Clinical trial NCT03020966
Conditions: Pain, Postoperative Opioid Use
Sponsor: Hospital for Special Surgery, New York
Start date: 2017-02-16; Completion date: 2019-06-16
Enrollment: 154 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine how well two different methods of administrating Tylenol reduce pain and improve patient satisfaction after total hip replacement (THR) surgery. The methods of administration are orally, via a pill that is to be swallowed, and intravenously. Our aim is to determine whether oral or intravenous administration of Tylenol will reduce opioid consumption and opioid-related side effects after THR.

Detailed description:
A) Opioid use after THA. Opioid use after THA can be 90 mg (+/-79) in morphine equivalents when using epidural bupivacaine / hydromorphone and multimodal analgesia. Less than 1/3 of this was via the epidural (26/90 mg). Patients reported ORSDS composite scores of 0.58

B) IV vs oral acetaminophen. The therapeutic blood concentration of acetaminophen for pain relief is 10 mcg/ml.

After an oral, single dose: In 24 fasting adult subjects, the maximal blood concentration (Cmax) of 7.7 to 17.6 mcg/mL occurred within 1 hour following a single 1000-mg dose of oral acetaminophen (liquid or caplet). Acetaminophen crosses the blood-brain barrier. Central diffusion to the brain and spinal fluid occurs within 15 to 45 minutes with maximum cerebrospinal fluid concentrations occurring at 2 to 4 hours. \[Product Information: TYLENOL(R) oral, acetaminophen oral. McNeil Consumer Healthcare, Skillman, NJ, 2010\].

In a randomized, double-blind, placebo-controlled, single-dose study, acetaminophen 1,000 mg provided significantly greater efficacy in treating postsurgical dental pain compared with acetaminophen 650 mg and placebo.

Oral, multiple-dose, immediate-release, elderly patients: In 12 very elderly patients (mean age, 89 years), the Cmax was 23.9 mcg/mL following the administration of acetaminophen 1000 mg orally 3 times daily for 5 days.

In adult subjects, the mean Cmax was 28 +/- 21 mcg/mL at the end of a 15-minute IV infusion of acetaminophen 1000 mg. \[Product Information: OFIRMEV(TM) intravenous infusion, acetaminophen intravenous infusion. Cadence Pharmaceuticals Inc., San Diego, CA, 2010\].

The oral medication has an excellent absorption and at least 85% bioavailability, but peak concentration occurs later than the IV, and the therapeutic blood concentration for pain relief (10mcg/ml) may not be achieved after one oral dose (7-17mcg/ml).A full stomach delays the absorption. With multiple doses, in elderly patients, or with renal/ liver failure, the blood concentration is higher.

Epidural bupivacaine / clonidine (Liu). Pain scores (NRS) after THA with activity on POD1 can be 3.4 mean (2.6 SD) when using epidural bupivacaine / clonidine and multimodal analgesia.

Low-opioid protocol (oxycodone may be too strong for some; cannot use Vicodin due to acetaminophen) Choice of instruments (CAM, ORSDS, Pain OUT). The ORSDS is a 4-point scale that evaluates 12 symptoms (nausea, vomiting, constipation, difficulty passing urine, difficulty concentrating, drowsiness or difficulty staying awake, feeling lightheaded or dizzy, feeling confused, feelings of general fatigue or weakness, itchiness, dry mouth and headache) via 3 symptom distress dimensions (frequency, severity, bothersomeness). It is validated for use after orthopaedic surgery, specifically including TKA patients receiving epidural analgesia and femoral nerve blockade.

Patients can meet criteria for delirium by CAM by having acute onset of inattention as well as either disorganized thinking or altered level of consciousness.Patients without acute onset can also meet criteria for delirium if inattention, disorganized thinking and altered level of consciousness are all present, with at least one factor judged to be fluctuating. CAM has been widely applied and has been specifically used to evaluate elderly TKA patients receiving epidural analgesia and femoral nerve blockade.

