Practical Indications for Sonography in Musculoskeletal Medicine-Knee Joint Injections
Phase: NA
Conditions: Knee Osteoarthritis
Sponsor: Andrews Research & Education Foundation

 
 
 
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Practical Indications for Sonography in Musculoskeletal Medicine- Knee 
Joint Injections (PRISMM-Knee) 
 
Date: 11/30/2011 
 
NCT03293238 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Practical Indications for Sonography in Musculoskeletal Medicine- Knee 
Joint Injections (PRISMM-Knee) 
 
Principal Investigators  
Capt Sean N. Martin, DO 
Title:  Faculty, Eglin Air Force Base Family Medicine Residency  
Phone Number: (540) 239-4686 
E-Mail:  martinusaf@hotmail.com 
 
Joshua Hackel, MD 
Title: Director, Primary Care Sports Medicine Fellowship 
Service and Department: Andrews Institute for Orthopaedics and Sports Medicine; Andrews-
Paulos Research and Education Institute 
Phone Number: (850) 698-2516 
E-Mail: jghackelmd@yahoo.com 
 
Associate Investigators    
COL Kevin deWeber, MD 
Title:  Director, Military Primary Care Sports Medicine Fellowship 
Service and Department:  Ft. Belvoir Community Hospital (FBCH) Sports Medicine;    
Department of Family Medicine, USUHS 
Phone Number: (301) 295-9466 
E-Mail:  kdeweber@usuhs.mil 
 
Christopher Dorvault, MD 
Title:  Musculoskeletal Radiologist 
Service and Department:  Radiology; Andrews Institute for Orthopaedics and Sports 
Medicine; Andrews-Paulos Research and Education Institute 
 
 
Purpose 
 
This study will compare the accuracy and patient-oriented outcomes between various 
techniques for intra-articular knee injections.  Historically, a joint line (intercondylar) 
technique of injection at the medial or lateral joint line, reliant solely upon clinical palpation, 
has been the most popular approach among primary care and orthopedic providers.  Newer 
approaches, making use of ultrasound visualization to accomplish access to the intercondylar 
recess and the anterolateral suprapatellar pouch, have gained in popularity.  Because of 
uncertain accuracy with the traditional approach, this study is designed to determine if 
sonographic visualization combined with either of these two newer techniques improves 
accuracy and affects patient-oriented outcomes.   
 
 
Research Design  

 
 
 
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Double-Blind Randomized Clinical Trial 
 
 
 
 
Methodology/Technical Approach  
 
Upon determination of the need for an intra-articular knee injection series of 
viscosupplementation (hyaluronan) and before the receipt of such injections, patients will be 
recruited into the study.  The series calls for three injections spaced approximately one week 
apart.  All three injections must be completed within one months time frame. The participants 
will be randomized into one of four treatment groups which will determine which approach 
will be used as well as the inclusion/exclusion of ultrasound guidance: 
Group 1:  Joint Line Ultrasound Guided 
Group 2:  Joint Line Landmark Based (sham Ultrasound) 
Group 3:  Suprapatellar Ultrasound Guided  
Group 4:  Suprapatellar Landmark Based (sham Ultrasound) 
 
The patients will be blinded to their group assignment prior to the first injection and will not 
be able to see which technique is employed.  The provider performing the injections will not 
be blinded.  The third injection (only) will be different in that contrast medium will be 
injected along with the hyaluronan.  Following the third injection, fluoroscopy will be used to 
determine presence/absence of the contrast medium into the joint.  The radiologist 
interpreting these images will be blinded to the technique employed.  At 3 months following 
the third injection, the patients will be contacted by a surveyor blinded to the group 
assignment.    
 
 
Objectives and Specific Aims 
 
1. To compare the accuracy of injections into the knee joint with two different 
approaches,  joint line and suprapatellar pouch  
2. To determine if the addition of ultrasound guidance to traditional landmark-based 
techniques enhances the accuracy of these techniques 
3. To examine differences in patient perceived pain and functioning of their knee joint 
following the injection series.     
 
 
Medical Application 
 
Injections into the knee joint are an exceedingly common procedure by a variety of 
specialists, primary care physicians, and non-physician clinicians.  Knowledge of the 
most accurate and clinically effective injection technique will positively impact countless 
future patients.  If we find that the addition of ultrasound guidance increases accuracy, as 

 
 
 
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we hypothesize, patient-oriented results should be better with fewer complications.  This 
will allow the patient to return to activity quicker. 
 
 
 
Background and Significance 
 
Literature Review (as of 18 November 2010) and Preliminary Data and/or Findings.  
 
