Clinical trial NCT02647788
Conditions: Pain, Postoperative
Keywords: Pain, Postoperative
Sponsor: University of Pennsylvania
Start date: 2015-12-01; Completion date: 2018-01-19
Enrollment: 144 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to find out if taking Acetaminophen with Ibuprofen (e.g. Tylenol + Advil), a non-opioid regimen, provides the same type of pain relief after hand surgery compared to Acetaminophen and codeine (e.g. Tylenol 3), an opioid regimen.

Detailed description:
Primary Objective:

To establish, through a randomized control trial, whether post-operative Acetaminophen and Ibuprofen (non-opioid regimen) would provide equivalent post-operative analgesia to ambulatory hand surgery patients compared to Acetaminophen and Codeine (opioid regimen).

Secondary Objective:

To establish whether the opioid versus non-opioid post-operative pain regimen influences patient satisfaction.

Sixty-three patients enrolled for each group (non-opioid and opioid). Approximately 145 patients will be required to achieve complete data for 63 patients in each group (assuming 15% lost to follow-up \& failure to comply with study protocol).

Arms: arm 1: Group 1: Acetaminophen 650 mg; Ibuprofen 400 mg arm 2: Group 2: Acetaminophen 300mg, Codeine 30 mg
Interventions: intervention 1: Acetaminophen/Ibuprofen intervention 2: Acetaminophen/Codeine
Intervention descriptions: intervention 1: After hand surgery, take Acetaminophen 650 mg/Ibuprofen 400 mg every 6 hours as needed for pain until postoperative clinic visit intervention 2: After hand surgery, take Acetaminophen 300mg/Codeine 30 mg every 6 hours as needed for pain until postoperative clinic visit

Protocol documents:
Prot_SAP_000.pdf: 
  
 
 
Pilot study, blinded randomized control trial, single center study to compare 
Acetaminophen & Codeine versus Ibuprofen/Acetaminophen for pain control and 
patient satisfaction after ambulatory hand surgery 
  
 
Principal Investigator (1) 
David Steinberg, MD.  
Assistant Professor of Orthopedic Surgery, University of 
Pennsylvania School of Medicine 
Director of Hand and Microsurgery Fellowship, University of 
Pennsylvania School of Medicine 
Attending Orthopedic Surgeon at Hospital of the University of 
Pennsylvania, Children’s Hospital of Philadelphia, Presbyterian 
Medical Center, Pennsylvania Hospital, and Philadelphia 
Veteran’s Affairs Medical Center 
3737 Market Street, 6th floor Orthopedic Department, Philadelphia, 
PA, 19104 
P: 215-662-3344; F: 215-614-0620; 
david.steinberg@uphs.upenn.edu 
 
Investigator (2) 
 
Stephanie Thibaudeau, MD. CM. 
Orthopedic Surgery, Hand Surgery Fellow 
3737 Market Street, 6th floor Orthopedic Department, Philadelphia, 
PA, 19104 
267-324-7480 
stephanie.thibaudeau@uphs.upenn.edu 
Funding Sponsor:  
Penn Presbyterian Medical Center Bach Fund Award 
Sami Khella 
Chair of Bach Fund Committee 
3642 Market St 
Philadelphia, PA 19104-2682  
Grant Number                             
 
Penn Presbyterian Medical Center Bach Fund Award 
 
Protocol Number: 
 
IRB Number: 
Penn-Hand 1.0 
823043  
ClinicalTrials.gov Number        
NCT02647788 
 