The Patient Outcome Questionnaire by the American Pain society is used for quality improvement, and measures 6 aspects of quality, including (1) pain severity and relief; (2) impact of pain on activity, sleep, and negative emotions; (3) side effects of treatment; (4) helpfulness of information about pain treatment; (5) ability to participate in pain treatment decisions; and (6) use of nonpharmacological strategies.

Arms: arm 1: Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo arm 2: Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo
Interventions: intervention 1: Acetaminophen intervention 2: Acetaminophen
Intervention descriptions: intervention 1: Oral acetaminophen, intravenous placebo intervention 2: Intravenous acetaminophen, oral placebo

Protocol documents:
Prot_SAP_000.pdf: 
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IV vs. Oral Acetaminophen as a Component of 
Multimodal Analgesia After Total Hip Arthroplasty: a 
Randomized, Blinded, Controlled Trial 
 
FUNDER: 
Mallinckrodt Pharmaceuticals 
PROTOCOL NO.: 
2016-209 
VERSION & DATE: 
V3.28.16 
 
 
 
 
 
 
 
 
 
 
 
 
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 


 
Protocol Number:2016-209  
Version Date: 3-28-2016 
 
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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. 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS................................................................................................................... 2 
PROTOCOL SYNOPSIS.................................................................................................................. 3 
1.0     INTRODUCTION .................................................................................................................... 4 
    2.0 
PRODUCT DESCRIPTION………………………..……………………………………………….4 
3.0      OBJECTIVE OF CLINICAL STUDY ...................................................................................... 4 
4.0      STUDY HYPOTHESIS ........................................................................................................... 4 
5.0      STUDY DESIGN .................................................................................................................... 4 
5.1 
Study Duration ................................................................................................................ 4 
5.2 
Endpoints ....................................................................................................................... 4 
5.2.1 
Primary Endpoint ...................................................................................................... 4 
5.2.2 
Secondary Endpoints ................................................................................................ 4 
5.2.3 
Safety Evaluations. ................................................................................................... 4 
5.3 
Study Site ....................................................................................................................... 4 
6.0        STUDY POPULATION ......................................................................................................... 4 
6.1 
Number of Subjects ........................................................................................................ 4 
6.2 
Inclusion Criteria............................................................................................................. 5 
6.3 
Exclusion Criteria: .......................................................................................................... 5 
    6.4        Randomization………………………………………………………………………………..5 
7.0         PROCEDURES .................................................................................................................... 5 
7.1 
Surgical Procedure ......................................................................................................... 5 
 
7.1.1. Investigational Product Administration………………………………………………. .…..5 
7.2 
Imaging Procedure ......................................................................................................... 5 
7.3 
Medical Record Requirements ....................................................................................... 5 
7.4 
Data Collection ............................................................................................................... 5 
    7.5        Schedule of Assessments……………………………………………………..…………….. 6 
7.6 
Radiological Evaluations ................................................................................................ 7 
7.7 
Clinical Evaluations ........................................................................................................ 7 
 
7.7.1. Revision Surgery………………………………………………………………………. .……7 
8.0         STATISTICAL ANALYSIS .................................................................................................. 7 
9.0         ADVERSE EVENT ASSESSMENT ..................................................................................... 7 
9.1 
Adverse Event (AE) ........................................................................................................ 7 
9.2 
Serious Adverse Events (SAE) ...................................................................................... 7 
9.3 
Subsequent Surgical Interventions Definitions .............................................................. 7 
9.4 
Adverse Event Relationship ........................................................................................... 7 
9.5 
Adverse Event Recording .............................................................................................. 7 
9.6 
Adverse Event Reporting ............................................................................................... 7 
10.0         INVESTIGATOR RESPONSIBILITIES, RECORD AND REPORTS ................................ 7 
10.1 
Subject Consent and Information ................................................................................... 7 
10.2 
Subject Data Protection ................................................................................................. 7 
10.3 
Staff Information ............................................................................................................. 8 
10.4 
Protocol Reviews............................................................................................................ 8 


 
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10.5 
Investigator Records ...................................................................................................... 8 
10.6 
Investigator Reports ....................................................................................................... 8 
 11.0  
REFERENCES……………………………………………………………….………………….8 
APPENDIX A: Case Report Forms .............................................................................................. 9 
 
