Ultrasound-Guided Genicular Nerve Block for Knee Pain in the Emergency Department: A Randomized Controlled Trial
Phase: NA
Conditions: Knee Pain
Sponsor: University of Pennsylvania

 
Protocol [Insert Study Number] - Genicular Block for Knee Pain: An RCT 
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CLINICAL RESEARCH PROTOCOL 
 
INVESTIGATIONAL 
PRODUCT(S): 
 
Not Applicable 
STUDY 
NUMBER(S): 
IRB   Number 
 
Other Protocol 
Identifiers  
 
 
PROTOCOL(S) TITLE: 
Ultrasound-Guided Genicular Nerve Block for Knee 
Pain in the Emergency Department: A Randomized 
Controlled Trial 
NUMBER: 
 
 
REGULATORY SPONSOR: 
 
 
FUNDING SPONSOR(S): 
Not applicable. 
MEDICAL DIRECTOR 
Michael Shalaby, MD 
ORIGINAL PROTOCOL DATE: 
 
VERSION NUMBER: 
Version 2.0 
VERSION DATE: 
5/16/2025 
 
 
 

 
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1 
Study Summary .......................................................................................................... 8 
1.1 
Synopsis .................................................................................................................. 8 
1.2 
Key Roles and Study Governance ..................................................................... 11 
1.3 Schema ....................................................................................................................... 12 
2 
Introduction and RationalE .................................................................................... 13 
2.1 
Study Rationale ................................................................................................... 13 
2.2 
Background .......................................................................................................... 13 
2.2.1 
Pharmacokinetics, Pharmacodynamics and Toxicology ........................... 14 
2.2.2 
Assessment for Potential Study Products Drug-Drug, Drug-Device, 
Device-Device Interactions ........................................................................... 15 
2.2.3 
Clinical Adverse Event Profile ..................................................................... 15 
2.2.4 
Dosing Rationale ........................................................................................... 15 
2.3 
Risk/Benefit Assessment ..................................................................................... 16 
2.3.1 
Known Potential Risks .................................................................................. 16 
2.3.2 
Known Potential Benefits ............................................................................. 16 
2.3.3 
Assessment of Potential Risks and Benefits ................................................ 17 
3 
Study Objectives and Endpoints............................................................................. 19 
4 
Study Plan ................................................................................................................. 20 
4.1 
Study Design ........................................................................................................ 20 
4.2 
Scientific Rationale for Study Design ................................................................ 21 
4.3 
Justification for Dose .......................................................................................... 22 
4.4 
End of Study Definition ...................................................................................... 22 
5 
Study Population ...................................................................................................... 23 
5.1 
Inclusion Criteria ................................................................................................ 23 
5.2 
Exclusion Criteria ............................................................................................... 23 
5.3 
Lifestyle Considerations ..................................................................................... 24 
5.4 
Screen Failures .................................................................................................... 24 
5.5 
Strategies for Recruitment and Retention ........................................................ 24 
6 
Study Intervention ................................................................................................... 26 
6.1 
Study Intervention(s) Administration ............................................................... 26 
6.1.1 
Study Intervention Description .................................................................... 26 
6.1.2 
Dosing and Administration .......................................................................... 27 
6.2 
Preparation/Handling/Storage/Accountability ................................................ 28 
6.2.1 
Acquisition and accountability .................................................................... 28 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................ 28 
6.2.3 
Product Storage and Stability ...................................................................... 28 
6.2.4 
Preparation .................................................................................................... 29 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................. 29 
6.4 
Study Intervention Compliance ......................................................................... 29 
6.5 
Concomitant Therapy ......................................................................................... 29 
 

 
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6.5.1 
Rescue Medicine ............................................................................................ 30 
7 
Study Intervention Discontinuation and Participant 
Discontinuation/Withdrawal ................................................................................... 31 
7.1 
Discontinuation of Study Intervention .............................................................. 31 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................... 31 
7.3 
Lost To Follow-Up .............................................................................................. 31 
8 
Study Assessment and Procedures ......................................................................... 32 
8.1 
Efficacy Assessments ........................................................................................... 32 
8.2 
Safety and Other Assessments ........................................................................... 32 
8.3 
Adverse Events and Serious Adverse Events ................................................... 32 
8.3.1 
Definition of Adverse Events (AE) .............................................................. 32 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................... 32 
8.3.3 
Unanticipated Adverse Device Effect (UADE) ........................................... 33 
8.3.4 
Classification of an Adverse Event .............................................................. 33 
8.3.5 
Time Period and Frequency for Event Assessment and Follow-Up ......... 34 
8.3.6 
Adverse Event Reporting ............................................................................. 35 
8.3.7 
Serious Adverse Event Reporting ................................................................ 35 
8.3.8 
Reporting Events to Participants ................................................................. 35 
8.3.9 
Events of Special Interest ............................................................................. 36 
8.3.10 
Reporting of Pregnancy ................................................................................ 36 
8.4 
Unanticipated Problems ..................................................................................... 36 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................ 36 
8.4.2 
Unanticipated Problem Reporting .............................................................. 36 
8.4.3 
Reporting Unanticipated Problems To Participants ................................. 37 
8.5 
Device Reporting ................................................................................................. 37 
9 
Statistical Considerations ........................................................................................ 37 
9.1 
Statistical Hypotheses ......................................................................................... 37 
9.2 
Sample Size Determination ................................................................................ 37 
9.3 
Populations for Analyses .................................................................................... 38 
9.4 
Statistical Analyses .............................................................................................. 38 
9.4.1 
General Approach ......................................................................................... 38 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................ 62 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................... 39 
9.4.4 
Safety Analyses .............................................................................................. 39 
9.4.5 
Baseline Descriptive Statistics ...................................................................... 40 
9.4.6 
Planned Interim Analyses ............................................................................ 40 
9.4.7 
Sub-Group Analyses ..................................................................................... 40 
9.4.8 
Tabulation of Individual Participant Data ................................................. 40 
9.4.9 
Exploratory Analyses .................................................................................... 40 
10 Supporting Documentation and Operational Considerations ............................. 40 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................. 40 

 
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10.1.1 
Informed Consent Process ............................................................................ 40 
10.1.2 
Study Discontinuation and Closure ............................................................. 41 
10.1.3 
Confidentiality and Privacy ......................................................................... 42 
10.1.4 
Future Use of Stored Specimens and Data ................................................. 42 
10.1.5 
Safety Oversight ............................................................................................ 43 
10.1.6 
Clinical Monitoring ....................................................................................... 43 
10.1.7 
Quality Assurance and Quality Control ..................................................... 43 
10.1.8 
Data Handling and Record Keeping ........................................................... 44 
10.1.9 
Protocol Deviations ....................................................................................... 44 
10.1.10 
Publication and Data Sharing Policy .......................................................... 44 
10.1.11 
Conflict of Interest Policy ............................................................................. 45 
10.2 
Additional Considerations .................................................................................. 45 
10.3 
Protocol Amendment History ............................................................................ 45 
11 References ................................................................................................................. 46 
12 APPENDIX ............................................................................................................... 48 
12.1 
Schedule of Activities (SoA) ............................................................................... 48 
 
 
 
 
 

 
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PRINCIPAL INVESTIGATOR SIGNATURE 
 
STUDY 
SPONSOR: 
Not applicable. 
STUDY TITLE: 
Ultrasound-Guided Genicular Nerve Block for Knee Pain in the Emergency 
Department: A Randomized Controlled Trial 
STUDY ID 
PROTOCOL 
VERSION 
 
I have read the referenced protocol. I agree to conduct the study in accordance to this protocol, in 
compliance with the Declaration of Helsinki, Good Clinical Practices (GCP), and all applicable 
regulatory requirements and guidelines. 
Principal 
Investigator Name  
Michael Shalaby 
 
Signature 
 
Affiliation: 
Department of Emergency 
Medicine 
 
Date 
3/19/2025 
 
 
 
 
 
 

 
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Abbreviations 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 

 
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OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SoA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UADE 
Unanticipated Adverse Device Effect 
UP 
Unanticipated Problem 
US 
United States 
GNB 
Genicular Nerve Block 
SMGN 
Superomedial Genicular Nerve  
SLGN 
Superolateral Genicular Nerve 
IMGN 
Inferomedial Genicular Nerve 
ILGN 
Inferolateral Genicular Nerve 
OA 
Osteoarthritis 
EM 
Emergency Medicine 
ED 
Emergency Department 
LAST 
Local Anesthetic Systemic Toxicity 
APS-POQ-RED 
American Pain Society-Patient Outcome Questionnaire-Revised for the ED 
NSAID 
Non-Steroidal Anti-inflammatory Drug 
NRS 
Numeric Rating Scale 
Cedar 
HUP Cedar  
RCT 
Randomized Clinical Trial 
PAH 
Pennsylvania Hospital  
HUP 
Hospital of the University of Pennsylvania 
PPMC 
Penn Presbyterian Medical Center 
 
 
 

 
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1 STUDY SUMMARY 
1.1 
Synopsis 
Title:  
Ultrasound-Guided Genicular Nerve Block for Knee Pain in the 
Emergency Department: A Randomized Controlled Trial 
Short Title: 
Genicular Block for Knee Pain: An RCT 
Study 
Description:  
Patients who present to the emergency department (ED) at any of the 
clinical sites of the University of Pennsylvania Heath System with 
atraumatic knee pain will be considered for enrollment to be randomized 
to receive an ultrasound-guided genicular nerve block (GNB) or 
conventional analgesia. Patients randomized to the intervention arm will 
receive a three-point GNB with weight-based dosing 0.5% bupivacaine 
augmented with 4 mg dexamethasone, divided into three separate aliquots 
to be injected around the superomedial genicular nerve (SMGN), 
superolateral genicular nerve (SLGN), and inferomedial genicular nerve 
(IMGN). This will be an open-labeled, investigator-initiated study with 
convenience enrollment. 
Objectives:  
Primary Objective:  
• To determine whether patients receiving a GNB for knee pain 
experience greater pain reduction compared to conventional 
analgesia  
Secondary Objectives: 
• To determine whether patients who receive a GNB experience a 
longer duration of analgesia compared to those who receive 
conventional analgesia  
• To determine whether patients who receive a GNB report higher 
patient satisfaction compared to those who receive conventional 
analgesia  
• To determine whether patients who receive a GNB have shorter 
ED length of stay (LOS) compared to those who receive 
conventional analgesia  
Primary 
Endpoint:  
• Difference in pain level as measured by NRS at pre-intervention 
(GNB or conventional analgesia) and at either 1-hour post-
enrollment or time of ED discharge, whichever occurs first 

