Conditions: Pain Total Knee Replacement Total Hip Replacement
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 350
Healthy volunteers: no

Brief summary:
The objective of this research study is to better understand patterns of recovery after Total Knee Arthroplasty (TKA) amd Total Hip Replacement (THA). The study will evaluate how pain, activity and cognitive (i.e., thinking style) responses determine patterns of recovery, and the study will evaluate the efficacy of gabapentin versus placebo for improving recovery after surgery.

Detailed description:
The investigators propose a two-site, longitudinal, double-blind, randomized clinical intervention study to examine three specific aims:

Aim 1: Characterize the dynamic pain experience, activity, and cognitive response after TKA and determine patterns of recovery in these domains

Aim 2: Test whether gabapentin alters time course of recovery after TKA or THA in a manner dependent on its interaction with pre-drug pupil diameter and preferred style in the catastrophizing-optimism dimension

Aim 3: Test whether gabapentin increases pupil diameter in patients undergoing TKA or THA who are on high dose opioids preoperatively and to examine whether opioid use moderates the associations in Aim 1

Primary Hypothesis: Novel variance beyond established associations in recovery from pain following TKA or THA surgery is accounted for by the interaction between pupil diameter and Cognitive-Affective (C-A) state, and this interaction predicts efficacy of gabapentin to speed recovery.

Key secondary hypotheses: Disability, impulsivity, and attentional deficits recover after TKA or THA surgery follow a log of time pattern, and are predicted by C-A state and its interaction with pupil diameter. Gabapentin increases resting pupil diameter in patients scheduled for TKA who are receiving high doses of opioids.

Arms:
arm 1: Subjects will be randomized, stratifying for norepinephrine serotonin reuptake inhibitor (NSRI) use, to equal number to receive gabapentin or placebo pills. Drug treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards. Subjects randomized to gabapentin will receive 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. arm 2: Subjects will be randomized, stratifying for norepinephrine serotonin reuptake inhibitor (NSRI) use, to equal number to receive gabapentin or placebo pills. Drug treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.

Interventions: intervention 1: Gabapentin intervention 2: Placebo
Intervention descriptions: intervention 1: Drug treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards. Subjects randomized to gabapentin will receive 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. intervention 2: Drug treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards. Subjects randomized to gabapentin will receive 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week.

Protocol document:
ICF_002.pdf: 
Official Title:  Predicting, Understanding, and Speeding Recovery After 
Total Knee Arthroplasty  
IRB Date Approved 12/14/2020
NCT02685735


