Clinical trial NCT02397278
Conditions: Osteochondritis Dissecans
Sponsor: University of Colorado, Denver
Start date: 2015-03-01; Completion date: 2020-01-08
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study plans to learn more about ways to treat a joint problem in the knee called Juvenile Osteochondritis Dissecans (OCD). The goal of this study is to see if injecting platelet-rich plasma (PRP) into the knee can help knee cartilage heal faster, and will try to determine whether the injections lead to improvements in pain, performance of activities of daily living, improvements is sports activities and overall function and symptoms reduction. The investigators will compare PRP treatment to conservative therapy.

Detailed description:

Arms: arm 1: Patients will receive three PRP injections into the symptomatic knee; they will also be fitted with a hinged brace locked in extension, with weight bearing as tolerated and crutches for those with pain upon weight bear, complete rest from impact activities with progression to weight bearing as tolerated for 6 weeks, and then followed according to the Sports Medicine department's protocol for OCD. arm 2: Patients will be fitted with a hinged brace locked in extension, with weight bearing as tolerated and crutches for those with pain upon weight bear, complete rest from impact activities with progression to weight bearing as tolerated for 6 weeks, and then followed according to the Sports Medicine department's protocol for OCD.
Interventions: intervention 1: Platelet rich plasma (PRP)
Intervention descriptions: intervention 1: Patient will receive 3 intra articular injections with autologous PRP in the affected knee and then follow conventional therapy.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
1 
 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD  
 
COMIRB PROTOCOL 
Campus box F490 
Telephone:  303-724-1055 
Fax:  303-724-0990 
 
Protocol #: 13-2797  
Version Date:   11-28-17 
Project Title: “Intra articular injections with platelet rich plasma in patients with Juvenile 
Osteochondritis Dissecans of the knee: Does it Help? A clinical and MR study. “ 
 
 
 
Principal Investigator:  Michael Fadell, M.D. 
1. Hypothesis:   
Intra articular injections with autologous platelet rich plasma (PRP) will improve symptoms, 
recovery time, and imaging appearance using delayed gadolinium enhanced MRI of cartilage 
(dGEMRIC) or Non-contrast MRI in patients suffering from stable juvenile osteochondritis 
dissecans of the knee when compared with conservative therapy. 
2. Specific Aims:  
In adolescents with osteochondritis dissecans of the knee: 
Aim 1. Compared to conservative therapy alone, determine whether intra-articular platelet 
injections combined with conservative therapy  lead to greater cartilage healing.  
Efficacy Endpoint – Measurement by glycosaminoglycan (GAG) content (T1GD) on 
dGEMRIC, or by healing changes of MRI diagnostic cartilage sequences, using the 
DiPaola classification system. 
 
Aim 2. Compared to conservative therapy, determine whether intra-articular platelet injections 
lead to improvements over time in: 
Efficacy Endpoint 2.1. Pain, as measured by the pain subscale of the KOOS-child. 
Efficacy Endpoint 2.2. Performance of activities of daily living, as measured by the ADL 
subscale of KOOS-child. 
Efficacy Endpoint 2.3. Sport performance, as measured by the sports subscale of the 
KOOS-child. 
Efficacy Endpoint 2.4. Overall function and symptom reduction, as measured by the 
pedi-IKDC. 
Aim 3. Correlate dGEMRIC findings or MRI diagnostic cartilage sequence findings on imaging 
studies with measures of functional recovery and symptom reduction. 


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
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Efficacy Endpoint – statistical evaluation of outcomes between the two patient 
populations 
3. Background:   
a.  Osteochondritis dissecans: 
Osteochondritis dissecans (OCD) is an osteochondrosis characterized by osseous necrosis 
followed by reossification and healing. There are both juvenile and adult forms of this 
condition. The most common anatomic location for this to occur is the knee, with the most 
frequent involvement being the medial femoral condyle.  This can also occur in the elbow, 
ankle, or hip. The etiology is unknown though repetitive micro trauma and or ischemia are 
postulated as possible inciting factors. MRI is frequently used in the diagnosis of osteochondral 
lesions associated with OCD.  Lesions can be stable or unstable. Stable lesions in patients with 
open physis, juvenile form, are typically treated conservatively, while unstable lesions 
traditionally require surgical intervention. The adult form is similar, though the patient’s physis 
are fused. This process affects adolescent males three times more than females.  
  
b.  Autologous platelet-rich plasma (PRP): 
The therapeutic use of autologous platelet-rich plasma (PRP) constitutes a relatively new 
biotechnology that has been a breakthrough in the stimulation and acceleration of soft-tissue, 
bone and cartilage healing [1-3]. The application of PRP has been extended to many different 
fields, including orthopedics, sports medicine, dentistry, cosmetic and periodontal medicine, 
plastic, and maxillofacial surgery [4]. The efficiency of this process lies in the local and 
continuous delivery of a wide range of growth factors and proteins, mimicking the needs of the 
physiological wound healing and reparative tissue processes [4].  
In this process a preparation rich in growth factors (PRGF) combines the advantage of an 
autologous fibrin clot that will aid in hemostasis as well as provide growth factors in high 
concentrations to the site of a tissue defect. The platelet-rich plasma preparation encourages 
the release and slow delivery of growth factors from harvested platelets, activated by 
endogenous thrombin, and is used as a biological enhancer in the healing of fractures, lumbar 
fusions, cartilage defects, muscle tears, and tendon lesions, thus promoting initiation and early 
maturation of bone and soft tissue formation [1, 2, 4-7] which involves a more physiologic 
repair with less scar tissue[7].  
Growth factors offer promising treatments for enhanced regeneration of cartilagein focal 
articular cartilage defects or in situations of more widespread cartilage loss such as those that 
occur in osteoarthritis (OA). Numerous anabolic growth factors stimulate chondrocytes 
synthesis of proteoglycans, aggrecan, type II collagen, induce synoviocyte and mesenchymal 
stem cell (MSC) proliferation, drive chondrogenic differentiation of MSCs, and decrease the 
catabolic effects of cytokines such as interleukin-1 (IL-1) and the matrix metalloproteinases 
(MMP) [3].   