 
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Secondary 
Endpoints: 
• Difference in duration of analgesia, assessed at 24-36 hours post 
intervention. 
• Difference in APS-POQ-RED between treatment arms, assessed at 
either 1-hour post-enrollment or time of ED discharge, whichever 
occurs first. 
• Difference in ED LOS between treatment arms, as determined by 
time from enrollment in study to time of ED discharge. 
Study 
Population: 
Patients presenting with knee pain at any of the four emergency 
departments: (1) Hospital of the University of Pennsylvania (HUP), (2) 
Penn Presbyterian Medical Center (PPMC), (3) Pennsylvania Hospital 
(PAH), and (4) HUP Cedar (Cedar)  
All genders, age ≥ 18, all demographic groups 
Moderate to severe knee pain (pain measured on NRS between 5 and 10) 
Exclusions based on general health status: cognitive impairment / 
dementia, inability to consent for study procedure 
Exclusion criteria: pregnant; incarcerated; large knee joint effusion as 
identified on plain film radiography; acute traumatic etiology for knee 
pain including fracture, dislocation, or suspected tendonous or 
ligamentous injury; concern for infection including septic joint, abscess, 
cellulitis, or sepsis; hemodynamic instability; allergy or contraindication 
to bupivacaine or any of its components 
Sample size: 17 patients per treatment arm 
Phase: 
N/A 
Description of 
Sites/Facilities  
(1) Hospital of the University of Pennsylvania 
(2) Penn Presbyterian Medical Center  
(3) Pennsylvania Hospital  
(4) HUP Cedar 
Enrolling Sites: 
EDs of the four previously mentioned sites 
Description of 
Study 
Intervention: 
The study intervention is an ultrasound-guided three-point GNB, which 
involves injection of local anesthetic with adjuvant (ideal bodyweight-
dosed bupivacaine 0.5% and dexamethasone 4 mg) around the genicular 
nerves of the knee. The genicular nerves are a series of four terminal 

 
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sensory nerve branches of the femoral nerve that provide sensory 
innervation to the joint capsule of the knee, thereby providing pain relief 
without motor blockade or paralysis. See detailed description of the study 
intervention in Section 6. The comparison control arm involves 
conventional analgesia for knee pain, which includes oral, intravenous, or 
topical analgesics (e.g., acetaminophen, non-steroidal anti-inflammatory 
drugs [NSAIDs], opioids, lidocaine patches, heating or cold packs) and 
will be determined at the discretion of the primary provider caring for the 
patient. See detailed description of study control arm in Section 6. 
Study Duration: 
12-months  
 
Participant 
Duration: 
24 to 36-hours 
Participant duration will end at 24 to 36-hours after treatment, at which 
time a research assistant or the participating physician will contact the 
patient via telephone call to assess for duration of analgesia. (See Section 
4.4 for complications which would extend participation duration beyond 
24 to 36 hours.) 
 
Resources 
Necessary for 
Human Research 
Protection  
This study is being conducted by the Division of Ultrasound within the 
Department of Emergency Medicine. The Principal Investigator is an 
ultrasound faculty member. The other investigator is an emergency 
medicine resident. Other research staff include a biostatistician, the 
ultrasound division's clinical research coordinator, and the research 
assistants within the Emergency Medicine Academic Associates program.  
All staff participating in the research will be trained on the protocol. Prior 
to the initiation of enrollment, the PI and co-investigator will meet with 
the research assistants to discuss recruitment including establishing an 
EPIC Haiku notification system, as well as inclusion and exclusion 
criteria. The clinical research coordinator is trained on data storage in 
REDCap. All resources required to complete this randomized controlled 
trial are provided by the Department of Emergency Medicine and the 
Division of Ultrasound, including the research assistants, the clinical 
research coordinator, and the biostatistician. Progress of the trial will be 
discussed at least every other week at the research meetings within the 
Division of Ultrasound. 
 
 

 
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1.2 
Key Roles and Study Governance 
 
Sponsor 
Medical Director 
Not Applicable 
Michael Shalaby, MD 
 
Department of Emergency Medicine, Hospital of the 
University of Pennsylvania 
 
3400 Spruce Street, Philadelphia, PA 19104 
 
504-417-0249 (personal); 267-624-4394 (work) 
 
Michael.Shalaby@pennmedicine.upenn.edu 
 
 

 
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1.3 Schema 
Prior to  
Enrollment 
 
 
 
 
 
 
 
Time Point 1 
 
  
 
Time Point 2 
(ED Discharge)  
 
Time Point 3 
(24-36-hours) 
 
 
 
 
24-hours post-intervention: Follow-up phone call 
Refer to: Appendix Section 12.1, Schedule of Activities 
34 participants:  Screen potential participants by inclusion and exclusion 
criteria, obtain history, document. Obtain informed consent. 
One-hour after enrollment OR time of ED Discharge (whichever occurs 
first): Follow-up assessments of study endpoints and safety 
Refer to: Appendix Section 12.1, Schedule of Activities 
Perform baseline assessment. Administer study intervention. 
Refer to: Appendix Section 12.1, Schedule of Activities 
Randomize 
Analysis 
Refer to: Appendix Section 
12.1, Schedule of Activities 
Control 
(standard analgesia) 
17 participants 
GNB  
17 participants 

 
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2 INTRODUCTION AND RATIONALE 
2.1 
Study Rationale 
Knee osteoarthritis (OA) is extremely prevalent, with a global incidence of greater than 20% of 
adults with age greater than 40 years (Cui 2020). Flares of chronic knee OA pain are common 
and are a frequent reason for presentation to the emergency department (ED). ED evaluation and 
management of exacerbations of chronic knee pain in patients with OA typically involves plain 
film radiography to evaluate for acute fracture or worsening of disease followed by oral, topical, 
or intravenous analgesics. However, these conventional therapies may often provide limited 
benefit in the acute setting and can be contraindicated in patients with certain concomitant 
comorbidities. In particular, the use of non-steroidal anti-inflammatory drugs is often limited in 
patients on anticoagulation or those with gastritis, gastrointestinal ulcers, gastrointestinal 
bleeding, or chronic kidney disease.  Opioids are also commonly used in the acute setting for 
multiple causes of musculoskeletal pain, including exacerbations of chronic knee pain. One study 
reported that nearly 17% of patients discharged from the ED received a prescription for opioids 
(Hoppe 2015).  While opioids are highly effective for acute pain management, they are 
associated with numerous adverse effects including respiratory depression, central nervous 
system effects, nausea, vomiting, and constipation, especially in elderly patients or those with 
certain comorbidities. Moreover, prolonged opioid use increases the risk for developing 
tolerance and dependence, which often leads to withdrawal, overdose, and death (Paul 2021). For 
this reason, identifying safe and effective alternatives to opioid analgesia is a research area of 
high priority in emergency medicine (Rech 2022). 
According to a 2017 practice guideline published by the American Academy of Emergency 
Medicine, “effective, efficient, and safe pain management is a cornerstone of state-of-the-art 
patient care in the ED and is a specialty-defining skill” and “emergency clinicians should 
consider regional and local nerve blocks for traumatic and nontraumatic painful conditions, alone 
or in combination with pharmacological and nonpharmacological treatment modalities.” With 
increased training and proficiency in ultrasound, emergency physicians are more commonly 
utilizing ultrasound-guided regional anesthesia techniques to facilitate multimodal pain control in 
the ED. The American College of Emergency Physicians released a policy statement in 2021 
endorsing that ultrasound-guided nerve blocks are “not only within the scope of the practice of 
emergency physicians, but represent a core component of a multimodal pathway to control pain 
for patients in the emergency department.” Development and implementation of safe alternative 
modes of analgesia may help to effectively manage breakthrough pain associated with knee OA 
and other etiologies of atraumatic knee pain without high doses of opioids or other potentially 
harmful non-opioid analgesics.  
2.2 
Background 
The genicular nerve block (GNB) is a relatively new regional anesthesia technique that has been 
used for a variety of operative and non-operative indications (Yasar 2015). There are four 

 
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distinct genicular nerve branches that the knee joint: the superolateral genicular nerve (SLGN), 
superomedial genicular nerve (SMGN), inferomedial genicular nerve (IMGN), and inferolateral 
genicular nerve (ILGN). The GNB classically involves deposition of a small volume of local 
anesthetic around the SLGN, SMGN, and IMGN. Due to the proximity of the ILGN to the tibial 
nerve, blockade of the ILGN is often avoided to minimize the risk of foot drop from inadvertent 
blockade of the tibial nerve (Sobel 2021). While this technique can be performed solely by 
landmark guidance, evidence favors utilizing ultrasound guidance, as the genicular nerves and 
associated genicular vascular structures can be easily visualized with real time ultrasound 
guidance (Singh 2023).  
The safety and efficacy of the GNB using perineural bupivacaine has been extensively evaluated, 
and studies within the orthopedic and rheumatology literature have demonstrated effective pain 
control of knee OA for up to three months following a single set of genicular nerve blocks (Tan 
2022). While several isolated cases of the GNB have been reported in the EM literature for knee 
OA and tibial plateau fractures (Bhattaram 2024, Kong 2023, Sobel 2021), no larger comparative 
studies or interventional trials have evaluated the utility of the GNB among ED patients who 
present with breakthrough knee pain.  
 