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Adult Consent Form
Version: March 5, 2020
Department/Section of Anesthesiology
PREDICTING, UNDERSTANDING AND SPEEDING RECOVERY 
AFTER TOTAL JOINT REPLACEMENT
Informed Consent Form to Participate in Research
James C. Eisenach, M.D., Principal Investigator
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you are scheduled to have a total knee replacement also called Total Knee 
Arthroplasty (TKA) or a total hip replacement (THA). Your participation is voluntary. Please 
take your time in making your decision as to whether or not you wish to participate. Ask your 
study doctor or the study staff to explain any words or information contained in this informed 
consent document that you do not understand. You may also discuss the study with your friends 
and family.
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to help researchers better understand patterns of recovery 
after TKA or THA surgery. We will evaluate how pain, activity and reasoning responses 
determine patterns of recovery.   We will also evaluate the effectiveness of gabapentin, a 
medication that is commonly used to treat nerve pain, compared to a placebo, which is an 
inactive substance, like a sugar pill, that is not thought to have any effect on your disease or 
condition. 
Placebos are used in research studies to see if the drug being studied really does have an effect.
We are also interested in studying the diameter of the pupil in your eye(s) to better understand 
how a corresponding brain region, the locus coeruleus, is related to processing and interpreting 
pain stimuli. We will look at changes in your pupils with the use of an infrared camera.
We will ask you to complete several psychological questionnaires that tell us about your 
reasoning responses, thoughts, and emotional feelings.
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
A total of 300 people at 2 research sites will take part in this study, including approximately 150 
people at this research site. In order to identify the 300 subjects needed, we may need to screen 
as many as 350 because some people will not qualify to be included in the study.
WHAT IS INVOLVED IN THE STUDY?
PREOPERATIVE PROCEDURES
Once you have agreed to participate, you will be scheduled to come to our Headache and 
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Pain Research Unit (HPRU).  We will have you wear a portable heart monitor during the study 
visit so that the researchers can record your heart rate to assess the state of arousal to coincide 
with the PAS questionnaire that will be completed. The heart rate monitor will be a non-invasive 
monitor.
 You have the option to choose to have study visits 2 and 3 occur at your surgeon’s office at 
Davie Medical Plaza.  
STUDY VISIT 1:
Approximately 2 weeks before your surgery we will have you come to the HPRU for your 
first study visit. This visit will take about 2 hours. We will ask you to complete 4 questionnaires 
the evening before your first study visit and bring them with you during your study visit. During 
the first visit we will ask you about your medical history, existing pain and any medications that 
you are taking. If you are a female subject of child-bearing potential we will also administer a 
urine pregnancy test. The rest of the visit will be divided into 3 parts. 
In the first part we will administer thermal heat temperatures ranging from warm but not 
painful to painfully hot. We will ask you to indicate when you feel warmth or pain, and to rate 
the pain using a scale from 0-10. The probe temperature will vary from skin temperature up to a 
temperature that is hot (102o F to 124 F) and uncomfortable, but does not burn your skin. This 
will take about 15 minutes.
Next we will ask you to complete a series of 3 questionnaires on the computer, 2 
questionnaires on paper, and play 2 simple card games. The card games will tell us about how 
you make decisions or how impulsive you are. This will take about 30 minutes.  
Next we will ask you to rate the warm and hot temperatures again while we make a recording 
of the size of your pupils. To do this we will have you sit in a comfortable chair and position 
your head so your chin is resting in a chinrest (very similar to the way an eye doctor would 
examine your eyes).  We will ask you to stay in this position for this portion of the testing.   A 
continuous video recording will be made of the size of your pupils while you are experiencing 
the thermal heat temperatures applied your forearm.  This video recording is being done so that 
we can record the changes in your pupil when you experience different temperatures allowing 
the researchers to better understand the role that your brain has in processing pain.
We will administer thermal heat temperatures in sequences of a low and a higher temperature to 
your forearm(s) and ask you to rate the pain by using a numerical rating score (NRS) from 0-10. 
We will use a thermal probe with a tip about the size of a penny which will be placed on the skin 
of your forearm and the temperatures applied will be held constant for 5 seconds. The probe 
temperature will vary from skin temperature up to a temperature that is hot (102o F to 124 F) 
and uncomfortable, but does not burn your skin. After 4 sequences of temperature stimuli we 
will also ask you to place your foot into a bucket of cold (50°F) water for 90 seconds while we 
are performing some of the thermal heat testing on your forearm. This testing will take about 45 
minutes.
Also during your visit we will train you to use an electronic tablet for daily diary entries, a 
weekly diary entry, and also in the use of an accelerometer (small device that will wear on a belt 
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around your waist or around your ankle to record your activity). The accelerometer tells us about 
your activity by counting the number of steps you take, the distance you walk while you are 
wearing it.
We will give you the tablet (or you may choose to use your own tablet/electronic device) and the 
accelerometer to take home after this visit and ask you to answer your daily diary questions each 
day before your surgery and wear the accelerometer each day before your surgery. We are asking 
you to do this so that you will be accustomed to doing these tasks before your surgery. At the end 
