee. 
Primary Endpoints  
 
Length of time to meet RTS criteria as measured in days 
Justification for Endpoints 
 
The ultimate goal of physical therapy treatment for knee apophysitis is to return children and 
adolescents to pain-free physical activity. The World Health Organization (WHO) recommends a 
minimum of 60 minutes a day of moderate to vigorous physical activity for school-aged 
children.19  It is well documented that regular physical activity is essential for healthy growth and 
development by promoting cardiorespiratory and muscular fitness, as well as cardiovascular, 
metabolic, and bone health.19 In addition to the vast physical benefits, regular physical activity 
also promotes psychological and social benefits.19  The WHO reports that physically active 
children have been shown to demonstrate better academic performance and are suggested to 
be more apt to avoid drugs, alcohol, and tobacco.19 Similarly, the risks of pediatric physical 


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inactivity are also well documented, and this inactivity in childhood can evolve into a lifetime of 
preventable comorbidities.20 Currently, physical inactivity is the fourth leading risk factor for 
mortality.20 Because the pain associated with knee apophysitis often results in a reduction in 
physical activity for the affected pediatric population, it is critical that they receive appropriate 
treatment to facilitate an expeditious return to pain-free return to physical activity for their 
physical, cognitive, and psychosocial well-being. 
 
The RTS criteria were developed to address pain-free, proper mechanics with common activities 
and movements to demonstrate patient readiness for safe RTS. The length of time to meet 
these criteria was selected as the specific endpoint to determine if one treatment produces 
faster resolution of symptoms. Expediting RTS has significant financial, physical, and 
psychosocial benefits. Decreasing the length of time for RTS will reduce the cost for 
rehabilitation by limiting the number of required PT visits. It will also reduce the negative 
physical, emotional, and social implications associated with the activity restrictions often 
imposed on patients with knee apophysitis.  
SECONDARY OBJECTIVES: 
To compare the patient reported outcomes of iontophoresis with DSP in combination with PT versus 
iontophoresis with placebo in combination with PT versus PT alone in pediatric patients diagnosed with 
apophysitis of the knee. 
To compare the safety of iontophoresis with DSP in combination with PT versus iontophoresis with 
placebo in combination with PT versus PT treatment alone in pediatric patients diagnosed with 
apophysitis of the knee.   
Secondary Endpoints   
 
Patient reported percent difficulty with activities as measured by the LEFS 
 
Patient reported pain as measured by the FACES Pain Scale 
 
Patient reported activity as measured by the Godin Leisure-Time Activity Questionnaire 
 
Safety as measured by number and intensity of iontophoresis or DSP-related adverse events 
Justification for Endpoints 
 
The LEFS is a validated patient reported outcome tool that assesses the patient’s ability to 
perform 20 different activities involving the lower extremity. It allows the patient to rate his/her 
level of difficulty with each task as a result of pain or impairments to the involved lower 
extremity. The LEFS was selected based on its ease of administration and its inclusion of both 
common Activities of Daily Living (ADL’s) and more advanced sport-specific activities.  
 
The FACES Pain Scale allows the pediatric patient to select the face that best represents his/her 
pain intensity. This is assumed to generate a more accurate pain rating than a quantitative 
estimation required with a numerical rating scale, where children may not all have a good 
understanding of the quantitative value of numbers. It has been documented that children 
prefer the FACES Scale to the Visual Analog Scale, which would require them to select a point on 
a horizontal line to indicate pain intensity. Using the FACES Pain Scale will allow Treating 
Therapists to track the patients’ subjective pain ratings throughout the rehabilitation process. 
 
The Godin Leisure-Time Activity Questionnaire is a patient reported outcome tool that 
quantifies the patient’s level of strenuous, moderate, and mild physical activity in a typical 
week. This provides the Treating Therapists with quantitative information regarding the 


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patient’s typical level of physical activity prior to the onset of knee apophysitis to facilitate a full 
return to prior level of function following completion of physical therapy. The Godin Leisure-
Time Activity Questionnaire was selected based of its inclusion of low, moderate, and high level 
physical activities with examples for each category for ease of completion by patient/parent. 
 
Tracking the number and intensity of adverse events (see Section 8.3.3.1 Definition of Adverse 
Events) will determine if iontophoresis with DSP is a safe treatment option for this population by 
providing quantitative and qualitative data. 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
The primary study hypothesis is that the time to achieve RTS criteria for pediatric patients with 
apophysitis of the knee who receive iontophoresis with DSP treatment and PT will be different than 
those who receive placebo or PT alone.  The secondary study hypotheses are: that the patient reported 
outcomes for pediatric patients with apophysitis of the knee who receive iontophoresis with DSP 
treatment and PT will be different than those who receive placebo or PT alone; and the frequency and 
intensity of adverse events among pediatric patients with apophysitis of the knee who receive 
iontophoresis with DSP treatment and PT will be different from those who receive placebo or PT alone.    
 
This is a Phase II trial.   It is a three-arm, randomized, double-blind, placebo-controlled comparison study 
looking at the functional and patient reported outcomes of iontophoresis (with DSP or placebo) in 
conjunction with PT versus PT alone to treat pediatric patients diagnosed with apophysitis of the knee.   
 
The study is double-blinded and placebo-controlled to minimize bias.  There will be three (3) study 
groups  
o  Iontophoresis using DSP (study drug) + PT 
o  Iontophoresis using placebo + PT 
o  PT alone 
 
Participants in all three groups will receive the standard PT protocol for apophysitis of the knee.  This 
will involve up to 20 visits.  Participants randomized to the iontophoresis groups will receive up to 12 
iontophoresis treatments over a maximum of eight (8) weeks. All participants will receive a phone 
follow-up call 30 days after they meet RTS criteria as well as an electronic survey follow-up 90 days after 
they meet RTS criteria.   
 
This study will only be conducted through the Children’s Hospital of the King’s Daughters Sports 
Medicine PT Department with study-related activities occurring at six of CHKD’s Hampton Roads PT 
clinics.  All study-related activities will be completed by Physical Therapists and Physical Therapist 
Assistants (Treating Therapists) trained on the protocol and CITI trained. 
 
Concomitant therapies, age, gender, and race will be conducted to analyze the possible effects of these 
covariates on length of time to RTS  
 


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Stratifications of age, gender, and race will be conducted to analyze the possible effect of these 
covariates on length of time to RTS as well as on patient reported outcomes LEFS, Godin Leisure-Time 
Activity, and FACES Pain Scale and on safety outcomes. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The study is designed to compare the efficacy of iontophoresis with DSP as part of a comprehensive PT 
treatment. This will be compared to a placebo group receiving iontophoresis with placebo in 
combination with PT and to a third group receiving PT alone. The use of these control groups is 
proposed due to the high placebo effect observed in the pediatric population. It is proposed that in 
groups receiving iontophoresis, both subjects and Treating Therapists will be blinded to whether the 
patient is receiving DSP or placebo to minimize bias. Due to the fact that the third group is receiving only 
PT, it will be impossible for the subjects or Treating Therapists to be blinded to group assignment. 
Because current literature on knee apophysitis treatment typically recommends Non-Steroidal Anti-
Inflammatory Drugs (NSAID’s), ice, rest, home exercises, bracing, and PT, the placebo group and the PT 
only group would still be receiving what is cited as appropriate treatment for the diagnosis. Therefore, 
there should be no ethical concerns with using a control group receiving iontophoresis with placebo or 
with a group receiving PT alone. 
4.3 
JUSTIFICATION FOR DOSE 
 
DSP will be supplied as a 4 mg/ml concentration, with 1.5 ml of the solution used for each iontophoresis 
treatment per the labeling instructions and current standard of practice. 
0.9% sodium chloride (placebo) will be supplied at a volume equal to that of the DSP to appear identical 
for blinding purposes.  
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3.  The clinical trial is considered completed when the last participant’s last scheduled study-
related activity is completed. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Written approval from the referring physician for potential subject to be considered for 
enrollment into this study 
2. Provision of signed and dated informed consent form 
3. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
4. In good general health as evidenced by written approval from referring physician for potential 
inclusion in study.  