Knee osteoarthritis is exceedingly prevalent.  While the exact worldwide incidence of 
symptomatic knee osteoarthritis is unknown, it is of note that 10% of people over the age 
of 55 experience disabling pain from knee osteoarthritis.1 Treatment of this disease 
process is multifaceted and often includes intra-articular injection of corticosteroids and 
viscosupplements.  Viscosupplements, with a mechanism of action that remains largely 
theorectical, was approved by the Food and Drug Administration in 1997.  There are 
numerous proprietary preparations available, all of which contain natural or synthetic 
sodium hyaluronate (hyaluronic acid).  Anecdotally speaking, injection of the knee joint 
is one of the most common procedures done in primary and specialty-based care.   
 
The tibiofemoral joint, colloquially referred to as the “knee joint” encompasses the area 
where the femur, tibia, fibula, and the patella come together.  The knee joint space extends 
from approximately two to three centimeters above the patella (suprapatellar pouch) to under 
the patella and to the top of the tibia (i.e., the tibial plateau).  There are a diversity of 
injection approaches for the knee joint used in clinical practice.   
 
Surface landmark–guided joint line technique.  Based on clinical practice, the most 
common technique involves injection at the physician-perceived tibiofemoral joint line, 
based on palpation (Figure 1).  This can be done either medial or lateral to the patellar 
tendon.  The joint line is commonly understood to be the anterior aspect of the synovial space 
between the femur and tibia.  Depending on the anatomy of the patient, this standard joint 
line approach may be difficult to achieve. For example, severe osteoarthritis and obesity can 
complicate the accuracy of this procedure.  Further, there are inherent risks in this traditional 
method (Reference: 5.2 Scientific Justification). 
 
Figure 1: Tibiofemoral joint line technique for knee joint 
injection using the lateral joint line.2  
 
 
 
 
 
 
Other techniques that have been described and used include  the suprapatellar pouch 
(described below) and the patellofemoral joint line at the midpoint between the superior 
and inferior poles of the patella (“midpatellar”), either from the medial or lateral sides. 
 

 
 
 
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Surface landmark–guided suprapatellar approach.  There has been a surge of interest 
in injection strategies that mitigate the difficulties of the surface landmark-guided joint 
line technique as described above.  One such technique, one in which the needle is 
inserted into the suprapatellar pouch, takes advantage of the fact that the true joint space 
extends superior to the patella and anterior to the femur.  This portion of the joint is 
commonly called the suprapatellar pouch (Figure 2).  The 
potential advantage of this technique is that the needle does 
not contact the fragile articular cartilage.  Its limitations are 
based on fact that in the absence of a knee effusion (fluid in 
the knee), the suprapatellar pouch is but a potential space 
that may be completely empty and collapsed and thus 
difficult to find with a needle tip.  Even when a small 
effusion is present, it may be difficult to find, depending on 
its size and the palpatory skills of the provider. 
 
Figure 2: Suprapatellar Technique for Knee Joint Injection3 
 
Technology may improve techniques.  The advent of sonographic (ultrasound) 
visualization has made the suprapatellar approach infinitely easier.  In the presence of an 
effusion, it is quite easy to do ultrasound-guided injection into the suprapatellar pouch.   
In the absence of an effusion, though, even ultrasound guidance into a potential tissue 
space can be challenging.  Another newer approach uses ultrasound to guide a joint line 
(intercondylar) injection with the thought that visualization will enhance accuracy.  While 
there are theoretical accuracy advantages with ultrasound-guided injections, the accuracy 
rates of these methods have not yet been evaluated.  There are also monetary costs to 
adding the use of ultrasound visualization, and assembling the necessary equipment and 
supplies may increase the time to perform the procedure.   
 
Studies have compared the accuracy of the landmark-based joint line approach to that of 
other injection approaches in the knee.  One study compared the accuracy of 
anteromedial, anterolateral, and lateral midpatellar over a series of 240 injections.6  All of 
these injections were landmark based (no ultrasound used for the procedure) and patients 
with an effusion were excluded from participation.  The lateral midpatellar approach was 
found to be the most accurate (93%) compared to the anteromedial (75%) and 
anterolateral (72%) approaches.4  Taken one step further, Esenyel et al compared the 
accuracy of four different approaches to knee injection in 78 cadaveric knees: 
anteromedial joint line, anterolateral joint line, lateral midpatellar, and medial 
midpatellar.7  This particular study found the anterolateral approach to be the most 
accurate at 85% success versus 73% for anteromedial, 76% for lateral midpatellar, and 
56% for medial midpatellar. Overall these studies show that the anterolateral aspect of the 
suprapatellar pouch may result in the highest accuracy for landmark-based injections.   
 