of this visit will give you a packet of 10 questionnaires that we will ask you to complete at home 
and bring with you on the day of your scheduled surgery.
You will be randomized into one of the study groups described below. Randomization means 
that you are put into a group by chance. It is like flipping a coin. You will have a one in two 
chance of being placed in either group.
The groups are: (1) gabapentin or (2) placebo.
Neither you nor the investigator will know which study medication you are receiving. This is 
done so that a fair evaluation of results can be made. This information is available to the 
researchers if needed in an emergency.
You will begin the study drug after this visit. You will take the blinded study drug as prescribed 
for the next five weeks. The study staff will call you weekly to talk to you about any questions 
you have about your study medication and you will be provided with a telephone number to call 
the study team for any questions you have. 
All questionnaires/surveys and thermal heat testing are for research purposes only. 
DAY OF SURGERY AND IN-HOSPITAL CARE
If you have elected to have spinal anesthesia we will also collect a small amount, less 
than ½ teaspoon of spinal fluid. The spinal procedure will be done per standard of care by 
anesthesiology faculty. After turning on your side, your back will be washed with antiseptic, 
local anesthetic will be injected to numb your skin, and a needle will be placed in the lower part 
of your back.  Once the spinal needle is in place and just before the spinal medication is 
administered, a small amount (less than ½ teaspoon) of cerebrospinal fluid will be withdrawn 
(this is the clear fluid that fills the cavities of the brain and covers the surfaces of the brain and 
spinal cord). This sample will be used to test for neurotransmitters (chemical molecules that 
“ferry” nerve impulses across the synapse from one neuron to the next in the brain) this is 
important because the neurotransmitters tell us about how your brain processes pain.
The amount of spinal fluid we take is half as big a volume as we inject with the numbing 
medicine.  The medication to make you numb for your surgery will then be administered.  
Please initial one of the following options:
____YES I will participate in providing a CSF sample for testing of neurotransmitters.
____NO I do not want to provide a CSF sample for testing of neurotransmitters.
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 We will also collect information from your medical record including the type of surgery you are 
having, the medications that you are taking, the type of anesthesia that you have for your 
surgery, the type of pain you have, the amount of pain medication that you use after your surgery 
and the number of days you are in the hospital after your surgery as well as any other significant 
events that happen during your hospital stay. 
HOSPITAL DISCHARGE 
A member of the research team will visit you while you are in the hospital after your 
surgery. 
We will ask you to make entries in the electronic diary as follows:  
A. Evening of discharge weeks 1 through 8:  You will be asked to complete an electronic 
diary entry each evening for 8 weeks.
B. Weeks 9 through 20: A member of the study team will call you and ask you 17 questions 
one evening a month for 3 months.
Each of the assessments will only require about 2 minutes to complete.  
The electronic diary (tablet) will be equipped with a pre-paid wireless card so that you may 
connect to the internet to access the diary for completion.
You will also be asked to wear your accelerometer daily for the first 8 weeks after your 
discharge. 
Additional postoperative hospital discharge assessments to be completed:
STUDY VISIT 2:
Approximately 8-10 weeks after your surgery we will have you return to the HPRU or we 
will arrange to meet you at your postoperative appointment at Davie Medical Center according to 
your preference and complete the set of 14 questionnaires that you completed before your 
surgery and you will complete the survey about how impulsive you are and play the card game. 
You will also return to the study team your electronic diary and the accelerometer at this visit.
STUDY VISIT 3:
Approximately 6 months after your surgery we will have you return to the HPRU or we 
will arrange to meet you at your postoperative appointment at Davie Medical Center according to 
your preference and complete the set of 14 questionnaires that you completed before your 
surgery and you will complete the survey about how impulsive you are and play the card game.
During your postoperative visits to your surgeon we will record information about your joint 
function.
HOW LONG WILL I BE IN THE STUDY?
You will be in the study for about 6-7 months.
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Adult Consent Form
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You can stop participating at any time. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. 
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. You may experience brief pain during the thermal heat testing. There is a 
small risk of thermal burn during the heating part of the experiment. The use of infrared video 
camera will not expose you to a greater amount of light than expected in normal use of an 
infrared camera. We will ask you to complete various psychological tasks, which may cause you 
to reflect on emotional experiences or feel emotional. If you find it necessary, a list of resources 
are included at the end of this consent form that you may find helpful. We will not be providing 
immediate feedback to you from your psychological questionnaires.
You may ask us to stop the testing at any time and you may withdraw from the study at any time.
 Pulmonary
Gabapentin has been associated with serious breathing difficulties in patients taking opioids and 
those with diseases that reduce lung function including chronic obstructive pulmonary disease 
(COPD).  Symptoms include confusion, unusual dizziness or lightheadedness, extreme 
sleepiness, slowed, shallow or difficult breathing, unresponsiveness, and bluish colored or tinted 
skin, especially on the lips, fingers, or toes.
The most common side effects (greater than 2%) of gabapentin are listed in the table below:
Body System/Preferred Term
 