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
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The source of the new PRP preparation consists of a limited volume of plasma enriched in 
platelets, which is obtained from the patient. Once the platelet concentrate is activated a 
myriad of growth factors and proteins are released, progressively, into the local environment, 
contributing to the accelerated postoperative wound healing, tissue repair, and vascularization 
[3, 8]. 
The application of PRP in cartilage repair is relatively new and therefore limited publications are 
available investigating its use. Chondrocytes and MSCs exposed to PRP both have increased cell 
proliferation and cartilage extracellular matrix synthesis of proteoglycans and collagen type II 
compared with controls [9]. Synoviocytes from patients with OA cultured in PRP demonstrated 
increased hyaluronic acid production and secretion, suggesting that PRP could potentially serve 
as an endogenous source of chondroprotection and joint lubrication after intra-articular 
application [10]. In a rabbit model, osteochondral defects were treated with either autogenous 
PRP in a poly-lacticglycolic acid (PLGA) carrier, PLGA alone, or left untreated [11]. The PRP 
group demonstrated a higher extent of cartilage regeneration as well as an increased 
production of the glycosaminoglycans in the ECM. 
In a cohort of 30 patients comparing injections of PRP with hyaluronic acid (HA) in the 
management of OA, the success rate for the pain subscale reached 33.3% for the PRP group 
compared with 10% for the HA group (p = 0.004)[12]. Additionally, the percent reductions in 
the physical function subscale and overall WOMAC at 5 weeks were also associated solely with 
treatment modality in favor of PRP with p =  0.043 and p =  0.010, respectively. 
Kon et al. treated 115 knees of patients with four intra-articular PRP injections given every 21 
days and followed the patients for 12 months [8]. Patients evaluated in this study included 58 
with degenerative chondral lesions (Kellgren-Lawrence 0), 33 with early OA (Kellgren- Lawrence 
I–III), and 24 with advanced OA (Kellgren- Lawrence IV). A substantial improvement in 
International Knee Documentation Committee (IKDC) and EuroQol (EQ-VAS) scores was noted 
at the end of therapy and at both the 6- and 12-month time points. The IKDC subjective scores 
as well as the EQ-VAS scores also demonstrated major improvements at the end of therapy. 
The authors concluded that treatment with PRP is safe and effective at improving pain, 
function, and quality of life in patients with degenerative articular pathology. 
A separate study by our sub-investigator, Dr. Mei-Dan showed that osteochondral lesions of the 
ankle treated with intra-articular injections of PRP and HA resulted in a decrease in pain scores 
and an increase in function for at least 6 months, with minimal adverse events. Platelet-rich 
plasma treatment led to a significantly better outcome than HA.[9] 
Recently, a randomized control trial (RCT) evaluating the effect of PRP on early osteoarthritis of 
the knee showed significant clinical improvement at both 6 months and 1 year. Platelet-rich 
plasma seemed to result in no change by MRI per knee compartment in at least 73% of cases at 
1 year. No adverse effect was reported with the use of PRP [13]. 
c.  dGEMRIC (delayed gadolinium-enhanced MRI of cartilage) 


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
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Intravenous injection of gadolinium allows for rapid penetration of contrast agent into the 
articular cartilage due to penetration both from the synovial fluid as well as the subchondral 
bone. The patient needs to move the joint after injection and the dGEMRIC imaging needs to 
occur within a 30–100 minute time window after injection for a reliable biochemical 
assessment of the articular cartilage [14, 15]. 
Gadolinium based biochemical MRI in the form of dGEMRIC has been established as an 
important modality in the imaging of articular cartilage. [14-25]. dGEMRIC is sensitive to the 
glycosominoglycan (GAG) content in the cartilage. When the negatively charged gadolinium 
contrast is administered, there is an uptake in hyaline cartilage in an inverse proportion to the 
GAG content [17]. Degenerated cartilage contains less overall quantity of GAG, therefore the 
concentration of gadolinium is high compared to the relatively low amount of gadolinium that 
accumulates in healthy cartilage. Consequently, T1 measurements performed post gadolinium 
injection can give an indirect reflection of GAG content of cartilage, due to the fact that 
gadolinium decreases the T1 relaxation time [16, 25, 26]. 
 
d.   Non-contrast MRI of the knee/lower extremity 
A non-contrast Magnetic Resonance Imaging (MRI) of the knee is a diagnostic imaging procedure which 
utilizes magnets to produce detailed images of the knee structure.  The delivery of contrast is not 
required for this imaging procedure. 
e. Preliminary Studies:  
The application of PRP in cartilage repair is relatively new and therefore limited publications are 
available investigating its use. Recently, a randomized controlled study comparing HA versus 
PRP in the short term treatment for symptomatic knee osteoarthritis showed plasma rich in 
growth factors showed superior short-term results when compared with HA in a randomized 
controlled trial, with a comparable safety profile, in alleviating symptoms of mild to moderate 
osteoarthritis of the knee [27]. Another study evaluating the effects of PRP in osteoarthritis of 
the knee together with MRI reported significant clinical improvements at 12 months post 
injection. According to MRI results, there was no change in the appearance of osteoarthritis 1 
year after platelet-rich plasma therapy in 83.3% of all cases when compared with baseline (N = 
12) with lateral femoral and tibial compartment involvement. Similarly, there was no change in 
73.3% of the cases with medial compartment involvement, although these values did not reach 
statistical significance. The appearance of medial compartment osteoarthritis improved in 1 
knee (6.7%) after 1 year. This is in contrast to some longitudinal studies that suggest an annual 
decrease of up to 4% to 6% of cartilage volume in knee osteoarthritis compartments. [13]  
Recently, Gobbi et al evaluated the effect of PRP in 50 patients with osteoarthritis.  At 12 
months follow up, patients had improved clinical symptoms with no adverse effects reported 
[28].  


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
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In a pilot study of 100 patients with osteoarthritis of the knee receiving intra-articular PRP 
injections, favorable results with pain reduction and improved function were reported. Patients 
were followed up at 2, 6, 12, and 24 months. Statistically significant improvement was observed 
in all the variables[29]. 
Our Sub-Investigator Dr. Mei Dan et al evaluated the effect of intra-articular injections of PRP 
compared to HA in osteochondral lesions of the talus. Both groups significantly improved 
clinical symptoms. When comparing both treatments groups, PRP produced a significantly 
greater improvement than HA [9]. Minor discomfort and mechanical pressure were common 
reports at the injection site in both groups.   
Battaglia et al recently reported the outcomes of injection of PRP for OA of the hip. Twenty 
patients, with a mean age of 52 years, who presented symptomatic OA of the hip were treated 
with a total of 3 intrarticular injections of PRP. Patients were prospectively evaluated at 1, 3, 6, 
and 12 months follow up. All patients had significantly improved clinical symptoms. No major 
complications or adverse events occurred at the moment of injection or in the follow-up period. 
Ten patients reported a slight pain during or after the injection, which spontaneously resolved 
in 1 or 2 days [30].  
Gillis et al evaluated autologous chondrocytee transplantation in patients with full thickness 
chondral lesions of the knee utilizing dGEMRIC to indirectly quantify the GAG content of 
cartilage at the site of transplant, adjacent to the site of transplant, and distant to the site of 
transplant. The study demonstrated that GAG levels in grafts that had been implanted at 12 
months or greater had GAG levels comparable to adjacent and remote cartilage. [31] 
 
Typically, patients with Juvenile Osteochondritis Dessicans will heal without treatment within a 
12 month period, therefore it was recently decided that the research dGEMRIC MRI would be 
performed 6 months from the time of the consent instead of 12 months. [32]  
4. Research Methods 
We propose a randomized controlled clinical trial in children (aged 10-17) with osteochondritis 
dissecans (OCD) comparing the use of platelet-rich plasma (PRP) therapy and conventional 
therapy compared to conventional therapy alone.   
The goal of this research is to test the hypothesis that intra articular injections with autologous 
PRP will improve symptoms, recovery time, and imaging appearance using delayed gadolinium 
enhanced MRI of cartilage (dGEMRIC) or MRI diagnostic cartilage sequence findings in patients 
suffering from stable juvenile OCD of the knee when compared to conservative therapy.  
Specifically, we aim to determine whether intra-articular platelet injections when compared to 
conservative therapy over time, lead to greater cartilage healing (measured by gadolinium 
accumulation or measured by healing on Non-contrast MRI, utilizing the DiPaola classification 
system), improvement in pain, improvement in performance of activities of daily living, 
improvement in sport performance, and improvement in overall function and symptom 
reduction.   