PROTOCOL SYNOPSIS 
Protocol Title: 
IV vs. oral acetaminophen as a component of multimodal 
analgesia after total hip arthroplasty: a randomized, blinded, 
controlled trial 
Protocol Number: 
2016-209 
Protocol Date: 
3.28.2016 
Sponsor: 
Mallinckrodt Pharmaceuticals 
Principal 
Investigator: 
Geoffrey Westrich, MD 
Products: 
IV Acetaminophen 
Objective: 
1. Does IV acetaminophen reduce pain after THA 
compared to oral acetaminophen? 
2. Does IV acetaminophen reduce opioid consumption after 
THA compared to oral acetaminophen? 
3. Does IV acetaminophen reduce opioid related side 
effects after THA compared to oral acetaminophen? 
Study Design: 
Experimental Randomized Controlled Clinical Trial 
Enrollment: 
154 
Subject Criteria: 
Inclusion Criteria: 
-Patient undergoing primary total hip replacement 
-Patient between the age of 1880 
-Patient planned for Combined Spinal Epidural anesthesia 
(CSE) and Patient Controlled Epidural Analgesia (PCEA) 
-Patient who is English speaking 
Exclusion Criteria: 
- Non-English speaking patients 
- Patients receiving periarticular injections 
- Patients who took opioids preoperatively 
- Patient with hepatic or renal insufficiency 
- Patient with hypersensitivity or contraindication to protocol 
medication 
-Patient with contraindication for CSE and PCEA 
 
-Patient undergoing revision or emergency surgery 


 
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Study Duration: 
 
Both groups will start treatment 30 minutes after surgery 
every six hours for a total of three days 
 
Between February 2017 and May 2018 
Data Collection: 
 
DOB 
 
Race 
 
Gender 
 
NRS pain scores at rest (patient report on POD1 am, 
POD 2 am) 
 
Name 
 
Pain NRS at rest (patient interview on POD0,1,2,3,14) 
 
Pain NRS with PT (POD0,1,2,3) 
 
CAM 
 
Opioid Dose 
 
ORSDS 
 
Satisfaction (0-10) 
 
Range of Motion (ROM) 
 
Discharge Time 
Outcome 
Parameters: 
Primary Outcome Parameters: 
-Pain with physical therapy (POD 1) via NRS scale (010). 
-Opioid use (oral morphine equivalents, cumulative, POD 03). 
-Opioid side effects (Opioid related symptom distress scale, 
ORSDS, composite score POD 1) 
Secondary Outcomes Parameters: 
-Pain with physical therapy (POD 03). 
-Pain at rest (POD 03). 
-Opioid use on individual days. 
-Pain OUT questionnaire, POD2. 
-Progress through physical therapy. 
-Discharge time. 
-Patient satisfaction (010 
-Likert scale) at discharge. 
-Confusion Assessment Method (CAM) 
Data Evaluation: 
The three primary outcomes will be compared between the IV 
and oral acetaminophen groups with two sample t-tests or 
Wilcoxon rank-sum tests, depending upon the distribution of the 
data. Effect sizes will be presented as differences in means or 
Wilcoxon Mann Whitney odds with 95% confidence intervals. 
Continuous secondary outcomes measured at a single time 
point will be analyzed in the same manner as the primary 
outcomes. Categorical secondary outcomes will be compared 
using chi-square or Fisher’s exact tests, with effect sizes 


 
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presented as risk differences and relative risks with 95% 
confidence intervals. Outcomes measured at multiple time 
points will be analyzed using regression based on a generalized 
estimating equations (GEE) approach. 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 0.2 or greater will be interpreted as 
more imbalance than would be expected by chance (Austin 
2009). 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(25):3083–107 
 