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5. Has the ability to effectively identify pain/burns and communicate with the investigators or their 
parents that they are experiencing pain or burning during treatment 
6. Referred to CHKD Sports Medicine PT by CHKD Primary Care Sports Medicine physicians or CHKD 
Orthopedics physicians with a diagnosis of apophysitis of the knee and with a prescription for 
standard PT treatment with iontophoresis 
7. Able and willing to complete iontophoresis treatments within eight (8) weeks of first treatment 
8. Must be ambulatory 
9. Males 7 to 14 years of age who have not reached skeletal maturity (skeletal maturity based on 
referring physician’s clinical judgement or as demonstrated via radiograph images taken within 
90 days of enrollment) 
10. Females 7 to 14 years of age who have not reached skeletal maturity (skeletal maturity based on 
referring physician’s clinical judgement or as demonstrated via radiograph images taken within 
90 days of enrollment) and who meet one of the following criteria:  
a. Pre-menarcheal 
b. Within two (2) year post onset of menses 
11. Males or females over the age of 14 only with radiographic evidence of skeletal immaturity, with 
images taken within 90 days of enrollment 
12. Index knee symptomatic for pain with activities of daily living or while playing sports. 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Index knee symptomatic for pain only with palpation and not with activities of daily living or 
while playing sport 
2. Diagnosis of bilateral apophysitis of the knee where both knees meet all of the inclusion criteria  
3. Systemic fungal infections  
4. Has an implanted electronic device 
5. Has a known sensitivity to DSP 
6. Presence of damaged skin, denuded skin, or other recent scar tissue on index knee 
7. Presence of active dermatologic conditions in the affected area (e.g., eczema, psoriasis) 
8. Presence of an abnormal neurological exam that indicates the subject would have a reduced 
ability to perceive pain (e.g. peripheral neuropathy) 
9. Has a known sensitivity to electrical current 
10. Is currently taking systemic steroids 
11. Has had iontophoresis with DSP treatment within the past 30 days 
12. Previously enrolled in this study 
13. Currently enrolled in another treatment research study 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
As part of standard of care, patients will be provided instructions for icing, limiting physical activity, and 
taking NSAIDs and bracing their knee as recommended by their referring physician.   Lifestyle 
considerations specific to this study, include: 
• 
Adhere to the SoA (see Section 1.1.3 Schedule of Activities) 
• 
Wear their patch for the full two (2) hours, then discard in a trashcan 


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5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants. 
Minimal information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Potential subjects for this study will include patients referred to CHKD Sports Medicine PT by CHKD 
Primary Care Sports Medicine physicians or CHKD Orthopedic physicians with a diagnosis of apophysitis 
of the knee and with a prescription for standard PT treatment and iontophoresis.  CHKD Primary Care 
Sports Medicine physicians and CHKD Orthopedic physicians may provide the patient and his/her family 
an informational flyer about the study and will be encouraged to contact the Principal Investigator if 
they are interested in learning more about it before their initial PT evaluation.     
Given the natural course of apophysitis of the knee, this study population will involve children.  All 
children ages 8 to 17 years old will give both verbal and written Assent as well as their parent/guardian 
providing written consent for those less than 18 years of age. 
 Based on the analysis plan, a total of approximately 49 subjects per group will be required, with a total 
enrollment of 147 subjects.   
All potential subjects who are screened to participate in the study will be documented on a Screening 
Log.   
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
The study intervention for this project is DSP administered via iontophoresis.  Iontophoresis is a non-
invasive delivery mechanism for transmitting a medication to a local area of the body. The I-Bresis™ 
System and I-Bresis™ Patch will be the delivery system utilized for this study.  The I-Bresis™ System is 
indicated for the administration of soluble salts or other drugs into the body for medical purposes as an 
alternative to hypodermic injection.   The I-Bresis™ System consists of three components: a Charging 
Station, a rechargeable Controller and a disposable Patch.  The I-Bresis™ Patch is a disposable, single-use 
patch with a battery and current-limiting circuitry, and can deliver both negatively and positively 
charged water-soluble drug/compounds across intact skin.   The I-Bresis™ System will be used in 
accordance with instructions for use. 
• 
Device size(s) Patch: 13.5cm x 6.5cm that holds 1.5mL of fluid on each side of the patch 
• 
Device model(s)  
 
I-Bresis™ charging station: 1360 
 
I-Bresis™ Controller: 1361 
 
I-Bresis™ Patch: 5000060 


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• 
Description of each component 
 
The I-Bresis™ charging station is a rectangular piece of equipment that has four 
charging ports to which I-Bresis™ Controller attaches. This device is plugged into a 
standard wall outlet for power. Each individual charging port has a light to signify if the 
device is charging (yellow) or fully charged (green).21 
 
The I-Bresis™ Controller: 1361 is a small triangular device that attaches to the I-Bresis™ 
Patch. There are three buttons on top of the device: Power, Start/pause, and standard 
mode. There is a light on the front of the device that blinks when the device is powered 
on. The light is solid when the device is running.22 
 
The I-Bresis™ Patch is a 13.5cm  x6.5cm adhesive patch with two “patch drug pads”, 
each of which are labeled with a polarity of either  positive (+) or negative (-).  Each 
drug pad holds ~1.5 ml of fluid.  Approximately 1.5 ml of a water-soluble drug/solution 
is placed on one drug pad and approximately 1.5 ml of the saline solution (supplied in 
the I-BresisTM Patch carton as single-use, sealed vials of sterile 0.9% saline solution) is 
placed on the other.23 
 
 
Device settings and programming : 3mA current for three (3) minutes then 0.67mA for 120 
minutes 
• 
Duration of exposure: 123 minutes (3 minutes of patch + controller, 120 minutes of patch only) 
• 
Frequency of exposure : maximum twice per week for a total of 12 sessions over a maximum of 
eight (8) weeks 
 
The I-BresisTM System is commercially available and will be used in accordance with approved labeling. 
 
The drug and solution administered via the iontophoresis patch will be DSP and 0.9% sodium chloride 
(placebo).   
 
Dexamethasone sodium phosphate (DSP) is a synthetic adrenocortical steroid that has potent anti-
inflammatory effects but lacks the sodium-retaining property of hydrocortisone. Corticosteroids inhibit 
multiple inflammatory cytokines resulting in decreased edema, fibrin deposition, capillary leakage, and 
migration of inflammatory cells thereby suppressing inflammation. DSP 0.75 mg has anti-inflammatory 
activity equivalent to approximately 5 mg of prednisone, 25 mg of cortisone, and 20 mg of 
hydrocortisone. DSP is long-acting (half-life 200 minutes) and is recommended as adjunctive therapy in a 
variety of inflammatory disorders and as an immunosuppressant agent.11  
  
0.9% Sodium Chloride injection: is a sterile, nonpyrogenic solution of sodium chloride in water for 
injection. The solution contains 9 grams/L sodium chloride, USP (NaCl), with 154 mEq/L sodium and 154 
mEq/L chloride. The nominal pH of sodium chloride is 5.0 (4.5 to 7.0) and osmolarity is 308 mOsmol/L.24 
 
6.1.2 DOSING AND ADMINISTRATION 
 
The I-Bresis patch is designed to hold 1.5mL of fluid on each side (negative and positive) of the patch.  
DSP is supplied in 120 mg/30 mL (4 mg/1 mL) multidose vials, and will be repackaged into blinded 
bottles holding 1.8 mL (7.2 mg).  0.9% sodium chloride will be repackaged into blinded bottles holding 
1.8 mL.  Both DSP and 0.9% sodium chloride will be administered using the I-Bresis System. 
 