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
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Finally, we aim to determine if dGEMRIC findings or MRI diagnostic cartilage sequence findings 
on imaging studies correlate with measures of functional recovery and symptom reduction.   
All protocol procedures other than patient randomization, PRP injections, and the 6 month  
dGEMRIC or Non-Contrast MRI are considered routine standard of care procedures.  These 
three procedures are being conducted for research purposes in this study.   
Description of Population to be Enrolled:  
This study aims to enroll 24 subjects, 12 patients for each of the two treatment arms, all with 
documented stable juvenile osteochondritis dissecans identified via imaging. We believe 24 
patients could be included during the time period allotted for the study based on the number of 
patients suffering from OCD seen annually at the Children’s Hospital Sports Medicine Clinic.  
Patient Recruitment 
A diagnostic knee MRI (through CHCO or an outside facililty) will have been performed as 
standard of care prior to study participation, utilizing dGEMRIC, a Non-contrast MRI or a MRI 
with and without contrast in patients with a high clinical suspicion for osteochondritis 
dissecans.  The study is posted on the clinicaltrials.gov website and patients and/or their 
parents may call and inquire about eligibility.   
Lesions will be classified according to Di Paola et al classification  [33]  
This uses 5 stages as follows:  
Grade 1: Small change of signal without clear margins of fragment,  
Grade 2: osteochondral fragment with clear margins but without fluid between 
fragment and underlying  bone,  
Grade 3: fluid is visible partially between fragment and underlying bone,  
Grade 4: fluid is completely surrounding the fragment, but the fragment is still in situ; 
Grade 5: fragment is completely detached and displaced.  
Only patients with Di Paola stage 1 or 2 lesions will be approached for study participation and 
consented into the study. 
Pre-Screening Visit 
Study subjects will be recruited from current patient population at Children’s Hospital Colorado 
or first time patients of Dr. Dahab/ Dr. Nagle or their colleagues at the Children’s Hospital 
Sports Medicine Clinic. They will be identified and recruited during routine office visits. Study 
subjects may also come directly to the PI/Research Associate through the clinicaltrials.gov 
website.  The initial MRI scan, initial x-rays, and any follow-up x-rays will be performed as 
standard of care and will follow hospital policy, and they will be used to assess and confirm 
eligibility. Female patients included in the study, over the age of 12 who have begun 
menstruation will undergo a urine pregnancy test prior to the research MRI obtained at 6 
months. 
Inclusion & Exclusion Criteria 


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
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Patients will be recruited based on the following eligibility criteria:  
Inclusion Criteria 
1. Male or female age  10 - 17 inclusive with open physis confirmed by MRI 
2. Documented symptomatic stable juvenile osteochondritis dissecans of the knee based 
on MRI without changes of osteoarthritis and no prior history of knee surgery.  The MRI 
diagnosis must be within a 3 month time period prior to consent. 
3. The patient must be able to hold still without sedation for approximately 1 hour and 
must pass MRI screening evaluation for retained metal.   
4. Patients with Di Paola stage 1 or 2 lesions 
 
Exclusion criteria 
1. Patients with polyarticular disease (not applicable to polyarticular disease of the knees 
as the most symptomatic knee will qualify for the study) 
2. Patients with blood disorders (Blood disorders (thrombopathy, thrombocytopenia, 
anemia with hemoglobin <9g/dL).  
3. Patients who had intra-articular treatment with steroids within 3 months  
4. Patients who are pregnant or nursing at the time of consent.  
5. Patients with inflammatory arthritic conditions (e.g. rheumatoid arthritis)  
6. Non-English speaking patients. (Scores used for evaluation have not been validated in 
Spanish)  
7. Patients who had previous knee surgery 
8. Additional disabilities in any of the lower limbs that would interfere with any of the 
clinical assessments. 
9. Chronic use of NSAID (defined as taking NSAID regularly every week for the last 6 
months), steroids or chemotherapy drugs 
10. Treatment with NSAIDs within 15 days prior to randomization in this study 
11. Patients with a BMI over 30. Due to the fact that this study utilizes an injection 
technique which may be inaccurate in obese subjects. 
12. Patients with a contraindication  to MRI including: patients with cardiac pacemaker or 
non-approved intracranial vascular clip, and those with orthopedic hardware  as the 
resulting artifact can complicate interpretation 
13. Patients with acute or chronic renal failure 
14. Patients with a previous anaphylactic reaction to gadolinium enhanced MRI. 
15. Patients with Di Paola stage 3 or 4 lesions 
16. Patients who received a MRI diagnosis of OCD but do not have the specific cartilage 
imaging sequences. 
17. Clinical or laboratory evidence of septicemia 
 
Consent/Assent 
Informed consent/assent will be obtained by the PI/ Pediatric Radiologist, Michael Fadell, MD, 
or his research staff, Sports Medicine  physicians, Dr. Dahab/Dr. Nagle or their research staff. 


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
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Consent will be obtained in the Interventional Radiology suite, Radiology Fluoroscopy suite, 
physician office or other private room.  A signed and dated copy of the consent/assent will be 
given to the subject.  Patients will be required to sign an assent form. The parent or legal 
guardian will be required to sign a consent form.  Subject comprehension will be assessed by 
asking the subject/subject family if they understand and are willing to participate. Patients will 
have the option to take the consent document home and review it before consenting to 
participate in the study.  Patients will have the option to combine the consent visit (visit 0) with 
the baseline visit (visit 1). 
Randomization 
After consent, the study personnel will open a sealed envelope containing the randomization 
assignment.   The envelopes will also contain the appropriate patient handouts and 
instructions.  Randomization will be balanced within the study to allow equal assignment to 
each treatment group.  The randomization envelopes will be prepared by Dr. Deborah H. 
Glueck, the study biostatistician or her designated staff, using a random balanced allocation 
randomization protocol.   
A study ID participant list in REDCap will be filled out by Dr. Dahab/Dr. Nagle, their research 
staff or the Radiology Research Associate, Elizabeth Carroll, and will record the treatment 
assignment.   The study personnel will e-mail the study statistician with the patient’s study id 
number and the treatment assignment, recorded as 1 or 2.  The study personnel will keep a key 
file containing the patients’ names and study id numbers. 
The study will not be blinded to the patient, to the patient’s parent, or the physician 
administering the PRP injections.  However, the study imaging and results will be kept blinded 
to the PI, Michael Fadell, Pediatric Radiologist and the study biostatistician until the blind is 
broken, shortly before manuscript submission. Thus, treatment assignment will simply be 
recorded as 1 or 2 for the datasets. 
The informed consent will make it clear to the patient and the patient’s parents that the child 
will be randomized to one of two treatments: platelet-rich plasma injection with standard of 
care, or standard of care alone.  Some patients may not like their assignment.  If the patient 
wishes to, the patient who does not like their assignment can at that point drop out of the 
study and proceed with whatever care they choose.  Such randomization related dropouts will 
be recorded.  
 