2.2.1 
Pharmacokinetics, Pharmacodynamics and Toxicology 
Mechanism of Action: Bupivacaine binds to the intracellular portion of voltage-gated sodium 
channels, thereby blocking sodium influx into neurons, preventing depolarization and 
subsequently preventing conduction of pain signals 
Onset of Action: 1 to 17 minutes (dose dependent) 
Duration of Action: 2 to 9 hours, depending on dosing; up to 24-hours with adjuvants 
Half-Life: 2.7 hours (in adults) 
Time to Peak Plasma Concentration: 30 to 45 minutes (for peripheral infiltration) 
Protein Binding: approximately 95% 
Metabolism: Primary hepatic metabolism in conjunction with glucuronic acid. Pipecoloxylidine 
is the major metabolite of bupivacaine. 
Excretion: Renal (4-10%) 
(Shafiei 2023, Becker 2012) 
 
 

 
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2.2.2 
Assessment for Potential Study Products Drug-Drug, Drug-Device, 
Device-Device Interactions 
Potential interactions of bupivacaine include: 
Local Anesthetics: Toxic effects of local anesthetics are additive, such that administration of 
multiple anesthetics can increase the risk of systemic toxicity if greater than weight-based dosing 
limit. 
Monoamine Oxidase Inhibitors and Tricyclic Antidepressants: Co-administration of bupivacaine 
with these agents can produce severe, prolonged hypertension if administered systemically. 
Ergot-Type Oxytocic Drugs: Co-administration of bupivacaine with these agents can produce 
severe, prolonged hypertension or cerebrovascular accidents if administered systemically. 
Nonselective Beta-Adrenergic Antagonists: Co-administration of bupivacaine with these agents 
can cause severe hypotension and bradycardia if administered systemically. 
Drugs Associated with Methemoglobinemia: Co-administration of bupivacaine with the 
following classes of agents can increase risk of developing methemoglobinemia: Nitrates (nitric 
oxide, nitroglycerin, nitroprusside, nitrous oxide), Antineoplastic agents (cyclophosphamide, 
flutamide, hydroxyurea, ifosfamide, rasburicase), Antibiotics (dapsone, nitrofurantoin, para-
aminosalicylic acid, sulfonamides), Antimalarials (chloroquine, primaquine), Anticonvulsants 
(phenobarbital, phenytoin, sodium valproate). 
2.2.3 
Clinical Adverse Event Profile 
General Adverse Effects: nausea, vomiting, chills or shivering, headache, back pain, sexual 
dysfunction, restlessness, anxiety, vertigo 
Local Anesthetic Systemic Toxicity (LAST): CNS Reactions (perioral tingling, tongue 
paresthesia, dizziness, tinnitus, blurry vision, tremors, seizures, myoclonic jerks), Cardiovascular 
Reactions (cardiovascular collapse, bradycardia, hypotension, cardiac arrest, ventricular 
arrhythmia) 
Allergic Reactions: urticaria, pruritus, erythema, angioneurotic edema (including laryngeal 
edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, 
elevated temperature, and severe hypotension 
2.2.4 
Dosing Rationale 
The weight-based maximal safe dosing for bupivacaine is 2.5 mg/kg. To minimize the risk of 
LAST, we will utilize weight-based dosing at 80% of the maximal safe dosing which will allow 
for effective and prolonged analgesia while minimizing the risk of complications and LAST. 
Patients with body mass index (BMI) greater than 25 kg/m2 will receive a total of 80% of their 
ideal body weight dosing in bupivacaine. Patients with a BMI of equal to or less than 25 kg/m2 
will receive a total of 80% of their actual body weight dosing in bupivacaine. This total dose will 

 
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be divided into three equal aliquots that will be injected around each of the three targeted 
genicular nerves. The use of dilute bupivacaine (0.5%) will allow for better spread to target 
nerves as well as a slower injection rate of anesthetic which is safer for monitoring for symptoms 
of LAST.  
2.3 
Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
Manufacturer Drug Information: 
LAST: As with all local anesthetics, the principal risk of bupivacaine is LAST, as previously 
described. To mitigate the risk of this, (1) anesthetic will be dosed by ideal body weight to not 
exceed the limit of safe dosing (e.g., 80% of maximal safe dosing by ideal body weight in 
patients with BMI greater than or equal to 25 kg/m2 and actual body weight in patients with BMI 
less than 25 kg/m2), (2) anesthetic will be administered slowly to identify any early signs of 
toxicity, (3) aspiration will be performed prior to each injection to ensure anesthetic will not be 
administered intravascularly, and (4) real-time ultrasound guidance with color doppler will be 
performed to visualize blood vessels to ensure anesthetic is not being administered 
intravascularly. The risk of LAST is extremely low (<1/10,000) (Neal 2018). 
Bleeding: With any percutaneous procedure, there is a risk of superficial and deep tissue 
bleeding. To minimize this risk, continuous real-time ultrasound visualization of the injection 
needle will be performed to ensure vasculature is not compromised. 
Infection: With any percutaneous procedure, there is a risk of soft tissue infection. To minimize 
this risk, the skin overlaying the injection sites will be prepped in standard fashion with 
chlorhexidine, sterile ultrasound probe covers will be used, operators will wear sterile gloves, 
and single-single use sterile needles will be used for each injection.  
Alternative Procedures: Considered using higher concentrations (0.75%), and while these have 
been proven safe for peripheral use, we elected to proceed with lower concentration (0.5%) for 
safety. Preliminary (non-published) data suggests that weight-based dosing of 0.5% bupivacaine 
can produce desired anesthesia. We will use ultrasound-guidance rather than landmark-guidance 
to visualize and avoid the genicular arteries that lay in proximity to the genicular nerves (Callese 
2023). 
 
2.3.2 
Known Potential Benefits 
Patients with knee OA can often have flares of severe pain, requiring ED visits for pain control. 
Several case reports and small case series have demonstrated the efficacy and safety of the 
genicular block performed in the emergency department for managing acute on chronic pain 
associated with knee osteoarthritis (Bhattaram 2024, Kong 2023, Sobel 2021). Moreover, a 
recent randomized controlled trial published in the rheumatology literature on ambulatory 

 
Protocol [Insert Study Number] - Genicular Block for Knee Pain: An RCT 
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patients demonstrated the that the genicular nerve block provides longer term pain relief in 
patients with knee osteoarthritis (Shanahan 2022). In this study, patients treated with a one-time 
three-point ultrasound-guided GNB reported improvements in pain scores and decreased 
disability as measured on the Western Ontario and McMasters Universities Osteoarthritis Index 
(WOMAC) and the Intermittent and Constant Osteoarthritis Pain scale compared to the control 
group who received a sham injection for up to 12-weeks after the block (Shanahan 2022). 
Immediate potential benefits include improved or relief of knee pain, improved mobility and 
ability to ambulate, reduced need for alternative analgesics (including opioids), reduced need for 
admission for pain control and need for inpatient physical therapy evaluation and treatment, 
quicker disposition from the emergency department due to quick and effective pain control. 
Moreover, in our anecdotal experience, patients whom we have treated with a GNB have 
reported high levels of satisfaction with the procedure and have reported complete pain relief for 
greater than 24-hours after the block. Even when symptoms began to return, patients reported 
that they were not as severe as those which initially promoted them to visit the ED. Moreover, to 
our knowledge, none of the patients on whom we have performed the GNB have returned to the 
ED for recurrent pain. Therefore, the GNB might also provide the appropriate bridge from ED 
care to outpatient follow-up, thereby reducing the need for patients to return to the ED for 
recurrent pain.  
2.3.3 
Assessment of Potential Risks and Benefits 
The GNB is low risk and has an excellent safety profile given the distal, superficial, and terminal 
location of the nerves and lack of major arteries. There have been no published reported 
complications of this block and in our anecdotal experience none of our patients have 
experienced complications from the GNB. To minimize the risk of theoretical complications and 
risks, we will take the following precautions. 
- 
Utilize use 80% of ideal body weight (actual body weight dosing for patients with BMI 
less than 25 kg/m2) dosing to minimize the risk of toxic effects and LAST  
- 
Utilize a dilute concentration (as described above) to allow for longer injection time, 
thereby allowing prompt identification of any signs of symptoms of toxicity which can 
prompt immediate termination of further injection 
- 
Aspirate prior to administration of each aliquot of anesthetic to further allow for early 
identification of any signs of symptoms of toxicity 
- 
Utilize direct ultrasound guidance to visualize the needle in relationship to anatomical 
structures to minimize the risk of damaging nearby structures and the risk of intravascular 
injection 
- 
Prior to the start of the procedure, all patients will be placed on the cardiorespiratory 
monitor and will have an updated blood pressure. During the procedure, their vitals will 
be monitored for either tachy- or bradyarrhythmia and for at least 30 minutes after (as 
suggested by ASRA guidelines) after blockade.  

 
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- 
Rescue therapy (20% intralipid) will be immediately available should local anesthetic 
systemic toxicity occur 
Despite these potential risks, bupivacaine and other local anesthetics are very frequently utilized 
for numerous indications within the scope of emergency medicine, anesthesiology, surgery, and 
the surgical subspecialties. With these precautions, the risks are far outweighed by the potential 
benefits in that adequate anesthesia can reduce the need for high doses of potentially harmful 
opioid anesthetics, which themselves can be associated with several severe adverse effects 
including but not limited to dependence and tolerance, delirium, nausea and vomiting, and 
respiratory depression leading to hypoxia and respiratory arrest. 

 
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3 STUDY OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Pain Reduction 
To determine whether 
patients receiving a GNB 
for knee pain experience 
greater pain reduction 
compared to conventional 
analgesia  
Difference in pain level as measured 
by NRS at pre-intervention (GNB or 
conventional) and at either 1-hour 
after enrollment or at time of ED 
discharge, whichever occurs first 
(post intervention)  
 
This endpoint will evaluate 
whether the GNB provides a 
clinically meaningful reduction 
in pain compared to 
conventional analgesia. 
Secondary 
 
 
Duration of Analgesia 
To determine whether 
patients who receive a 
GNB experience a longer 
duration of analgesia 
compared to those who 
receive conventional 
analgesia 
Difference in duration of analgesia, 
assessed by a follow-up telephone call 
at 24-36 hours post intervention  
 
This endpoint will evaluate 
whether the GNB will result in 
longer duration of analgesia 
compared to conventional 
analgesia. 
Patient Reported 
Outcomes, including 
Patient Satisfaction 
To determine whether 
patients who receive a 
GNB report higher patient 
satisfaction compared to 
those who receive 
conventional analgesia 
Difference in functionality/ 
satisfaction as measured by  the APS-
POQ -RED between GNB and 
conventional analgesia. Questionnaire 
administered at either 1-hour post 
enrollment or at time of ED 
discharge, whichever occurs first. 
 