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6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 
ACQUISITION AND ACCOUNTABILITY 
 
DSP injection and 0.9%  sodium chloride injection will be supplied by the CHKD Pharmacy Department in 
identical looking single-use bottles, each containing 1.8 mL of solution and labeled in a blinded fashion 
as either Iontophoresis Study Drug “A” or “B”. These bottles will be provided by the pharmacy to the 
outpatient PT clinics and administered by the investigators to the patients. Trained site staff in the PT 
clinics will be responsible for accountability of the study drug, exercising accepted medical and 
pharmaceutical practices. Expired or unused study drug bottles will be returned to the CHKD 
Investigational Pharmacy and disposed of per the CHKD Pharmacy Investigational Drug Policy. 
 
For all study bottles prepared, the CHKD Investigational Pharmacy will keep a compounding log to 
record the following information: date of preparation, manufacturer, lot number, manufacturer 
expiration date, number of bottles prepared, expiration date of the study bottles, and assigned numbers 
of the bottles. This compounding log will only be accessible to study pharmacists to ensure blinding is 
maintained. 
 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
DSP Injection, USP 4 mg/mL (Fresenius Kabi USA, LLC) is a clear colorless solution of DSP in water for 
injection. DSP will be provided in individual empty bottles, each containing 1.8 mL (7.2 mg DSP). Each 
bottle will contain 1.5 mL (6 mg) DSP for study administration and 0.3 mL of overfill to account for loss 
during transfer. Each bottle will be labeled identically to the placebo with the label designating assigned 
bottle number, study drug “A” or “B” and the expiration date clearly marked on the label. 
 
0.9% Sodium Chloride Injection, USP (Baxter Healthcare Corporation) is a clear colorless solution of 
sodium chloride in water for injection. The 0.9% sodium chloride solution will be provided in individual 
empty bottles, each containing 1.8 mL (no active drug). Each bottle will contain the 1.5 mL dose to be 
administered and 0.3 mL overfill to account for loss duringtransfer. Each bottle will be labeled identically 
to the DSP with the label designating assigned bottle number, study drug “A” or “B” and the expiration 
date clearly marked on the label. 
 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
All bottles (study drug and placebo) will be stored in a secured space at each of the study sites. These 
bottles will be stored between 20° to 25°C (68° to 77°F), and will be protected from freezing and 
excessive heat.  All bottles will have a shelf life of 30 days from transfer and the expiration date will be 
clearly marked on the label.  All bottles will be protected from light. 
 
Iontophoresis supplies, controlling stations, chargers, and patches will be stored in the outpatient clinics 
at room temperature per the device labeling instructions.   
 
 


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6.2.4 PREPARATION 
 
DSP and 0.9% sodium chloride will be supplied by the CHKD Pharmacy Department in identical looking 
bottles, each containing 1.8 mL of solution and labeled in a blinded fashion as either Drug “A” or “B”.  
Trained Therapists will be responsible for the preparation of the iontophoresis patches.  Aseptic 
techniques will be utilized when preparing the patches.  Upon randomizing a subject, the treating 
physical therapist will retrieve the appropriately labeled bottle (“A” or “B”, based on the subject’s 
randomization assignment) from the locked cabinet and check the expiration date. The treating physical 
therapist will apply 1.5 mL liquid (from the assigned bottle) to the negative side of the patch per the 
instructions listed in the I-Bresis Instruction for Use. The Therapist will then apply 1.5mL of 0.9% sodium 
chloride from the saline ampoules provided in the I-BresisTM carton to the positive side of the patch and 
will then obtain two patient identifiers (ex. Full name, DOB) from the patient prior to patch application 
per clinic policy.  
The treatment site will be cleaned thoroughly with alcohol prep (ensuring the area being treated is free 
from other creams and topical medications, including topical steroids) as described in the instructions 
listed in the I-Bresis Instructions for Use.23 The negative side of the patch will be applied over the tibial 
tubercle in patients with OSD and over the inferior patellar pole in patients with SLJ. 
The I-Bresis controller will be turned on then connected to the patch. At that time, the start button will 
be pressed and the current will be initiated at 3mA for an initial 3minutes of treatment. Following this 
three minutes, the controller will be removed and turned off. The Patch will remain in place and an 80 
mA-minute dose will be applied over two hours. The therapist will ensure that the patch fully conforms 
to the patient and that it will maintain full contact with the skin. To improve adhesion of the patch, the 
therapist may lightly wrap the patch with Pre-Wrap and secure the end with tape, ensuring the tape is 
not being applied over the patch so as not to bind it. 
Subjects will be monitored by their therapist for adverse events for 15 minutes after the patch is applied 
following the initial application and for an appropriate amount of time following all subsequent 
applications.  Subjects will leave the PT clinic with the patch in place.  The patch will be programed to 
deliver medication over a two-hour period, automatically switching off iontophoresis after the 
maximum dose has been administered.  Subjects will be instructed to remove the patch 2 hours after it 
has been applied as leaving the patch on longer than the recommended time may increase the risk of 
skin irritation. Subjects will be instructed to wrap the patch in paper towels and discard the Patch in a 
receptacle out of reach of children and pets.   
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
A center-stratified randomization method will be used to maintain balance between treatment groups 
and centers. Equal number of participants per intervention will be considered to maximize study power. 
The CHKD Pharmacy Department will hold the randomization key and will prepare bottles of study drug 
and placebo (see Section 6.2.2 Formulation, Appearance, Packaging, and Labeling).  
 
Treating therapists will assign randomization codes in chronological order as participants enroll in the 
study.  Since the study drug and sodium chloride are identical in appearance, the Treating Therapists will 


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be blinded to study assignment.  Those participants assigned to “Group C”, or standard PT alone, will be 
unblinded to treatment as they will not receive iontophoresis.   
 
In the case of an unexpected and serious adverse event in which knowing the study assignment is critical 
to the medical care of the participant, the CHKD pharmacist may release this information to the 
Independent Safety Monitor only, who may share this information with the treating physician.   
 
Both the Treating Therapist and the participants assigned to one of the two iontophoresis groups will be 
blinded to study treatment.  The DSP injection and 0.9% sodium chloride injection are clear, colorless 
liquids that will be supplied by the CHKD Pharmacy Department in identical looking single-use bottles.  
Each bottle will contain 1.8 mL of solution and will be labeled in a blinded fashion as either 
Iontophoresis Study Drug “A” or “B”. 
In this study, the Treating Therapists will also perform all physical therapy assessments. While having a 
separate group of “assessing therapists” and “treating therapists” minimizes bias even further than the 
current study design, combining their roles is preferred as it reduces error by minimizing the number of 
therapists involved, improves completion consistency of the RTS Criteria Checklist, and minimizes 
scheduling conflicts caused when trying to coordinate two therapist’s schedules for every study visit 
conducted. 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
All participants will be asked to attend up to 12 Study Treatment Visits within an 8-week period.  
Compliance with this request will be documented by the primary Treating Therapist with assistance 
from front office staff. The Treating Therapist will review all active study participants at his/her site to 
ensure each participant attended the two scheduled visits. Any study participants who missed a visit will 
be contacted by the therapist within 24 hours of the missed visit to be counseled on the importance of 
maintaining the assigned visit schedule and to ascertain if the participant wishes to continue with the 
study, as described in section 7.3. Lost to Follow-Up. 
 
Participants and/or parents will be asked to verbally confirm or describe compliance with their HEP, 
patch wear time (for those assigned to Groups A and B), icing recommendations, activity modifications, 
and bracing and NSAID use as recommended by their referring physician.    
 