 
Statistical Analysis: 
1. Proposed analysis (e.g., student’s ttest, ANOVA, 
chisquare, regression, etc.): 3 two-sample t-tests 
2. Alpha level: 0.05/3 = 0.0167 (Bonferroni correction) 
3. Beta or power level: > 80% (90% for NRS pain, 80% for 
opioid use, 82% for ORSDS) 
4. Primary outcome variable estimate (mean +/s.d. for 
continuous outcome, frequency/percentage for categorical 
variable): 
-Mean ± SD NRS pain with activity (POD1) = 1.9 ± 2.0 (Jules 
2015) 
-Mean ± SD opioid use (cumulative POD0POD3) = 105 ± 92 mg 
OME (Jules 2015) 
-Mean ± SD ORSDS total score (POD 1) = 0.58 ± 0.50 (Jules 
2015) 
5. Number of groups being compared (use 1 for paired 
analysis within the same subjects): 2 
6. Effect size or change expected between groups: 
-NRS pain with activity (POD1): 1.3 points (Todd 1996) 
-Opioid use (cumulative POD0POD3): 53 mg OME (50% 
reduction) 
-ORSDS total score (POD1) = 0.29 (50% reduction) 
 
Resulting number per group: 70 
Total sample size required: 140 + additional 10% to account 
for attrition = 154 


 
Protocol Number:2016-209  
Version Date: 3-28-2016 
 
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Who conducted your sample size calculation? Kara Fields 
 
 
References: 
 
1. JulesElysee 
KM, Goon AK, Westrich GH, Padgett DE, Mayman DJ, Ranawat 
AS, Ranawat CS, Lin Y, Kahn RL, Bhagat DD, Goytizolo 
EA, Ma Y, Reid SC, Curren J, YaDeau JD. PatientControlled 
Epidural Analgesia or Multimodal Pain Regimen with 
Periarticular Injection 
After Total Hip Arthroplasty. J Bone Joint Surg Am, May 2015; 
97 (10): 789798 
2. Todd KH, Funk KG, Funk JP, et al. Clinical significance of 
reported changes in pain severity. Ann Emerg Med 1996; 27(4): 
485–489 
 
 
 


 
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1.0 INTRODUCTION 
 
Over 500,000 total hip arthroplasty (THA) procedures were performed in the United States 
in 2014 [1]. Recent mortality trends associated with opioid use have emphasized the 
desirability of minimizing use of opioids [2]. Pain management after THA remains 
problematic and opioids are frequently employed. For example, after THA, 90 mg oral 
morphine equivalents (OME) was taken over postoperative days (POD) 0-2 despite 
multimodal analgesia including epidural analgesia [3]. This high level of opioid use was 
not regimen specific, as THA patients receiving a periarticular injection in lieu of epidural 
anesthesia used 51% more opioids and experienced higher pain levels [3]. Acetaminophen 
allows for reduced administration of perioperative opioids [4]. Although acetaminophen has 
traditionally been administered orally, an intravenous (IV) preparation has recently become 
available. IV acetaminophen after major orthopedic surgery provides effective analgesia and 
reduces morphine administration by 33%, compared to placebo [5]. When compared to oral 
acetaminophen, IV administration has earlier and greater blood-brain barrier penetration and 
twice the cerebrospinal fluid bioavailability over the first 6 hours [6]. Thus, IV acetaminophen 
could have improved analgesic effects compared to oral. However, it is not clear whether IV 
acetaminophen has clinical benefits, such as reduced pain or opioid usage, over oral 
acetaminophen for THA patients. A recent meta-analysis found IV acetaminophen provided 
no clinical benefit over oral for total joint arthroplasty [7]. In the study protocol, opioids were 
only administered upon patient request, in order to promote minimal use of opioids. We 
hypothesized that IV acetaminophen would reduce 1 or more of the following 3 primary 
outcomes: (1) pain with activity on POD 1; (2) opioid use (cumulative, POD 0  POD 3); and 
(3) opioid-related side effects (POD 1). 
 
