Clinical trial NCT02543801
Conditions: Total Hip and Knee Arthroplasty
Sponsor: Kootenai Health
Start date: 2016-01-25; Completion date: 2018-08-21
Enrollment: 239 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates two routinely used drug combinations for periarticular injection following total hip and knee arthroplasty for pain control. One group will receive liposomal bupivacaine, bupivacaine, clonidine, epinephrine and ketorolac. The other group will receive ropivacaine, clonidine, epinephrine and ketorolac.

Detailed description:
A key component of the multimodal approach to pain management is the intra-operative surgical site injection of a local anesthetic or drug cocktail. There are many formulations used for this purpose. A formulation documented in the literature was implemented by this institution which has dropped the average length of stay dramatically. Concern over the limited half-life of the administered anesthetic and the continued need for opioid administration has led to a search for better drug formulations and administration vehicles. Recently, the FDA approval of an extended release bupivacaine called liposomal bupivacaine was thought to extend the effective half-life of the anesthetic agent and thereby prolong post-operative anesthesia. Use of liposomal bupivacaine in total joint surgery was almost universally adopted after its recent approval and has been an integral part of the "same day total joint" movement.

Studies have suggested improvement in pain control and shortened hospitalizations with the use of liposomal bupivacaine. Other studies have raised questions about the effectiveness of this agent. Recently a randomized double blind study was performed with total knees which demonstrated no improvement in pain management with the addition of liposomal bupivacaine to the multimodal pain management protocol. This study has not been performed in the hip arthroplasty population.

Arms: arm 1: Liposomal bupivacaine Bupivacaine Clonidine Epinephrine Ketorolac arm 2: Ropivacaine Clonidine Epinephrine Ketorolac arm 3: Liposomal bupivacaine Bupivacaine Clonidine Epinephrine Ketorolac arm 4: Ropivacaine Clonidine Epinephrine Ketorolac
Interventions: intervention 1: Liposomal Bupivacaine intervention 2: Ropivacaine intervention 3: Bupivacaine intervention 4: Clonidine intervention 5: Ketorolac intervention 6: Epinephrine
Intervention descriptions: intervention 1: Periarticular injection intervention 2: Periarticular injection intervention 3: Included as an element of the Liposomal bupivacaine intervention periarticular injection intervention 4: Included as an element of both interventions as a standard of care periarticular injection intervention 5: Included as an element of both interventions as a standard of care periarticular injection intervention 6: Included as an element of both interventions as a standard of care periarticular injection

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 
A Prospective, Randomized Clinical Trial of Two Periarticular Multimodal Drug Injections in 
Total Hip and Knee Arthroplasty 
Principal Investigator 
Joe Bowen MD 
Version Date 
June 9,2016 
Background 
Perioperative pain control is a fundamental part of patient satisfaction. Many therapies are aimed 
at improving this critical component during a hospitalization. Current pain management 
techniques use several different mechanisms simultaneously and are termed "multi-modal". 
Multi-modal therapy has demonstrated improvement in pain control after surgery while 
minimizing side effects. Advancement in the understanding and practice of multimodal pain 
management is one of the prime reasons for shorter hospital stays. 
A key component of the multimodal approach to pain management is the intra-operative surgical 
site injection of a local anesthetic or drug cocktail. There are many formulations used for this 
purpose. A formulation documented in the literature was implemented by this institution which 
has dropped the average length of stay dramatically. Concern over the limited half-life of the 
administered anesthetic and the continued need for opioid administration has led to a search for 
better drug formulations and administration vehicles. Recently, the FDA approval of an extended 
release bupivacaine called liposomal bupivacaine was thought to extend the effective half-life of 
the anesthetic agent and thereby prolong post-operative anesthesia. Use of liposomal bupivacaine 
in total joint surgery was almost universally adopted after its recent approval and has been an 
integral part of the "same day total joint" movement. 
Upon the approval of liposomal bupivacaine by the FDA, there have been a number of studies 
examining the efficacy of the drug in the orthopedic patient population. Liposomal bupivacaine 
is expensive and adds to the burden of procedural cost. Studies, often conflicted by industry 
sponsorship, have suggested improvement in pain control and shortened hospitalizations with the 
use of liposomal bupivacaine. Other studies have raised questions about the effectiveness of this 
agent. Recently a randomized double blind study was performed with total knees which 
demonstrated no improvement in pain management with the addition of liposomal bupivacaine to 
the multimodal pain management protocol. This study has not been performed in the hip 
arthroplasty population. 
Primary Objective: 
The aim of this study is to determine whether the use of a liposomal bupivacaine based 
periarticular injection versus a ropivacaine based periarticular injection improves pain control in 
patients undergoing Total Hip and Knee arthroplasty at Kootenai Health. We intend to evaluate 
pain control by using a Pain Score measured every four hours during hospitalization. 
Page 1 of 8 