This endpoint will evaluate 
whether patients will have 
improved satisfaction with 
treatment when receiving the 
GNB as compared to 
conventional analgesia using a 
modified version of the APS-
POQ designed for the ED 
Reduce ED LOS 
To determine whether 
patients who receive a 
GNB have shorter ED 
length of stay (LOS) 
compared to those who 
receive conventional 
analgesia 
Difference in ED LOS between GNB 
and conventional analgesia, as 
determined by time from enrollment 
in study to time of ED discharge.  
This endpoint will evaluate 
whether treatment with the 
GNB can shorten ED LOS 
compared to conventional 
analgesia 

 
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4 STUDY PLAN 
4.1 
Study Design 
This is a prospective, open-label, investigator-initiated, convenience-enrollment, randomized-
controlled trial comparing the efficacy of the ultrasound-guided three-point GNB versus 
conventional analgesia of atraumatic knee pain. Patients who present to the ED with atraumatic 
knee pain will receive plain film radiography of the knee to evaluate for acute fracture or large 
knee joint effusion. Patients without radiographic evidence of fracture or large knee joint 
effusion will be eligible for enrollment. Patients for whom there are concerns for infection, 
including cellulitis or septic arthritis will be excluded. Other exclusion criteria are listed in 
Section 5.2. We hypothesize that patients who receive a GNB will experience a greater reduction 
in pain and longer acting analgesia compared to those managed with conventional analgesia. 
Patients who present to one of the four primary ED sites within the Penn Medicine health system 
(HUP, PPMC, PAH, HUP Cedar) will be eligible for inclusion as participants. Research 
assistants (RAs), who are present in the ED at HUP and PPMC daily, will assist with recruitment 
at those sites, and potentially eligible patients at PAH and HUP Cedar will be recruited by 
participating physicians. The study team will review inclusion and exclusion criteria with the 
RAs prior to the initiation of patient enrollment. Furthermore, an EPIC Haiku notification will be 
created to alert the study team of any patient who presents to the ED with knee pain.  Prior to 
recruitment, it is assumed that most patients who will become participants will have been offered 
conventional oral, intravenous, or topical analgesics as part of their normal treatment regimen. If 
completion and radiologist read of plain film imaging (1) does not show evidence of acute 
fracture and (2) does not show evidence of a large knee joint effusion, patients will be screened 
for eligibility by either an RA or the performing physician. Patients with small or moderate sized 
effusions will be eligible for inclusion if there is no clinical concern for septic arthritis of the 
knee. Large effusions will be excluded as this may distort the anatomical and sonographic 
landmarks for performing the GNB. The physician who performs the GNB for participants may 
not necessarily be the physician who is primarily caring for the patient clinically in the ED.   
Those patients who satisfy all inclusion criteria will be offered enrollment and consented by a 
participating emergency physician or RA. Upon consenting, patients will be asked to rate their 
knee pain on the NRS. This initial evaluation is based on the current severity of the pain, 
regardless of whether patients received any analgesics prior to obtaining radiography. Study will 
not begin until plain film imaging has been reviewed by a radiologist, at which point patients 
will be considered for eligibility.  
Utilizing a random number generator, patients will be randomized to either the intervention arm 
(GNB) or the control (conventional analgesia) arm. Within the intervention arm, a three-point 
GNB will be performed under ultrasound guidance using 80% of ideal body weight (80% of 
actual body weight if BMI is less than 25 kg/m2) dosing of 0.5% bupivacaine with 4 mg 
dexamethasone, divided into three separate aliquots (5 mL of 0.5% bupivacaine with 1-2 mg 
dexamethasone) which will be administered to the SMGN, SLGN, and IMGN. The performing 

 
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physician will first identify all landmarks via ultrasound, which include the superomedial and -
lateral knee (aligning the probe longitudinally with the femoral condyle) and the inferomedial 
knee (aligning the probe longitudinally with the tibial condyle). Color doppler will be applied to 
note any vascular structures within the field of view of injection. The patient will be placed on 
the cardiopulmonary monitor prior to the GNB. The GNB will be performed via ultrasound 
guidance in real-time.  
The control arm will be treated with oral, intravenous, or topical analgesics, as per the treating 
clinician’s discretion. Patients will be observed on continuous cardiorespiratory monitoring in 
the ED for at least 30-minutes following treatment to evaluate for treatment effect and adverse 
events. Patients will be discharged from the ED when their pain is sufficiently controlled, and 
they are agreeable for discharge. Of note, patients in both treatment arms will be eligible for 
additional analgesics, as needed, at any point after enrollment. This will be recorded and 
evaluated during analysis. At either 1-hour after enrollment or at the time of discharge from the 
ED (whichever occurs first), patients of both treatment arms will be again asked to rate their pain 
severity on the NRS and asked to complete the modified APS-POQ-RED. This survey will be 
conducted either by RAs (during daytime hours, if available) or the performing physician (if 
overnight). Patients will subsequently receive a phone call approximately 24 to 36 hours after the 
treatment by a member of the study team (performing physician, RA, or the clinical research 
coordinator (CRC) from the Emergency Ultrasound Division) to evaluate the duration of 
analgesia. If the block is performed during overnight hours, the follow-up call will take place the 
next day (between 24 to 36 hours after treatment). After this assessment, the participant’s 
involvement in the study will be concluded. Only in cases where an adverse event occurred that 
either requires hospitalization or ambulatory follow-up will a participant’s participation last 
longer than 24 hours. All data collected by the RA, the CRC, or the performing physician will be 
stored in REDCap. The RAs will transmit all research data, including an encrypted medical 
record number (MRN) and all pain scale responses obtained from the study participants to the 
Ultrasound Division’s CRC, who will be responsible for storing and managing data on REDCap. 
Patients with large knee effusions will not be included in the study as large effusions can make 
the GNB more difficult to perform by distorting the anatomical and sonographic landmarks, and 
we wish to avoid the additional risk of inadvertent intra-articular injections. In our experience, 
we have been able to perform the GNB on patients with small and moderate sized effusions 
without difficulty.  
 
4.2 
Scientific Rationale for Study Design 
This study seeks to evaluate whether an ultrasound-guided GNB can provide a clinically 
significant reduction in pain among patients suffering with acute on chronic knee, which in most 
cases will be attributed to knee OA. Knee OA is very prevalent, and flares of knee OA are a 
common reason why patients present to the ED, where patients typically receive oral, topical, or 
intravenous analgesics. However, these therapies are often ineffective for managing 

 
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breakthrough knee OA pain. Alternative analgesia strategies, such as the GNB, have shown 
efficacy in the rheumatology and orthopaedic literature for managing chronic knee OA pain. 
Development and implementation of safe alternative modes of analgesia may help to effectively 
manage breakthrough pain associated with knee OA without high doses of opioids or other 
potentially harmful non-opioid analgesics. Several isolated case reports have demonstrated 
success in the ED; however, comparative or randomized studies have not evaluated the utility of 
the GNB among ED patients who present with breakthrough knee OA pain. 
4.3 
Justification for Dose 
For the GNB arm, the maximum recommended dosing for bupivacaine for regional anesthesia is 
2.5 mg/kg. To minimize the risk of LAST, we will utilize weight-based dosing at 80% of the 
maximal safe dosing which will allow for effective and prolonged analgesia while minimizing 
the risk of complications and LAST. Patients with body mass index (BMI) greater than 25 kg/m2 
will receive a total of 80% of their ideal body weight dosing in bupivacaine. Patients with a BMI 
of equal to or less than 25 kg/m2 will receive a total of 80% of their actual body weight dosing in 
bupivacaine. This total amount will be divided into three equal aliquots that will be injected 
around the three genicular nerves), which will would be well below the recommended maximal 
dose for both female and male patients. Dexamethasone dosing ranging from 4-8 mg has shown 
to prolong regional anesthesia by the prevention of enzymatic processing of local anesthetics, 
and is commonly used as an adjuvant in both the perioperative setting and in the ED. Given the 
relatively low volume and dose of anesthetic that will be administered, we plan to supplement 
the blocks with 4 mg dexamethasone, divided equally into the three injections. 
4.4 
End of Study Definition 
A participant will have completed this study at 24 to 36 hours after blockade, when the research 
assistant or performing physician will contact the patient via telephone for follow-up assessment, 
to evaluate for duration of analgesia. For patients that experience an adverse event that requires 
admission to the hospital or ambulatory follow-up, their participation in the study might be 
extended beyond 24 to 36-hours as these adverse events and outcomes will be tracked. 
Patients who receive the GNB and rate their pain on the NRS before and after the procedure, 
even those who refuse the APS-POQ-RED survey responses and who are not available to be 
reached by phone the next day, will still be included in the data analysis for the primary and one 
secondary endpoint (pain levels, LOS). 

 
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5 STUDY POPULATION 
5.1 
Inclusion Criteria 
To be eligible to participate in this study, an individual must meet all the following criteria: 
1. Patient presenting to ED with atraumatic knee pain 
2. Provision of signed and dated informed consent form and stated willingness to comply 
with all study procedures and availability for the duration of the study 
3. Equal to or over the age of 18 years 
4. Have plain film radiography of the knee obtained during the encounter  
5. Pain measured on NRS between 5 and 10  
5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Fracture or dislocation on plain film imaging 
2. Large knee joint effusion identified on plain film imaging 
3. Allergy to bupivacaine or local anesthetics, contraindication to local anesthetics (e.g., 
G6PD deficiency), or history of LAST after receiving anesthetics.  
4. Pregnancy 
5. Incarcerated 
6. History of ipsilateral partial or total knee arthroplasty (patients with previous knee 
surgeries that are unrelated to the joint, e.g., arthroscopy, ligamentous repair will be 
eligible) 
7. Clinical or radiographic concern for infection (e.g., septic joint) 
8. Hemodynamic instability 
9. Altered mental status or inability to consent for the procedure 
Justification of selected inclusion and exclusion criteria: 
• Large knee effusion on x-ray: Patients with large knee effusions will not be included in 
the study as large effusions can make the GNB more difficult to perform by distorting the 
anatomical and sonographic landmarks, and we wish to avoid the additional risk of 
inadvertent intra-articular injections. In our experience, we have been able to perform the 
GNB on patients with small and moderate sized effusions without difficulty. Given that 
many patients with knee OA and chronic knee pain have small to moderate knee 

 
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effusions, including them in this study would provide a more accurate representation of 
the population suffering with chronic and acute on chronic knee pain. 
• Patients <18 years old: pediatric patients typically do not suffer from knee OA 
• Pregnant patients have decreased levels of alpha-1 glycoprotein which places them at 
inherently increased risk for LAST. 
• Incarcerated patients will be difficult to follow up with and we will not be able to obtain 
2 of the 3 secondary endpoints on these patients. 
 