    Version 
  
 
         1.7, 03-04-2016 
 
 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
Table of Contents 
 
Contents 
LIST OF ABBREVIATIONS.......................................................................................................................... V 
STUDY SUMMARY ...................................................................................................................................... 1 
BACKGROUND AND STUDY RATIONALE ................................................................................................ 4 
INTRODUCTION ............................................................................................................................................ 4 
1.1 
BACKGROUND AND RELEVANT LITERATURE ..................................................................................... 4 
2 
STUDY OBJECTIVES ......................................................................................................................... 4 
2.1 
PRIMARY OBJECTIVE: ..................................................................................................................... 5 
2.2 
SECONDARY OBJECTIVES: .............................................................................................................. 5 
3 
INVESTIGATIONAL PLAN .................................................................................................................. 5 
3.1 
GENERAL DESIGN .......................................................................................................................... 5 
3.1.1 
Screening Phase ..................................................................................................................... 6 
3.1.2 
Study Intervention Phase ........................................................................................................ 6 
3.1.3 
Follow Up Phase ..................................................................................................................... 6 
3.1.4 
Allocation to Interventional Group ........................................................................................... 7 
3.2 
STUDY ENDPOINTS......................................................................................................................... 7 
3.2.1 
Primary Study Endpoints ......................................................................................................... 7 
3.2.2 
Secondary Study Endpoints .................................................................................................... 7 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ........................................................ 7 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 7 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 7 
4.3 
SUBJECT RECRUITMENT ................................................................................................................. 7 
4.4 
DURATION OF STUDY PARTICIPATION .............................................................................................. 8 
4.5 
TOTAL NUMBER OF SUBJECTS AND SITES........................................................................................ 8 
4.6 
VULNERABLE POPULATIONS: NONE ...................................................................................................... 8 
5 
STUDY INTERVENTION (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE, FOOD ETC.) ............... 8 
5.1 
DESCRIPTION ................................................................................................................................. 8 
5.2 
INTERVENTION REGIMEN ................................................................................................................ 8 
5.3 
SUBJECT COMPLIANCE MONITORING ............................................................................................... 9 
5.3.1 
Return or Destruction of Investigational Product ..................................................................... 9 
6 
STUDY PROCEDURES ....................................................................................................................... 9 
6.1 
SCREENING ................................................................................................................................... 9 
6.2 
STUDY INTERVENTION PHASE ....................................................................................................... 10 
6.2.1 
Visit 1 (operative day) ............................................................................................................ 10 
6.2.2 
Follow Up ............................................................................................................................... 10 
6.2.3 
End of Study Visit .................................................................................................................. 10 
6.3 
UNSCHEDULED VISITS .................................................................................................................. 10 
6.4 
SUBJECT WITHDRAWAL/EARLY TERMINATION VISITS ..................................................................... 10 
6.4.1 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 10 
6.5 
MEDICAL RECORD REVIEW ........................................................................................................... 10 
6.6 
PHYSICAL EXAMINATION ............................................................................................................... 11 
6.7 
VITAL SIGNS: N/A ........................................................................................................................ 11 
6.8 
LABORATORY EVALUATIONS ......................................................................................................... 11 
6.9 
PREGNANCY TESTING .................................................................................................................. 11 
6.10 
OTHER EVALUATIONS, MEASURES ................................................................................................ 11 
7 
STATISTICAL PLAN ......................................................................................................................... 11 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
ALL ANALYSES COMPARING THE TREATMENT GROUPS WERE CONDUCTED ON AN 
INTENTION-TO-TREAT BASIS. TWO-TAILED TESTS WERE USED AT ALL TIMES, AND 
STATISTICAL SIGNIFICANCE WAS SET A PRIORI AT P<0.05. ............................................................ 11 
7.1 
PRIMARY ENDPOINT ..................................................................................................................... 11 
THE PRIMARY END POINT OF THIS STUDY IS PAIN INTENSITY, MEASURED WITH A 100-MM VAS (WITH 0 MM BEING 
NO PAIN AND 100 MM BEING MAXIMUM PAIN), AND ANALYZED AS DAILY MEAN SCORES.  IN PATIENTS THAT WILL 
HAVE FORGOTTEN TO COMPLETE THE VAS SCORES 4 TIMES DAILY, THE MISSING VALUES WILL BE COMPLETED WITH 
THE LAST RECORDED SCORE. ....................................................................................................................... 11 
7.2 
SECONDARY ENDPOINTS .............................................................................................................. 11 
7.3 
SAMPLE SIZE AND POWER DETERMINATION ................................................................................... 11 
7.4 
STATISTICAL METHODS ................................................................................................................ 11 
7.4.1 
Baseline Data ........................................................................................................................ 11 
7.5 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 12 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 12 
8.1 
DEFINITIONS ................................................................................................................................ 12 
8.1.1 Adverse Event ........................................................................................................................... 12 
8.1.2 
Serious Adverse Event .......................................................................................................... 12 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 12 
8.3 
RELATIONSHIP OF AE TO STUDY ................................................................................................... 12 
8.4 
REPORTING OF ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ............................................... 12 
8.2 
UNBLINDING PROCEDURES ........................................................................................................... 13 
8.3 
MEDICAL MONITORING ................................................................................................................. 13 
9 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING .................................... 13 
9.1 
CONFIDENTIALITY ......................................................................................................................... 13 
9.2 
DATA COLLECTION AND MANAGEMENT .......................................................................................... 13 
THE DEPARTMENT OF ORTHOPAEDICS HAS TWO STANDARD METHODS TO CAPTURE ELECTRONIC DATA: THESE ARE 
REDCAP AND SECURE DEPARTMENTAL SHARED DRIVES ON THE UPHS SERVERS BEHIND THE UPHS FIREWALLS. 
WE ALSO ROUTINELY CODE FILES BY ASSIGNING SUBJECT STUDY ID NUMBERS. ................................................ 13 
DATA WILL ONLY BE ACCESSED BY INVESTIGATORS IDENTIFIED ON THE IRB.  DATA WILL BE STORED FOR AT LEAST 
7 YEARS AFTER THE STUDY ENDS. ................................................................................................................ 13 
9.3 
RECORDS RETENTION .................................................................................................................. 13 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 13 
10.1 
AUDITING AND INSPECTING ........................................................................................................... 13 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 13 
11.1 
RISKS .......................................................................................................................................... 14 
11.2 
BENEFITS .................................................................................................................................... 14 
11.3 
RISK BENEFIT ASSESSMENT ......................................................................................................... 14 
11.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION .............................................................. 14 
PATIENTS WILL BE ADULTS CAPABLE OF PROVIDING INFORMED CONSENT FOR THEMSELVES. PATIENTS WILL BE 
IDENTIFIED FROM ROUTINE CLINICAL ENCOUNTERS AND WILL BE INVITED TO PARTICIPATE IN THE STUDY BY A 
MEMBER OF THE STUDY TEAM. THE PATIENT WILL BE PROVIDED THE INFORMED CONSENT FORM (ICF) AND THE 
STUDY TEAM MEMBER WILL DESCRIBE THE STUDY. THE PATIENT WILL ALSO BE GIVEN AN OPPORTUNITY TO READ 
THE ICF AND TO ASK QUESTIONS ABOUT THE STUDY. WE WILL LET PATIENTS KNOW THAT THEY ARE ABLE TO 
WITHDRAW FROM THE STUDY AT ANY TIME. WRITTEN CONSENT WILL BE OBTAINED FROM THE PATIENT AT THE 
TIME OF CLINICAL ENCOUNTER FOR SURGICAL SCHEDULING. .......................................................................... 14 
12 
STUDY FINANCES ............................................................................................................................ 14 
12.1 
FUNDING SOURCE ........................................................................................................................ 14 
12.2 
CONFLICT OF INTEREST ................................................................................................................ 14 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 14 
13 
PUBLICATION PLAN ........................................................................................................................ 14 
14 
REFERENCES ................................................................................................................................... 14 
 