Refrences: 
 
[1] Healthcare cost and utilization project. Washington, DC: U.S. Department of Health & Human Services; 2018. 
[2] Collins FS, Koroshetz WJ, Volkow ND. Helping to end addiction over the longterm: the research plan for the NIH HEAL 
initiative. JAMA 2018;320:129e30. 
[3] Jules-Elysee KM, Goon AK, Westrich GH, Padgett DE, Mayman DJ, Ranawat AS, et al. Patient-controlled epidural 
analgesia or multimodal pain regimen with periarticular injection after total hip arthroplasty: a randomized, doubleblind, 
placebo-controlled study. J Bone Joint Surg Am 2015;97:789e98. 
[4] Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine side-effects and consumption after major surgery: 
meta-analysis of randomized controlled trials. Br J Anaesth 2005;94:505e13. 
[5] Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Efficacy and safety of single and 
repeated administration of 1 gram intravenous acetaminophen injection (paracetamol) for pain management after major 
orthopedic surgery. Anesthesiology 2005;102:822e31. 
[6] Singla NK, Parulan C, Samson R, Hutchinson J, Bushnell R, Beja EG, et al. Plasma and cerebrospinal fluid 
pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract 
2012;12:523e32. 
[7] Sun L, Zhu X, Zou J, Li Y, Han W. Comparison of intravenous and oral acetaminophen 
for pain control after total knee and hip arthroplasty: a systematic 
review and meta-analysis. Medicine (Baltimore) 2018;97:e9751. 
 


 
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2.0 PRODUCT DESCRIPTION 
 
Enrolled patients received either IV acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals) 
and an oral placebo or oral acetaminophen and an IV placebo in a randomized, blinded 
fashion. Patients were randomized in a 1:1 ratio in blocks of size 6 and 8 via a computer-
generated randomization schedule (using SAS version 9.4; SAS Institute, Cary, NC) by a 
statistician not otherwise involved in the trial. Pharmacists dispensed the study medication. 
Patients, physicians, and research assistants were blinded throughout the study. 
3.0 OBJECTIVE OF CLINICAL STUDY 
 
 
Pain after total hip arthroplasty (THA) is an active field of investigation at HSS. THA is 
frequently performed at HSS, and patients are often managed with an epidural and 
multimodal analgesia. IV acetaminophen has favorable kinetics compared to oral, and may 
improve pain outcomes. If there is a clinically meaningful benefit to IV acetaminophen then 
IV acetaminophen may be more widely used in THA patients in particular, and among 
orthopedic patients in general. 
4.0 STUDY HYPOTHESES 
 
1. There will be a difference in pain with activity (POD 1) between patients who receive 
IV vs. oral acetaminophen. 
2. There will be a difference in opioid use (cumulative, POD 0 POD 3) between patients 
who receive IV vs. oral acetaminophen. 
3. There will be a difference in opioid side effects between patients who receive IV vs. 
oral acetaminophen. 
5.0 STUDY DESIGN 
 
5.1 
Study Duration 
 
Both groups will start treatment 30 minutes after surgery every six hours for a total of 
three days. 
 
Between February 2017 and May 2018 
5.2 
Endpoints 
 
5.2.1 
Primary Endpoint 
 
Enrolment of 154 patients.  
 


 
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5.2.2 
Safety Evaluations: 
 
If a patient experiences complications, they will be kept at HSS for observation and 
withdrawn from the study. Such complications that would cause safety and toxicity 
concerns include local anesthetic toxicity, cardiac toxicity, and central nervous 
toxicity. 
5.3 
Study Sites 
 
Hospital for Special Surgery 
535 E 70th St, New York, NY 10021 
6.0 STUDY POPULATION 
6.1 
Number of Subjects 
 
154 
 
 
6.2 
Inclusion Criteria 
Subjects of either gender will be included if they: 
 
1. Patient undergoing primary total hip replacement 
2. Patient between the age of 1880 
3. Patient planned for Combined Spinal Epidural anesthesia (CSE) and Patient 
Controlled Epidural Analgesia (PCEA) 
4. Patient who is English speaking 
 
6.3 
Exclusion Criteria 
Subjects will be excluded from the study if they: 
 
1. Non-English speaking patients 
2. Patients receiving periarticular injections 
3. Patients who took opioids preoperatively 
4. Patient with hepatic or renal insufficiency 
5. Patient with hypersensitivity or contraindication to protocol medication 
6. Patient with contraindication for CSE and PCEA 
7. Patient undergoing revision or emergency surgery 
 
 
 
 