5.3 
Lifestyle Considerations 
Not applicable. 
 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
5.5 
Strategies for Recruitment and Retention 
Patients presenting to the EDs of HUP, PPMC, PAH, or HUP Cedar with knee pain for whom 
plain film imaging has been obtained will be screened by a member of study team to determine 
eligibility based on inclusion and exclusion criteria described in sections 5.1 and 5.2. If the 
patient is eligible, a member of study team will approach the patient to obtain informed consent. 
• Target sample size: 17 patients in both the intervention and control treatment arms 
• Anticipated accrual rate: 100% 
• Anticipated number of sites and in which participants are to be enrolled: 4 clinical sites 
(EDs of HUP, PPMC, PAH, or HUP Cedar) 
• Source of participants: ED patients 
• Recruitment venues: ED 
• How potential participants will be identified and approached: (1) Potentially eligible 
patients under the care of a participating physician will be identified and approached 

 
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during the usual course of care. (2) Potentially eligible patients who are not under the 
direct care of a participating physician will be identified by chart screening and direct 
communication with the primary physician by either participating physicians or research 
assistants. 

 
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6 STUDY INTERVENTION 
6.1 
Study Intervention(s) Administration 
6.1.1 
Study Intervention Description 
The study interventions are either conventional analgesia or a one-time three-point GNB with 
weight-based 0.5% bupivacaine and 4 mL dexamethasone divided into three separate injections, 
around the SMGN, SLGN, and IMGN. Bupivacaine and dexamethasone are commercially 
available and are being used in accordance with approved labeling. 
For participants randomized to the GNB arm, pre-procedural ultrasound will be performed to 
evaluate the target sites of injection (e.g., superomedial femoral condyle, the superolateral 
femoral condyle, and the inferomedial fibular condyle) on the superomedial, superolateral, and 
inferomedial aspects of the knee. Color doppler will be used to identify any of the geniculate 
arteries (superomedial, superolateral, and inferomedial geniculate arteries) which may be present 
in proximity to their respective genicular nerves. Once the target signs have been obtained; the 
entire knee will be prepped with chlorhexidine antiseptic and draped in standard fashion. Using 
sterile conditions (including single sterile gloves), a 5-15 MHz linear ultrasound transducer will 
be prepared with a sterile ultrasound probe cover and sterile ultrasound gel. The ultrasound will 
be placed in a cephalad to caudad direction with the probe indicator facing cephalad, and color 
doppler will be always on during the procedure for real time visualization of potential 
vasculature. For each injection, a separate needle will be used to minimize the risk of infection. 
In most cases, we will use 1.5-inch 20 or 22-gauge hypodermic needles, however for patients 
with larger body habitus requiring more depth and a longer needle, a 20- or 22-gauge 3.5-inch 
Quincke spinal needle will be used. For the superomedial and superolateral blocks, the needle 
will be introduced from a cephalad to caudad direction (toward the knee) and for the 
inferomedial block, the needle will be advanced from a caudad to cephalad direction (toward the 
knee). In all cases, the needle will be advanced toward the periosteum under constant 
visualization, taking care to avoid any potential vascular structures. Once the needle contacts the 
periosteum, aspiration will be performed to ensure the needle tip is not within a vascular 
structure, at which time a small aliquot of anesthetic will be injected to lift the muscle off the 
periosteum and periosteal fat pad. Once proper lifting has been visualized, the remainder of 
anesthetic will be slowly administered over the span of 30-seconds while maintaining 
sonographic visualization of the needle tip. Upon deposition of anesthetic at each site, the needle 
will be removed, and the site of skin puncture will be covered with a taped piece of gauze or 
bandage.  
Participants randomized to conventional analgesia, will be treated with standard medication(s) 
which include any oral, topical, or intravenous analgesic, including but not limited to 
acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), lidocaine patches, opioids. 
These are all commercially available, many of which available over the counter, and are being 
used in accordance with approved labeling. 

 
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No experimental agents are being used in this study. No experimental off label devices are being 
used in this study. 
 
6.1.2 
Dosing and Administration 
For the GNB arm, dosing is determined based on ideal body weight such that the total amount of 
bupivacaine will fall well under the maximum recommended dosing by weight (2.5 mg/kg ideal 
body weight). In this case, 80% of ideal body weight-based (actual body weight for patients with 
BMI less than 25 kg/m2) dosing of 0.5% bupivacaine (as previously described) and 4 mg 
dexamethasone, divided into three injections around the affected knee, one each around the 
SMGN, SLGN, and IMGN. Administration of each injection will occur over the span of one 
minute to monitor for potential adverse effects to ensure the maximal degree of safety. If any 
signs or symptoms of LAST occur (e.g., tachy- or brady-dysrhythmias, hyper- or hypotension), 
or if a patient reports subjective feelings of dizziness, confusion, or tingling (including perioral 
or tongue paresthesia), the injection will be halted immediately. Participants will be instructed to 
immediately alert the physician if any of these symptoms occur. 
There is a precaution issued by the FDA regarding use of bupivacaine in geriatric patients 
specifically stating that "Clinical studies of bupivacaine did not include sufficient numbers of 
subjects aged 65 and over to determine whether they respond differently from younger subjects. 
In general, dose selection for an elderly patient should be cautious, usually starting at the low end 
of the dosing range." While this is not contraindicated in geriatric patients, caution is 
recommended as elderly patients may have age-related physiological changes that can affect the 
pharmacokinetics and pharmacodynamics of bupivacaine including decreased metabolism and 
reduced plasma protein binding. Therefore, it is recommended to utilize dosing at less than 
maximally recommended doses and monitor closely for adverse effects. To minimize these risks, 
we are utilizing 80% of their ideal body weight dosing of bupivacaine. Furthermore, all patients 
will be monitored in the ED for at least 30 minutes after the block. Should an adverse event 
occur, reversal therapy will immediately be available (see Section 6.5 for details). 
The GNB will be performed under clean conditions (e.g., sterile gloves, chlorhexidine skin prep 
that will be allowed to completely dry before puncturing the skin) and under ultrasound 
guidance.  
For the control arm, conventional anesthetics will be dosed at the discretion of the primary 
provider caring for the patient and will include standard dosing of medications. This includes but 
is not limited to: 1) oral acetaminophen 325 mg to 975 mg, 2) oral ibuprofen 400 mg to 600 mg, 
3) intravenous ketorolac 15 mg to 30 mg, 4) topical 5% lidocaine patches, 5) oral oxycodone 5 
mg to 20 mg, 6) intravenous morphine 0.05 mg/kg to 0.1 mg/kg, or 7) intravenous 
hydromorphone 0.015 mg/kg to 0.03 mg/kg.  

 
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6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and accountability 
For the GNB arm, bupivacaine 0.5% is a commonly used medication in the ED. The 
participating physician will obtain this medication as they would during typical interventions. 
Briefly, the participating physician will order the bupivacaine and dexamethasone with specific 
instructions to nursing to hold and provide the medications (in their commercially available 
storage vials) to the participating physician. Clinical pharmacists will approve the ordered 
medications, after which nursing will retrieve the medications from the secured drug rooms (i.e., 
Omnicell) and directly hand the unopened vials to the participating physician.  
For the control arm, the participating physician will order conventional analgesic medications as 
they normally would, at which time nursing would retrieve the medications and administer them 
to the patients in accordance with electronic orders.  
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
For the GNB arm, bupivacaine 0.5% is stored in either the Omnicell (immediately available 
medication storage within the emergency department) or central pharmacy, where it can be sent 
down to the ED. The medication is stored at room temperature in individually sealed vials. No 
preparation other than drawing up the medication with a needle and syringe will be necessary, 
which will be the responsibility of the participating physician administrating the GNB. Vials are 
single use and clearly labelled. Bupivacaine will be mixed at the bedside with dexamethasone 
prior to injection. Bupivacaine on formulary is manufactured by Xellia Pharmaceuticals LLC. 
Dexamethasone 4mg/mL is also available in the ED Omnicell and commonly utilized in 
emergency patient care. Bupivacaine 0.5% is distributed by Hospira and dexamethasone sodium 
phosphate 4mg/mL is distributed by Hikma. 
6.2.3 
Product Storage and Stability 
Bupivacaine 0.5% is stored at room temperature (68F to 77F, per manufacturer drug information 
sheet) and is relatively stable. Little or no changes in concentration have been observed at four 
weeks of storage at room temperature. 
Dexamethasone phosphate 4 mg/ml is refrigerated (35F-46F) but is stable for 24 hours at 77F. 
See drug datasheet. 
There is a theoretical risk of crystallization when combining certain local anesthetics and 
dexamethasone. However, this risk is significantly reduced given that we are using bupivacaine 
as the local anesthetic. Moreover, the formulation of dexamethasone we are using for this study 
(water soluble dexamethasone sodium phosphate) is compatible with bupivacaine, whereas more 
lipophilic formulations (dexamethasone palmitate or acetate) have a higher risk of precipitating 
when mixed with local anesthetics. Nonetheless, the crystals that may be formed are typically 
less than 10 microns in diameter, which do not pose any clinical risk (Choi 2021). No published 