 
 
 
This participant list in REDCap will contains the following information: At a minimum, empty 
columns are provided to record the following:  


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
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• Subject name  
• Medical record number 
• Patient and parent email addresses 
• Initials of person enrolling the subject  
• Date of enrollment.  
• Treatment assignment 
• List of required surveys to indicate completion 
Other empty columns can be added on request.  
. When a subject is enrolled in the study, s/he is assigned a confidential study identifier by 
adding his/her name in chronological order, to the very next empty row available on the 
REDCap participant list. The subject maintains this study ID for the remainder of the trial and, 
thereafter, the Study ID is used on all research files, randomization Lists, and other research 
documents.  
A research assistant, Dr. Dahab/Dr. Nagle, or Dr. Mei-Dan will fill out the assignment log and 
randomized assignment list.  
Subject Study ID Assignment Log Sample:  
Assignment log will go from study ID 1 to study ID 24.  Each one will correspond to a 
randomized number.  Table 1 below is an example of the excel sheet that will be used. 
 
 
 
 
i.  
ii.  
? 
 
Once randomization is performed, a randomized assignment list will also be filled out. Each 
randomization number will correspond to either of two treatments (PRP-Conservative).   
 
 
Randomized Assignment Sample List 
Table 2 – Randomized Assignment List Sample  
Enrollment 
Randomization 
Table 1 – Subject Study ID Assignment Log Sample 
Randomization 
# 
Subject 
Name 
MR# 
Study 
ID 
Treatment 
Assignment 
Date 
Randomized  Initials 
CH1 
  
  
 1 
PRP 
  
  
CH2 
  
  
 2 
PRP 
  
  
CH3 
  
  
 3 
PRP 
  
  
CH22 
  
  
 22 
Conservative    
  
CH 23 
  
  
 23 
Conservative   
  
CH 24 
  
  
 24 
Conservative   
  


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
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Study 
ID # 
Subject 
Name 
Subject 
MR# 
Date 
Enrolled Initials Randomization # 
Date 
Randomized Initials 
01-A 
  
  
  
  
CH1 
  
  
02-B 
  
  
  
  
CH2 
  
  
03-C 
  
  
  
  
CH3 
  
  
04-D 
  
  
  
  
CH4 
  
  
05-E 
  
  
  
  
CH5 
  
  
06-F 
  
  
  
  
CH6 
  
  
 
Subject ID Assignment Log 
Randomization #: CH-F-1 Treatment Assignment: PRP 
Study ID #: ___________________________ 
Date envelope opened: __ __ /__ __ / __ __ 
Time opened: __ __ : __ __ (24 hour clock) 
Signature of the person who is randomizing the subject: ___________________ 
 
  
 
 


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
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Study Team  Physicians 
Assess Patient Eligibility 
 
 
 
 
 
 
 Handout:  What is PRP? 
 
 
 
 
 
 
Enrollment 
 Consent / Assent Forms 
 
 
 
 
 
 
Randomization Envelopes 
 
 
 
 
 
 
Conservative Treatment 
 Timeline of Activity -No PRP  
 Baseline IKDC 
 Baseline KOOS 
 Compliance Surveys via emailed 
REDCap hyperlink 
 
PRP & Conservative Treatment 
 Timeline of Activity - PRP Treatment 
 Pre and Post-Injection handout 
 Baseline IKDC 
 Baseline KOOS 
 Compliance Surveys via emailed 
REDCap hyperlink 
 
 
 
 
 
 
 
 
 
 
Patient receives 3 PRP Injections at  
 Children’s Hospital Colorado 
 
 
 
 
 
 
 
 
Follow-Up 
Sports Medicine Visits 
KOOS and IKDC 
(6 & 12 weeks and 6 months) 
 
 
 
 
 
 
6 month Research 
dGEMRIC MRI or Non-contrast MRI 
 
 
 
 
 
 
Follow-Up 
Sports Medicine Visits 
KOOS and IKDC 
(9, and 12, months) 
 
 
 
 
 
 
 
 


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
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Treatment Regimens and Dosing 
All eligible patients will be randomized to a treatment or conservative therapy group. Those 
within the conservative therapy group  will be fitted with a hinged brace locked in extension, 
with weight bearing as tolerated and crutches for those with painful to weight bear,  complete 
rest from impact activities, progressing to weight bearing as tolerated for 6 weeks, and then 
followed according to the Orthopedic department’s protocol for OCD. 
 The PRP treatment group will receive three injections per randomization table into the 
symptomatic knee, they will also be fitted with a hinged brace locked in extension, with weight 
bearing as tolerated and crutches for those with pain upon weight bear, complete rest from 
impact activities with progression to weight bearing as tolerated for 6 weeks, and then followed 
according to the Sports Medicine  department’s protocol for OCD.  Study subjects in the PRP 
treatment arm will receive a total of 3 intra-articular injections, one week apart +/- 10 days. All 
subjects will have a physical exam performed to assess their knee function. 
If a patient has bilateral symptomatic knee osteochondritis dissecans, the more symptomatic 
side will be injected while the less symptomatic side will not be injected, the patient will then 
follow the same treatment regimen as the treatment   group on the treated side.  
PRP Dosing and Protocol 
Several phlebotomy and processing kits are FDA approved for safe and rapid preparation of 
PRP, and are commercially available. Dose, preparation and regimen of intra-articular injections 
of PRP have been variable in the literature. Doses vary between one to three injections, given 
consecutively within one or two week intervals [30]. 
For this protocol, we will use the FDA approved Harvest PRP Procedure Pack kit (BK000037) 
from Terumo-Harvest.  The Harvest PRP system is designed to be used for the safe and rapid 
preparation of autologous platelet-rich plasma (PRP) from a small sample of blood at the 
patient’s point of care. Each Harvest PRP kit consists of components necessary to collect whole 
blood from the patient into a syringe containing anticoagulant and to separate the centrifuged 
sample into fractions (including the one containing platelet-rich plasma).  
 
Each PRP preparation requires a total of 30 mL of peripheral blood. Blood will be obtained via 
direct venipuncture by radiology nursing staff, Michael Fadell or one of the study team 
phyisicians using the provided tourniquet and butterfly needle. Blood will be collected into a 
30mL syringe containing 3mL ACDA.  30 mL of acid-citrate-dextrose Formula (ACD-A) 
anticoagulated whole blood will be processed according to the manufacturer’s directions.  In 
brief, the anticoagulated whole blood will be transferred into the first chamber, which has a 
floating shelf of a proprietary density.  Following an initial centrifugation of 4 minutes, the 
supernatant, containing plasma and the cellular elements less dense than the floating shelf, will 
be decanted into the second chamber of the disposable and centrifuged for 10 minutes.  The 


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
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PRP volume of 3 or 4 mL will be prepared using the appropriate spacer to remove the desired 
volume of the supernatant platelet-poor plasma (PPP).  The PRP is resuspended in the 
remaining volume of PPP. 
This PRP preparation process takes place in the Interventional Radiology suite, Flouroscopy 
suite or a Co-Investigator’s clinic office. 
All sites/clinics are amenable for sterile procedures.  
Immediately prior to PRP injection into the study subject, calcium chloride is drawn up from the 
activator ampoule and will be added to the PRP. The activated PRP will then be injected in its 
entirety into the knee joint. All the preparation is performed under strict aseptic technique and 
follows the appropriate manufacturer instructions.  
 