 
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6.4 
Randomization 
  
This is a double blinded study; group assignment is concealed from the patients and the 
treating physicians. A computer generated randomization table will be generated by a 
statistician. The table will be used by pharmacy to prepare medications. Patients will be 
randomized to one of two groups: 
Group 1: Postoperative iv acetaminophen 1g q6h / placebo pills q6h for a total of 
three days. 
Group 2: Postoperative po acetaminophen 1g q6h / placebo iv solution q6h for a 
total of three days. 
After entry into the study, the pharmacist will provide to the PACU iv solution for infusion 
containing identical volume of either normal saline or 1g of Acetaminophen. Additionally, 
pills will be provided containing either 1g of Acetaminophen, or placebo. 
7.0 PROCEDURES 
7.1.1 Surgical Procedure 
 
Total Hip Arthroplasty (THA) 


 
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7.1.2 Anesthetic Procedure 
Intraoperative. 
IV sedation with midazolam (up to 5 mg) and propofol only. No opioids, no ketamine. 
Combined spinal epidural anesthesia (CSE) with mepivacaine, 1.5%. Spinal dose: 60 mg. 
Epidural dose or mepivacaine as needed to achieve desired degree of hypotension. 
Intraoperative intravenous medications: 
 
Dexamethasone, 4 mg. 
 
Ondansetron, 4 mg. 
 
Famotidine, 20 mg. 
 
Ketorolac 1530mg (30 mg unless age >70 years or weight <60 kg) 
Postoperative. 
IV / oral analgesics 
 
IV ketorolac 1530mg q 8 hr, for a total of 6 doses (1 dose in OR, 5 doses postop). 
(30 mg unless age >70 years or weight <60 kg) 
 
Then, once ketorolac is finished, meloxicam 7.5 15mg PO for POD2,3. (15 mg 
unless age >70 years or weight <60 kg 
PRN analgesics: 
 
Tramadol 50 mg PO q 6 hr prn mild pain 
 
Tramadol 100 mg PO q 6 hr prn moderate pain 
 
Oxycodone 5 mg PO q 3 hr prn severe pain 
(at patient request, can proceed to oxycodone 5/10/15 mg if tramadol is viewed as 
ineffective). 
 
 


 
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7.1.3 Investigational Product Application 
 
 
Group 1: Postoperative iv acetaminophen 15min infusion of 1g (100ml vial) 
every 6 hours starting 30min after surgery for a total of three days (or until 
discharge, if discharged prior to 3 full days). Patients in this group will receive 
placebo pills every 6 hours starting 30min after surgery for a total of three 
days. 
 
 
Group 2: Postoperative po acetaminophen 1g every 6 hours starting 30min 
after surgery for a total of three days (or until discharge, if discharged prior to 
3 full days). Patients in this group will receive a 15min placebo iv infusion 
(100ml normal saline) every 6 hours starting 30min after surgery for a total of 
three days. 
7.2 
Medical Record Requirements 
 
Patient undergoing primary total hip replacement 
 
Patient between the age of 18-80 
 
Patient planned for Combined Spinal Epidural anesthesia (CSE) and Patient 
Controlled Epidural Analgesia (PCEA) 
 
Patient who is English speaking 
7.3 
Data Collection 
 
The following data will be collected: 
 
Pre-operative/Baseline 
 
basic demographic data 
 
patient weight & height, BMI 
 
Confusion assessment Method (CAM) 
 
Surgical procedure 
 
date of surgery 
 
type of surgery 
 


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7.4 
Schedule of Assessments 
 
 
Procedures 
Pre-Op 
POD 0 
POD 1 
POD 2 
POD 3 
POD 14 
Discharge 
Name  
X 
 
 
 
 
 
 
DOB 
X 
 
 
 
 
 
 
Gender 
X 
 
 
 
 
 
 
Race 
X 
 
 
 
 
 
 
NRS Pain Scores at Rest (Morning) 
 
 
X 
X 
 
 
 
Pain NRS (0-10) at Rest 
 
X 
X 
X 
X 
X 
 
Pain NRS with PT 
 
X 
X 
X 
X 
 
 
CAM 
X 
 
X 
 
 
 