 
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studies to date have demonstrated adverse clinical effects relating to possible crystallization of 
dexamethasone and local anesthetics.  
6.2.4 
Preparation 
For the GNB arm, bupivacaine 0.5% is available in single-use vials as a ready-to-use liquid. It 
will be drawn up with a blunt needle and syringe and requires no special preparation prior to 
administration. In this case, three separate syringes will be loaded with the appropriate volume 
0.5% bupivacaine (weight-based dosing as described above). To each syringe, 1-2 mg of 
dexamethasone will be added to the bupivacaine (for a total of 4 mg of dexamethasone). 
Preparation of medications for the control arm will be prepared and administered to the patient 
by nursing as per the electronic orders, as is standard of care.  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Participants will be randomly assigned to either the intervention arm (GNB) or standard-of-care 
(control) arm using a commercially available random number generator. Patient consent will 
explicitly state that they will be randomized into either treatment arm. As this is an open-labeled 
trial, there will be no blinding of intervention to participants, performing physicians, or research 
assistants.  
6.4 
Study Intervention Compliance 
Protocol adherence will require the participant to initially rate their pain on the NRS then to 
receive either the GNB (intervention arm) or standard-of-care therapy (control arm). At either 1-
hour post enrollment or time of discharge from the ED (whichever occurs first), protocol 
adherence will require the participant to rate their pain on the NRS and complete the APS-POQ-
RED questionnaire. At 24 to 36 hours after treatment, participants will be contacted by the 
performing physician or research assistant to evaluate duration of analgesia received in the ED.  
Administration of the trial drugs will be documented (unblinded) in the electronic medical record 
(PennChart, Epic) as administered medications. These will similarly be documented by the 
participating physician or research assistant in REDCap. Similarly, medications administered 
prior to study initiation and medications administered to the control arm and any additional 
medications administered after treatment will be documented in the electronic medical record 
(PennChart, Epic) as administered medications as well as in REDCap by the participating 
physician or a research assistant. Clinical outcome data will be documented in REDCap by the 
participating physician or a research assistant. 
6.5 
Concomitant Therapy 
For the GNB arm, in addition to bupivacaine, the GNB will be augmented with adjuvant 
dexamethasone (4 mg divided into three aliquots). Dexamethasone is commonly used in the 

 
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perioperative setting by regional anesthesiologists and in the ED to extend the duration of 
regional anesthesia (Fernández Martin 2023).  
6.5.1 
Rescue Medicine 
For the GNB arm, if signs or symptoms of LAST were to develop at any point during 
administration of the intervention drug or after administration, patients will be assessed for the 
need for rescue medications. At all study sites, benzodiazepines and lipid emulsion therapy will 
be available and administered if deemed necessary by the performing physician (Shalaby 2024). 
For seizures, a benzodiazepine such as midazolam or lorazepam will be administered as per 
established dosing guidelines. Intralipid will be administered as per institutional guidelines to 
help reverse LAST. The date and time of rescue medication administration as well as the name 
and dosage regimen of the rescue medication will be recorded. 

 
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7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
The intervention in this study is a one-time three-point GNB performed with bupivacaine and 
dexamethasone. Moreover, both prior to and after the intervention, patients will continue to 
receive analgesia as needed in accordance with standard of care (e.g., a patient receives a GNB 
but still has significant pain 60-minutes afterward will be offered additional conventional 
analgesics, at the discretion of the primary physician). 
7.2 
Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request. 
7.3 
Lost To Follow-Up 
A participant will be considered lost to follow-up if he or she does not respond via telephone at 
the 24-hour follow-up after three attempts by the participating emergency physician or clinical 
research assistant. However, patient intervention and any outcome data that has previously been 
obtained (e.g., data collected at time of discharge from the ED) will still be included. All 
participants who complete the initial assessment by the time of discharge will be included in the 
analysis. No follow-up visits will be required.   

 
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8 STUDY ASSESSMENT AND PROCEDURES  
8.1 
Efficacy Assessments 
Patients presenting to the ED of one of the four study locations (HUP, PPMC, PAH, HUP Cedar) 
with knee pain attributed to knee OA with plain film radiography who are eligible for enrollment 
based on the inclusion and exclusion criteria described in sections 5.1 and 5.2 will be approached 
by a member of the study team to obtain informed consent.  
Prior to randomization, a pain score will be obtained using the NRS by the performing physician. 
Patients will be randomized to either the intervention arm (GNB) or the control arm, at which 
point they will receive treatment. At either 1-hour after enrollment or at time of discharge from 
the ED (whichever occurs first), the performing ED physician, or research assistant will ask the 
patient to rate their pain severity on the NRS. At that same time, a  member of the study team 
will also have the patient complete the APS-POQ-RED. At 24 to 36-hours after treatment, a 
clinical research assistant or the treating emergency physician will contact the patient to obtain 
follow-up assessment and duration or analgesia.  
8.2 
Safety and Other Assessments 
Patients will have a set of vital signs obtained prior to initiation of treatment and after 30 minutes 
of treatment. During this time, patients will be observed in the ED. Either the treating physician 
who performed the intervention or the CRC will follow up with patients via phone call 24 to 36 
hours after the procedure to determine the presence of complications. 
8.3 
Adverse Events and Serious Adverse Events 
8.3.1 
Definition of Adverse Events (AE) 
An adverse event (AE) is any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention related. Intercurrent illnesses or 
injuries should be regarded as adverse events. 
A pre-existing condition should be recorded as an adverse event if the frequency, intensity or the 
character of the condition changes. 
8.3.2 
Definition of Serious Adverse Events (SAE)  
Serious Adverse Events (SAE) 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that, 
in the view of either the investigator or the sponsor, is: 
• fatal 
• life-threatening 

 
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• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event when the event does not fit the other outcomes, but the event 
may jeopardize the patient and may require medical or surgical intervention (treatment) 
to prevent one of the other outcomes. 
• required intervention to prevent permanent impairment or damage (for devices only) 
Important medical events are those that may not be immediately life threatening but are clearly 
of major clinical significance. They may jeopardize the subject and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious. 
8.3.3 
Unanticipated Adverse Device Effect (UADE) 
Not applicable. 
8.3.4 
Classification of an Adverse Event 
8.3.4.1 
Severity of Event 
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity. 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious”. 
8.3.4.2 
Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to <study intervention> assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the categories 
below. In a clinical trial, the study product must always be considered. 
• Related – The AE is known to occur with the GNB, there is a reasonable possibility that 
the GNB caused the AE, or there is a temporal relationship between the GNB and event. 

 
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Reasonable possibility means that there is evidence to suggest a causal relationship 
between the GNB and the AE. 
• Not Related – There is no temporal relationship between the GNB and event onset, or an 
alternate etiology has been established. 
8.3.4.3 
Expectedness  
The medical director, Dr. Michael Shalaby, will be responsible for determining whether an 
adverse event (AE) is expected or unexpected. An AE will be considered unexpected if the 
nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the GNB. 
8.3.5 
Time Period and Frequency for Event Assessment and Follow-Up 
Safety will be assessed by monitoring and recording potential adverse effects using the Common 
Terminology Criteria for Adverse Events (CTCAE) at each study visit. Participants will be 
monitored by medical histories, physical examinations, and vital signs. If CTCAE grading does 
not exist for an adverse event, the severity of mild, moderate, severe, life-threatening, and death, 
corresponding to Grades 1-5, will be used whenever possible. 
At each contact with the subject, the investigator will seek information on adverse events by non-
directive questioning and, as appropriate, by examination. Adverse events may also be detected 
when they are volunteered by the subject during the screening process or between visits, or 
through physical examination, laboratory test, or other assessments. Information on all adverse 
events will be recorded in the source documentation. To the extent possible, adverse events will 
be recorded as a diagnosis and symptoms used to make the diagnosis recorded within the 
diagnosis event. 
As much as possible, each adverse event or follow-up information will be evaluated to 
determine: 
1. Severity grade (CTCAE Grade 1-5) 
2. Duration (start and end dates) 
3. Relationship to the study treatment or process – [Reasonable possibility that AE is 
related: No (unrelated/ not suspected) or Yes (a suspected adverse reaction)]. If yes 
(suspected) - is the event possibly, probably or definitely related to the investigational 
treatment? 
4. Expectedness to study treatment or process – [Unexpected – if the event severity and/or 
frequency is not described in the investigator brochure (if applicable) or protocol]. 
5. Action taken with respect to study or investigational treatment or process (none, dose 
adjusted, temporarily interrupted, permanently discontinued, unknown, not applicable) 

 
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6. Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
7. Whether the event is serious 
Once an adverse event is detected, it should be followed until its resolution or until it is judged to 
be permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
8.3.6 
Adverse Event Reporting 
Reporting Period 
Adverse events will be reported from the time of informed consent until study completion. 
Investigator Reporting: Notifying the Study Sponsor 
Not Applicable. 
Investigator Reporting: Local Reporting Requirements 
The investigator will report AEs and SAEs to the IRB/EC of record and other local regulatory 
groups per the local requirements. 
8.3.7 
Serious Adverse Event Reporting  
The study clinician will immediately report to the sponsor any serious adverse event, whether or 
not considered GNB related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the GNB caused the 
event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported 
in accordance with the protocol unless there is evidence suggesting a causal relationship between 
the GNB and the event (e.g., death from anaphylaxis). In that case, the investigator must 
immediately report the event to the sponsor. 
New information regarding the SAE will be reported as it becomes available and in the same 
manner that the initial SAE (i.e. SAE form). All serious adverse events (SAEs) will be followed 
until satisfactory resolution or until the site investigator deems the event to be chronic or the 
participant is stable. Other supporting documentation of the event may be requested by the Data 
Coordinating Center (DCC)/study sponsor and should be provided as soon as possible. 
8.3.8 
Reporting Events to Participants  
Any expected adverse events are anticipated to occur within the first 30 minutes of the GNB, 
such that all participants will be monitored during that time in person. Any concerns of potential 
adverse events will be communicated to participants at this time.  