 
 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
 
 
 
 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
 
List of Abbreviations 
 
AE: Adverse event 
OTC: Over the counter 
T3: Tylenol-3 
VAS: Visual Analogue Scale 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
Study Summary 
Title 
Blinded Randomized Control Trial 
Optimizing Post-Operative Pain Control in Ambulatory Hand Surgery: 
 Acetaminophen & Codeine versus Ibuprofen/Acetaminophen  
 
Short Title 
Acetaminophen & Codeine versus Ibuprofen/Acetaminophen in Ambulatory 
Hand Surgery 
 
IRB Number 
823043  
Protocol Number 
Penn-Hand 1.0 
Phase 
Pilot Study 
Methodology 
Double blinded randomized control trial 
Study Duration 
12 months  
Study Center(s) 
University of Pennsylvania Hospital System 
Objectives 
Primary: 
To establish, through a randomized control trial, whether post-operative 
Acetaminophen and Ibuprofen (non-opioid regimen) would provide equivalent post-
operative analgesia to ambulatory hand surgery patients compared to Acetaminophen 
and Codeine (opioid regimen). 
Primary Outcome variable: VAS pain score 
Secondary: 
To establish whether the opioid versus non-opioid post-operative pain regimen 
influences patient satisfaction. 
Secondary outcome variables: Quality of Recovery (QoR) scores; Rate of side effects; 
Rate of medication discontinuation 
Number of Subjects 
Sixty-three patients enrolled for each group (non-opioid and opioid). Approximately 
145 patients will be required to achieve complete data for 63 patients in each group 
(assuming 15% lost to follow-up & failure to comply with study protocol). 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
Main Inclusion and 
Exclusion Criteria 
Inclusion criteria: Patients > 18 years old, undergoing ambulatory hand surgery for 
carpal tunnel and trigger finger, under local anesthesia +/- sedation. 
Exclusion criteria: ASA> 3; coagulopathy; renal disease, liver disease, history of 
recent gastro-intestinal bleeding, peptic ulcer disease, congestive heart failure, 
previous stroke, pregnancy. Patients with a diagnosis of chronic pain currently taking 
opioid pain medication or with a history of drug abuse. Patients with a self-described 
allergy to ASA, acetaminophen, NSAIDS and codeine. All patients receiving a 
brachial plexus block for anesthesia and/or analgesia will be excluded. 
 
Investigational 
Product (drug, 
biologic, device, etc.) 
For Device include 
the planned use 
For Drug, food, 
cosmetic, etc. 
include the dose, 
route of 
administration and 
dose regiment 
This is a non-superiority trial to compare two over the counter drug medications 
(OTCs) on post-operative pain control in ambulatory hand surgery: 
Group 1: Acetaminophen 650 mg;  Ibuprofen 400 mg  
Group 2: Acetaminophen and codeine (acetaminophen 300mg, codeine 30 mg) 
Route: oral tablets 
Frequency: Every 6 hours as needed for pain (4 times daily) 
All of the medications are administered according to their drug monographs. 
Duration of 
administration  
Thirty tablets of analgesic medication will be provided to the patient 
Reference therapy 
In this non-superiority randomized trial, the medications (acetaminophen, ibuprofen 
and acetaminophen/codeine) and the doses in this randomized control trial are 
currently prescribed by physicians at the University of Pennsylvania Health Services 
Orthopedics Department as standard of care and will be used according to drug 
monographs and FDA regulations. 
Statistical 
Methodology 
All analyses comparing the treatment groups will be conducted on an intention-to-treat 
basis for patients that will have taken at least one dose. Statistical significance set a 
priori at P<0.05.  
Safety Evaluations  
Potential psychological and physical risks to the study participants are minimal as we 
are not altering standard of care. Acetaminophen, ibuprofen and codeine have well 
described pharmacokinetics and minimal side effect profile in appropriately selected 
patients (refer to inclusion/exclusion criteria)16.  
If the patient experiences self-described pain that is poorly controlled or an adverse 
event, their physician or treatment team will evaluate the patient as deemed 
appropriated and prescribe alternative medications if necessary.  
Contact information will be provided to all study participants to ask questions at any 
time during the study. 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
Data and Safety 
Monitoring Plan  
Data will be collected using the Research Electronic Database Capture (RedCap), a de-
identified database.  
 