6.5 
CONCOMITANT THERAPY 
 
Concomitant therapy during this study to include: 
 
NSAIDs for pain as recommended by referring physician, if applicable 
 
Brace use as recommended by referring physician, if applicable 
 
Ice for pain per standard of care as described on handout provided to all patients 
 
Patients and/or parents will be asked at the beginning of each PT treatment about use of the 
concomitant treatment options listed above. This will be documented by the treating physical therapist 
each visit. Each of these concomitant treatments may help reduce pain, but they will be recommended 
to participants across all three treatment groups, so it is feasible to analyze and distinguish independent 
effects of the study intervention compared to any potential effects from the concomitant therapies 
described above. 


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For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications and supplements. 
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Iontophoresis will be discontinued at the earlier of the following time points: 
 
The participant meets the RTS criteria 
 
The participant has completed  12 iontophoresis patch applications 
 
The participant has been receiving iontophoresis treatment  for 8 weeks    
 
The participant develops any medical condition for which full participation in PT (including, but 
not limited to iontophoresis) would be contraindicated  
 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
Discontinuation from iontophoresis does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol.  If a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
 
Brief physical exam of the affected knee  
 
Adverse event review and evaluation 
 
Concomitant medication review  
 
FACES Pain Scale 
 
RTS Checklist 
 
30-day Phone Follow-up 
 
90-day Survey Follow-up 
 
LEFS 
 
Subjects who experience a relapse of pain after the Clinic Check Visit and prior to the 90-day Follow Up 
will not receive additional iontophoresis treatment as part of the study plan.  Subjects who fall into this 
category will be treated with standard of care treatment as determined by the Treating Therapist or 
referring physician. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 


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 
If any clinical adverse event (AE), or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the participant 
 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Early 
Termination Case Report Form (CRF). Subjects who sign the informed consent form and are randomized 
but do not receive the study intervention may be replaced.  Subjects who sign the informed consent 
form, are randomized and receive the study intervention, and subsequently withdraw, or are withdrawn 
or discontinued from the study, will not be replaced. 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 3 consecutive scheduled 
visits or has gone ten (10) days without treatment, whichever comes first, and is unable to be contacted 
by the study site staff. The following actions will be taken if a participant fails to return to the clinic for a 
required study visit: 
 
The site will attempt to contact the participant and reschedule the missed visit within 24 hours 
of missed visit and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts will be documented in the participant’s medical record or study file.  
 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
As Standard of Care: 
 
All patients who are referred to the participating PT clinics with a diagnosis of apophysitis of the 
knee and a prescription for PT with iontophoresis will receive a PT Initial Evaluation (IE).  
Per department policy, the PT IE must take place within 90 days of referral date as indicated on 
the script.   
o The IE includes: review of demographics, medical history, medication regime, strength 
and balance tests, pain assessment, review of home exercise program, icing instructions, 
activity restrictions, and bracing and NSAID instructions as recommended by their 
referring physician.   
 
After the IE, and as part of standard of care, all participants, regardless of group assignment, will 
receive a standardized PT treatment progression provided by qualified therapists.   
o As standard of care, PT progression visits may include up to 19 visits 
 
Clinic Check Visit – Two (2) to three (3) business days after a participant is cleared for RTS, or has 
received treatment for eight (8) weeks, whichever is sooner, the participant will return to the 


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clinic for the Treating Therapist to confirm the participant remains pain free and able to meet 
the RTS criteria.   
o Physical therapy progression visits to further fine tune mechanics, strength, and stretch 
may occur after this visit as part of their standard of care. 
 
Study-related: 
Study-related procedures will begin on the first PT Treatment Day, which may be the same day as the IE 
or at the next PT visit, but never before the Consent is signed. If subjects meet inclusion/exclusion 
criteria and the potential participant consents to participate at the Initial PT Evaluation Visit, the IE and 
Enrollment/Randomization Study Treatment Visit 1 visits may be combined. 
 
The following procedures/evaluations will be obtained by the Treating Therapists:  
 
 
Lower Extremity Function Scale (LEFS) - (see Appendix 12.1) – a patient reported paper-based 
questionnaire that asks the patient to choose the level of difficulty of completing 20 different 
activities. Assessed at Study Treatment Visits 1, 5, 12/RTS Criteria Met Visit, and 30-day Follow 
Up.  Note: the LEFS will be administered over the phone at the 30-day Follow-Up Visit. 
 
FACES Pain Scale - (see Appendix 12.2) – a patient reported paper-based questionnaire that asks 
the patient to choose the face that best represents the pain they are experiencing in their knee. 
Assessed at the end of each Study Treatment Visit and again at the end of the Clinic Check Visit. 
 
RTS Criteria Checklist - (see Appendix 12.3) – a paper-based checklist completed by the Treating 
Therapist to determine whether or not the participant is ready to safely return to sport. The 
checklist was created to include the basic movements typically required for sports activities, 
though these activities are also applicable for return to PE participation and free play, making it 
appropriate for all patients, even those not involved in organized sports. These movements 
include squatting, running, bilateral and unilateral jumping, back pedaling, and quick direction 
changes. The checklist includes qualifying criteria for proper mechanics and requires that all 
activities be pain-free. The checklist was created to assess readiness for sports participation 
without actually requiring that the patient return to sport participation to meet criteria, as not 
all patients participate in organized sports or are in-season year round. The items assessed as 
part of this checklist are all part of normal standard of care for physical therapy. Assessed at 
each Study Treatment Visit and again at the Clinic Check Visit.  
 
Godin Leisure-Time Exercise Questionnaire (see Appendix 12.4) – a paper-based subject self-
reporting questionnaire comprised of four (4) items that address the amount of time an 
individual engages in mild, moderate, and strenuous leisure time physical activity of at least 15 
minutes in duration during a typical week.  Assessed at Study Treatment Visit 1 and at the 30-
day phone follow-up (see Appendix 12.5 30-Day Phone Follow Up) and 90-Day Follow-Up (see 
appendix 12.6 90-Day Follow-Up – Electronic Survey). 
 
Study Treatment: 
o Iontophoresis (Groups A and B only) - ~ 3 minutes in clinic and 2 hours at home - The 
iontophoresis patch will be applied by a trained therapist in blinded fashion for all 
participants assigned to groups A and B (see section 6.1.2 Dosing and Administration). 
Performed at Study Treatment Visits 1 – 12 (Maximum of 12 treatments, maximum of 8 
weeks since first Study Treatment Visit, or when RTS criteria are met and confirmed at 
the Clinic Visit Check, whichever is sooner). 
o For subjects assigned to Group “C” (PT only Group), Study Treatment Visits 1 – 12 
(maximum of 8 weeks since first Study Treatment Visit, or when RTS criteria is met) will 


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include only their standard PT Treatment Visits: Study Treatment 1 = Standard PT 
Treatment 1, Study Treatment 2 = Standard PT Treatment 2….). 
 
Note: Participants who initially meet RTS Criteria but fail to meet the RTS criteria when they 
return for their Clinic Visit Check will continue with their assigned study treatment until the 
sooner of: they once again achieve RTS criteria, they have received 12 study treatments, or 
they have received study treatment for eight (8) weeks.   
 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
The following procedures/evaluations will be obtained by qualified Therapists treating the subjects: 
Assessed At Enrollment/Randomization Study Treatment Visit 1: 
 
Inclusion/Exclusion Criteria - Based on the patient’s medical history and review of the initial 
evaluation, the Treating Therapists will determine whether patients meet eligibility criteria for 
the study. 
Note: if radiograph images were obtained to determine skeletal maturity, the Treating Therapist 
will ensure the results are documented in the radiologist’s notes or noted in the physician’s 
notes in the electronic medical record.   
 
Informed Consent - Treating Therapist will conduct the informed consent process as outlined in 
Section 10.1.1.2 of this document. 
 
Randomization - After a patient signs Consent, the Treating Therapist will assign the patient to 
the research group per the randomization log at the Site (see section 6.3 Measures to Minimize 
Bias: Randomization and Blinding).  
Assessed at All Study Treatment Visits: 
 
Brief Physical examination of the affected knee - an evaluation made by the treating physical 
therapist to include: skin color, temperature, presence of edema, turgor, pain with 
palpation/pressure, changes to skin texture, and integrity. Also assessed at Clinic Check visit. 
 