 
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8.3.9 
Events of Special Interest  
Not applicable.  
8.3.10 
Reporting of Pregnancy 
Not applicable. 
8.4 
Unanticipated Problems 
8.4.1 
Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
8.4.2 
Unanticipated Problem Reporting 
Unanticipated problems (UPs) such as: 
• 
Post-marketing withdrawal of a drug, device, or biologic used in a research protocol due 
to safety concerns. 
• 
FDA ban of a drug, device, or biologic used in a research protocol due to safety concerns. 
• 
Complaint of a participant when the complaint indicates unexpected risks, or the 
complaint cannot be resolved by the research team 
• 
Breach of confidentiality 
• 
Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain on 
the study 
• 
Premature closure of a study (e.g., due safety, lack of efficacy, feasibility, financial 
reasons, etc.) 

 
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should be reported by the investigator to the medical director. The UP report will include the 
following information: 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• A detailed description of the event, incident, experience, or outcome;  
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
• UPs that are serious adverse events (SAEs) will be reported as any other SAE. 
• Any other UP will be reported to the IRB and to the DCC within 48 hours of the 
investigator becoming aware of the problem. 
• All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), and 
the Office for Human Research Protections (OHRP) within 48 hours of the IRB’s receipt 
of the report of the problem from the investigator. 
8.4.3 
Reporting Unanticipated Problems To Participants  
Not applicable.  
8.5 
Device Reporting 
Not applicable.  
9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
Primary endpoints: 
• H0: Mean change in pain levels pre / post GNB = Mean change in pain levels pre / post 
conventional therapy 
• H1: Mean change in pain levels pre / post GNB ≠ Mean change in pain levels pre / post 
conventional therapy 
Secondary endpoints: 

 
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• H0: Mean duration of analgesia for patients receiving GNB = Mean duration of analgesia 
for patients receiving conventional therapy 
• H1: Mean duration of analgesia for patients receiving GNB ≠ Mean duration of analgesia 
for patients receiving conventional therapy 
• H0: Mean APS-POQ-RED score for patients receiving GNB = Mean APS-POQ-RED 
score for patients receiving conventional therapy 
• H1: Mean APS-POQ-RED score for patients receiving GNB ≠ Mean APS-POQ-RED 
score for patients receiving conventional therapy 
• H0: Mean ED LOS for patients receiving GNB = Mean patient satisfaction for patients 
receiving conventional therapy 
• H1: Mean ED LOS for patients receiving GNB ≠ Mean patient satisfaction for patients 
receiving conventional therapy 
9.2 
Sample Size Determination 
To determine the number of patients needed in each study arm for sufficient sample size we 
considered the primary outcome of change in pain levels pre/post treatment as measured by the 
NRS as this was the largest sample size needed to detect a clinically meaningful effect.  
The sample size was loosely based on an RCT by Shanahan et al. 2023, for which the mean 
change in  the visual analog scale (VAS: 0-10 scale) from baseline at 2 weeks was  3.5 (GNB) 
and 0.7 (sham injection group). Assuming the mean change in NRS pain score pre/post treatment 
between the GNB and standard analgesia (difference in difference) will be smaller in a shorter 
period of time, group sample size of 17 (each group) will achieve 80% power to detect a 
difference in NRS between treatment arms as small as 1.6, with alpha set at 0.05 and standard 
deviation of differences set at 2.0 using a two-sided two-sample equal-variance t-test with a 5-
10% loss to follow-up at the 24 hour mark.  
 
9.3 
Populations for Analyses 
All patients who are enrolled and receive either the GNB or conventional analgesia as part of the 
study will be included in the analysis dataset. 
9.4 
Statistical Analyses 
9.4.1 
General Approach 
Prior to analysis, all primary and secondary outcome measures will be summarized with 
descriptive statistics (mean ± standard deviation (SD) or median and IQR), their distributions 
examined, tested for normality and transformed using log base 10 as needed. Additionally, all 

 
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demographics will be summarized using mean ± SD or median and IQR, for continuous 
variables and frequencies and percentages for categorical variables. Results from statistical 
testing for continuous variables, will be presented with p-values and 95% confidence intervals 
for tests using means or medians and IQR if a non-parametric test is used. For categorical 
variables, the chi-square or Fisher’s exact test will be performed to examine whether treatment 
arms differ with regard to demographics and other baseline variables. Similarly, for side effects, 
descriptive statistics and Fisher’s exact tests will be performed for possible differences between 
the treatment arms. Regardless of type statistical test, all will be two-sided. 
The primary efficacy endpoint is change in pain level as measured on the NRS at baseline (pre 
intervention) and at post intervention (either 1-hour post-enrollment or at time of ED discharge, 
whichever occurs first) in both treatment arms. The NRS is an ordinal variable, measured on a 0-
10 scale and will be treated as a repeated measure.  To determine differences in pain level 
between GNB and conventional analgesia treatment arms, a 2-factor analysis of variance in 
repeated measures will be performed where treatment arm is the grouping factor and time 
(pre/post) is the repeated measure. To adjust for multiple comparisons, post-hoc pairwise Tukey-
Kramer tests will be performed. Results will be presented as means ± 95% confidence intervals for 
each treatment arm/time point. Shapiro-Wilkes test will be used to test for normality.  If not normally 
distributed, data will be transformed using log base 10 transformation. If missing time points, 
analysis type will change to a mixed general linear model where treatment arm is a fixed factor and 
time is random. 
9.4.2 
Analysis of the Secondary Endpoint(s) 
Two secondary endpoints to be measured are length of time until additional analgesia needed 
after initial treatment (GNB or conventional analgesia) and ED LOS.  Both of these endpoints 
are interval/ratio variables measured in hours. Additional analgesia time will be assessed at 24-
36 hours after intervention by phone call or EMR if still in the ED or admitted to the hospital. 
ED-LOS will be assessed by EMR chart review.  To assess differences between treatment arms 
for  both these time endpoints, either a 2-sample t-test (normally distributed) or a Wilcoxon rank-
sum test (positively skewed) will be performed.  
The final secondary endpoint is the 6 questions on the modified APS-POQ-RED administered .  
Each of 5 questions are on an ordinal scale from 0-10.  For each question, a 2-sample t-test will 
be performed.   
 
9.4.3 
Safety Analyses 
Adverse events will be coded as previously described and Section 8. Safety analyses will be 
reported and presented as summary statistics. For side effects, descriptive statistics and Fisher’s 
exact tests will be performed for possible differences between the treatment arms. 

 
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9.4.4 
Baseline Descriptive Statistics 
All demographics will be summarized using mean ± SD, for continuous variables and 
frequencies and percentages for categorical variables. Standard statistical tests (chi-square and 2-
sample t-tests or Wilcoxon rank-sum test) will be performed to examine whether patients differ 
with regard to demographics and other baseline variables in the 2 study arms.  
 
9.4.5 
Planned Interim Analyses  
An interim analysis of the primary and secondary endpoints will be conducted after the 
enrollment of 30 patients, with 15 patients in each arm. This analysis will assess the data 
collected up to that point to ensure the study’s integrity and to make any necessary adjustments 
based on the findings.  
9.4.6 
Sub-Group Analyses 
None. 
9.4.7 
Tabulation of Individual Participant Data 
Individual patient data will be listed by endpoint of pain rating on NRS at either 1-hour after 
enrollment or at time of discharge from the ED (whichever occurs first), via pain questionnaire 
administered at at that same time, and duration of analgesia (which will be assessed during a 
follow-up phone call performed by a research assistant) at 24 to 36 hours after enrollment.  
9.4.8 
Exploratory Analyses 
None. 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Informed Consent Process 
10.1.1.1 
Consent/Assent and Other Informational Documents Provided To 
Participants 
Consent forms describing in detail the GNB, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering GNB. The following consent materials are submitted with this 
protocol: Informed Consent Form. 

 
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10.1.1.2 
Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the participant will be asked to read and review 
the document. The investigator will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants. Participants will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their family or surrogates or think about it prior to agreeing 
to participate. The participant will sign the informed consent document prior to any procedures 
being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of 
the informed consent document will be given to the participants for their records. The informed 
consent process will be conducted and documented in the source document (including the date), 
and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
10.1.2 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated by the Sponsor or the PI at 
any site if there is sufficient reasonable cause. Written notification, documenting the reason for 
study suspension or termination, will be provided by the suspending or terminating party to the 
investigator. If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension. Study participants will be contacted, 
as applicable, and be informed of changes to the study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 

 
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In terminating the study, the Sponsor and the Principal Investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. 
10.1.3 
Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
the clinical information relating to participants. Therefore, the study protocol, documentation, 
data, and all other information generated will be held in strict confidence. No information 
concerning the study or the data will be released to any unauthorized third party without prior 
written approval of the sponsor.  
All discussions with potential participants, including by not limited to recruitment, consent 
discussion, and the study procedures will occur in private rooms behind closed doors within the 
emergency department.   
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to 
such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored on REDCap. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and research staff will be secured and password protected. At the 
end of the study, all study databases will be de-identified and archived on REDCap. 
10.1.4 
Future Use of Stored Specimens and Data  
Data collected for this study will be analyzed and stored on REDCap. After the study is 
completed, the de-identified, archived data will be on REDCap for use by other researchers 
including those outside of the study. Permission to store data on REDCap will be included in the 
informed consent. 
When the study is completed, access to study data and/or samples will be provided through 
REDCap. 

