Clinical trial NCT04749615
Conditions: Total Knee Athroplasty
Keywords: TKA PAI ACB IPACK Knee Arthroplasty
Sponsor: Hospital for Special Surgery, New York
Start date: 2020-12-17; Completion date: 2022-07-01
Enrollment: 94 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical trial is to determine whether Periarticular Injection (PAI) alongside Adductor Canal Block (ACB) and Infiltration between the Popliteal Artery and Capsule of the Knee (IPACK) block can decrease post-operative pain in patients undergoing primary total knee arthroplasty. The main question it aims to answer is:

• Is ACB/IPACK without PAI as effective as ACB/IPACK with PAI for TKA patients?

Participants will be assigned to one of the following groups at random:

* ACB/PACK with PAI
* ACB/IPACK with saline injection

Participants will also be asked to complete pre- and post-operative questionnaires.

Detailed description:
Kim et al (2019) have shown that addition of ACB/IPACK to PAI improves analgesic outcomes (the nerve blocks reduced pain with ambulation and reduced opioid consumption). TKA patients receiving PAI + ACB/IPACK (along with a comprehensive multimodal analgesic program) had low pain scores with ambulation on POD1: 1.7 +/- 1.4 (mean +/- SD, NRS, 0-10 scale). The opioid consumption in the first 24 hours was 40.6 +/- 32.1 (mg oral morphine equivalents).

It is not clear if the PAI component is necessary, given the theoretically nearly complete analgesic effects of the ACB/IPACK block. Additionally, anecdotal evidence indicates that some surgeons at HSS routinely use the PAI and some do not, without obvious large differences in analgesic outcomes. While there may be a 'belt and suspenders' advantage to using PAI in addition to ACB/IPACK, it is not desirable to perform unnecessary procedures.

In this study, we seek to compare the efficacy of ACB/IPACK with and without PAI in TKA patients.

Arms: arm 1: Control: saline injection (same injection technique and volumes as described for the active intervention, of normal saline) arm 2: Active intervention: Periarticular injection: one deep injection prior to cementation and then a second more superficial injection prior to closure. The deep injection will consist of bupivacaine 0.25% with 1:200,000 epinephrine, 30 cc; morphine, 8 mg/ml, 1cc; methylprednisolone, 40 mg/ml, 1 ml; cefazolin, 500 in 10 ml; normal saline, 22cc. The superficial injection will be 20 ml 0.25% bupivacaine
Interventions: intervention 1: Periarticular Injection (PAI) intervention 2: Saline Control Periarticular Injection (PAI)
Intervention descriptions: intervention 1: PAI is a widely-utilized, surgeon-performed, analgesic intervention for TKA patients. intervention 2: equal volume of saline will be used in place of analgesics used in PAI injections

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Page 1 of 11 
 
 
 
 
 
 
 
 
Does Periarticular Injection (PAI) reduce pain after 
TKA among knee arthroplasty patients receiving 
Adductor Canal Block and Infiltration between the 
Popliteal Artery and the Capsule of the Posterior 
Knee (ACB&IPACK)? 
FUNDER: 
Department of Anesthesiology 
PROTOCOL NO.: 
2019-2096 
VERSION & DATE: 
Version 1, 4/14/2022 
 
This document contains the confidential information of the Hospital for Special Surgery.  It is provided to you and your company’s personnel for 
review.  Your acceptance of this document constitutes an agreement that you will not disclose the information contained herein to others without 
the prior written consent of the Hospital for Special Surgery.  No other use or reproduction is authorized by Hospital for Special Surgery, nor does 
the Hospital for Special Surgery assume any responsibility for unauthorized use of this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ............................................ 2 
PROTOCOL SYNOPSIS ........................................... 3 
1.0 
INTRODUCTION ............................................. 5 
2.0 
OBJECTIVE(S) OF CLINICAL STUDY .......... 6 
3.0 
STUDY HYPOTHESES .................................. 7 
4.0 
STUDY DESIGN ............................................. 7 
4.1 
Endpoints ....................................................................................................................... 7 
4.1.1 
Primary Endpoint ...................................................................................................... 7 
4.1.2 
Secondary Endpoints ................................................................................................ 7 
4.2 
Study Sites ..................................................................................................................... 7 
5.0 
STUDY POPULATION ................................... 7 
5.1 
Number of Subjects ........................................................................................................ 7 
5.2 
Inclusion Criteria............................................................................................................. 7 
5.3 
Exclusion Criteria ........................................................................................................... 8 
6.0 
PROCEDURES ............................................... 8 
6.1 
Intraoperative Protocol ................................................................................................... 8 
6.2 
Postoperative Protocol ................................................................................................... 9 
6.3 
Data Collection ............................................................................................................... 9 
7.0 
STATISTICAL ANALYSIS ............................ 10 
8.0 
ADVERSE EVENT ASSESSMENT .............. 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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PROTOCOL SYNOPSIS 
 