 
 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
BACKGROUND AND STUDY RATIONALE 
This study will be conducted in full accordance all applicable University of Pennsylvania Research Policies and 
Procedures and all applicable Federal and state laws and regulations. 
Introduction 
1.1 
Background and Relevant Literature  
 
Prescription drug overdose has become a serious public health issue and with exploding associated health care costs7 8. This 
opioid epidemic is not an isolated problem as underlined by a 2013 report by Trust for America’s Health in which Philadelphia 
was ranked as 14th nationwide for drug overdose related deaths.  
Ninety-nine percent of carpal tunnel surgery and other hand soft tissue releases such as trigger finger, are performed in the 
ambulatory setting 9,10. Post-operative pain prescriptions vary widely across hand surgeons in North America. In one study, 
Canadian hand surgeons prescribed opioids to 5% of their ambulatory hand surgery patients whereas physicians in the United 
States prescribed opioids for 66% of their patients for similar surgeries11. Studies have investigated the role of post-operative 
non-steroidal anti-inflammatory (NSAIDS) in post-operative pain control for outpatient general surgery2,3. Given that there is no 
gold standard regimen for post-operative pain control after ambulatory hand surgery and considering the current opioid epidemic 
in the United States, it would be of utmost importance to establish whether a non-opioid pain regimen would provide equivalent 
post-operative analgesia to hand surgery patients. Our long term goal is to decrease opioid drug diversion while maintaining 
adequate pain relief and patient satisfaction. 
Patient satisfaction has become an increasingly important metric in healthcare quality and importantly in healthcare payment 
policies12. In fact the Centers for Medicare & Medicaid Services (CMS) incorporated patient satisfaction in part of their value 
based incentive payments since 201213. Quality of Recovery has been linked to patient satisfaction after anesthesia and surgery6. 
Determining if the post-operative pain regimen has an influence on the Quality of Recovery Score is of prime importance in the 
consumer model of health care.  
 
2 
Study Objectives 
 
The purpose of our study is to conduct a randomized control trial to determine whether a non-opioid based pain regimen is 
equivalent to an opioid analgesic to control post-operative pain after ambulatory hand surgery (Aim 1). At the UPHS 
Orthopedics Department, approximately 600 cases of carpal tunnel and trigger finger releases are performed yearly. These 
patients commonly receive a Tylenol 3 script (acetaminophen 300mg, codeine 30 mg). If the script is placed electronically, the 
system automatically reverts it to the generic equivalent.  If the patient self-describes a previous adverse events to Tylenol 3 
(T3), the script is commonly substituted for oxycodone-acetaminophen (5mg-325mg). Drug diversion and the opioid epidemic in 
the United States is a public health concern and surgeons have the obligation to responsibly prescribe opioids for post-operative 
analgesia. Our ambulatory hand surgery patient population represents a unique opportunity for hand surgeons at UPHS to 
optimize post-operative pain prescription habits and study its impact on patient satisfaction. Our long term goal is to optimize 
post-operative prescription practices at our institution and in hand surgery nationwide, while maintaining patient satisfaction 
(Aim 2) and ultimately decrease drug diversion potential.  
 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
2.1 
Primary Objective: 
 
To establish, through a randomized control trial, whether post-operative Acetaminophen and Ibuprofen (non-opioid regimen) 
would provide equivalent post-operative analgesia to ambulatory hand surgery patients compared to Acetaminophen and 
Codeine (opioid regimen). 
Rationale: In the setting of ambulatory hand surgery, many of the opioid pain scripts are not utilized. In a telephone survey of 
patients undergoing ambulatory hand surgery, 52% of patients reported taking their prescribed analgesics for 2 days or less1. 
Ninety-nine percent of these patients received a 30-tablet script for narcotics, leaving the left-over narcotics available for 
diversion. Studies have investigated the role of post-operative non-steroidal anti-inflammatory (NSAIDS) in post-operative pain 
control for outpatient surgery23,4, though never as a randomized control trial in hand surgery.  
Hypothesis: A non-opioid post-operative regimen of ibuprofen and acetaminophen is equally effective with less side effects as 
Acetaminophen and codeine for pain relief in the context of ambulatory hand surgery. 
Primary Outcome Variable: Visual Analogue Scale Pain Score 
2.2 
Secondary Objectives: 
 
To establish whether the opioid versus non-opioid post-operative pain regimen influences patient satisfaction through Quality of 
Recovery (QoR) scores in ambulatory hand surgery.  
Rational: Quality of Recovery score is a validated health measure based on the answers of a 9-item questionnaire administered to 
patients after anesthesia5. The Quality of Recovery score has been shown to correlate with patient satisfaction post-operatively6.  
Hypothesis: A non-opioid post-operative regimen will have equivalent Quality of Recovery scores to an opioid post-operative 
pain regimen.  
Secondary Outcome Variables: Adverse events, duration of medication intake, reason for medication discontinuation, patient 
satisfaction as determined by the Quality of Recovery-9 (QoR-9). 
3 
Investigational Plan  
3.1 
General Design 
 