Neurontin
®  
Placebo 
N=336 
N=227 % % 
Body as a Whole 
Asthenia (abnormal weakness)
5.7 
4.8 
Infection 
5.1 
3.5 
Headache 
3.3 
3.1 
Accidental injury 
3.3 
1.3 
Abdominal pain 
2.7 
2.6 
Digestive System 
Diarrhea 
5.7 
3.1 
Dry mouth 
4.8 
1.3 
Constipation 
3.9 
1.8 
Nausea 
3.9 
3.1 
Vomiting 
3.3 
1.8 
Flatulence (passing gas)
2.1 
1.8 
Metabolic and Nutritional Disorders 
Peripheral edema (swelling in hands/feet) 
8.3 
2.2 
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Nervous System 
Dizziness 
28.0 
7.5 
Somnolence (sleepiness) 
21.4 
5.3 
Ataxia (lack of muscle coordination) 
3.3 
0.0 
Thinking abnormal 
2.7 
0.0 
Special Senses 
Amblyopia
a 
2.7 
0.9 
(Blurred Vision)
a Reported as blurred vision 
Other events in more than 1% of patients but equally or more frequent in the placebo group 
included pain, tremor (shaking), neuralgia (pain along the nerves), back pain, dyspepsia 
(indigestion), dyspnea (difficulty breathing), and flu syndrome (flu symptoms). 
The incidence of depression (feeling sad) and confusion were reported as frequent (defined as 
occurring in at least 1/100 patients).  
There has been one subject in this current study that reported a rash on the hands and wrists.
These side effects limit therapy in clinical trials in less than 10% of cases with chronic (3 month) 
dosing.
In addition, there is a slight risk of a breach of confidentiality.  We will do our best to protect 
your confidential information.  There also may be other side effects that we cannot predict. You 
should tell the research staff about all the medications, vitamins and supplements you take and 
any medical conditions you have. This may help avoid side effects, interactions and other risks.
The risk of harm or discomfort that may happen as a result of taking part in this research study is 
not expected to be more than in daily life or from routine physical or psychological examinations 
or tests.  You should discuss the risk of being in this study with the study staff.
Taking part in this research study may involve providing information that you consider 
confidential or private.  Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
your information safe.
 A Data Safety and Monitoring Committee, an independent group of experts, will be reviewing 
the data from this research throughout the study.
Reproductive Risks and other Issues to Participating in Research
Due to unknown risks and potential harm to the unborn fetus, sexually active women of 
childbearing potential must use a reliable method of birth control while participating in this 
study. Reliable methods of birth control are: abstinence (not having sex), oral contraceptives, 
intrauterine device (IUD), DepoProvera, tubal ligation, or vasectomy of the partner (with 
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Adult Consent Form
Version: March 5, 2020
confirmed negative sperm counts) in a monogamous relationship (same partner). An acceptable, 
although less reliable, method involves the careful use of condoms and spermicidal foam or gel 
and/or a cervical cap or sponge. We encourage you to discuss this issue further with your 
physicians if you have any questions.
Pregnant women are excluded from participation in this study. Because some methods of birth 
control are not 100% reliable, a pregnancy test is required at least 10 days from your last normal 
menstrual period, if you are a sexually active woman of childbearing potential.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
You are not expected to receive any direct benefit from taking part in this research study. We 
hope the information learned from this study will benefit other people in the future.
WHAT OTHER CHOICES ARE THERE?
This is not a treatment study. Your alternative is to not participate in this study.
WHAT ARE THE COSTS?
There are no costs to you for taking part in this study. All study costs, including procedures 
related directly to the study will be paid for by the study. Costs for your regular medical care, 
which are not related to this study, will be your own responsibility.
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published 
in scientific journals.  Your identity and/or your personal health information will not be disclosed 
unless it is authorized by you, required by law, or necessary to protect the safety of yourself or 
others.  There is always some risk that even de-identified information might be re-identified. 
Participant information may be provided to Federal and other regulatory agencies as required.  
The Food and Drug Administration (FDA), for example, may inspect research records and learn 
your identity if this study falls within its jurisdiction.
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. The researchers with this Certificate may not disclose or use information, documents, or 
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a 
court subpoena, unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that requires 
disclosure (such as to report child abuse or communicable diseases but not for federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings, see below); if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other 
scientific research, as allowed by federal regulations protecting research subjects. 
 The Certificate cannot be used to refuse a request for information from personnel of the United 
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States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the National Institute of Health which is funding this project or for 
information that must be disclosed in order to meet the requirements of the federal Food and 
Drug Administration (FDA).  You should understand that a Certificate of Confidentiality does 
not prevent you from voluntarily releasing information about yourself or your involvement in 
this research. If you want your research information released to an insurer, medical care 
provider, or any other person not connected with the research, you must provide consent to allow 
the researchers to release it.
As part of this research study, you will be videotaped.   We will only videotape the size of your 
pupils, your face or any other identifying characteristics will not be videotaped. This is being 
done so we can have a measurement of your pupils during the thermal heat testing.  You 
understand that you may request the filming or recording be stopped at any time during the 
course of the research study. You can also withdraw your consent to use and disclose the 
photograph/videotape/audiotape before it is used. You should also understand that you will not 
be able to inspect, review, or approve the photographs, videotapes, audiotapes or other media 
(including articles containing such) before they are used in this study. The video files will be 
stored on a password protected network computer for indeterminate period of time.
Please choose one of the following regarding the use and disclosure of the 
photograph/videotape/audiotape used in this research study:
_____ I would like the videotapes of me to be destroyed once their use in this study is finished.
____ The videotapes of me can be kept for use in future studies provided they are kept secure 
and any future study will be reviewed by an IRB.   I understand that I will not be able to inspect, 
review or approve their future use.
WILL YOU BE PAID FOR PARTICIPATING?
You will be paid a total; of $1000 for completion of the entire study. If you complete only part of 
the study or withdraw during the study you will be paid according to the schedule below:

$300 for completion of the first  HRRU study visit 

$50 for completion of questionnaires 2 months after surgery and return of study supplies 
(electronic tablet, charge, wireless internet card)Visit 2 at the HPRU or Davie Medical 
Center

$50 for completion of questionnaires 6 months after surgery Visit 3 at the HPRU or 
Davie Medical Center $200 for completing at least 90% of the daily diary entries on the 
electronic tablet and wearing the accelerometer weeks 1 through 8 at least 90% of 
required time

$400 for completion of all the scheduled study visits and postoperative assessment/questionnaires
You must return the electronic diary (including the charger) and the wireless card (if one was 
used) before your payment will be processed.
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For your participation in the electronic survey that tells about your impulsivity, you will be given 
raffle tickets according to your performance. You will be given 1 ticket each time you complete 
the survey but according to how well you perform you will be given additional raffle tickets. 
Once a year, after each 40 subjects are completed, we will enter the raffle tickets for each subject 
and hold a drawing for the winner to receive a one-time winning of $500. You will have a 
minimum of 3 raffle tickets if you complete your study visits.
If you withdraw for any reason from the study before completion you will be paid according to 
the schedule of payment above.  The accelerometer and electronic tablet must be returned if you 
withdraw from the study prior to completion.  
To receive payment, you must provide your social security number, name and address so that we 
can comply with IRS (Internal Revenue Service) reporting requirements.  When payments are 
reported to the IRS we do not let them know what the payment is for, only that you have been 
paid.  If you do not wish to provide this information you can still take part in this study but you 
will not be paid.
The findings from this research may result in the future development of products that are of 
commercial value. There are no plans to provide you with financial compensation or for you to 
share in any profits if this should occur.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored National Institutes of Health. The sponsor is providing money or 
other support to Wake Forest University Health Sciences to help conduct this study. The 
researchers do not, however, hold a direct financial interest in the sponsor or the product being 
studied.
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at 
If you are injured, the insurer may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the insurer is required by 
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law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call Dr. James C. Eisenach at 
during 
regular business hours and after hours you may contact the study coordinator by calling 
  