Although ultrasound-guided injections are superior to surface landmark-guided 
techniques into the subacromial space (defined as the extra-articular area between the 
superior aspect of the humerus and the inferior surface of the acromion) of the shoulder; 
there are no consistent data regarding landmark-guided versus ultrasound guided 

 
 
 
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techniques for accuracy of injections specific to the knee joint.  One study compared 
landmark-based and ultrasound-guided techniques in 184 patients receiving corticosteroid 
injections of their shoulder, elbow, wrist, knee, or ankle3.  In aggregate, ultrasound-
guided injections were found to be more accurate (83%) compared to clinical 
examination-guided injections (66%).  However, this study was not powered to determine 
a difference in accuracy among the individual joints.  Self-reported pain and function 
scores at two and six weeks following the injection were no different based on the 
technique employed.  There was, however, a trend towards improvement in function 
based on a visual analog scale at two weeks post ultrasound-guided injection and a 
statistically significant improvement at six weeks post injection.  Additionally, a trend 
was seen for improvement in pain (VAS scale) at two and six weeks post injection.  
Although there was lack of power to adequately reach a conclusion, this study suggests a 
potential therapeutic benefit with ultrasound-guided injections of the knee versus a 
landmark-based technique.   
 
Wiler et al, compared the amount of fluid aspirated from 66 knee joints by emergency 
department physicians using an ultrasound-guided suprapatellar versus a landmark-based 
joint line approach.4 This study found no difference in amount of fluid aspirated.  
However, participants reported significantly less pain when the ultrasound guided 
approach was used (3.71 versus 5.19 on a 10-cm VAS scale).  Providers believed that the 
ultrasound approach was easier to perform (1.67 versus 2.11 units on a five-point scale) 
and the procedure time was shorter (10.58 versus 13.37 minutes).  No analysis of target 
acquisition accuracy was obtained in this study.   
 
One study showed increased accuracy of injections into the knee with ultrasound 
guidance, but the researchers used a medial midpatellar approach.5  With this technique 
the patient lies supine and the needle is inserted medially at the patellofemoral joint line 
at the midpoint between the superior and inferior patellar poles .  Among 89 injections, 
ultrasound guided medial midpatellar injections were found to have an accuracy rate of 
95.6% compared to 77.3% with a landmark-guided medial midpatellar injection.  
However, the theoretical disadvantage to this technique in damage to the cartilage from 
the needle tip, a risk that typically precludes this approach from our standard practice. 
 
Our clinical experience has been that ultrasound visualization of the suprapatellar 
injection plane is best accomplished with an anterolateral orientation and is made 
significantly easier by the presence of effusion.  An effusion appears on ultrasound 
imaging as an easily identifiable homogenous black fluid pocket.  We typically look for 
the presence of an effusion when performing suprapatellar knee joint injections since the 
effusion is our needle target.  Visualization of an effusion was investigated in a small 
study on eight cadavers.  In this study, Hong et al correlated five different ultrasound 
views of the suprapatellar pouch (longitudinal: medial, midline, lateral; transverse: 
medial, lateral) with varying amounts of solution (5, 10, 15, and 20 ml) used to simulate 
an effusion.  Sensitivity was highest with at least 10ml of solution present and using a 
combination of lateral transverse and lateral longitudinal views.8  We, therefore, 
hypothesize, that in the presence of approximately 10ml of fluid in the suprapatellar 

 
 
 
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pouch, the ultrasound-guided suprapatellar approach using a combination of lateral 
transverse and lateral longitudinal visualization will result in the highest accuracy.   
 
 
 Scientific Justification  
 
We will examine three primary questions:   
1. Whether there is a difference in the accuracy of injections into the knee joint using joint 
line approach compared to a suprapatellar pouch approach. 
2. Whether the use of ultrasound guidance enhances the accuracy of these techniques. 
3. Whether participants perceive a difference in pain and functioning depending on the 
technique. 
 
To date, the data have not demonstrated that any of these four approaches (i.e., joint line 
approach without ultrasound, joint line approach with ultrasound, suprapatellar pouch 
approach without ultrasound, suprapatellar pouch approach with ultrasound) is the most 
accurate or should be the standard of care.  By examining these questions we will determine 
the most appropriate approach to knee joint injections while balancing patient safety and 
accuracy of the procedure.  This conclusion will be augmented by determination of patient-
oriented outcomes following the procedure to include the WOMAC index (pain and function) 
as well as overall procedure satisfaction. 
 