Primary Outcome Variable 
Pain Scores as averaged over length of stay. The Pain Scale routinely used at Kootenai Health 
will be utilized. This is the standard 0-10 scale with 0 being no pain to 10 which is the worst 
possible pain the patient has experienced. 
Secondary Outcome Variable 
Narcotic consumption (calculated in oral morphine equivalent dose) 
Length of Stay (hours) 
Setting/Resources for the Study 
Kootenai Health will be the setting for the surgeries while Dr. Bowen's clinic will be the setting 
for subject recruitment. Subjects will be screened and enrolled by Dr. Bowen. Surgery will be 
performed by Dr. Bowen. Other surgeons may join the study but all will be performing the same 
injection technique. Dr. Bowen will oversee the training of the surgeons and any other key 
research personnel that may join the study. 
Study Design 
This study will employ a prospective, randomized, double-blind, study design methodology. 
Study Subjects 
All subjects who have been routinely referred to Dr. Bowen for total hip or knee arthroplasty will 
be screened for inclusion into this study. 
Inclusion Criteria 
30 - 85 years of age 
Hip or knee Arthritis (osteoarthritis, post traumatic, inflammatory, and avascular 
necrosis) 
Exclusion Criteria 
Multiple daily doses of long acting Narcotics (such as Oxycontin, MS Contin, or 
Fentanyl patches etc.) 
Revision surgery 
Surgical complication (femoral fracture with implant insertion) 
Inability to provide Informed Consent 
Subject Recruitment/Screening/Consent 
Patients will be screened and consented during a routine pre-operative office visit to discuss their 
pending surgery. This will take place in a private consultation room to ensure privacy. It will be 
made very clear to patients that their participation is voluntary and that choosing not to 
participate in the study will in no way affect their future care by Dr. Bowen or Kootenai Health. 
Study Procedures 
Total Hip and Knee athroplasty is a standard procedure at Kootenai Health and routinely 
performed by the principal investigator. Patients will be randomized to either a ropivacaine based 
periarticular injection or a liposomal bupivacaine based periarticular injection (See Table 1). 
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Table 1. Periarticular Injection Assignments 
Group A 
Group B 
20 mL Liposomal Bupiva.caine 
25 mL Bupivacaine 0.5% 
49.25 mL 5mg/m1 Ropivacaine 
1.0 mL 1:1000 Epinephrine 
1.0 mL 1:1000 Epinephrine 
0.8 mL Clonidine 100 mcg/mL 
0.8 mL Clonidine 100 mc• m 
13.7 mL NaC1 0.9% 
13.7 mL NaC1 0.9% 
1.0 mL Ketorolac (15 — 30 mg)* 
1.0 mL Ketorolac (15 — 30 mg)* 
*May be deleted for patients with compromised renal function 
The randomization schedule will be set up using a routine alternating treatment assignment 
between each patient in a 1:1 pattern using an excel spreadsheet. The group assignment will be 
written on an order sheet and will be taken to the pharmacy where the pharmacist will mix the 
injection according to standard of care and as noted in Table 1. The Investigator will not be 
blinded to the treatment but the post-operative providers will be blinded to the randomized 
assignment group. An Advanced Registered Nurse Practitioner who routinely rounds on post-
operative patients to evaluate their pain control will be blinded to the assignment group. 
Early Withdrawal of Subjects 
A patient may be withdrawn from the study prior to the expected completion of that subject for 
failure to adhere to protocol requirements, or subject consent withdrawal or the investigator may 
withdraw the patient for safety concerns. Patients may choose to withdraw from the study at any 
time. Data that have already been collected prior to consent withdrawal will still be used. 
Statistical Plan 
This is a non-inferiority trial. Therefore, the main output from the analysis above will be a 95% 
confidence interval for the difference between average pain scores for the hospitalization. It is 
anticipated that 14-8 130 patients will be enrolled into each cohort with an enrollment period of 3 
years. A biostatistician will be consulting on the study and performing statistical calculations. 
Mean pain scores will be compared between the two groups within each cohort. Opioid use 
(morphine equivalents) will be compared from PACU admission to discharge. Length of stay, 
calculated in hours from the start of the surgical procedure until time of discharge, will be 
compared between the two groups within each cohort. 
Potential Benefits 
Patients may not benefit from their participation in this study and will receive usual care for 
patients undergoing Total Hip and Knee arthroplasty. It is hoped that their participation will 
enable the investigators to determine if there are differences in pain control between the two 
regimens for future patients. 
Potential Risks 
All procedures and medications used in this study are standard of care. The risks of bupivacaine 
and ropivacaine are noted in the tables below and the profiles are similar for drugs of this class. 
Patients may receive these medications outside the setting of this research. 
Page 3 of 8 