Harvest PRP kits and centrifuge are provided free of charge from the vendor, Harvest 
TERUMOBCT . The PRP kit/device is not intended to provide data to support the claim for the 
device but rather to study the clinical effect of the device. 
PRP and Conservative Treatment Schedules Following Randomization 
Patients will be assessed during a standard of care visit for basic eligibility to participate in this 
study or via a telephone call with one of the Study Team Physicians.  Patients who meet the 
basic inclusion criteria will be given the option of participating in the study either at this first 
visit, or a subsequent visit after they are given the opportunity to review the informed consent 
documents.  
 
PRP study participants:  A total of 8 visits (9 visits, if consent is done as a separate visit) are 
expected during a 12-month time period for patient follow up. All initial visits will include a 
patient assessment using basic standard of care to determine eligibility for study enrollment. 
This first visit, if the patient decides to enroll, may also include patient consenting.  The second 
through fourth visits, one week apart +/- 10 days, will include treatment with PRP injections. 
After the 3rd injection, subjects will be seen for clinical evaluation and survey assessment per 
schedule of assessment below as the standard of care. MRI obtained prior to enrollment for 
initial evaluation of the knee is performed as standard of care in the management of knee OCD. 
The research MRI performed at 6 months post treatment will be obtained to assess cartilage 
healing utilizing physiologic imaging of cartilage with the dGEMRIC technique or a Non-contrast 
MRI of the knee.  
The three injection visits (1 through 3) will take approximately 30-45 minutes per visit. This 
includes time for the baseline patient reported outcomes and blood draw.  


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
14 
 
Follow up visits (5 through 9) last around 30 minutes and will include patient reported surveys, 
physical examination,  and x-rays to assess the injury in accordance with the  standard of care 
at CHCO.  
Conservative treatment participants:  A total of 5 visits (6 visits, if consent is done as a 
separate visit) are expected during a 12-month time period for patient follow-up.  The first visit 
will include initial assessment and possible recruitment. The second through fifth visits will 
include patient reported surveys, physical examination and x-rays to assess the injury in 
accordance with the standard of care at CHCO. MRI obtained prior to enrollment for initial 
evaluation of the knee is performed as standard of care in the management of knee OCD. The 
research MRI performed at 6 months post treatment will be obtained to assess cartilage healing 
utilizing physiologic imaging of cartilage with the dGEMRIC technique or a Non-contrast MRI of 
the knee.  Please refer to the patient schedule matrix, Table 3, below. 
 
 


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
15 
 
Informational patient brochure/Compliance Surveys/ Baseline and Follow-up KOOS and IKDC 
surveys/Clinical Assessments 
An informational brochure (see attached) will be used to assist in the recruitment of eligible 
patients.  The brochure will describe the autologous platelet rich plasma treatment, process, 
risks, appointment information and post procedure information. 
 
Patients randomized to the PRP Treatment arm will receive a Pre and Post-Injection Instruction 
handout (see attached).  The handout describes how the patient should prepare for the PRP 
injections and what to expect after the injection. 
 
The study personnel who consents the patient will request the patient's and parent's email 
addresses which will be used to send out the weekly and monthly surveys.   
For the first 6 weeks of the study, all patients will receive a weekly Compliance Survey (see 
attached) created by the Sports Medicine physicians to validate compliance with 1. non-weight 
bearing,  2. wearing a brace, 3. at home PT exercises, and 4. no high impact activity.   
 
KOOS/IKDC surveys:  All patients will receive a baseline survey and repeat surveys at 6 wks, 12 
wks, 6 m, 9m, and 12 months, which is considered standard of care, on the CHCO main campus 
or one of the following satellite locations (South, Parker, Centennial, Uptown/St Joseph’s or 
Broomfield.  The surveys will include the following outcome scales: Pedi IKDC and KOOS-child.  
The Pedi-IKDC is a modified version of the widely used International Knee Documentation 
Committee (IKDC) Subjective Knee Form, which is a knee specific measure of symptoms, 
function and sports activity.  The Pedi-IKDC was developed for use with children and 
adolescents ages 10-17.  The reliability and validity of the Pedi-IKDC has been demonstrated to 
be acceptable in young patients with a variety of knee disorders.   
Similarly, the KOOS – child is a pediatric version of the Knee Injury and Osteoarthritis Outcome 
Score (KOOS).  The KOOS-child score is subdivided and scored in five categories: Pain, Other 
Disease-Specific Symptoms, Activities of Daily Living Function (ADL), Sport and Recreation 
Function and Knee-related Quality of Life (QOL).  
http://www.actaorthop.org/sup_files/5292.pdf 
http://www.sportsmed.org/uploadedFiles/Content/Medical_Professionals/Research/Grants/IKDC_Forms/Pedi-
IKDC%20Form.pdf 
Clinical follow up will also be performed following injections or the commencement of 
conservative therapy at 6 weeks, 12 weeks, 6 months, 9 months, and 12 months.by Dr. 
Dahab/Dr. Nagle or their colleagues on the CHCO main campus or one of the following satellite 
locations (South, Parker, Centennial, Uptown/St Joseph’s or Broomfield). The clinical findings 
documented will include presence or absence of a joint effusion, overall range of motion, 
presence or absence of joint line tenderness and positive or negative Wilson's test 6 week 
follow up for both groups will also include radiographic evaluation, which is standard of care.  If 


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
16 
 
the patient is clinically or radiographically improving, physical therapy will be started as 
standard of care, following the same treatment protocol initially with closed kinetic chain, non-
impact exercises.  Patients will then slowly return to impact activities as tolerated over 3 to 4 
months.    
 
A patient Timeline of Activity has been created for each arm of the study (see two 
attachments).  The Timeline describes the weekly and monthly events that will occur during this 
study and can be handed to the patient following the consent and randomization process. 
6 month Research MRIs 
• If the patient received their initial diagnostic MRI by a Non-contrast MRI, 
the patient will receive a Non-contrast MRI at their 6 month research MRI 
visit. 
• If the patient received their initial diagnostic MRI by a dGEMRIC MRI, the 
patientwill receive a dGEMRIC MRI at their 6 month research MRI visit. 
• If the patient recived their initial diagnostic MRI by a MRI with and without 
contrast, the patient will receive a Non-contrast MRI at their 6 month 
research MRI visit. 
 