 
Human Use Justification  
 
It is appropriate to use human subjects as research volunteers for this study.  As this is a 
clinical trial, it would be impossible to do the study without human subjects.  Due to the 
variation of ultrasound appearance and palpatory feedback used during an injection 
between live versus preserved tissue, it is not preferable to perform this trial on cadaveric 
subjects.  Further, this study seeks patient oriented outcomes to further elucidate the 
applicability of these techniques.  All of the techniques described above are currently 
used in clinical practice and will be recommended as part of the treatment plan per usual 
standard of care.  As such, there are no additional risks associated with completion of this 
study other than reaction to the contrast agent.   
 
 
Type of the Subject Population 
 
Male and female subjects age 18 to 90 years presenting to a sports medicine clinic with knee 
pain justifying injection of a hyaluronic acid product will comprise the study population.  
The decision to use one of these products does not typically follow an algorithm that takes 
into account duration of symptoms or failure of modalities.  Instead, this procedure is 
typically performed after the risks and benefits of various treatment options are discussed 
with the patient and he/she elects to receive this injection in concert with or as opposed to 
any number of other treatment modalities for knee osteoarthritis. 
 

 
 
 
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Inclusion and Exclusion Criteria 
 
a.  Inclusion Criteria 
1. Male or female, age 18 to 90 
2. Clinician determined need for intra-articular knee injection 
 
b.  Exclusion Criteria 
1. Allergy to contrast dye, shellfish 
2. Allergy to egg products or hyaluronate 
3. Allergy to lidocaine 
4. Localized skin infection at planned site of injection 
5. Inability to complete follow-up phone call three months following the injection 
 
 
Recruitment 
 
Any adult-aged individual that meets inclusion and exclusion criteria will be eligible to 
participate in the study.  Due to the expected large cohort of participants already present 
within the patient population at the trial site, no advertising will be necessary for this 
study.   
 
 
Compensation for participation   
 
No compensation will be provided to subjects.  
 
 
Consent Process   
 
a. There will be a Research Coordinator at the trial site who will administer the consent and 
HIPAA authorizations.  This will be performed with a standardized consent form 
(Appendix A), including a scripted discussion of the study procedures and a scripted 
discussion of risks inherent in the injection techniques 
 
b. Upon completion of consent, the Coordinator will have the subject explain their 
understanding of the concept of treatment in their own words to ensure the subjects 
understand the consent. 
 
Study Design 
 
The study will be a randomized, double-blinded clinical study comparing four techniques for 
intra-articular knee injections.   
 
The study investigators will receive a list of 120 computer generated random numbers from 

 
 
 
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one to four.  No more than 30 will be in each group to ensure that each group is the correct 
size.  Upon entry into the study, and prior to the first injection,  subjects will randomized by 
selecting a sealed envelope from a box containing an equal number of envelopes for each of 
the four treatments groups. The envelope will be given, unopened, to the study doctor. The 
subject will be blinded to their study group assignment.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Double-blinding will be done as follows:  The subjects will be blinded to whether ultrasound 
was used to guide their treatment.  The radiologist, who will review the fluoroscopic images 
after the injections, will be blinded to treatment group assignment.  The injecting physician 
will not be blinded to the treatment group assignment.  Treating physicians (injecting 
physicians) will perform the technique as detailed below based on the assignment of the 
participant.  Subjects and the radiologists will both be asked to guess their treatment group at 
each point in the data collection to determine the effectiveness of the blinding process.  The 
Surveyor will also be blinded to the treatment group allocation.   
 
The injecting physicians will consist of orthopedic surgeons, sports medicine fellows, or 
sports medicine fellowship trained primary care physicians.  All injecting physicians will 
receive a minimum of 2 hours of hands-on training specific to the procedures employed in 
this study.  Additionally, they will be supervised for their first several ultrasound-guided 
procedures to assure competence with the techniques.   
 
 
Study Methodology/Procedures 
 
Appointment 1 
1. Based on usual standard of care for knee pain, the treating physician will determine 
whether a series of viscosupplemental intra-articular knee joint injections is 
recommended.  Patients who would likely benefit from the injections will be invited to 
participate in the study but will still receive usual care if they decide not to participate. 
 
Study Population 
N = 120 
Group 1:  
Joint Line 
(Ultrasound) 
N = 30 
Group 2:  
Joint Line 
Landmark 
(Sham Ultrasound) 
N = 30 
Group 3:  
Suprapatellar Pouch 
(Ultrasound) 
N = 30 
Group 4:  
Suprapatellar Pouch 
Landmark 
(Sham Ultrasound) 
N = 30 

 
 
 
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2. The informed consent document will be reviewed with and signed by interested patients. 
 