Protocol Title: 
Does Periarticular Injection (PAI) reduce pain after TKA among 
knee arthroplasty patients receiving Adductor Canal Block and 
Infiltration between the Popliteal Artery and the Capsule of the 
Posterior Knee (ACB&IPACK)? 
Protocol Number: 
2019-2096 
Protocol Date: 
 
Sponsor: 
Department of Anesthesiology 
Principal Investigator: 
Jacques YaDeau, MD 
Objective: 
The purpose of this study is to compare two anesthesia methods 
in reducing pain with movement 24 hours after a total knee 
replacement surgery. Both groups use standard of care 
treatment, and the two anesthesia methods are: 1) Adductor 
Canal Block (ACB) and an Interspace between Popliteal Artery 
and Capsule of the posterior Knee (IPACK) block plus 
Periarticular Injections (PAI) with active medication and 2) 
Adductor Canal Block (ACB) and an Interspace between 
Popliteal Artery and Capsule of the posterior Knee (IPACK) 
block plus Periarticular Injections (PAI) with placebo saline.  All 
patients receive the ACB and IPACK blocks.  The study is aimed 
to see whether or not the PAI is helpful. 
Study Design: 
Experimental - Noninferiority Randomized Control Trial 
Enrollment: 
94 
Subject Criteria: 
 
• 
Age 25-80 
• 
Planned use of regional anesthesia 
• 
Ability to follow the major components of the study protocol 
• 
English speaking (Secondary outcomes include 
questionnaires validated in English only) 
• 
Osteoarthritis diagnosis 
Data Collection: 
Sources: EPIC, Patient Reported 
Variables: Name, DOB, Race, Gender, NRS Pain scores at rest 
and with movement, opioid use, PAIN OUT questionnaire, 
QOR9 survey, ORSDS, Pain management satisfaction, blinding 
assessment, Orthopedic outcomes, DN4 neuropathic 
assessment, Hospital length of stay 
Statistical Analysis: 
• 
Alpha level: 0.025 (non-inferiority) 
• 
Beta or power level: 90% 
 


 
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1.0 INTRODUCTION 
 
PAI is a widely-utilized, surgeon-performed, analgesic intervention for TKA 
patients.  “Overall, the RCTs in TKA reported an analgesic efficacy of LIA [Local Infiltration 
Analgesia – another term for PAI] in the early postoperative period when compared with 
placebo and no injection and most trials have reported decreased postoperative pain and 
reduction in opioid requirements in the early (<48h) postoperative period”.  (Andersen and 
Kehlet, BJA 2014). 
  
PAI was initially promoted at HSS as a way to discharge patients early.  An RCT performed 
at HSS on TKA patients compared PAI to epidural analgesia with femoral nerve block.  We 
found that time until ready for discharge (the primary outcome) was the same in both 
groups.   Patients in the PAI group had higher pain scores when walking (0.81 NRS points) 
and with CPM (0.88 points), and used much more opioids (228 mg vs 142 mg, cumulative 
oral morphine equivalents, POD 0-2).  Despite this paper, PAI remained popular with some 
surgeons, who noted that patients perceived benefits from not being attached to an epidural 
pump and a urinary catheter.   Furthermore, the generalizability of this paper is limited by 
the nationwide current relatively rare use of epidural + femoral nerve block for postoperative 
analgesia after TKA. 
 
(YaDeau JT, Goytizolo EA, Padgett DE, Liu SP, Mayman DJ, Ranawat AS, Rade 
MC.  Analgesia after total knee arthroplasty: Local infiltration analgesia vs. epidural + 
femoral nerve blockade.  A prospective, randomized pragmatic trial.  The Bone & Joint 
Journal 2013 (May) 95-B:629-35). 
  
The idea arose that (similar to the addition of peripheral nerve blockade to epidural 
analgesia) perhaps LIA would benefit from addition of ACB.  Goytizolo et al (Goytizolo EA, 
Lin Y, Kim DH, Ranawat AS, Westrich GH, Mayman DJ, SU EP, Padgett DE, Alexiades MA, 
Soeters R, Mac PD, Fields KG, YaDeau JT.  Addition of adductor canal block to periarticular 
injection for total knee replacement.  A randomized trial.  J Bone Joint Surg 
Am.  2019;101:812-20.) compared PAI to PAI/ACB and found no difference for the primary 
outcome, which was time to meeting discharge criteria.  However, the PAI/ACB group had 
lower worst pain (difference in means -1.4) and more pain relief (difference in means 
12%).  Despite the negative primary outcome, PAI/ACB became increasingly popular at 
HSS. 
  