Research MRI  utilizing dGEMRIC or Non-contrast MRI  
Once the intrarticular PRP injections have been administered, a follow-up MRI will be 
performed utilizing dGEMRIC or Non-contrast MRI at 6 months from the initial visit.  Mean T1 
values on dGEMRIC will be calculated by drawing a region of interest at the site of hyaline 
cartilage pathology, adjacent to the site of pathology within the hyaline cartilage, and distant to 
the site of pathology within the hyaline cartilage on initial and follow up imaging.  If the follow-
up imaging is with a Non-contrast MRI, the DiPaolo classification system will be used to quantify 
interval change. 
Knee MRI with dGEMRIC will be performed in the standard manner. Upon arriving to the 
radiology department for the MRI, a pregnancy test will be administered for all female 
participants of child bearing potential.  An institutional MRI screening form will be given to each 
patient and parent and reviewed with the MRI technologist.  If there is any retained metal 
(pacemaker, metallic bb, orthopedic hardware), MRI will not be performed.  If there is no 
contradiction to MRI based on the institutional screening form, the patient will have an IV 
placed.  Using weight based dosing, .04 ml/kg, injection of gadolinium will be administered.  
The patient will then be asked to exercise for 30 minutes, which will be performed by walking 
around the hospital.  The patient will then return to the MRI suite in the department of 
radiology. Standard screening for retained metal will be performed prior to entering the MRI 
scanning area. If the parent/guardian wishes to accompany the child for the MRI scan, they will 
be screened in identical fashion.  In the MRI scanner, the patient will be required to lie still for 
approximately 1 hour, the duration of the scan. The patient will have the option of watching a 


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
17 
 
movie or listening to music on ipod or similar device (plugged in outside the scanner in 
technologist area) during imaging.  No sedation will be given.  There is no ionizing radiation 
associated with MRI. 
Each patient will have four values of GAG (T1GD) measured at the baseline MRI and again at the 
6 month MRI, via dGEMRIC.  The locations of the measurements will be designated using the 
lateral view of the femoral condyle as a clock face with the medial femoral condyle superior 
location being designated as 12 o’clock, the inferior location being designated as 6 o’clock and 
the anterior location being designated as 3 o’clock; the lateral view of the femoral condyle as a 
clock face with the lateral femoral condyle superior location being designated as 12 o’clock, the 
inferior location being designated as 6 o’clock and the anterior location being designated as 9 
o’clock.  The values will be measured at four locations:  the medial side at a weight bearing 
surface, the medial side at a non-weight bearing surface of the posterior condyle (4 o’clock), 
the lateral side at a weight bearing surface, and the lateral side at a non-weight bearing surface 
of the posterior condyle (8 o’clock).  The side with the lesion will be designated as the affected 
side, and the side without the lesion will be designated as the non-affected side.  GAG (T1GD) 
will be measured on the affected weight bearing surface at the site of the lesion.  GAG (T1GD) 
will be measured on the non-affected side at the corresponding weight bearing surface of the 
femoral condyle.  
Research MRI utilizing Non-contrast MRI 
A Non-contrast MRI will be performed in the standard manner. Upon arriving to the radiology 
department for the MRI, a pregnancy test will be administered for all female participants of 
child bearing potential.  An institutional MRI screening form will be given to each patient and 
parent and reviewed with the MRI technologist.  If there is any retained metal (pacemaker, 
metallic bb, orthopedic hardware), MRI will not be performed.   
 
 
 
 
 
 
 


Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
18 
 
 
 
Table 3 – Patient Schedule of Assessment 
 
Procedure Step 
Pre-
Screen 
Visit 
Week 1 
+/- 10 d 
Week 2 
+/- 10 d 
Week 3 
+/- 10 d 
Week 4 
Week 5 
Week 6 
+/- 1wk 
Week 12 
+/- 1wk 
Month 6* 
+/- 1wk 
Month 9 
+/- 1wk 
Month 12 
+/- 2wk 
 
Non-contrast MRI, MRI with and 
without contrast, or dGEMRIC for 
OCD lesion (standard of care) 
XA 
 
 
 
 
 
 
 
XR 
 
 
 
Initial & Follow-up x-rays dependent  
on symptoms (standard of care) 
X 
 
 
 
 
 
 
XD 
XD 
XD 
XD 
 
Informed Consent 
(research) 
XB 
 
 
 
 
 
 
 
 
 
 
 
Inclusion 
/ 
Exclusion 
Criteria 
confirmation (research) 
 
XR 
 
 
 
 
 
 
 
 
 
 
Patient Reported Outcomes IKDC, 
KOOS-child  (research) 
 
XR 
 
 
 
 
XR 
XR 
XR 
XR 
XR 
 
Randomization (research) 
 
X 
 
 
 
 
 
 
 
 
 
 
Compliance Survey (research) 
 
XR 
XR 
XR 
XR 
XR 
XR 
 
 
 
 
 
Physical exam  
(research for PRP arm patients 
weeks 1, 2, & 3 and  standard of 
care visits for both treatment arms 
for  weeks 6, 12 and months 6, 9, 12) 
 
XC 
XC 
XC 
 
 
X 
 X 
 X 
 X 
 X 
 
Blood draw & processing using the 
Harvest PRP kit(research) 
 
PRP 
only 
PRP 
only 
PRP only 
 
 
 
 
 
 
 
 
Autologous 
PRP 
Injection 
(research) 
 
PRP 
only 
+/- 
7days 
PRP 
only +/- 
7days 
PRP only 
+/- 7days 
 
 
 
 
 
 
 
 
Hinged Brace in extension  for 6 wks 
(standard of care )  
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X = occurs for both patient groups;  
A = Standard of care visit to pre-screen for minimal inclusion criteria; all patients will undergo the same standard of care MRI procedure 
B = Patient consenting can occur at either the initial screening visit, or when given the option to take the consenting material home for review they will be consented at their 2nd visits if they choose to enroll in the 
study.   
C = PRP Arm – Physical Exam will be performed for research only and will be take place prior to the injection of PRP.  
D = X-rays are performed  as standard of care depending on the conditions of each individual patient.  
R=Research             *  6  months from initial visit 


 
Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
19 
 
Participant Discontinuation Criteria  
Patients may be withdrawn from the trial for one of the following reasons: 
1. Noncompliance with the protocol procedures 
2. The patient has been given other or additional treatment, which may interfere with the 
study treatment (such as intra-articular steroid injection). 
3. The patient wishes to withdraw from the trial 
4. A severe adverse reaction by treatment applied is evident.  Such as joint infection which 
requires IV antibiotics and possible surgical irrigation and drainage. 
5. Patient becomes pregnant prior to completion of the third injection 
6. Patients receiving conservative treatment whose lesion becomes unstable, requiring 
surgery during the study period will be excluded from participating in the remainder of 
the study 
7. The investigator may withdraw patients from the trial if it is in the best interest of the 
patients. The reason for withdrawal shall be clearly described and the patient shall, 
whenever possible irrespective of the reason for withdrawal, as soon as possible be 
called for a final visit. All relevant assessments shall be completed, preferably according 
to the schedule for the final visit. 
Risks associated with study 
a. Risks associated with PRP 
Intra-articular injections have been proposed to be a safe procedure, with low complication 
rate, if performed while taking adequate precautions [34].  The risks related to the intra-
articular injections are infection, with an incidence of 1 in 50,000 inoculations, pain at the 
injection site, and erythema.  
Intra-articular injections with PRP, as with every intra articular injection (and not due to the PRP 
itself) can result in cutaneous rashes or urticaria, pain at the injection site, or erythema, all of 
which are considered very rare based on previous level 1 studies [3, 8, 9].  Pain, swelling, 
redness, warmth, and bruising at the injection site or headache may occur, all which are rather 
rare. 
As with every joint injection, a joint infection could potentially occur.  
 