Ro Divacaine 
Most common (>10%) 
Common (5% - 10%) 
Rare (<5%) 
Nausea 
Fever 
Chills 
Vomiting 
Back Pain 
Anxiety 
Low Blood Pressure 
Headache 
Urine retention or low urine 
output 
Low blood count 
High blood pressure 
Bleeding 
Dizziness 
Low Heart Rate 
Chest pain 
Itching 
Low potassium 
Pain 
Allergic Reaction: hives, rash, 
itching; sneezing, difficulty 
breathing; severe dizziness, 
vomiting, swelling of your face, 
lips, tongue or throat 
"Pins and Needles" feeling 
Shortness of Breath 
Urinary tract infection, urgency, 
incontinence 
Numbness 
Heart Attack (<1%) 
Irregular heart rate 
Yellowing of the skin and eyes 
Low Magnesium level 
Blood clots in legs and/or lungs 
Coughing 
Agitation, confusion, sleepiness, 
nervousness, forgetfulness, 
inability to sleep, hallucination, 
nightmares 
Nervous Disorders: Trembling, 
coma, convulsions, weakness, eye 
drooping, stupor, pain or 
numbness in hands and feet 
Ringing in ears 
Muscle aches 
Fainting 
Li osomal Bu ivacaine 
Most common (>10%) 
Common (2% - 10%) 
Rare (less than 2%) 
Nausea 
Fever 
Chills 
Vomiting 
Dizziness 
Rash 
Constipation 
Swelling in hands or feet 
Urine Retention 
Low blood count 
High blood pressure 
Bleeding 
Lightheadedness 
Page 4 of 8 


Low blood pressure 
Neck pain 
Itching 
Numbness and tingling in the 
mouth or lips 
Fast heart rate 
Allergic Reaction: hives, red 
rash, itching; sneezing, difficulty 
breathing; severe dizziness, 
vomiting, swelling of your face, 
lips, tongue or throat 
Headache 
Shakiness 
Inability to sleep 
Low heart rate 
Muscle spasms 
Irregular heart rate 
Back pain 
Ringing in the ears 
Sleepiness 
Blurry vision 
Low oxygen level 
Pain 
Anxiety, confusion, depression, 
agitation, restlessness, 
Swelling at the incision site 
The formulation of liposoma bupivacaine allows for a longer duration of action and a slower 
absorption into systemic circulation, avoiding high plasma concentrations. Local infiltration can 
result in significant system plasma concentrations for up to 96 hours; however, significant levels 
are not correlated with local efficacy and differ between surgical procedures. Because of the 
longer lasting plasma concentrations there is concern for potential drug interactions should 
another local anesthetic be used during this 96-hour time period. Kootenai Health recently 
instituted a procedure placing a colored armband on every patient receiving liposomal 
bupivacaine and providing written information about the drug including time the drug was given 
and when the 96-hour time period is over. Patients are blinded to their treatment assignment and 
to maintain the blind, all study patients will receive the armband and information. This will 
provide the same standard of care to participants randomized to the liposomal bupivacaine group 
and will not incur risk to those randomized to the ropivacaine group. This information will be 
included in the consent form. 
Breach of confidentiality is a risk of this study in the transfer of data for research purposes. 
Reporting of Serious Adverse Events 
Reports of unanticipated adverse events will be submitted to the IRB upon discovery following 
the correct policies and procedures. Copies of each report and documentation of IRB 
notification and receipt will be kept in the Investigator's records. 
Data and Safety Monitoring Plan 
Because both groups are receiving well established standard of care treatment, the Principal 
Investigator will oversee the safety of the study. This safety monitoring plan will include careful 
assessment and appropriate reporting of adverse events as noted above. Ongoing evaluation of 
subject eligibility, adverse events, and the informed consent process will occur with compliant 
reporting to the IRB of protocol deviations. The Principal Investigator will closely monitor for 
Page 5 of 8 


trends in the data or a higher than expected rate of occurrence for any adverse effect such as a 
higher than expected use of pain medication in either group. 
In addition, a blind interim analysis of the data will be conducted by the statistician when 50% of 
the sample is accrued. If the results show statistically overwhelming significant differences 
between groups, the blind will be broken and the study stopped. 
Confidentiality and Management and protection of Data 
Information about study subjects will be kept confidential and managed according to the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). 
Patient data will be entered into electronic spreadsheets and paper data forms. One spreadsheet, 
enrollment form, will contain the patient name, medical record number, study number and 
randomization group. The second spreadsheet will contain the study number, patient 
demographic and study data. Only the investigators will have access to the files and their 
passwords. Data will be stored on the Kootenai Health protected and secured main computer 
system. Any paper records will be stored in hard copy in a locked filing cabinet in the 
investigator's office for a minimum of five years. At this time the information will be destroyed 
in accordance with the Kootenai Health document destruction policy. An electronic database 
such as REDCap may be used for data storage and will have password protected, limited access. 
Results and Publication Plan 
The data from this study will be shared at Kootenai Health. External dissemination of the results 
in journal publication is under consideration. All data will be aggregated and de-identified. 
Medical Care and Compensation for Injury 
If patients are injured from taking part in this research study, medical care will be provided. The 
costs of the care will be billed to the patient or his/her insurance. No funds have been set aside to 
pay the patient in the event of a research related injury. Study participants will be instructed to 
contact the investigator for more information. 
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