Concomitant Medication Review - a paper-based form completed by the Treating Therapist to 
document drug, dose, frequency, start and stop dates, and reason for taking. Also assessed at 
Clinic Visit Check visit.  
 
Adverse Event Evaluation - a paper-based form completed by the Treating Therapist to 
document occurrence, severity, relatedness, duration, and expectedness of the event. Subjects 
receiving iontophoresis will be specifically monitored for possible burns.  This data will be 
captured during the examination of the affected knee as well as for 15 minutes post patch 
application. 
Also assessed at Clinic Visit Check visit, 30-Day Phone Follow Up and electronically at the 90-Day 
Follow Up (see Appendix 12.6 90-Day Follow Up – Electronic Survey) 
 
Compliance Checks – a paper-based form completed by the Treating Therapist to assess 
participant compliance with: study visits, length of time iontophoresis patch worn, home 
exercise program, icing, activity restriction, and bracing instructions. Also assessed at Clinic 
Check visit. 
 
 
 
 
 


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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
 
8.3.1 DEFINITION OF ADVERSE EVENTS  AND SUSPECTED ADVERSE REACTION  
 
Adverse event (AE) means any untoward medical occurrence associated with the use of an intervention 
in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the 
drug caused the AE.  For the purposes of IND safety reporting, “reasonable possibility” means there is 
evidence to suggest a causal relationship between the drug and the AE. 
 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) OR SERIOUS SUSPECTED ADVERSE 
REACTION 
 
An AE or suspected adverse reaction is considered "serious" if, in the view of the investigator or 
Sponsor, it results in any of the following outcomes: death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
 
The Treating Therapists trained on this protocol will be responsible for classifying an AE.  All AEs will be 
assessed for severity using the definitions below:   
 
Severity of Event (Intensity) – The following guidelines will be used to describe severity: 
 
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.   
 
 
 
 
 


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8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) will have their relationship to study intervention assessed by the Treating 
Therapist who examined and evaluated the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the categories below:  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
 
8.3.3.3 EXPECTEDNESS  
 
The Treating Therapist who examined and evaluated the participant will be responsible for determining 
whether an AE or suspected adverse reaction is expected or unexpected.  An AE or suspected adverse 
reaction will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with either: 
 
The known or foreseeable risk of adverse events associated with the procedures involved in the 
research that are described in (a) the protocol-related documents (the IRB-approved research 
protocol and the current IRB-approved informed consent document), and (b) other relevant 
sources of information, such as product labeling and package inserts; or 
 
The expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile for 
the adverse event. Whether or not the event is consistent with risk information described in the 
device package insert, drug package insert, or consent form. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an AE or serious adverse event (SAE) may come to the attention of study personnel 
during study visits, during the 30-day follow up phone call or from the 90-day electronic survey.  AEs will 
be assessed at each treatment visit through the performance of a brief physical exam, interview by the 
Treating  Therapist, review of concomitant medications, as well as from patient-reported responses to 
the FACES Pain scale and LEFS (assessed only at Study Treatment  Visit 1, 5, 12, and 30-day follow-up).    
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a clinical assessment), expectedness, and time of resolution/stabilization 
of the event. All AEs occurring while on study will be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution or stabilization. 
 


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Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The treating Therapist will record all reportable events with start dates occurring any time after 
informed consent is obtained until 90 days after RTS criteria met or participant has received study 
treatment for eight (8) weeks, whichever is the shorter of the two time periods.  At each study visit, the 
treating Therapist will inquire about the occurrence of AE/SAEs since the last visit.  Events will be 
followed for outcome information until resolved or deemed by PI and Independent Safety Monitor as 
chronic or stable. 
 
 
8.3.5 ADVERSE EVENT REPORTING  
 
The Treating Therapist will record all adverse events on an Adverse Event Log and will evaluate for 
seriousness, severity, expectedness, and relatedness.  Adverse events that impact the safety of the 
subject or the ability of the subject to continue on with the study will be communicated immediately 
(within 24 hours) to the referring physician.  On a monthly basis, the Principal Investigator will provide 
the Independent Safety Monitor cumulative AE reports.  The Independent Safety Monitor, in 
consultation with a physician as needed, will monitor for accuracy and will have the authority to 
recommend continuation of the trial, modification to the trial, or termination of the trial in the event of 
unacceptable adverse events.  
The Sponsor will notify all participating Investigators and the FDA (via an IND Safety Report) of any 
potential serious risks as soon as possible, but no later than 15 calendar days after the Sponsor 
determines that the information qualifies for reporting. Any adverse event not initially determined to be 
reportable but later determined to be reportable, will be submitted as an IND Safety report to the FDA 
as soon as possible, but no later than 15 calendar days after the determination is made.  
 
The following AE reporting guidelines will be utilized in this protocol:  
EVENT 
REPORTED BY WHOM 
TO WHOM (TIMEFRAME TO 
REPORT) 
AE deemed Serious – see Section 8.3.6  Serious Adverse Event Reporting 
AE deemed Not Serious 
Treating Therapist 
 
Principal Investigator 
 Principal Investigator (provide 
in  weekly AE Report)  
 Independent Safety Monitor 
(ISM) (provide in monthly AE 
Report) 
AE deemed Severe 
Treating Therapist 
 
 
Principal Investigator 
 Principal Investigator – 
Immediately (within 24 hours 
of becoming aware of event) 
 Referring Physician – 


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immediately (within 24 hours 
of becoming aware of event) 
 ISM - Immediately (within 24 
hours of becoming aware of 
event) 
AE deemed Related 
Treating Therapist 
 
Principal Investigator 
 
 
 Principal Investigator (provide 
in weekly AE Report)  
 ISM (provide in weekly AE 
Report) 
AE deemed Unexpected 
Treating Therapist 
 
 
 
 
 
Principal Investigator 
 
 
 
 Principal Investigator – 
Immediately (within 24 hours 
of becoming aware of event) 
 Referring Physician – 
immediately (within 24 hours 
of becoming aware of event) 
 1. ISM - Immediately (within 
24 hours of becoming aware of 
event) 
 2. Eastern Virginia Medical 
School (EVMS) Institutional 
Review Board (IRB) 
(immediately upon becoming 
aware of the event and in 
writing within five (5) business 
days) 
 3. CHKD Hospital Research 
Coordination (HRC) (in writing 
within five (5) business days) 
 4. All Investigators and FDA 
(IND Safety Report)  (as soon 
as possible, but not later than 
15 calendar days after the 
Sponsor determines the 
information qualifies for 
reporting) if unexpected + 
serious 
 
 
 
 
 
 
 
 
 
 


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8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
 
The treating Physical Therapist will record all serious adverse events on a Serious Adverse Event (SAE) 
Form.   The following SAE reporting guidelines will be utilized in this protocol:  
EVENT 
REPORTED BY WHOM 
TO WHOM (TIMEFRAME TO 
REPORT) 
AE deemed Serious 
Treating Therapist 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 Principal Investigator – 
Immediately (within 24 hours 
of becoming aware of event) 
 Referring Physician – 
immediately (within 24 hours 
of becoming aware of event) 
 
 1. ISM - Immediately (within 
24 hours of becoming aware of 
event) if determined to meet 
criteria for unanticipated 
problem 
 2. EVMS IRB (immediately 
upon becoming aware of the 
event and in writing within five 
(5) business days) if 
determined to meet criteria 
for unanticipated problem 
 3. CHKD HRC (in writing within 
five (5) business days) if 
determined to meet criteria 
for unanticipated problem 
 
 
The Principal Investigator is responsible for signing all SAE forms.  All serious adverse events (SAEs) will 
be followed until satisfactory resolution or until the Principal Investigator, in coordination with the ISM, 
deems the event to be chronic or the participant is stable.  
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Should an AE occur in the study that affects the risks or possible willingness for participants to continue, 
the Site will provide all study participants with an IRB-approved letter of notification.   
 