 
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10.1.5 
Safety Oversight 
Safety oversight will be under the direction of the PI and centralized monitoring group consisting 
of the Division of Ultrasound in the Department of Emergency Medicine. As this is a minimal 
risk study, a Data and Safety Monitoring Board is not planned for this study. 
10.1.6 
Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s). 
• Centralized monitoring of this study will be completed by the Division of Ultrasound in 
the Department of Emergency Medicine, including a statistician, five faculty members, 
five fellows, and a research coordinator. The monitoring will occur once every two 
months and will consist of a random review of the data for verification of endpoint and 
safety.  
• Independent audits may be conducted by the Office of Clinical Research at the University 
of Pennsylvania to ensure monitoring practices are performed consistently across all 
participating sites.  
10.1.7 
Quality Assurance and Quality Control 
All monitoring and audits are to be performed according to ICH GCP E6(R2). 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management.  
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated, and specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 

 
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10.1.8 
Data Handling and Record Keeping  
10.1.8.1 
Data Collection and Management Responsibilities  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in REDCap and follow ALCOAC standards 
(attributable, legible, contemporaneous, original, accurate, and complete). 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into REDCap. The data system 
includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the source documents. 
10.1.8.2 
Study Records Retention  
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an International Conference on Harmonization (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the phrenic nerve 
block. These documents should be retained for a longer period, however, if required by local 
regulations. No records will be destroyed without the written consent of the sponsor, if 
applicable. It is the responsibility of the sponsor to inform the investigator when these documents 
no longer need to be retained.  
10.1.9 
Protocol Deviations 
The PI and the study team should document all scenarios where the protocol is not followed and 
provide, in particular: 
• Who deviated from the protocol 
• What was the deviation 
• When did the deviation occur 
• How did the deviation happen 
• What is the impact of the deviation 
• A root cause analysis of why the deviation occurred 
If the assessment results in a determination that any of the following are potentially affected, the 
deviation would be considered of significant impact: 
• having the potential to adversely affect subject safety; OR 

 
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• increases risks to participants; OR 
• adversely affects the integrity of the data; OR 
• violates the rights and welfare of participants, OR 
• affects the subject’s willingness to participate in research.  
• there is a potential for an overall impact on the research that should be shared with the 
IRB for consideration and development of next best steps to address it 
10.1.10 
Publication and Data Sharing Policy 
This study will comply with the data sharing agreement. 
The Sponsor must approve all sharing of information/data prior to its occurrence. 
10.1.11 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. 
10.2 Additional Considerations 
Not applicable. 
10.3 Protocol Amendment History 
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
5.16.2025 
First IRB review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 REFERENCES 
Becker DE, Reed KL. Local anesthetics: review of pharmacological considerations. Anesth Prog. 
2012 Summer;59(2):90-101; quiz 102-3. doi: 10.2344/0003-3006-59.2.90. PMID: 22822998. 
Callese TE, Cusumano L, Redwood KD, Genshaft S, Plotnik A, Stewart J, Padia SA. 
Classification of Genicular Artery Anatomic Variants Using Intraoperative Cone-Beam 
Computed Tomography. Cardiovasc Intervent Radiol. 2023 May;46(5):628-634. doi: 
10.1007/s00270-023-03411-3. Epub 2023 Mar 22. PMID: 36949185. 
Choi EJ, Kim DH, Han WK, Lee HJ, Kang I, Nahm FS, Lee PB. Non-Particulate Steroids 
(Betamethasone Sodium Phosphate, Dexamethasone Sodium Phosphate, and Dexamethasone 
Palmitate) Combined with Local Anesthetics (Ropivacaine, Levobupivacaine, Bupivacaine, and 
Lidocaine): A Potentially Unsafe Mixture. J Pain Res. 2021 May 27;14:1495-1504. doi: 
10.2147/JPR.S311573. PMID: 34079364. 
Cui A, Li H, Wang D, Zhong J, Chen Y, Lu H. Global, regional prevalence, incidence and risk 
factors of knee osteoarthritis in population-based studies. EClinicalMedicine. 2020 Nov 26;29-
30:100587. doi: 10.1016/j.eclinm.2020.100587. PMID: 34505846. 
Bhattaram S, Shinde VS. Novel use of motor-sparing genicular nerve blocks for knee injuries in 
the emergency department. Am J Emerg Med. 2024 Jan;75:196.e1-196.e4. doi: 
10.1016/j.ajem.2023.10.038. PMID: 37923691. 
Fernández Martin MT, Alvarez Lopez S, Aldecoa Alvarez-Santullano C. Role of adjuvants in 
regional anesthesia: A systematic review. Rev Esp Anestesiol Reanim (Engl Ed). 2023 
Feb;70(2):97-107. doi: 10.1016/j.redare.2021.06.006. Epub 2023 Feb 20. PMID: 36813032. 
Hoppe JA, Nelson LS, Perrone J, Weiner SG; Prescribing Opioids Safely in the Emergency 
Department (POSED) Study Investigators; Prescribing Opioids Safely in the Emergency 
Department POSED Study Investigators. Opioid Prescribing in a Cross Section of US 
Emergency Departments. Ann Emerg Med. 2015 Sep;66(3):253-259.e1. doi: 
10.1016/j.annemergmed.2015.03.026. PMID: 25952503. 
Hughes JA, Hazelwood S, Lyrstedt AL, Jones L, Brown NJ, Jarugula R, Douglas C, Chu K. 
Enhancing pain care with the American Pain Society Patient Outcome Questionnaire for use in 

 
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the emergency department (APS-POQ-RED): validating a patient-reported outcome measure. 
BMJ Open Qual. 2024 Mar 5;13(1):e002295. doi: 10.1136/bmjoq-2023-002295. PMID: 
38448040. 
Kong C, Bubic IJ, Tran AA, Tan G, Medak AJ, Oswald J. Genicular nerve block for emergency 
department patient: a successful management of subacute osteoarthritic knee pain. Pain Manag. 
2023 Jul;13(7):373-378. doi: 10.2217/pmt-2022-0104. PMID: 37458263. 
Neal JM, Barrington MJ, Fettiplace MR, et alThe Third American Society of Regional 
Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity: 
Executive Summary 2017Regional Anesthesia & Pain Medicine 2018;43:113-123. 
Paul AK, Smith CM, Rahmatullah M, Nissapatorn V, Wilairatana P, Spetea M, Gueven N, Dietis 
N. Opioid Analgesia and Opioid-Induced Adverse Effects: A Review. Pharmaceuticals (Basel). 
2021 Oct 27;14(11):1091. doi: 10.3390/ph14111091. PMID: 34832873. 
Rech MA, Griggs C, Lovett S, Motov S. Acute pain management in the Emergency Department: 
Use of multimodal and non-opioid analgesic treatment strategies. Am J Emerg Med. 2022 
Aug;58:57-65. doi: 10.1016/j.ajem.2022.05.022. PMID: 35636044. 
Shafiei FT, McAllister RK, Lopez J. Bupivacaine. [Updated 2023 Aug 17]. In: StatPearls 
[Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: 
https://www.ncbi.nlm.nih.gov/books/NBK532883/ 
Shanahan EM, Robinson L, Lyne S, Woodman R, Cai F, Dissanayake K, Paddick K, Cheung G, 
Voyvodic F. Genicular Nerve Block for Pain Management in Patients With Knee Osteoarthritis: 
A Randomized Placebo-Controlled Trial. Arthritis Rheumatol. 2023 Feb;75(2):201-209. doi: 
10.1002/art.42384. PMID: 36369781. 
Shalaby M, Sahni R, Hamilton R. Local anesthetic systemic toxicity: awareness, recognition, and 
risk mitigation in the emergency department. Clin Exp Emerg Med. 2024 Jun;11(2):121-126. 
doi: 10.15441/ceem.24.231. PMID: 38778495. 
Singh S, Singh S, Nachimuthu M, Kassim AF, Bhullar AK, Veerakumaran R, Kol GN, Roslan 
NAM. Effectiveness of Ultrasound-guided versus Anatomical Landmark-guided Genicular 
Nerve Block to Treat Chronic Knee Osteoarthritis: A Retrospective Cohort Study. Oman Med J. 
2023 Sep 28;38(5):e550. doi: 10.5001/omj.2023.103. PMID: 38225997. 
Sobel J, Oswald J. Novel Use of 3-Point Genicular Nerve Block for Acute Knee Pain in the 
Emergency Department. J Emerg Med. 2021 Oct;61(4):416-419. doi: 
10.1016/j.jemermed.2021.04.012. PMID: 34176690. 
Tan YL, Neo EJR, Wee TC. Ultrasound-guided Genicular Nerve Blockade With 
Pharmacological Agents for Chronic Knee Osteoarthritis: A Systematic Review. Pain Physician. 
2022 Jul;25(4):E489-E502. PMID: 35793174. 

 
Protocol [Insert Study Number] - Genicular Block for Knee Pain: An RCT 
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Yasar E, Kesikburun S, Kılıç C, Güzelküçük Ü, Yazar F, Tan AK. Accuracy of Ultrasound-
Guided Genicular Nerve Block: A Cadaveric Study. Pain Physician. 2015 Sep-Oct;18(5):E899-
904. PMID: 26431143. 
 
12 APPENDIX  
12.1  Schedule of Activities (SoA) 
  
 
 
 

 
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12.2 The American Pain Societies – Patient Outcome Questionnaire Revised for 
the Emergency Department (APS-POQ-RED) 
 
The following question is about the pain you experienced during your stay in the 
emergency department: 
 
- 
On this scale, please tick the current pain you have after treatment in the emergency 
department (from “0” = no pain to “10” = worst possible pain). 
 
Tick the one number below that describes how your current pain interferes with or 
prevents you from different activities (from “0” = no did not interfere  to “10” = completely 
interfered). 
 
- 
During activities in bed such as turning, sitting up, repositioning: 
- 
During activities out of bed such as walking, sitting in a chair, standing: 
 
On this scale, please tick the number describes how your current pain causes you to feel 
different emotions (from “0” = not at all to “10” = extremely) 
 
- 
Anxious 
- 
Frightened 
- 
Helpless 
 
In the emergency department, how much pain relief did you receive? 
 
- 
Please tick the percentage that best shows how much relief you have received for all your 
pain treatments combined. 
 
This question asks about your overall satisfaction with your pain control. 
 
- 
Tick the number that best shows how satisfied with the results of your pain treatment in 
the emergency department (from “0” = extremely dissatisfied to “10” = extremely 
satisfied) 
 
Modified from: 
Hughes JA, Hazelwood S, Lyrstedt AL, Jones L, Brown NJ, Jarugula R, Douglas C, Chu K. 
Enhancing pain care with the American Pain Society Patient Outcome Questionnaire for use in 
the emergency department (APS-POQ-RED): validating a patient-reported outcome measure. 
BMJ Open Qual. 2024 Mar 5;13(1):e002295. doi: 10.1136/bmjoq-2023-002295. 
 

 
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END OF DOCUMENT