Small scale, pilot, blinded randomized non-superiority control trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
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3.1.1 
Screening Phase 
Patients will be screened through the clinical practices of Penn Orthopaedics. Scheduled clinic encounters are documented in EPIC. 
Chief complaint or reason for visit is typically captured which will be the primary source of identifying possible patients. Once it is 
determined either through EPIC or in the course of the clinical encounter that a patient is presenting with carpal tunnel syndrome or 
trigger fingers they will be evaluated for eligibility by for this study by the study team. 
3.1.2 
Study Intervention Phase  
Patients who meet the inclusion criteria will be randomized into one of two post-operative analgesia treatment groups: an opioid 
treatment group versus anti-inflammatory and acetaminophen (400mg/650mg) treatment group. Patients in one group will receive 
either 650 mg of acetaminophen and 400 mg of ibuprofen per dose. Patients in group two will receive 300mg of acetaminophen and 
30 mg of codeine (T3 equivalent) per dose. The active medications will be encapsulated into identical capsules containing half of the 
full dose (2 capsules = 1 dose). The capsules will then be dispensed in identical bottles. The first dose will be administered in the post-
anesthesia care unit (PACU). The visual analogue scale (VAS) is simple and commonly used in the clinical setting to measure pain 
severity14,15. The patients will complete a post-operative pain diary. The entries will consist of a VAS, time of medication intake 
and side effects (nausea, vomiting, constipation, dizziness, other). Date and reasons for medication discontinuation (pain free 
versus adverse effect) will also be recorded. The first entry will be recorded pre-operatively to ensure comprehension of the 
VAS as well as to obtain baseline pain score. The second entry will be in the recovery room. The patients will complete four 
entries daily which corresponds to allowed intake of pain medication over a period of 5 days. Patient will return the diary on the first 
post-operative visit (ranging from 6 to 8 days post-operatively). All patients will be called on post-operative day 2 in order to complete 
the Quality of Recovery Questionnaire. The 9-item questionnaire will be administered via a telephone interview by a clinical assistant 
who is blinded to the treatment arm.  
  
3.1.3 
Follow Up Phase 
 
Outpatient 
Clinic 
Appointmen
t 
Patient 
booked for 
carpal tunnel 
or trigger 
finger release 
Patient meets 
inclusion 
criteria 
Introduced to 
protocol 
Consent 
signed 
Surgery 
Patient 
Randomized 
to 
 Treatment 
Group 
Post-op d2:  
Telephone 
reminder: 
pain diary; 
QOR-9 
Post-op d6:  
Telephone 
reminder: 
bring pain 
diary to clinic 
Post-op d7:  
1st post-
operative 
follow-up 
Data entry 
completed 
Post-op day 0 to day 6 
Patient completes pain diary 4x daily 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
Patients will return to hand clinic per their usual post-operative visit schedule. Their first visit generally ranges from 6 to 8 days after 
their surgery. At this visit the patient will return the diary and remaining medication. This will conclude the patient’s participation in 
the study.  
3.1.4 
Allocation to Interventional Group  
Stratified block randomization using tables of random numbers, stratified according to hand surgery type (carpal tunnel, trigger finger) 
will be used to ensure equivalent numbers of patients in each treatment group for each of the 2 procedures. Patients will be 
randomized in blocks of 4. Randomization will be performed by the Investigational Drug Service (IDS) using computer-generated 
tables.  The treatment allocation will be concealed from the study investigators, physicians, nurses, patients, and statistician. 
Allocation assignments will be held securely in the IDS until all primary analyses are performed; this code will be broken for 
subgroup and post hoc analyses. Patients who meet the inclusion criteria will be randomized into one of two post-operative analgesia 
treatment groups: an opioid treatment group versus anti-inflammatory and acetaminophen (400mg/650mg) treatment group. Patients 
in one group will receive either 650 mg of acetaminophen and 400 mg of ibuprofen per dose. Patients in group two will receive 300mg 
of acetaminophen and 30 mg of codeine (T3 equivalent) per dose. The active medications will be encapsulated into identical capsules 
containing half of the full dose (2 capsules = 1 dose). The capsules will then be dispensed in identical bottles. In this manner, both 
patients and investigators are blinded. 
3.2 
Study Endpoints  
3.2.1 
Primary Study Endpoints 
Ten millimeter Pain Visual Analogue Scale.  
 
We chose a threshold of 5 mm difference in VAS score to ensure that even a smaller efficacy difference could be identified 
statistically. 
 
3.2.2 
Secondary Study Endpoints 
Adverse events, duration of medication intake, reason for medication discontinuation, patient satisfaction as determined by the Quality 
of Recovery-9 (QoR-9). 
4 
Study Population and Duration of Participation  
4.1 
Inclusion Criteria 
Patients > 18 years old, undergoing ambulatory hand surgery for carpal tunnel and trigger finger, under local anesthesia with or 
without sedation. 
4.2 
Exclusion Criteria 
ASA> 3; coagulopathy; renal disease, liver disease, history of recent gastro-intestinal bleeding, pregnancy. Patients with a diagnosis of 
chronic pain currently taking opioid pain medication or with a history of drug abuse. Patients with a self-described allergy to ASA, 
acetaminophen, NSAIDS and codeine. Finally all patients receiving a brachial plexus block for anesthesia and/or analgesia will be 
excluded.  
4.3 
Subject Recruitment  
Subjects will be recruited from the investigators clinical practices. If the patient meet the inclusion criteria, they will be approach by 
the physicians. Should they show interest in the study, a member of the clinical research team will review the study, consent and 
answer any additional questions regarding the protocol. 
 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
4.4 
Duration of Study Participation 
Enrollment Timeline: With an average of 10 operations for trigger finger or carpal tunnel per week, we estimate that with a voluntary 
participation rate of 50%, the enrollment of patients should be complete within 8 months.  
 