.
What About My Health Information?
In this research study, any new information we collect from you and/or information we get from 
your medical records or other facilities about your health or behaviors is considered Protected 
Health Information. The information we will collect for this research study includes: 

Name 

Age (date of birth)

Health history

Current medications

Questionnaires 

Surgical Experience (ie: surgeon, procedure, anesthesia, pain, medications, 
complications, length of hospitalization)

Postoperative function 
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, to 
provide required reports and to get approval for new products.  
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; central laboratories, reading centers or analysis 
centers; the Institutional Review Board; representatives of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital; representatives from government agencies such as 
the Food and Drug Administration (FDA) or the Office of Human Research Protections (OHRP), 
the Department of Health and Human Services (DHHS), the National Institutes of Health (NIH) 
and similar agencies in other countries. 
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
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regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
Monitors, auditors, IRB or other regulatory agencies will be granted direct access to the 
participant’s original medical record for verification of clinical trial procedures or data, without 
violating confidentiality of the participant and to the extent permitted by other applicable laws.
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
Information is shared with any of these groups it may no longer be protected by federal or state 
privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for an indeterminate period of time. This authorization does not 
expire and the study sponsor (National Institutes of Health) will be granted direct access to the 
participant’s original medical record for verification of clinical trial procedures or data, without 
violating confidentiality of the participant and to the extent permitted by other applicable laws.
 You will not be able to obtain a copy of your Protected Health Information in the research 
records until all activities in the study are completely finished.
You can tell Dr. James C. Eisenach that you want to take away your permission to use and share 
your Protected Health Information at any time by sending a letter to this address:
James C. Eisenach, M.D.
 
However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
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IRB Number:IRB00032506
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Adult Consent Form
Version: March 5, 2020
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time. 
Laboratory test results and other medical reports created as a result of your participation in the 
research study may be entered into the computer systems of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital.  These will be kept secure, with access to this 
information limited to individuals with proper authority, but who may not be directly involved 
with this research study.
A North Carolina Baptist Hospital (NCBH) medical record will be created for all study 
participants. Information about your participation in the study will be placed in the NCBH 
medical record, along with any routine medical test results that were obtained at NCBH as part 
of this study. 
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. The investigators also have the right to stop your 
participation in the study at any time. This could be because we have not been able to contact 
you or you are not completing your questionnaires and diaries as agreed upon. You will be given 
any new information we become aware of that would affect your willingness to continue to 
participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Dr. James C. Eisenach at 
 during regular business hours and after 
hours you may call the study coordinator by calling 
 
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB 
You will be given a copy of this signed consent form. 
WFU School of Medicine 
Institutional Review Board 
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Version Valid Until: 12/13/2021


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Adult Consent Form
Version: March 5, 2020
SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
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Below is a list of resources that you may find helpful:
Emergencies:
Local Emergency Department
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Non-Emergent:
Wake Forest Psychiatry (medical or counseling):  
Check with your insurance panel to identify therapists, doctors and other healthcare providers
Websites such as www.findatherapist.com
http://www.findatherapist.com 
http://www.therapists.psychologytoday.com
http://www.find-a-therapist.com
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00032506
Meeting Date Approved 12/14/2020          
Version Valid Until: 12/13/2021

SAP_003.pdf: 
 
1
Section 1: Administrative information 
 
1.a. 
Title  
 
 
Statistical analysis plan for Predicting, Understanding, and Speeding Recovery after Total Joint 
Replacement; a Randomized, Controlled Clinical Trial. 
 
1.b. 
Trial registration  
 
 
Trial Registration: NCT02685735 
 
2. 
SAP version  
 
 
Version: 
2.1  Date: February 6, 2023 
 
3. 
Protocol Version 
 
 
This document has been written based on information contained in the study protocol version 
7.0, dated March 20, 2020. 
 