Participants will complete the Western Ontario and McMaster Universities Arthritis Index 
(WOMAC), a validated, widely used instrument that measures self-reported pain, joint 
stiffness, and physical function.  This index consists of 24 questions (5 pain, 2 stiffness, 17 
physical function) and takes less than 5 minutes to complete.  Raw scores are normalized to 
fit within a range of 0 (worst) to 100 (best).  Additionally, there is a normalized raw Global 
Score that considers the variables of pain, stiffness, and physical function as a collective. The 
WOMAC will be issued four times during the study; prior to the three injections and again at 
the three month follow up phone call.  
3. The injection procedure will be completed based on group assignment (see below). For the 
third injection in the series, all four groups will receive a “one needle, two syringe” 
injection as follows:   
a. A 21 gauge two inch needle attached to a 5 ml syringe filled with 5 ml of 
Omnipaque 300 ® (General Electric Healthcare, Princeton, NJ) contrast medium 
will be introduced into the skin at the predetermined site and directed either with 
or without ultrasound guidance based upon group assignment.  Injection site, 
landmarks, and intended path of the needle are detailed further in the group 
description below.   
b. The entire contents of the syringe will then be injected. Following delivery of the 
contrast medium, the syringe will be removed while the needle remains in place. 
c. A second syringe with the pre-determined medication (Hyaluronic Acid) will be 
attached to the needle and this medication will be delivered. 
d. The needle and syringe will be removed from the knee and the injection will be 
bandaged.   
4. The first and second injections will be performed based on the group assignment (see 
below) but will not include the use of contrast medium.   
 
Group 1: Joint Line Ultrasound (JLUS) 
 
The Joint Line Ultrasound (JLUS) group will receive a standard medial or lateral joint line 
injection aided by ultrasound guidance.  Specifically, this technique will entail palpation by 
the clinician of the soft tissue triangle formed by the tibial plateau, border of the patellar 
tendon, and the distal femoral condyle as found on both the medial and lateral joint line with 
the patient sitting on the edge of an examination table.  Their knees will be bent to 90 degrees 
of flexion.  The decision between a medial versus a lateral approach will be made by the 
provider performing the injection and based on the patient’s anatomy and the provider’s 
determination of the most facile side in which to perform the injection, as is the traditional 
practice of performing this technique.  The triangle felt to be most prominent (i.e. largest 
joint space) will be chosen as the injection site.  The area will be prepped in the usual sterile 
fashion.  
 
The injection will be performed as detailed above with real time ultrasound guidance. To 
accomplish this a 10 MHz linear array transducer from a standardized ultrasound unit (Logiq 
E ®, General Electric Healthcare, Chalfont St. Giles, United Kingdom) will be placed in an 
oblique orientation on the opposite soft tissue triangle from the intended injection site so that 

 
 
 
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the inner aspect of the opposite femoral condyle is visualized, but the ultrasound display will 
be positioned so that the patient cannot visualize the screen.  The injection will occur through 
the soft tissue triangle and directed at a 45 degree angle to the inner aspect of the opposite 
femoral condyle, with the needle being advanced parallel to (in the longitudinal axis of) the 
US probe.  When the needle is visualized to be adjacent to the articular cartilage, a small 
bolus of saline will be injected.  When the provider is satisfied that the needle tip is 
underneath the synovium overlying the condyle, as evidence by the saline easily dispersing 
underneath the synovium and not accumulating adjacent to it, the viscosupplement will be 
injected followed by the contrast. 
 
Group 2: Joint Line Landmark (JLL) 
 
The same determination of medial versus lateral approach as described in Group 1 will be 
made.  The injection will be performed as described above. The ultrasound probe will be 
placed in an oblique orientation on the opposite soft tissue triangle from the intended 
injection site, but the ultrasound display will be positioned so that the patient cannot visualize 
presence or absence of the needle, and the image will be placed on “FREEZE” so that no 
active images are being viewed.  The injection will be completed based strictly on tactile 
feedback from the injecting physician.  The needle will enter the predetermined soft tissue 
triangle and directed toward the joint space.  Once the injecting physician believes that the 
needle is positioned within the joint space, the viscosupplement will be injected followed by 
the contrast. 
 