The next relevant development came from the observation that ACB does not provide 
complete analgesia after TKA – there remains significant posterior knee pain.  IPACK was 
developed as a motor-sparing analgesic injection intended to alleviate posterior knee pain 
after surgery.  Kim et al randomized TKA patients to PAI or PAI + ACB/IPACK  (Kim DH, 
Beathe JC, Lin Y, YaDeau JT, Malouf DB, Goytizolo E, Garnett C, Ranawat AS, Su EP, 
Mayman DE, Memtsoudis SG.  Addition of infiltration between the popliteal artery and the 
capsule of the posterior knee and adductor canal block to periarticular injection enhances 


 
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postoperative pain control in total knee arthroplasty: A randomized controlled trial.  Anesth 
Analg 2019;129:526-535.).  Addition of ACB/IPACK to LIA resulted in benefit for the primary 
outcome (pain with ambulation POD1), with a difference in means of -3.3.  The intervention 
also was associated with reduced pain on POD 0 and POD2, reduced opioid consumption 
and higher satisfaction.  ACB/IPACK came into widespread use at HSS, typically performed 
in combination with either LIA, epidural analgesia, or both.  However, it is not clear whether 
PAI is needed in the context of multimodal analgesia, ACB and IPACK.  
  
Several studies are listed in clinicaltrials.gov that look at ACB and IPACK. Most of these 
studies seek to understand how ACB and IPACK interact independently, together, and in 
comparison to other interventions such as surgical infiltration and LIA. These studies can be 
seen below. However, none of these studies have looked at the efficacy of ACB/IPACK with 
PAI. Although one study (Malkani) is similar, it has not started recruiting. 
 
References: 
  
1. Malkani (Louisville) (NCT03840122): not yet recruiting: similar plan of ACB + IPACK 
with/without PAI 
2. Capdevilla (Montpellier) (NCT03704831): compares IPACK and surgical infiltration: no 
mention of ACB. 
3. Kalampokini ((Greece) NCT03692858).ACB with/without IPACK 
4. Biswas (Ontario) (NCT03944005).LIA vs ACB catheter + IPACK 
5. Patterson (Ochsner) (NCT03921034).ACB catheter with/without IPACK 
6. Lai (Mt Sinai) (NCT036553416).ACB catheter/IPACK/PAI vs ACB catheter/PAI 
7. Jin (Toronto).(NCT03954379) ACB catheter with/without IPACK and multimodal 
2.0 OBJECTIVE(S) OF CLINICAL STUDY 
 
The purpose of this study is to compare two anesthesia methods in reducing pain with 
movement 24 hours after a total knee replacement surgery. Both groups use standard of 
care treatment, and the two anesthesia methods are: 1) Adductor Canal Block (ACB) and an 
Interspace between Popliteal Artery and Capsule of the posterior Knee (IPACK) block plus 
Periarticular Injections (PAI) with active medication and 2) Adductor Canal Block (ACB) and 
an Interspace between Popliteal Artery and Capsule of the posterior Knee (IPACK) block 
plus Periarticular Injections (PAI) with placebo saline.  All patients receive the ACB and 
IPACK blocks.  The study is aimed to see whether or not the PAI is helpful. 
The Adductor Canal and IPACK blocks are injections of localized numbing medicine near 
the nerves leading to the knee and in the back of the knee. Both ACB and IPACK blocks will 
be performed by your anesthesiologist when you are under sedation and right before the 
start of surgery. The PAI consists of two injections around the knee,  of either pain medicine 
or placebo saline, depending on which group you are assigned to. These PAI injections will 
be performed by your surgeon during surgery while you are under anesthesia. Patients in 
both groups will receive a regimen of post-operative oral and intravenous pain medications 


 
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in addition to the injections in the operating room. The study will also look at your numeric 
pain scores with movement and at rest, the amount of pain medication taken after surgery, 
medication related side effects, your quality of recovery, and satisfaction with your pain 
management. 
A total of 94 subjects will participate in this study at HSS. 
3.0 STUDY HYPOTHESES 
This is study hypothesize that TKA patients with ACB/IPACK have NRS pain scores with 
ambulation on POD1 that is non-inferior to that of patients with PAI + ACB/IPACK. 
4.0 STUDY DESIGN 
4.1 
Endpoints 
4.1.1 
Primary Endpoint 
The primary outcome (NRS pain with ambulation) will be compared between the 
PAI+ACB& IPACK group and ACB& IPACK only group using two-sample t-test or 
Wilcoxon rank-sum test, depending on the distribution of the data. Upper limit of the 
95% confidence interval of group difference will be compared to the pre-specified 
absolute equivalence margin (|EM|=1). 
 