Subject Participation: Individual subjects will participate in the study from the day of their surgery to their first post-operative visit 
(generally 6 to 8 days after their surgery).  
4.5 
Total Number of Subjects and Sites  
 
Site: Penn Presbytarian Medical Center 
 
Sample size: 63 per group. Assuming a 15% lost to follow-up and failure to comply with study protocol, 145 patients will be required 
to achieve complete data for 63 patients in each group.  
4.6 
Vulnerable Populations: none 
5 
Study Intervention  
 
Group 1: Acetaminophen 650 mg; Ibuprofen 400 mg  
Group 2: Acetaminophen 300mg, Codeine 30 mg 
5.1 
Description 
 
Acetaminophen 
 
Please refer to full monograph:  Acetaminophen Entire Monograph - Epocrates Online. 
https://online.epocrates.com/u/10a307/acetaminophen. 2015. Accessed 6/28/2015 
 
Ibuprofen 
 
Please refer to full monograph: Ibuprofen Entire Monograph - Epocrates Online. https://online.epocrates.com/u/10a234/ibuprofen. 
2015. Accessed 6/28/2015 
 
Acetaminophen and Codeine Phosphate Tablets: combined analgesic effect of a centrally acting analgesic, codeine, with a peripherally 
acting analgesic, acetaminophen. 
 
Please refer to the following FDA reference: 
 
Food and Drug Administration. http://www.accessdata.fda.gov/spl/data/f1762dc1-b238-47bb-b5ab-33c0156724c5/f1762dc1-b238-
47bb-b5ab-33c0156724c5.xml. 5/2011. Accessed 6/28/2015.  
5.2 
Intervention Regimen 
 
Dose: Acetaminophen 650 mg; Ibuprofen 400 mg; Codeine 30 mg 
Route: blinded opaque oral capsules 
Frequency: 1st dose given in PACU on day of surgery; every 6 hours as needed for pain (4 times daily) 
Duration: Total of 30 capsules will be distributed to the subjects  
 
5.3 
Receipt  
For each subject, IDS would prepare 30 blinded capsules (containing either APAP 300/Codeine 30, or APAP 325/IBU 200 per 
capsule) and dispense from IDS main location (Ground Maloney, HUP) the day before surgery or the IDS satellite (1 Mutch, Penn 
Presbytarian Medical Center) on day before or the morning of surgery. 
 
The IDS will purchase APAP 300mg/Codeine 30mg tablets, APAP 325mg tablets and Ibuprofen 200mg tablets commercially.  IDS 
will purchase pharmaceutical-grade opaque gelatin capsules and NF (National Formulary) grade inert fillers (microcrystalline 
cellulose NF) from FDA-registered facilities.  All encapsulation takes place using 316-grade surgical stainless steel equipment.  


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
 
5.4 
Storage 
All medication will be stored in the Investigational Drug Service, which maintains high level security and is inaccessible to non-IDS 
personnel, including other members of the study team.  Medication is maintained at USP controlled room temperature (20-25 Celsius) 
in tightly-sealed containers which comply with USP<671> and the Poison Prevention Packaging Act. 
  
5.5 
Preparation and Packaging 
 
Encapsulation will take place in a controlled environment following cGCP and USP<795> guidelines, with all activities performed by 
trained research technicians and research pharmacists. 
 
Medication will be packaged in standard USP<671>-compliant prescription packaging by IDS personnel, pursuant to an individual 
signed or electronically-transmitted legal prescription for each study participant.  Medication will be dispensed in a sealed, labeled 
package on the day of surgery and transferred to a member of the study team who will provide the medication to the participant prior 
to discharge from the surgery center.   
 
5.6 
Blinding 
 
The Investigational Drug Service will prepare medication for both treatment conditions, which is indistinguishable to the study team 
or to study participants.  IDS staff will assign subjects sequentially to treatment arms following the secure randomization tables 
(maintained in the IDS) as prescriptions are received and medication dispensed. 
 
The IDS maintains an emergency unmasking website through Penn Medicine Academic Computing Services, through which the PI 
can, in an emergency situation, obtain access to the treatment assignment for one individual participant.  The website is secured both 
through PennKey authentication and because only an IDS pharmacist can grant individual user access to an individual trial.  The 
website maintains an audit trail of all unmasking activity and categorizes requests for later follow-up.   
 
 
5.7 
Administration and Accountability    
 
The IDS accounts for all study medications, including bulk purchased medications as well as blinded capsules, through an electronic 
accountability record system in compliance with 21CFR11.  The record system is accessible only to IDS personnel and the Director of 
IDS has ultimate control over all user accounts.  The system uses electronic, time/date-stamped signatures for every transaction, as 
well as maintains patient profiles which span all research participation longitudinally as well as across all schools and researchers who 
use IDS services, in compliance with Pennsylvania Code. 
 