 
Opioid Dose 
 
X 
X 
X 
X 
 
 
ORSDS 
 
 
X 
X 
X 
 
 
Satisfaction (0-10) 
 
 
X 
X 
X 
 
 
Range of Motion (ROM) 
 
 
 
 
 
X 
 
Discharge Time 
 
 
 
 
 
 
X 


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8.0 STATISTICAL ANALYSIS 
 
1. Proposed analysis (e.g., student’s ttest, ANOVA, chisquare, regression, etc.): 3 two-
sample t-tests 
2. Alpha level: 0.05/3 = 0.0167 (Bonferroni correction) 
3. Beta or power level: > 80% (90% for NRS pain, 80% for opioid use, 82% for ORSDS) 
4. Primary outcome variable estimate (mean +/s.d. for continuous outcome, 
frequency/percentage for categorical variable): 
-Mean ± SD NRS pain with activity (POD1) = 1.9 ± 2.0 (Jules 2015) 
-Mean ± SD opioid use (cumulative POD0POD3) = 105 ± 92 mg OME (Jules 2015) 
-Mean ± SD ORSDS total score (POD 1) = 0.58 ± 0.50 (Jules 2015) 
5. Number of groups being compared (use 1 for paired analysis within the same 
subjects): 2 
6. Effect size or change expected between groups: 
-NRS pain with activity (POD1): 1.3 points (Todd 1996) 
-Opioid use (cumulative POD0POD3): 53 mg OME (50% reduction) 
-ORSDS total score (POD1) = 0.29 (50% reduction) 
 
Resulting number per group: 70 
Total sample size required: 140 + additional 10% to account for attrition = 154 
 
 
Who conducted your sample size calculation? Kara Fields 
 
 
References: 
 
1. JulesElysee 
KM, Goon AK, Westrich GH, Padgett DE, Mayman DJ, Ranawat AS, Ranawat CS, Lin Y, Kahn RL, Bhagat DD, Goytizolo 
EA, Ma Y, Reid SC, Curren J, YaDeau JD. PatientControlled Epidural Analgesia or Multimodal Pain Regimen with Periarticular 
Injection After Total Hip Arthroplasty. J Bone Joint Surg Am, May 2015; 97 (10): 789798 
2. Todd KH, Funk KG, Funk JP, et al. Clinical significance of reported changes in pain severity. Ann Emerg Med 1996; 27(4): 
485–489 
 
9.0 ADVERSE EVENT ASSESSMENT 
All Adverse Events (AEs) will be reported in the final study report. Definitions for Adverse 
Event (AE) used in this study are listed below and are based on FDA and international 
guidelines: 
 
 


 
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9.1 
Adverse Event (AE) 
 
Any untoward or unfavorable medical occurrence in a human study participant, including 
any abnormal sign (e.g. abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the participants’ involvement in the research, whether or 
not considered related to participation in the research. 
 
9.2 
Serious Adverse Events (SAE) 
Any adverse event that: 
 
Results in death  
 
Is life threatening, or places the participant at immediate risk of death from the event 
as it occurred  
 
Requires or prolongs hospitalization  
 
Causes persistent or significant disability or incapacity  
 
Results in congenital anomalies or birth defects  
 
Is another condition which investigators judge to represent significant hazards 
 
9.3 
Adverse Event Reporting  
All AEs are collected on an Adverse Event Form, either in paper or electronic format. All AEs 
experienced by the participant during the time frame specified in the protocol (e.g., from the 
start of intervention through the end of the study) are to be reported, as outlined in the 
protocol. The reporting requirements to the IRB, to the NIA and to the FDA (in case of drug 
and device studies) may differ and must be complied with. Please note that the AE form 
contains a column to indicate whether the event is SERIOUS. Thus, SAEs are a subset of 
the reported AEs. Routine reporting of AEs is described in the DSMP and may be monthly 
or quarterly as determined with the NIA staff and /or the DSMB/Safety Officer. 
10.0 INVESTIGATOR RESPONSIBILITIES, RECORD AND REPORTS 
 