4.1.2 
Secondary Endpoints 
Secondary outcomes measured at multiple time points (NRS with ambulation, NRS at 
rest, OME, PainOUT, KOOS, VAS) will be analyzed using regression based on a 
generalized estimating equation (GEE) approach. Secondary outcomes collected at 
single time point (ORSDS, Satisfaction) will be compared between groups using two-
sample t-test or Wilcoxon rank-sum test, depending on the distribution of the data. All 
secondary statistical hypothesis tests were 2-sided. 
4.2 
Study Sites 
This study will take place at the main campus of the Hospital for Special Surgery 
(HSS). 
5.0 STUDY POPULATION 
5.1 
Number of Subjects 
94 
5.2 
Inclusion Criteria 
Subjects of either gender will be included if: 
• 
Age 25-80  
• 
Planned use of regional anesthesia 


 
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• 
Ability to follow the major components of the study protocol 
• 
English speaking (Secondary outcomes include questionnaires validated in 
English only) 
5.3 
Exclusion Criteria 
Subjects will be excluded from the study if: 
• 
Patients younger than 25 years old and older than 80 
• 
Non-English speaking 
• 
Patients intending to receive general anesthesia 
• 
Contraindication to nerve blocks or peri-articular injection 
• 
Patients with an ASA of IV or higher 
• 
Renal insufficiency (ESRD, HD, estimated creatinine clearance < 30 ml/min) 
• 
Patients with major prior ipsilateral open knee surgery 
• 
Chronic gabapentin/pregabalin use (regular use for longer than 3 months) 
• 
Chronic opioid use (taking opioids for longer than 3 months) 
6.0 PROCEDURES 
6.1 
Intraoperative Protocol 
 
A randomization schedule will be created using SAS software by a biostatistician not 
otherwise involved in the study. 
  
A total of 94 patients will be enrolled and will receive the standard analgesic protocol in 
addition to being assigned one of the following: 
• 
Active intervention: Periarticular injection: one deep injection prior to cementation 
and then a second more superficial injection prior to closure. The deep injection will 
consist of bupivacaine 0.25% with 1:200,000 epinephrine, 30 cc; morphine, 8 mg/ml, 
1cc; methylprednisolone, 40 mg/ml, 1 ml; cefazolin, 500 mg in 10 ml; normal saline, 
22cc. The superficial injection will be 20 ml 0.25% bupivacaine 
• 
Control: saline injection (same injection technique and volumes as described above 
for the active intervention, of normal saline 
 
Standardized Anesthetic/Analgesic protocol: 
Spinal epidural anesthetic (mepivacaine, 60). No intrathecal opioids. If surgery is prolonged, 
may administer 10 ml lidocaine, 2% via epidural. Remove epidural prior to leaving the OR.  
 
Adductor canal nerve block 
     (15 cc bupivacaine, 0.25% with 2mg PF-dexamethasone / 30 ml). 
 
IPACK technique: 
     (25 cc 0.25% bupivacaine, 0.25% with 2mg PF-dexamethasone / 30 ml] 
 
(IV) 4 mg ondansetron, 20 mg famotidine, 15 mg ketorolac. 
 
All patients receive IV dexamethasone: dose of 4 mg (PAI) and 10 mg (no PAI) 
 
All patients receive 1g TXA IV prior to incision.  


 
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6.2 
Postoperative Protocol 
 
No routine PCA. 
 
Ketorolac (15 mg IV q 8hr, 4 doses total, including OR dose) with subsequent oral 
meloxicam (7.5-15 mg PO daily, based on age; 15 mg unless age >= 75). 
Acetaminophen (1000 mg IV once, then 650 mg PO q 6hr).  Our recent study indicates little 
benefit to IV acetaminophen vs oral acetaminophen, other than perhaps the first dose 
(Westrich, GH, Birch GA, Muskat AR, Padgett DE, Goytizolo EA, Bostrom MP, Mayman DJ, 
Lin Y, YaDeau JT.   Intravenous vs oral acetaminophen as a component of multimodal 
analgesia after total hip arthroplasty: A randomized, blinded trial. J. Arthroplasty 2019; 34: 
S215-S220.). 
Duloxetine, 60 mg PO daily, unless already taking an antidepressant.  This is an opioid-
sparing dose.  (YaDeau et al.  Anesthesiology 2016).Oxycodone (5/10 mg PO q 4 hr PRN). 
PRN IV hydromorphone in the PACU for NRS >6 , 0.5 mg q 10 m PRN for 2 mg maximum.  
If NRS >6 for 2 hours, may start IV hydromorphone PCA. 
Patients in either limb of the study may have their opioid and other analgesic medications 
adjusted by the pain management team as clinically indicated. 
6.3 
Data Collection 
The following data will be collected: 
 