 
 
 
 
 
 


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8.4 
UNANTICIPATED PROBLEMS 
 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The Treating Therapist will record all unanticipated problems.   The following UP reporting guidelines 
will be utilized in this protocol:  
EVENT 
REPORTED BY WHOM 
TO WHOM (TIMEFRAME TO 
REPORT) 
Unanticipated Problems  
Treating Therapist 
 
 
Principal Investigator 
 
 
 
 Principal Investigator – 
Immediately (within 24 hours 
of becoming aware of event) 
 1. ISM - Immediately (within 
24 hours of becoming aware of 
event) 
 2. CHKD HRC (in writing within 
five (5) business days) 
 3. EVMS IRB (immediately 
upon becoming aware of the 
event and in writing within five 
(5) business days)* 
 4. Office of Human Research 
Protections (OHRP) with 
guidance from EVMS IRB and 
CHKD HRC 
 
The UP report will include the following information: 
 
• 
Name of the Institution conducting the research 


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• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
*A follow-up or final report will follow by the earlier of 14 days or when an investigation has been 
completed or a corrective action plan has been implemented.   
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Should a UP occur in the study that affects the risks or possible willingness for participants to continue, 
the Site will contact all study participants, inform them of the new information, request that they come 
back to the clinic to discuss if deemed necessary, provide them with an IRB-approved letter of 
notification, and follow any instructions from the EVMS IRB regarding reconsenting or withdrawing from 
the study.   
 
9 
STATISTICAL CONSIDERATIONS  
 
  
9.1 
STATISTICAL HYPOTHESES 
 
 
Primary Efficacy Endpoint(s):  
 
Length of time to meet RTS criteria as measured in days 
Null Hypothesis: Time to achieve RTS criteria for Pediatric patients with apophysitis of the 
knee who receive iontophoresis with DSP and PT is the same as those who receive 
iontophoresis with placebo and PT or PT alone.   
 
Alternative Hypothesis: Time to achieve RTS criteria for Pediatric patients with apophysitis of 
the knee who receive iontophoresis with DSP and PT will be different from those who receive 
iontophoresis with placebo and PT or PT alone.   
 
 
Secondary  Endpoint(s): 
 
Efficacy: Patient reported outcomes: 
Null Hypothesis: There is not any significant difference in patient reported outcomes (LEFS, 
FACES pain scale, and Godin Leisure-Time Exercise) between pediatric patients with 
apophysitis of the knee who receive iontophoresis with DSP and PT and those who receive 
iontophoresis with placebo and PT or PT alone.  
 
Alternative Hypothesis: Patient reported outcomes (LEFS, FACES pain scale, and Godin 
Leisure-Time Exercise) of pediatric patients with apophysitis of the knee who receive 
iontophoresis with DSP and PT will be different from those who receive iontophoresis with 
placebo and or PT alone.  


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Safety: Frequency and intensity of adverse events 
Null Hypothesis: There is not any significant difference in frequency and intensity of adverse 
events between pediatric patients with apophysitis of the knee who receive iontophoresis 
with DSP and PT and those who receive iontophoresis with placebo and PT or PT alone.  
 
Alternative Hypothesis: Frequency and intensity of adverse event among pediatric patients 
with apophysitis of the knee who receive iontophoresis with DSP and PT will be different 
from those who receive iontophoresis with placebo and PT or PT alone.  
 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
To assess the primary variable of interest, a power analysis indicated that a total sample of 126 
participants would be required to detect medium effects (𝑓= 0.28) with 80% power and 𝛼= 0.05 
using Generalized Linear Model (GLM).   
 
The required sample size to test secondary hypotheses was calculated as 87 and 108 participants for 
patient reported outcomes and safety, respectively. Therefore, a total sample of 126 participants 
provides sufficient power for testing secondary hypotheses.  
 
Given an estimated 15% non-compliance rate, the sample size will be increased by 15%, for a total 
sample size of 147 participants (49 per group).   
 
 
9.3 
POPULATIONS FOR ANALYSES 
 
A  Modified Intention-to-Treat Analysis Dataset will be utilized, so that participants who received at least 
one dose of study intervention will be included in the analysis dataset.   
 
 
9.4 
STATISTICAL ANALYSES 
 
 
9.4.1 GENERAL APPROACH 
 
Continuous variables will be expressed as mean, standard deviation, median, and range. Categorical 
variables will be presented as frequency and percentage. All statistical tests will be two-sided and 𝑝<
0.05 will be considered as statistically significant. 
 
 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
A GLM will be conducted to test for significant difference in time to RTS (in days) between pediatric 
patients with apophysitis of the knee who receive iontophoresis with DSP treatment and PT and those 


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who receive placebo or PT alone.  The result will be presented as average time to RTS with 95% 
confidence interval for intervention groups. Non-informative censoring will be checked to ensure 
mechanism of censoring is independent of treatment groups.    
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
For each secondary endpoint: 
 
A Generalized Estimation Equation (GEE) Model, including baseline records, will be used to check for 
changes in LEFS, FACES pain scale, and Godin Leisure-Time Exercise between treatment groups over 
time. Results for LEFS and Godin Leisure-Time Exercise will be presented as mean with 95% confidence 
interval, and results for FACES pain scale will be reported as odds ratio and 95% confidence interval. 
 
9.4.4 SAFETY ANALYSES 
 
A GEE model will be conducted to estimate likelihood of occurring and intensity of adverse events for 
Pediatric patients with apophysitis of the knee who receive iontophoresis with DSP treatment and PT as 
compared to those who receive placebo or PT alone.   
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Age at admission and baseline patient reported outcomes will be compared between treatment groups 
using Analysis of Variance (ANOVA) test. Chi-square test will be conducted to test comparability of 
intervention groups in terms of gender and race distribution. Continuous variables will be presented as 
mean and standard deviation. Categorical variables will be expressed as frequency and percentage. All 
tests will be two-sided and 𝑝< 0.05 will be considered statistically significant. 
 
9.4.6 SUB-GROUP ANALYSES 
 
A Generalized Linear Model (GLM), including concomitant therapies, age, gender, and race will be 
conducted to analyze the possible effect of these covariates on length of time to RTS outcomes.  
 
Generalized Estimation Equation model including concomitant therapies, age, gender, and race will be 
conducted to assess the effect of these covariates on LEFS, FACES, Godin Leisure-Time Exercise, and 
safety outcomes.  
 
9.4.7 INTERIM ANALYSES 
While  recruitment is ongoing, interim results will be supplied, in strict confidence, to the ISM   as frequently as 
requested. All individuals involved in the interim analyses, including the biostatistician, will be blinded to 
intervention assignment.   
Interim analysis of the study will be conducted based on the alpha spending rule .26  The proportion of the 
observed sample size (number of patients observed divided by the target sample size) will be considered as the 
information statistics. The p-value will be adjusted  to maintain the overall study power of 0.05, two-sided.  


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The ISM will inform the PI of the results only if the test statistics exceeds the adjusted p-value in the primary 
efficacy or safety outcome and if, in the opinion of the ISM, the study should be  considered for early termination.  
The study would not be terminated early if the difference is found only in a  secondary outcome of efficacy, the p-
value is smaller but close to the adjusted p-value, or when the variance is small.  The decision to terminate the 
study early would be made by the ISM with consultation of a non-treating physician as needed.   
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
 
Consent forms describing in detail the study intervention, study procedures, and risks will be given to 
the participant and written documentation of informed consent will be completed either in written form 
in the participant’s chart or directly into the electronic medical record. The following consent materials 
are submitted with this protocol: 
 
Informational Flyer - this flyer describes the basics of the study and contact information 
of the PI.  This flyer serves as a means of providing the potential participant and their 
parent general information to review prior to their first visit with the physical therapist.  
This flyer will be available in the office settings of the CHKD Primary Care Sports 
Medicine physician’s offices and CHKD Orthopedic Surgeon’s offices.    
 