Group 3: Suprapatellar Ultrasound Guided (SPUS) 
 
Real time ultrasound guidance using a standardized ultrasound unit with a 10 MHz linear 
array transducer (Logiq E ®, General Electric Healthcare, Chalfont St. Giles, United 
Kingdom) will be used to guide the injection for this group. The ultrasound display will be 
positioned so that the patient cannot visualize the screen.   After sterile prep of the 
anteriolateral suprapatellar area (approximately 1 cm superior to the patella at a level 
approximating that of the lateral patellofemoral joint space), the suprapatellar pouch will be 
visualized.  First, a longitudinal view capturing the proximal patella and the plane between 
the prefemoral fat pad (superficial to the femur) and suprapatellar fat pad (deep to the 
quadriceps tendon) will be obtained.  Presence or absence of an effusion, visualized as a 
localized collection of anechoic material within this plane, will be noted.  Next, the probe 
will be turned 90 degrees to a transverse view of the plane just proximal to the patella.  Small 
adjustments in probe positioning will be done to create the best visualization of the 
suprapatellar pouch.  After the desired visualization is achieved the needle will be inserted 
just lateral to the vastus lateralis in the longitudinal axis of the US probe and angled medially 
until the tip of the needle is within the suprapatellar pouch.  Should an effusion be present, 
this will serve as the target landmark.  In this instance, the effusion will be aspirated using a 
clean 5ml syringe prior to the injection.  In the absence of an effusion, the target landmark 
will be the plane between the prefemoral and suprapatellar fat pads.  In the absence of an 
effusion, injection of saline will be done first to dissect this plane further to assure that the 
needle tip is within the suprapatellar pouch.  Once the injecting physician is confident of 
needle position with the pouch, the viscosupplement will be injected followed by the 

 
 
 
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contrast.   
 
Group 4: Suprapatellar Landmark (SPL) 
 
Patients randomized to the Suprapatellar Landmark (SPL) group will receive the same 
procedure as the Suprapatellar Ultrasound Guided (SPUS) group., with the exception of the 
sham ultrasound.  To accomplish this, the ultrasound probe will purposely be positioned in 
the transverse plane of the suprapatellar area but the ultrasound display will be positioned so 
that the patient cannot visualize the screen, and the “FREEZE” button will be activated so 
that no active image is transmitted.  The display will be positioned such that visualization by 
the patient will not be possible.  The injecting physician will insert the needle lateral to the 
vastus lateralis toward the suprapatellar pouch.  When the injecting physician believes the 
needle tip is in the pouch, the viscosupplement will be injected followed by the contrast.   
 
It should be noted, that none of the participants in the study will be given the ability to 
visualize the ultrasound screen or injection procedure. 
 
5. Following each injection, all patients will conclude their encounter with the injecting 
physician by being asked to rate on a scale of 0 to 10 their procedural pain from the 
procedure.  For pain, a score of 0 will correspond to no pain and 10 will correspond to 
the worst pain they have ever experienced. After each injection, and at the three 
month follow up telephone call, the subjects will be asked to rate their overall 
procedure satisfaction on a 0-10 scale where “0” represents complete dissatisfaction 
and “10” represents complete satisfaction. 
6. . After the third injection,  and after answering these questions, the patient will proceed 
directly to the Radiology Department.   
 
7. Images of the joint will be obtained following the third injection.  These images will be 
analyzed by a radiologist blinded to the technique employed and used to determine 
presence of or absence of the contrast medium within the joint.   
 
Appointment 4 (telephone) 
 
8.  Subjects will be contacted approximately three months after the procedure by a Surveyor 
and the WOMAC Osteoarthritis Index will be repeated.  The patients will be asked to rate 
their procedural satisfaction and also detail other therapies they have employed since the 
injection. This will include supplements, exercise (frequency and duration), acupuncture, 
physical therapy, etc.   
 
 
Data Collection  
 
Data collection will occur at three points during the investigation: 
• Initial evaluation: Screening instrument for first visit (history and physical, diagnostic 
and inclusion/exclusion criteria), WOMAC (prior to receiving each of the three 
injections), and intervention 

 
 
 
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The clinical staff will collect the following data: 
• Name, email, phone number 
• Demographics: age, gender, type and number of injections received 
previously 
• Informed consent/HIPAA  document  
• WOMAC Osteoarthritis Index 
 
• Post Procedure 
The Injecting physician will record the following data: 
• Group Assignment  
• Amount and type of therapeutic substance injected 
• Total time to complete procedure from sterilization to bandaging 
• Procedural Pain Score (0 to 10) 
• Procedural Satisfaction Score (0 to 10) 
• Complications 
 
In a separate electronic database, the radiologist will record the following data: 
• Name 
• Presence or absence of contrast material within the knee joint 
 
•  Three months after intervention (telephone) 
• WOMAC Osteoarthritis Index 
• Procedure Satisfaction Score (0 to 10) 
 
 
Study Time Line  
 
Assessment 
 
 
Study Day / 
Period 
Initial Evaluation and
First Injection 
Second  
Injection 
Third Injection 
With contrast 
3 months 
Post Treatment 
Screening            
x 
 
 
  
Informed  
Consent, discuss  
Plan, etc. 
x 
 
 
 
Randomization 
x 
 
 
 
Demographics, 
History & 
Physical 
x 
 
 
 