5.3 
Subject Compliance Monitoring 
Patients enrolled in the study are asked to complete a post-operative pain diary (please refer to attached).  
In this diary, they are asked to record side effects and the number of doses taken within a 24 hour period.  
The patients will be asked to return the remaining tablets. This number of remaining tablets should match their diary entries.  
5.3.1 
Return or Destruction of Investigational Product 
 
The patients will be asked to return the remaining number of tablets on their first post-operative visit.  
 
Any unused medication at the end of a subject’s course of treatment, is returned to the IDS, where research technicians count and log 
the returned quantities under the subject’s profile in the accountability system.  Electronic, blinded patient-return reports can be 
generated for the study team to assist in calculating patient compliance with the regimen. 
6 
Study Procedures 
6.1 
Screening  
The screening visit will take place during the patient’s clinical encounter to schedule an operation for trigger finger or carpal tunnel. 
 
Informed Consent  
 
Medical Record Review to determine eligibility 
 
Physical Exam (Height and Weight)  


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
6.2 
Study Intervention Phase 
6.2.1 
Visit 1 (operative day)  
Patients will be randomized to either study group the day of their surgery.  They will receive the first dose of the study medication 
while they are in the recovery room.  Subjects will complete the pain diary 4 times every day following surgery (3 times the day of 
surgery).   
6.2.2 
Follow Up  
 
Telephone: Patients will be contacted by telephone on their 2nd post-operative day to administer the QoRs-9. Patients will also be 
telephoned on the day prior to their first post-operative visit as a reminder to bring the diary and remainder of the medication. 
Clinic Visit: Patients will return to clinic for their first post-operative visit (generally 6 to 8 days after their surgery).  
 
6.2.3 
End of Study Visit 
 
The study will conclude at the time of the patient’s first post-operative encounter with their treating hand surgeon (usually between 6 
to 8 post-operative days). After conclusion of the study, the patient’s will continue on their regular post-operative schedule as deemed 
necessary by the treating hand surgeon. 
 
Patients will be unblinded after final data analysis. 
6.3 
Unscheduled Visits 
All patients will be able to contact their treating physician during the course of the study, and/or schedule an early visit if deemed 
necessary. Data collection will proceed as initially described unless the patient requires unblinding. 
6.4 
Subject Withdrawal/Early Termination Visits  
If the patient experiences self-described pain that is poorly controlled or an adverse event, their physician or treatment team will 
evaluate the patient as deemed appropriated and prescribe alternative medications if necessary. Subjects who withdraw early will 
continue to follow with their treating hand surgeons as per standard of care. We will follow intention to treat in our statistical analysis. 
Hence if a patient requires unblinding, the last available measurement for each individual at the time point prior to withdrawal from 
the study will be retained in the analysis. 
6.4.1 
Data Collection and Follow-up for Withdrawn Subjects 
Data collection will stop for withdrawn subjects.  If patients fail to follow-up, they will be contacted by telephone. If they were 
compliant with the diary completion, we will ask the patient to mail the diary or to bring the diary at their next scheduled appointment. 
We will follow ITT in our statistical analysis, thereby the last available measurement for each individual at the time point prior to 
withdrawal from the study will be retained in the analysis. 
 
6.5 
Medical Record Review 
 
Date of birth 
 
Height 
 
Weight 
 
Past medical history with particular focus on: 
 
coagulopathy 
 
renal disease  
 
liver disease 
 
thromboembolic disease (stroke) 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
 
history of recent gastro-intestinal bleeding or peptic ulcer disease 
 
 pregnancy 
 
chronic pain currently taking opioid pain medication or with a history of drug abuse 
 
self-described allergy to ASA, acetaminophen, NSAIDS and codeine  
6.6 
Physical Examination 
 
Height 
 
 
Weight 
6.7 
Vital Signs: N/A 
6.8 
Laboratory Evaluations 
 
Standard pre-operative work-up as indicated for the patient’s past medical history and surgical risk factors. 
6.9 
Pregnancy Testing 
A urine pregnancy test will done the day of the surgery for all women of child-bearing age per usual pre-operative work-up. Patients 
with a positive urine pregnancy test will be excluded from the study. 
6.10 Other Evaluations, Measures 
Visual Analogue Scale, diary and QoR-9 (please refer to attached) 
 
7 
Statistical Plan 
All analyses comparing the treatment groups were conducted on an intention-to-treat basis. Two-tailed tests were used at all times, and 
statistical significance was set a priori at P<0.05.  
7.1 
Primary Endpoint 
The primary end point of this study is pain intensity, measured with a 100-mm VAS (with 0 mm being no pain and 100 mm being 
maximum pain), and analyzed as daily mean scores.  In patients that will have forgotten to complete the VAS scores 4 times daily, the 
missing values will be completed with the last recorded score. 
7.2 
Secondary Endpoints  
Adverse events, duration of medication intake, reason for medication discontinuation, patient satisfaction as determined by the Quality 
of Recovery-9 (QoR-9). 
7.3 
Sample Size and Power Determination 
A sample size of 63 in each group has 80 % power to detect a difference in means of 5 mm assuming a common standard deviation of 
10 mm by a two-group Student’s t test with a 0.05 two-sided significance level. Assuming a 30% lost to follow-up and failure to 
comply with study protocol, 145 patients will be required to achieve complete data for 63 patients in each group. 
7.4 
Statistical Methods 
7.4.1 
Baseline Data 
We will use means and standard deviations (SDs), medians and interquartile ranges (IQRs) or frequencies and percentages, as 
appropriate, to summarize baseline characteristics. We will assessed comparisons between participants who did and did not take 
analgesia using an unpaired t test for continuous variables and a Pearson χ2 test for categorical variables. We will use a parametric 
student t test to assess the primary end point (VAS).  
 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
7.5 
Subject Population(s) for Analysis 
All-treated population:  Any subjects randomized into the study that received at least one dose of either Acetaminophen/codeine or 
acetaminophen/ibuprofen. 
8 
Safety and Adverse Events 
8.1 
Definitions 
8.1.1 Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during the course of the 
study.  Intercurrent illnesses or injuries should be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
8.1.2 
Serious Adverse Event 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
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.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious adverse events.  
 