Patient Informed Consent Form  
 
Assent Form  
 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Patients seen by CHKD Primary Care Sports Medicine physicians or CHKD Orthopedic physicians with a 
diagnosis of apophysitis of the knee and referred to CHKD PT for PT treatment and iontophoresis 
treatment will be potential subjects for the study.  The referring physician will provide written approval 
to the Treating Therapist that the patient may be considered for enrollment into this study.  The 
referring physician may provide an IRB-approved Informational Flyer to the parent and child for their 
review prior to meeting with the Physical Therapist.  The Principal Investigator’s (PI) contact information 
will be provided on the Informational Flyer.  Parents may choose to call the PI to discuss the study or 
request that the informational packet be emailed or mailed to them in advance of their IE Visit.   
As standard of care, all patients referred for PT treatment and iontophoresis receive an IE in one of the 
CHKD PT clinics.  After the Treating Therapist receives the referral and prior to the IE, the Treating 
Therapist will ensure the referring physician has provided written approval for the patient to be 


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considered for enrollment in the study.  Once approval is secured, the Treating Therapist may contact 
the parent to discuss the study and answer any questions they may have.  At the IE, the Treating 
Therapist will discuss the study with the patient and his/her parent/legally authorized representative 
(LAR) in detail and if interested in participating in the study, will provide them a copy of the IRB-
approved informed consent and assent forms for review.  
Patients will have the opportunity to carefully review the written consent form and ask questions prior 
to signing. The patients will have the option to sign Consent on the day of the IE or take more time to 
consider it and decide at the beginning of their next Standard PT Treatment visit.    
Informed consent will only occur at the PT clinics and will be conducted by the Treating Therapists who 
have been CITI trained.  The Informed consent process will be initiated prior to the individual’s agreeing 
to participate in the study and will continue throughout the individual’s study participation. No study-
specific procedures will be conducted until the Consent and Assent Forms are signed and dated. 
Participants will be informed that participation is voluntary and that they may withdraw from the study 
at any time, without prejudice. A copy of the informed consent document will be given to the 
participants for their records and the original scanned into the medical record and then stored in a 
locked office with the other essential documents of the study. The informed consent process will be 
conducted and documented in the source document.  Participants who turn 18 years old or are 
emancipated during the course of the study will be re-consented.  
The rights and welfare of the participants will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the Principal Investigator to the Study Team, study participants, the EVMS IRB, and the 
CHKD HRC. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the IRB, and will provide the reason(s) for the termination or 
suspension.  Study participants will be contacted, as applicable, and be informed of changes to study 
visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Demonstration of efficacy that would warrant stopping 
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Determination that the primary endpoint has been met 
 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the IRB.  
 
10.1.3 CONFIDENTIALITY AND PRIVACY  


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Participant confidentiality and privacy is strictly held in trust by the participating investigators, and their 
staff.  This confidentiality is extended to cover the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
Authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), and 
regulatory agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy 
records for the participants in this study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the regulations, the reviewing IRB, and institutional policies. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be maintained in REDCap per institutional policy. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by 
clinical sites will be secured and password protected.  
 
 
10.1.4 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Independent Safety Monitor 
Dana Reesman, PT, DPT 
CHKD Sports Medicine PT 
Christopher Bertani, PT, DPT, MS, OCS, SCS, CSCS 
CHKD Sports Medicine PT 
CHKD  
CHKD 
702 W. 21st Street, Norfolk, VA 23507 
1924 Landstown Centre Way, Virginia Beach, VA 23456 
757-668-4894 
757-668-2733 
Dana.reesman@chkd.org 
Christopher.bertani@chkd.org 
 
Sub-Investigators: 
Joel Brenner, MD, MPH – CSG Primary Care Sports Medicine 
David Smith, MD – CSG Primary Care Sports Medicine 
Beth Ackerman, PT, DPT, SCS – CHKD Sports Medicine PT  
Christopher Bertani, PT, DPT, MS, OCS, SCS, CSCS – CHKD Sports Medicine PT 
Ashley Koto, PT, DPT, ATC CHKD Sports Medicine PT 
Alexandra McVicker, PT, DPT, OCS CHKD Sports Medicine PT 
Tyler Miller, LPTA, CSCS, CES CHKD Sports Medicine PT 
Lauren Pierce, PT, DPT, ATC CHKD Sports Medicine PT 
Sara Stites, PT, DPT, ATC CHKD Sports Medicine PT 


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Alyssa Tieber, PT, DPT, ATC CHKD Sports Medicine PT 
Christina Hellauer, PharmD – CHKD Pharmacy 
 
 
10.1.5 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of an ISM, an individual with the education, skills, and 
relevant expertise whose primary responsibility is to provide independent safety monitoring in a timely 
fashion.  This is accomplished by review of adverse events with follow-up through resolution.  The ISM, 
in consultation with a physician as needed, will evaluate individual and cumulative participant data 
when making recommendations regarding the continuation of the trial, modification to the trial, or 
termination of the trial in the event of unacceptable adverse events.  
 
     
 
10.1.6 CLINICAL MONITORING 
 
Internal site monitoring will be conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is in compliance with the currently approved protocol/amendment(s), and with applicable 
regulatory requirements.  
 
• 
On-site monitoring of this trial will be performed by qualified individuals within the CHKD Sports 
Medicine Team who have not participated in the enrollment or treatment of participants in this 
study.  Monitoring will consist of 100% review of consent forms, inclusion/exclusion criteria, 
and RTS Checklist, and random review of remaining data points.  A Monitoring Report will be 
provided to the Treating Therapist with a copy to the PI.  
 
 
10.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
 
All Treating Therapists will perform internal quality management of their own data collection, 
documentation and completion.  The Treating Therapists will be responsible for correcting errors found 
by the Monitor. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks on the database will be generated. Any missing data or data anomalies will be communicated to 
the appropriate Treating Therapists for clarification/resolution. 
 
The monitor will verify that the clinical trial is conducted and data are collected, documented 
(recorded), and reported in compliance with the protocol and applicable regulatory requirements.  
 
The CHKD Investigational Pharmacist will monitor the Drug Accountability Logs for drug accountability.  
Any errors found will be corrected by the Treating Therapist. 
 
All Treating Therapists will undergo site-specific protocol training as well training on obtaining and 
documenting Informed Consent and Good Documentation Principles. All Treating Therapists will 


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participate in training sessions conducted by the PI on adverse events (identifying, assessing, 
documenting, and reporting), the PT exercise protocol, Y balance testing, quad strength testing with 
hand-held dynamometer, iontophoresis patch preparation and application, administration of the 
patient-reported outcome measures (FACES Pain Scale and Godin Leisure-Time Activity Questionnaire), 
administration of the LEFS, and the RTS checklist. These sessions will include instructional handouts, 
demonstrations, and practice sessions to ensure good intra- and inter-examiner reliability. 
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
 
10.1.8 DATA HANDLING AND RECORD KEEPING  
 
10.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the Treating Therapists at the site under the supervision of the 
Principal Investigator. Treating Therapists will follow “Good Documentation Principles” when completing 
study related documentation.  These principles will ensure data are: attributable, legible, 
contemporaneous, original, accurate, enduring, available and accessible, complete, consistent, credible, 
and corroborated.   
 