WOMAC (pre 
injection) 
x 
x 
x 
x 
Treatment 
x 
x 
x 
 
Procedural Pain 
(post injection) 
x 
x 
x 
 
Procedural 
x 
x 
x 
x 

 
 
 
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Satisfaction (post 
injection) 
Fluoroscopic  
Analysis 
 
 
x 
 
Complications  
(post injection) 
 
 
x 
 
 
 
Statistical Consideration 
 
Primary endpoints are presence/absence of contrast medium in the joint, the WOMAC 
osteoarthritis index, and overall satisfaction with the injection technique.  Our statistical 
analysis of the WOMAC index will consider a mean change from baseline to post-injection 
with the variables of pain, stiffness, and function.  We will also study the mean change of the 
Global Score from the WOMAC.   
 
 
Data Analysis 
 
Statistical analysis of the WOMAC score will consist of one-way analysis of variance 
(ANOVA) followed by Tukey’s post-hoc multiple comparisons between the four groups with 
a 5%, two-sided familywise significance level (which allows for comparisons between all 
possible pairs of treatments).  Chi square tests will be used to compare the percent accuracy 
among the four groups.  We will also perform sub-analysis to determine if any trends can be 
linked to the type of medication (viscosupplementation) injected versus accuracy.   
 
 
Safety Monitoring and Analysis Plan  
 
Since treatments are provided at the onset of the study, “stopping rules” will not apply in this 
study.  Since the primary outcome includes pain and functioning at baseline and 3 months 
following the intervention, the entire study must be carried out in order to gather the desired 
data.  There have been no unexpected side effects other than local pain and swelling at the 
injection site that have been reported in the studies using these injection techniques, so we do 
not believe any other specific side effects will need to be monitored.  Patients will not be 
included in the study if a contraindication applies to them.  Of note, viscosupplementation is 
not contraindicated in pregnant patients.   
 
 
Sample Size Estimation 
 
For the comparison of accuracy, a two group chi square test with a 5% two-sided 
significance level will have 80% power to detect a difference of 33 percentage points 
between groups when the accuracy in the less-accurate condition is 60% and the sample 
size in each group is 25. 
 

 
 
 
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Previous studies have demonstrated an effect size of the WOMAC ranging from 0.5 to 
1.0 when medication interventions were studies on patients with knee pain.  A sample 
size of 25 in each group will have 80% power to detect an effect size of 0.809 using a two 
group t-test with a 5% two-sided significance level.   
 
Reference: Lenth, R. V. (2006-9).  Java Applets for Power and Sample Size [Computer 
software].  Retrieved November, 2010, from http://www.stat.uiowa.edu/~rlenth/Power. 
 
 
Reporting Adverse Events 
 
Definitions: 
Adverse events (adverse effects, adverse reactions): any occurrence of injury, 
dysfunction, disease, or abnormality of any organ or tissue that occurs in a subject 
enrolled in a clinical protocol.  Manifestations of an adverse event may include 
symptoms, physical exam abnormalities, diagnostic study abnormalities, and/or death.   
 
Expected adverse events: adverse events previously known or anticipated to result from: 1) 
the interventions and interactions used in the research (these events must be included as 
potential risks in the consent form); 2) the collection of identifiable private information under 
research (these events must be included as potential risks in the consent form); 3) an 
underlying disease, disorder, or condition of the human subjects; and/or 4) other 
circumstances unrelated to the research or any underlying disease, disorder, or condition of 
the subject.  
 
Unexpected adverse events /Unanticipated problems: adverse events that 1) are not expected 
given the nature of the research procedures and the subject population being studied; and 2) 
suggest that the research places subjects or others at a greater risk of harm or discomfort 
related to the research than was previously known or recognized. 
 
Serious adverse event: an adverse event that is fatal, life-threatening, permanently disabling, 
require inpatient hospitalization, or result in congenital anomalies/birth defect, overdose or 
cancer, or any other adverse event that, based on appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention to prevent 
one of the other outcomes listed above. 
 
 
Expected Adverse Events from Research Risks and Reporting 
 
• Rare but serious (Event Rate < 1%): infection at the site of injection; contrast dye 
allergic reaction. 
• Likely (5% ≤ Event Rate < 10%): 8% incidence of pseudo-synovitis with the use of 
Synvisc® products. 
• More likely (Event Rate ≥ 10%): bruising, swelling and increased pain at site of 
injection for several days to a few weeks. 
 