 
 
 
 
b. Risks Associated with dGEMRIC MRI and Non-contrast MRIs  


 
Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
20 
 
The initial MRI performed for this study is considered standard of care in the management of 
knee osteochondritis dissecans. The follow-up MRI at 6 months is for research purposes.  
If a patient receives a dGEMRIC MRI, the gadolinium based contrast agents used for this type of 
imaging can result in nausea, vomiting, cutaneous rashes, shortness of breath, or chest pain, all 
of which are considered very rare [35]. Death attributed to gadolinium based contrast agents is 
extremely rare, “The overall rate of gadolinium-based contrast agent deaths reported to the 
FDA Medwatch database is less than 1 in a million (40 deaths in 51 million administrations), 
similar to the risk of death from a chest radiograph, drinking one half liter of wine, smoking 1.4 
cigarettes (tobaccodocuments.org/lor/03732381-2387.html), or traveling 86 miles by car 
(www-nrd.nhtsa.dot.gov/Pubs/811291.PDF).”  
The specific gadolinium based contrast agent used at Children’s Hospital Colorado, gadobenate 
dimeglumine (MultiHance), was recently evaluated for safety in children without any adverse 
effects observed during the first twenty-four hours after contrast administration [36]. 
Nephrogenic systemic fibrosis is a fibrosing disorder associated with exposure to gadolinium-
based contrast agents in people with severely compromised renal function [36]. There have 
been seventeen documented cases in patients 18 years or younger with documented exposure 
to gadolinium-based contrast agents [37].  Proposed risk factors are dialysis patients with GFR 
below 
30 
ml/min, 
high-dose gadolinium, 
proinflammatory 
conditions, 
acute 
renal 
failure, postoperative state, and hyperphosphataemia. The American College of Radiology 
recommends that people with severe chronic kidney disease (eGFR <30 mL/min/1.73 m2) or 
acute kidney injury should avoid exposure to gadolinium-based contrast agents. The American 
College of Radiology recommends that people with severe chronic kidney disease (eGFR 
<30 mL/min/1.73 m2) or acute kidney injury should avoid exposure to gadolinium-based 
contrast agents [37]. 
Risk which apply to either dGEMRIC or Non-contrast MRIs:  There are no major risks associated 
with the magnetic fields and radio waves associated with extremity MRI.  Rarely, one in 
thousands of exams, a sunburn-like skin burn might occur over a small area of the body, but 
special precautions are taken to avoid this.  The patient must lie still in a small space which 
could create stress or anxiety.  The patient might also feel cold because the MRI scanner room 
is kept cool, but blankets can be provided.  The scanner makes a loud knocking noise when it is 
operating, but earplugs or headphones can be worn.  Expected adverse events include 
stress/anxiety, claustrophobia, discomfort, or having a non-diagnostic study as a result of 
motion artifact. Some patients are unable to hold adequately still resulting in motion artifact on 
the images which could deem them uninterruptable.  The amount of motion artifact for this to 
occur would have to be extensive, and will therefore most likely occur in few study participants, 
if any.   


 
Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
21 
 
c.  Complications and Pain associated with Study 
Follow-up visits will take place on the CHCO main campus or one of the following satellite 
locations (South, Parker, Centennial, Uptown/St Joseph’s or Broomfield). All PRP injections will 
be performed at Children’s Hospital Colorado. The clinic, being a well-equipped outpatient 
facility, has additional rescue devices. Adverse events and pain medications used will be 
reported and monitored by Dr. Dahab/Dr. Nagle or their colleagues during each follow-up visit 
using the electronic medical records clinical encounter  notes.  Patients are reminded to contact 
Dr. Dahab/Dr. Nagle or Dr. Michael Fadell with questions or to discuss adverse events they 
might sustain.  
We will assist in arranging care for any injuries patients may sustain by participating in this 
study. However patient’s insurance will be billed for any care that is provided.  
d.   Recording and Reporting Adverse Events 
The study investigators will monitor all subjects enrolled for any potential adverse effects (AE) 
associated with the treatments provided. Clinically significant results will be reported as 
adverse events and will be graded on a three- point scale (mild, moderate, and severe)[38].  In 
the event that AE occurs the following will be documented and reported to the IRB: 
• Nature of adverse effect. 
• Clinically significant adverse events will be graded on a three- point scale 
(mild, moderate, severe)  
• Statement as to why it is considered unanticipated or anticipated but with 
change in nature or severity or frequency of occurrence from baseline 
• Statement as to the degree to which it is considered treatment related 
(unrelated, remote, possible, probable), and why. 
• Results of any diagnostic tests that were performed 
• Description of any treatment implemented 
• Statement of subject’s current clinical status 
• Investigator’s signature and date. 
Local side effects and irritations such as cutaneous rashes or urticaria, painful injection site, 
local heat, swelling, painful knee, and erythema will be recorded. 
The investigator will supply a report for COMIRB if the adverse effects are unanticipated or if 
anticipated adverse effects change in intensity, frequency, or duration.  
 
 


 
Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
22 
 
Safety Measurements 
The nature, onset, duration, severity, and outcome of all adverse events, as well as any 
association of an adverse event related to the study medication, will be assessed and 
documented at each visit. Patients will be asked to avoid intake of NSAIDs. If symptoms require 
pain medications during the initial follow up period (6 months after last injection),  NSAID 
consumption will be recorded, as well as other pain medications taken. Patients will be allowed 
to have non-NSAIDs rescue medication as needed to treat pain. This includes acetaminophen 
and in select cases opioids such as Vicodin or Percocet. To evaluate the safety profile of the 
treatments, all complications and/or adverse events will be reported with their level of severity 
and their causal relationship to the study treatment.   
Data Analysis Plan 
The anatomical location of osteochondritis dissecans will be documented for each patient on 
each of two MRI scans. Mean T1 values with dGEMRIC imaging will be measured by two 
separate pediatric radiologists at the site of  cartilage pathology, adjacent to the site of 
pathology within the  cartilage, and distant to the site of pathology within the  cartilage on both 
initial and follow up imaging.  Di Paola classification [33] will be used on the diagnostic imaging 
sequences to score the lesion pre-inoculation and on post-inoculation imaging.  
Proposed statistical analysis for Aim 1: Cartilage healing 
The T1GD value on dGEMRIC measures GAG content in cartilage.  Higher T1GD values are 
associated with higher GAG content in the tissue, a positive measure of cartilage health.  We 
assume that the value is approximately normal. 
We plan to fit a general linear mixed model [39] for the outcome of T1GD.  Predictors will 
include the visit at which the T1GD test was performed (initial MRI and 6 months), whether the 
site was weight bearing or not, and whether the side was affected or not, and the treatment 
group.  Age will be included as a covariate.  An unstructured covariance will be used to account 
for correlation between T1GD measurements on the same participant.   Jacknifed-studentized 
residuals will be examined to assess normality, and transformations will be applied as 
appropriate. 
We will test the null hypothesis of no time by treatment by weight bearing surface by affected 
side interaction.  Given a non-significant interaction, we will test the main effects of time and 
treatment, comparing the difference between the weight-bearing and non-weight bearing 
surface for the affected and non-affected sides.  Estimates, 95% confidence intervals, and p-
values will be produced.  All hypothesis tests will be performed using the Wald test with 
Kenward and Roger degrees of freedom[40] .  Hypothesis tests will be performed at the 
Bonferroni corrected alpha of 0.05/3 = 0.017.  