Data will be collected by an investigator or research assistant. Sources of data include medical 
records and patient physical assessments/interviews conducted by study personnel. Data will 
be recorded and managed using REDCap electronic data capture tools hosted at the Clinical 
and Translational Science Center (CTSC) at Weill Cornell Medical College. REDCap 
(Research Electronic Data Capture) is a secure, web-based application designed to support 
data capture for research studies, providing: 1) an intuitive interface for validated data entry; 
2) audit trails for tracking data manipulation and export procedures; 3) automated export 
procedures for seamless data downloads to common statistical packages; and 4) procedures 
for importing data from external sources. Connection to REDCap occurs via the hospital’s 
encrypted cable and wireless networks, and data will be entered through a password 
protected computer terminal or iPad. 
 


 
Protocol Number:2016-209  
Version Date: 3-28-2016 
 
Confidential 
 
 
10.1 Subject Consent and Information 
 
Any information collected electronically will be stored on the REDCap server. The REDCap 
server and data are hosted by Weill Cornell Medical College CTSC, with the servers physically 
located in the Payson building of Weill Cornell New York Presbyterian Hospital. Access 
to this space is limited to members of the Hospital’s informatics department. Electronically, 
several intrusion protection mechanisms, including firewalls and encryption, are in place to 
protect the server and its data. Any paper based data sheets utilized for the study will be 
stripped of all personal identifiers whenever possible and stored the department’s locked 
office. 
 
All patients will be identified by a specific study number. Any patient information taken from 
medical records will be kept strictly confidential. Only the previously mentioned investigators 
will have access to this information. Thus our research presents a minimal risk of harm to 
subjects’ privacy. 
10.2 Subject Data Protection 
 
Informatics staff in the Weill Cornell Medical College CTSC will have access to the REDCap 
server as needed for administrative purposes. HSS IRB members, upon request, may also 
review study records and/or data. Data will be released to Mallinckrodt Pharmaceuticals (the 
study sponsor) and the project’s statistician, at designated intervals, including interim 
analysis (if appropriate) and at end of study. Any identifiers not essential for data analysis 
will be removed from the data set, which will be sent to the statistician as a password 
protected, encrypted file. After data analysis, the study data set will be stored as an Excel or 
SPSS file. A unique feature of REDCap is that data fields marked as protected health 
information (PHI) can be automatically de-identified when data is exported. We will utilize 
this option when closing out the study after data analysis, so that no identifiers remain in the 
stored Excel or SPSS data set. In the REDCap program, the study will be changed from 
production mode to archive mode. This means the data and study forms will no longer be 
accessible to REDCap users. Only the research assistant and research manager will have 
rights to unarchive the study. The study will be maintained in REDCap for the period of time 
required by hospital/federal regulations, at which point it will be deleted. 
 
Access to the REDCap program is password protected, and access to a specific 
study’s information within the program is limited to the research assistant and other IRB 
approved study personnel who have been given permission to view and/or enter study data. 
REDCap program access is authorized by the CTSC; particular study access is granted by 
the research assistant. For data exports, fields marked as protected health information (PHI) 
in REDCap will be de-identified, if feasible. All transmission of data will occur via encrypted 
networks and in password protected files. Any paper based data sheets utilized for the study 
will have personal identifiers removed whenever possible and will be stored in the 
department’s locked office. Each subject will be assigned a unique study number for 
identification, and that number will not be derived from or related to information about the 


 
Protocol Number:2016-209  
Version Date: 3-28-2016 
 
Confidential 
 
 
individual. Presentations and publications that result from this study will not contain any 
individual identifiers other than unique study numbers. 
10.3 Staff Information 
PI: Geoffrey Westrich, MD 
 
Co Investigators: 
(First Name, Middle Name, Last Name, Title) 
 
 
Jacques YaDeau, MD, PhD ,IRB Vice Chair 
 
Philippe Ortiz 
 
Kara Fields, Volunteer 
 
Denesy Mancenido, Assistant Director, Research 
 
Phuong Dinh Mac 
 
 
 


 
Protocol Number:2016-209  
Version Date: 3-28-2016 
 
Confidential 
 
 
APPENDIX A: CASE REPORT FORMS