8.2 Recording of Adverse Events 
 
At each contact with the subject (such as the post-op telephone calls and the post-op clinic visit), the investigator will seek information 
on adverse events by specific questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report form (CRF).  All clearly 
related signs, symptoms, should be recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period will be recorded.  The clinical course of each event will be followed until 
resolution, stabilization, or until it has been determined that the study intervention or participation is not the cause.  Serious adverse 
events that are still ongoing at the end of the study period will be followed up to determine the final outcome.  Any serious adverse 
event that occurs after the study period and is considered to be possibly related to the study intervention or study participation will be 
recorded and reported immediately. 
8.3 Relationship of AE to Study  
The principal investigator will determination the relationship of the AE to the study and will be classified as definitely related, 
probably related, possibly related, unlikely or unrelated. 
8.4 Reporting of Adverse Events and Unanticipated Problems 
We will report adverse events and/or unanticipated problems in accordance with the Penn IRB policy on Reportable Events.   


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
 
8.2 
Unblinding Procedures 
The IDS maintains an emergency unmasking website through Penn Medicine Academic Computing Services, through which the 
PI can, in an emergency situation, obtain access to the treatment assignment for one individual participant.  The website is 
secured both through PennKey authentication and because only an IDS pharmacist can grant individual user access to an 
individual trial.  The website maintains an audit trail of all unmasking activity and categorizes requests for later follow-up.   
8.3 
Medical Monitoring 
The Principal Investigator will oversee the safety of the study.  This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above.  
 
9 
Study Administration, Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the ability to use all 
information collected prior to the revocation of subject authorization.  For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end of their 
scheduled study period. 
9.2 
Data Collection and Management  
The Department of Orthopaedics has two standard methods to capture electronic data: these are RedCap and secure departmental 
shared drives on the UPHS servers behind the UPHS firewalls. We also routinely code files by assigning subject study ID numbers.  
Data will only be accessed by investigators identified on the IRB.  Data will be stored for at least 7 years after the study ends.   
9.3 
Records Retention  
Study records will be stored for at least 7 years after the study ends.  The storage of the study records will be in accordance with 
departmental and institutional policies/requirements.   
10 Study Monitoring, Auditing, and Inspecting 
10.1 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the sponsor, government regulatory 
bodies, and University compliance and quality assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The investigator will ensure the capability for inspections of applicable 
study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government regulatory authorities and 
applicable University compliance and quality assurance offices. 
11 Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations and international standards of Good Clinical 
Practice, and applicable institutional research policies and procedures. 
 


CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics Committee (EC) or Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  The decision of the 
EC/IRB concerning the conduct of the study will be made in writing to the investigator and a copy of this decision will be provided to 
the sponsor before commencement of this study.  
11.1 Risks 
Potential psychological and physical risks to the study participants are minimal as we are not altering standard of care. Risks to subject 
confidentiality are minimized by the use of vigilant de-identification processes, secure data storage, and private facilities as applicable. 
The patients can choose to opt out of the study at any point in time with no impact on their surgical or medical care.  
11.2 Benefits 
This randomized control study will enable us to determine if pain after ambulatory hand surgery can be adequately controlled with 
non-opioid pain medication as effectively as with opioid pain medication. Results of this study will be submitted to a peer reviewed 
journal such that the results can benefit the medical and general population.  
11.3 Risk Benefit Assessment 
The risks of participating in the study are outweighed by the potential benefits of participating in the study.  
11.4 Informed Consent Process / HIPAA Authorization  
Patients will be adults capable of providing informed consent for themselves. Patients will be identified from routine clinical 
encounters and will be invited to participate in the study by a member of the study team. The patient will be provided the informed 
consent form (ICF) and the study team member will describe the study. The patient will also be given an opportunity to read the ICF 
and to ask questions about the study. We will let patients know that they are able to withdraw from the study at any time. Written 
consent will be obtained from the patient at the time of clinical encounter for surgical scheduling. 
12 Study Finances 
12.1 Funding Source 
This study is financed through a grant from the Presbytarian Hospital Bach Fund in the amount of $11,000 
12.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts of Interest Related to 
Research.  
12.3 Subject Stipends or Payments 
There are no subject payments or stipends. 
 
Patients will receive the medication (either  Acetaminophen and codeine or Acetaminophen-ibuprofen) free of charge during their 
participation in the study.  
13 Publication Plan 
This is a single site study. The investigators of this study will submit the results for publication in a peer-reviewed scientific journal.  
 
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