Pre-operative/Holding Area 
• 
Identify eligible patients on schedule day before surgery 
• 
Obtain consent 
• 
NRS Pain at rest and with movement 
• 
PAIN OUT questionnaire 
• 
Opioid use 
• 
Orthopedic outcomes 
• 
DN4 Neuropathic Assessment 
 
Post-Operative Day 0 (POD 0) 
• 
NRS Pain at rest and with movement 
• 
Opioid use 
 
Post-Operative Day 1 (POD 1) 
• 
NRS Pain at rest and with movement 
• 
PAIN OUT questionnaire 
• 
Opioid use 
• 
ORSDS 
• 
QoR9 
• 
Pain Management Satisfaction 


 
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• 
Blinding Assessment 
 
Post-Operative Day 2 (POD 2) 
• 
NRS Pain at rest and with movement 
• 
Opioid use 
 
Discharge 
• 
Hospital length of stay 
 
Post-Operative 2 Weeks 
• 
PAIN OUT questionnaire 
• 
Opioid use 
 
Post-Operative 6 Weeks 
• 
Orthopedic Outcomes 
 
Post-Operative 3 months 
• 
NRS Pain at rest with movement 
• 
PAIN OUT questionnaire 
• 
Opioid use 
• 
Orthopedic outcomes 
• 
DN4 Neuropathic Assessment 
 
Surgeon’s Office Visit 
• 
Orthopedic outcomes 
 
7.0 STATISTICAL ANALYSIS 
1. Interim analysis planned?  No 
2. Alpha level:  0.025 (non-inferiority) 
3. Beta or power level:  90% 
4. Primary outcome variable estimate (mean +/- s.d. for continuous outcome, 
frequency/percentage for categorical variable):   1.7 +/- 1.4 (NRS pain with 
ambulation POD1; from Kim et al, 2019 IPACK paper) 
5. Number of groups being compared (use 1 for paired analysis within the same 
subjects):  2 
6. Effect size or change expected between groups:   Equivalence margin = 1.  
7. Resulting number per group: 43 
8. Total sample size required:  43*2+10% attrition=94 
 
Primary outcome: 
The primary outcome (NRS pain with ambulation) will be compared between the 
PAI+ACB& IPACK group and ACB& IPACK only group using two-sample t-test or 
Wilcoxon rank-sum test, depending on the distribution of the data. Upper limit of the 
95% confidence interval of group difference will be compared to the pre-specified 
absolute equivalence margin (|EM|=1).  
 


 
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Secondary outcome: 
The secondary outcomes will also be compared between the ACB and ACB + IPACK 
groups. Specific statistical approaches will be determined by the observed distribution of 
these outcomes: 
Secondary outcomes measured at multiple time points (NRS with ambulation, NRS 
at rest, OME, PainOUT, KOOS, VAS) will be analyzed using regression based on a 
generalized estimating equation (GEE) approach. Secondary outcomes collected at 
single time point (ORSDS, Satisfaction) will be compared between groups using two-
sample t-test or Wilcoxon rank-sum test, depending on the distribution of the data. All 
secondary statistical hypothesis tests were 2-sided.  
 
Balance on demographics and baseline characteristics will be assessed by calculating 
standardized differences (difference in means or proportions divided by the pooled standard 
deviation) between groups. An absolute value of 0.4 or greater will be interpreted as more 
imbalance than would be expected by chance (Austin 2009). 
 
The success of blinding in each group will be formally assessed by calculating the Bang 
Blinding Index (Bang 2010). 
 
All analyses will be performed on an intention to treat basis. 
 
References: 
 
• 
Austin PC. Balance diagnostics for comparing the distribution of baseline 
covariates between treatment groups in propensity score matched samples. 
Stat Med 2009; 28: 3083107. 
 
• 
Bang H, Flaherty SP, Kolahi J, Park J. Blinding assessment in clinical trials: A 
review of statistical methods and a proposal of blinding assessment protocol. 
Clin Res Regul Aff 2010; 27:4251   
 
 
8.0 ADVERSE EVENT ASSESSMENT 
All Adverse Events (AEs) will be reported in the final study report.