 
Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
23 
 
Proposed statistical analysis for Aim 2: Functional Recovery and Symptoms 
We will analyze scores for each subscale of the KOOS-child, and the overall score produced by 
the pedi-IKDC range from 0 to 100, with higher scores indicating improved knee function.  Each 
measure is approximately normal. 
We describe the analysis for Aim 2, Sub-aim 2.1.  The analyses for the other sub-aims are 
exactly parallel. 
We plan to fit a general linear mixed model  [39] with the pain subscale of the KOOS-child as the 
outcome.  Predictors will include the visit at which the survey was given (6 weeks, 12 weeks, 6 
months, 9 months and 12 months) and treatment group.  Age will be included as a covariate.   
An unstructured covariance will be used to account for correlation between measurements on 
a single participant.  If the resulting model fails to converge, a spatial exponential covariance 
will be used.  Jacknifed-studentized residuals will be examined to assess normality, and 
transformations will be applied as appropriate. 
We will test the null hypothesis of no polynomial time trend by treatment interaction.   If the 
time-by-treatment test is non-significant, we will step down to test the main effects of time and 
treatment. Estimates, 95% confidence intervals, and p-values will be produced.   
All hypothesis tests will be performed using the Wald test with Kenward and Roger degrees of 
freedom [40]  . Three hypothesis tests may be performed for each outcome, for a total of 12 
tests.  To control for multiple comparisons, all hypotheses will be tested at the Bonferroni 
corrected alpha level of 0.05/12=0.004.    
Proposed statistical analysis for Aim 3: Correlation of MR Findings and Measures of 
Functional Recovery and Symptoms 
We plan to fit four general linear unviariate models with 6-month T1GD as the outcome.  The 
primary predictor for each model will be the 6 month measurements of the pain subscale of 
KOOS-child, the ADL subscale of the KOOS-child, the sports subscale of the KOOS-child, and the 
pedi-IKDC, respectively.  In each model, age will be included as a covariate.  We will test the null 
hypothesis of no association between the functional measure and T1GD findings on MR and/or 
no decrease in DiPaolo score, using an F test.  All hypotheses will be tested at the Bonferroni 
corrected alpha level of 0.05/4 = 0.0125. 
Interim analysis and planned interim power analysis. 
Because this study has never been done in children, the estimates for power analysis may be 
incorrect, and the effect of the treatment may be better or worse than that reported in the 
literature.  Thus, after the first six study participants have been recruited, treated, and 
followed, the investigators will report blinded data to the study statistician, who will perform 
an interim power analysis using the methods of Gurka et al., 2007 [41]. 


 
Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
24 
 
Power Analysis 
We conducted a power analysis for Aim 1, the primary endpoint of the study.  The maximum 
sample size for the proposed trial is fixed at 12 patients per arm (24 participants total).  The 
sample size is limited due to costs associated with dGEMRIC.  
We calculated power for the test of no difference in T1GD between the treatment groups.  We 
assumed a standard deviation of 50 ms for T1GD values, and a correlation of 0.2 between the 
baseline MRI and the 12-month T1GD measurements.  Estimates were based on T1GD values 
reported by Neuman et al[42].    We expect T1GD values to be 85 ms higher in the injection 
group when compared to conservative therapy at the 6 month time point with no difference at 
baseline. We calculated power for 10, 11, or 12 participants per arm.  Power was calculated 
using GLIMMPSE version 2.0.1.[43] 
To detect a mean difference of 85 ms in T1GD between the treatment groups, power will be 
0.93 with a Type I error rate of 0.05, for 12 participants per treatment group.  To ensure a 
conclusive study, we will target an effective sample size of 10 participants per group.  Over the 
12 months, we expect to lose up to two participants per treatment group.  To account for the 
attrition, we have set an enrollment goal of 24 participants, or 12 participants per treatment 
group. 
 
Data Security 
Data collection and management will be performed by Drs. Michael Fadell, , Research Associate 
Elizabeth Carroll and/or a Sports Medicine Research Associate utilizing “REDCap.” REDCap’s 
internet registration and data collection system has a built-in security feature that encrypts all 
data for transmission, preventing unauthorized access to confidential participant information.  
Access to the system will be controlled by a sequence of identification codes and passwords. 
Pertinent radiologic images will be archived in the Children’s Hospital Colorado PACS system.  
A hard copy file of each study subject will be kept by the research coordinator at Children’s 
Hospital Colorado and will include the signed consent/assent.  The files will be kept in a locked 
cabinet in the primary investigator’s private office which has a locking door,  and saved in 
Children’s Hospital Colorado’s Redcap.  
9.  Summarize Knowledge to be Gained 
The study is designed to objectively evaluate whether intra articular injections with autologous 
platelet rich plasma (PRP) will improve recovery time and cartilaginous healing in patients 
suffering from (stable) osteochondritis dissecans of the knee when compared with conservative 
therapy. 


 
Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
25 
 
Radiation-free MRI with dGEMRIC or a non-contrast MRI will be used to assess osteochondritis 
dissecans healing by comparing mean T1 values obtained at the site of pathology on initial and 
follow up exams in comparison to mean T1 values of cartilage adjacent to the site of pathology 
and distant to the site of pathology on initial and follow up imaging and/or interval change in 
DiPaolo score with Non-contrast MRI. 
The benefit of more rapid healing of osteochondritis dissecans is reduction in morbidity, as well 
as potentially eliminating surgical treatment.   Dissemination of results will occur via publication 
in a peer reviewed journal in the fields of radiology, orthopedic surgery, or both. 
 
 
 


 
Protocol #: 13-2797 
 
 
 
 
 
 
 
 
 
26 
 
1. 
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Andía I (2007) Platelet-released growth factors enhance the secretion of 
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Sun Y, Feng Y, Zhang CQ, Chen SB, Cheng XG (2010) The regenerative effect of 
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Sánchez M, Anitua E, Azofra J, Aguirre JJ, Andia I (2008) Intra-articular injection 
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Fortier LA, Barker JU, Strauss EJ, McCarrel TM, Cole BJ (2011) The role of 
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Cole BJ, Seroyer ST, Filardo G, Bajaj S, Fortier LA (2010) Platelet-rich plasma: 
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Kon E, Buda R, Filardo G, Di Martino A, Timoncini A, Cenacchi A, Fornasari 
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Mei-Dan O, Carmont MR, Laver L, Mann G, Maffulli N, Nyska M (2012) 
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