 
 
 
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Monitoring of adverse clinical events will be done during each of the two scheduled follow-
up assessments.  These will be managed as follows: 
• Infection at injection site, or blood-borne infection: manage as clinically indicated 
based on assessment by physician. 
• Contrast dye reaction:  treat as clinically indicated based on severity. 
• Pseudo-synovitis: NSAIDs, ice, compression, elevation. 
• Bruising, swelling and increased pain at site of injection: treat with compression, 
ice, and prescribed pain medications (no NSAIDs), and patient reassurance that 
these resolve with time. 
 
 
Reporting Serious and Unexpected Adverse Events to the IRB 
 
Serious Adverse Events: The PI, within one working day, will report all serious adverse 
events (SAE) occurring in subjects enrolled in the study.  This is accomplished by 
submitting an adverse event report memorandum to the IRB.  Serious adverse events will 
be reported even if the PI believes that the adverse events are unrelated to the protocol.  
 
Unexpected (but not serious) adverse events occurring in subjects enrolled in the study, in the 
opinion of the PI, are possibly related to participation in the protocol will be reported by the 
PI within 10 (ten) working days to the IRB using the same procedure. 
 
For all serious and/or unexpected adverse events, the PI will forward a copy of the adverse 
event report to IRB.  A summary of all serious or unexpected side effects also will be 
included in the APR. 
 
 
Protected Health Information 
 
 
All participant PHI and study results will be located in a password protected 
spreadsheet on a computer.  The radiologist will also maintain a password protected 
spreadsheet on his/her personal work computer with password protected access and will 
provide this data as requested to the Principle Investigator.  The Principle Investigator will 
maintain a central file of all PI and data on a password protected spreadsheet on a computer 
with password protected access.   
 
Research documents that contain PHI will be destroyed when the study results have 
been published in a medical journal.  Non-PHI results will be maintained indefinitely in the 
possession of the PI. 
 
 
Reporting Protocol Deviations 
 
Any protocol deviations during the course of the study will be promptly reported to the IRB 
and sponsor if applicable, through the medical monitor of the protocol if applicable.  
Examples of deviations include but are not limited to variances from the treatment schedule 

 
 
 
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for an individual patient, failure to use the most current consent form, and/or incomplete or 
lost records.   
 
Reporting protocol deviation is accomplished by submitting a protocol deviation 
memorandum to the IRB.    
 
Cost 
 
The trial participants will not be charged any fees above the typical cost of their encounter 
with their physician and the cost of the injection of their medication.  The expected cost of 
the Omnipaque 300 will be $6.25 per injection, totaling $750.00 for the entire study ($6.25 x 
120 participants).  Dr. Dorvault will provide accomplishment and interpretation of the 
fluoroscopic images at no additional charge.   
 
 
References 
 
1.  Peat G, McCarney R, Croft P.  Knee pain and osteoarthritis in older adults: a review of 
community burden and current use of primary health care.  Ann Rheum Dis.  2001; 60: 
91-97.   
2.  Arthritiscenter.com [Internet].  Arthritis Center of Connecticut.  Available from: 
http://www.arthritiscenter.com/html/joint_injection.php. 
3.  Aafp.org [Internet].  American Family Physician.  Available from: 
http://www.aafp.org/afp/2002/1015/p1497.html. 
4.  Jackson DW, Evans NA, Thomas BM.  Accuracy of needle placement into the intra-
articular space of the knee.  Journal of Bone and Joint Surgery.  2002; 84(9): 1522-1527. 
5.  Wiler JL, Costantino TG, Filippone L, et al.  Comparison of ultrasound-guided and 
standard landmark techniques for knee arthrocentesis.  The Journal of Emergency 
Medicine.  2010; 39(1): 76-82.   
6.  Esenyel C, Demirhan M, Esenyel M, et al.  Comparison of four different intra-
articular injection sites in the knee: a cadaver study.  Knee Surg Sports Traumatol 
Arthrosc.  2007; 15: 573-577. 
7.  Naredo E, Cabero F, Beneyto P, et al.  A randomized comparative study of short term 
response to blind injection versus sonographic-guided injection of local corticosteroids in 
patients with painful shoulder.  J Rheumatol.  2004; 31(2): 308-314.   
8.  Cunnington J, Marshall N, Geoff H, et al.  A randomized, double-blind, controlled 
study of ultrasound-guided corticosteroid injection into the joint of patients with 
inflammatory arthritis.  Arthritis Rheum.  2010; 62(7): 1862-69.  
9.  Im SH, Lee SC, Park YB, et al.  Feasibility of sonography for intra-articular injections 
in the knee through a medial patellar portal.  J Ultrasound Med.  2009; 28(11): 1465-70. 
10.  Hong BY, Lim SH, Cho YR, et al.  Detection of knee effusion by ultrasonography.  
Am J Phys Med Rehabil.  2010; 89(9): 715-21.