Source data may take the form of hardcopy worksheets or electronic data, obtained from the 
participant’s electronic medical record or paper chart, or through a REDCap survey. Per the CHKD Policy 
C1107 “Approval of Research”, a copy of the signed Informed Consent will be scanned into the 
participant’s electronic medical record. The treating physical therapist obtaining informed consent will 
place a consent note in the participant’s paper chart as well as scan a copy into the electronic medical 
record.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  The 30-Day Phone Follow Up Visits will be 
conducted by the Treating Therapist via a phone call to the participants and data obtained will be 
documented directly onto a visit worksheet.  90-Day Follow-Up Visits will be administered as REDCap 
surveys sent to the participant’s email or cell phone with phone follow up as needed for new adverse 
events identified or new medications identified that may be associated with an adverse event.    
 
All original source documents for a single participant will be collected from the treating PT clinic, 
following CHKD’s Policy C3400.1 Transporting Protected Health Information, and transported and stored 
in the research office in a locked and secure cabinet. 
 
All study-related clinical data will be entered into REDCap, a 21 CFR Part 11-compliant data capture 
system. The data system includes password protection and internal quality checks, such as automatic 
range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents. 
 
 
 


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10.1.8.2 STUDY RECORDS RETENTION  
 
Study-related documents will be retained per the CHKD record retention policy.  
 
10.1.9 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol or regulatory requirements. 
The noncompliance may be either on the part of the participant, the investigator, or the study site staff. 
As a result of deviations, corrective actions will be developed by the site and implemented promptly.  
 
It is the responsibility of the Treating Therapists to use continuous vigilance to identify and report 
deviations within two (2) working days of identification of the protocol deviation to the Principal 
Investigator.  All deviations will be documented in study source documents. Protocol deviations that 
result in a change to the risk/benefit ratio or affect the integrity of the study will be reported to the 
EVMS IRB per their SOPs.25   
 
10.1.10 
PUBLICATION AND DATA SHARING POLICY 
 
This study will comply with the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.   
 
Naming of authors and contributors to publications resulting from this research project will be 
determined in line with the International Committee of Medical Journal Editors’ (ICMJE) 
recommendations. 
 
10.1.11 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence is critical.  None of the persons 
who have a role in the design, conduct, analysis, publication, or any aspect of this trial have a conflict of 
interest.  Should one develop, or be perceived to be present, it will be managed by following the CHKD 
Human Subjects Research – Conflict of Interest Policy C1108 and the EVMS IRB Conflict of Interest 
Policies.25 
 
10.2 ABBREVIATIONS 
 
ADLs 
Activities of Daily Living 
AE 
Adverse Event 
ANCOVA Analysis of Covariance 
CFR 
Code of Federal Regulations 
CHKD 
Children’s Hospital of the King’s Daughters 
CITI 
Collaborative Institutional Training Initiative 
CMP 
Clinical Monitoring Plan 


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CRF 
Case Report Form 
DHHS 
Department of Health and Human Services 
DSP 
Dexamethasone Sodium Phosphate 
eCRF 
Electronic Case Report Forms 
FACES 
Wong Baker Faces Pain Scale  
FDA 
Food and Drug Administration 
GEE 
Generalized Estimation Equation 
GLM 
Generalized Linear Model 
HEP 
Home Exercise Program 
HIPAA 
Health Insurance Portability and Accountability Act  
HRC 
Hospital Research Coordination 
ICMJE 
International Committee of Medical Journal Editors 
IE 
Initial Evaluation 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
LAR 
Legally Authorized Representative 
LEFS 
Lower Extremity Function Scale 
OHRP 
Office for Human Research Protections 
OSD 
Osgood Schlatter Disease 
PI 
Principal Investigator 
PT 
Physical Therapy 
QA 
Quality Assurance 
QC 
Quality Control 
RTS 
Return To Sport 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
 SLJ 
Sinding-Larsen-Johansson 
SM 
 Sports Medicine 
SoA 
Schedule of Activities 
UP 
Unanticipated Problem 
 
 
 


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10.3 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
2018_08_27 Added IND#; Added language 
regarding potential burns; 
Revised inclusion criteria; Revised 
exclusion criteria; Revised 
preparation of study treatment; 
Added burn-specific AE 
monitoring and post-patch 
application AE monitoring; Added 
language regarding IND Safety 
Reporting; Clarified “Pain free” 
criteria for RTS; Added additional 
adverse event reporting 
requirements 
 
3.0 
2018_09_18 Clarified data handling of 90-day 
electronic survey and added 
actual 90-Day Follow Up REDCap 
Survey 
 
4.0 
2019_07_11 Lowered inclusion age to 7; 
added two study sites; raised 
estimated time to meet study 
enrollment; added email 
reminders  
 
5.0 
2019_08_15 Added language differentiating 
between first time patch 
application monitoring and 
subsequent patch application 
monitoring. 
 
6.0 
2020_05_20 Added language for conducting 
interim analyses; removed two 
(2) Investigators who left the 
organization. 
 
 
 


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12 APPENDICES 
12.1 LOWER EXTREMITY FUNCTIONAL SCALE (LEFS) 
 
 
 
 


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12.2 WONG BAKER FACES PAIN SCALE 
 
 
 


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12.3 RETURN TO SPORT CHECKLIST 
 
Phase 1 - Nonimpact 
☐Pain-free ADL’s 
☐Squats x 10 pain-free with proper mechanics (all of the following must be met:) 
☐No anterior tibial translation 
☐Heels stay in contact with the ground 
☐Neutral/slight external rotation foot placement 
☐Knee stays in line with 2nd toe 
☐Trunk upright 
☐No trunk shift 
 
NOTE: Must meet both Phase 1 criteria before progressing to Phase 2 criteria. Phase 2 criteria must be 
assessed/completed in the order listed below. 
 
Phase 2 - Impact 
☐Broad jumps x10 pain-free with proper mechanics (all of the following must be met:) 
☐Knee in line with 2nd toe on take-off and landing 
☐No anterior tibial translation on landing 
☐Even footing on take-off and landing 
☐Soft landing 
☐Pain free 
☐Single leg triple hop for distance (all of the following must be met:) 
 
☐Met all above criteria for broad jumping 
☐No loss of balance 
 
☐No extra hop on landing 
 
☐No touching down of either the contralateral lower extremity or the upper extremity 
 
☐Stick and hold final landing for at least 3 seconds 
 
☐Affected lower extremity within 85% of the unaffected lower extremity 
☐Pain-free 
☐ Modified T-test  
 
☐Met all above criteria for single leg triple hop for distance 
 
☐100% effort 
 
☐Pain-free 
 
 
 
 


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12.4 GODIN LEISURE-TIME EXERCISE QUESTIONNAIRE 
 
 
 
 
 


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12.5 30-DAY PHONE FOLLOW UP 
The treating therapist may choose to send the subject’s guardian a reminder email prior to the 30-day 
phone follow-up to confirm date, time, and number to call, as well as to remind the subject to complete 
the LEFS and GLTAQ prior to the call.  An electronic copy of the LEFS and GLTAQ will be included in the 
email in case the subject misplaced their copy provided at the Clinic Visit Check.  
The following information will be gathered at the 30-day phone follow-up call: 
Date of Call: 
Adverse Events 
 
Ongoing: Review Adverse Event Log to determine if there were any unresolved AEs from last 
clinic visit. 
If yes, ask about AE to determine whether severity changed, if AE resolved, or if any new 
intervention was required. 
Complete AE Log 
New: Question: Since your last clinic visit, have you been seen by a doctor or had any new 
medical problems? 
If yes, complete entry on AE Log  
Concomitant Medications 
Ongoing:  Review current medications to confirm no change to drug, dose, and frequency 
New: Question: Since your last clinic visit, have you started any new medications?  
If yes, document drug, date started, reason for taking (if an AE, complete entry on AE 
Log), dose, frequency  
Administer the LEFS 
Administer the Godin Leisure-Time Activity Questionnaire 
 


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12.6 90-DAY FOLLOW UP (ELECTRONIC SURVEY) 
 


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