4. 
SAP Revisions  
Protocol 
version 
Updated 
SAP 
version no. 
Section 
number 
changed 
Description and reason for change 
Date changed 
7.0 
2.0 
Section 6 
Details provided after data acquisition 
and before unblinding 
May 21, 2022 
7.0 
2.1 
Sections 2 
and 6 
Corrected primary analysis to utilize 
resting pupil diameter rather than its 
response to pain as proposed in the 
NIH funding and protocol documents. 
Feb 6, 2023 
7.0 
2.2 
Section 6 
Corrected the primary analysis to 
remove adjustment for baseline pain 
and in secondary analyses to remove 
adjustment for baseline activity, 
disability score, and opioid self 
administration. 
April 26, 2023 
 
5. 
Roles and Responsibilities – non-signatory names and contribution 
 
James C. Eisenach, M.D.  
 
Timothy T. Houle, M.D. 
 
Professor of Anesthesiology 
 
Associate Professor of Anesthesiology 
 
Wake Forest School of Medicine  
Massachusetts General Hospital 
 
Winston-Salem, NC  
 
 
Boston, MA 
 
Role: Chief investigator 
  
 
Role: Co-investigator and Senior Statistician 
 
6.a. 
Roles and Responsibility – signature of the person writing the SAP 
 
 
 
 
 
 
 
 
April 26, 2013  
 
James C. Eisenach, M.D.  
 
Date 
 
Chief Investigator 
 


 
2
6.b. 
Roles and Responsibility – signature of senior statistician responsible 
 
 
 
 
 
 
 
 
 
April 26, 2013 
 
Timothy T. Houle, Ph.D. 
 
 
Date 
 
Co-Investigator & Senior Statistician 
 
 
Section 2: Introduction 
 
7. 
Background and Rationale 
 
 
People recover from pain after major surgery with very different speeds. In rats, recovery from 
hypersensitivity after major surgery also exhibits large variability, some of which is accounted for by 
individual differences in pain-induced activation of the locus coeruleus (LC) resulting in central 
norepinephrine release that dampens sensitization of pain circuits. Gabapentin alters LC coeruleus 
tonic activity in animals.  We designed a study to assess, via pupillometry, LC tonic activity and 
responsiveness to pain prior to surgery in patients scheduled for lower extremity total joint 
arthroplasty and to test whether tonic activity and responsiveness to pain modulate the speed of 
recovery and efficacy of gabapentin to alter recovery from postoperative pain.    
 
8. 
Objectives  
 
 
The objective of this research study is to better understand patterns of recovery after total hip 
arthroplasty (THA)  and total knee arthroplasty (TKA). The study will evaluate how pain, pupil 
diameter as a measure of LC activity and cognitive (i.e., thinking style) determine patterns of 
recovery, and the study will evaluate the efficacy of gabapentin versus placebo for improving recovery 
after surgery. 
 
Research hypothesis: The null hypothesis (H0) is that modeled trajectory of change in pain 
intensity report after THA and TKA does not differ between oral gabapentin and placebo in a manner 
dependent on its interaction with preferred cognitive style and pre-surgery pupil resting diameter . The 
alternative hypothesis (H1) is that there is a difference between the two groups which is dependent on 
these interactions. The null hypothesis will be tested through contrasting the fit of a null model (m0), 
with only change parameters and prognostic covariates, and the full model (m1), which includes all of 
the predictors in null model with the addition of randomized treatment group, cognitive style, resting 
pupil diameter, and all two and three-way interactions. The difference in fit will be evaluated using a 
likelihood ratio test, as further described below.  
 
H0: -2 * (loglik[m0] – loglik[m1]) = 0 
H1: -2 * (loglik[m0] – loglik[m1]) > 0 
 
 
 
Study objective:  The primary objective is to determine the effectiveness of oral gabapentin to 
speed recovery from pain, as measured by growth curve modeling, after THA or TKA and how this 
effectiveness is modified by preferred cognitive style and pre-surgery resting pupil diameter .  
 
Secondary objectives are planned to explore the role of these factors interact to predict other 
outcomes from surgery, including speed of gain in activity, assessed by actigraphy, speed recovery 
from self-assessed disability, and time to cessation of opioid use; to explore whether change in pupil 
diameter to acute experimental pain explains additional variance in a 4-way interaction compared to 
the 3-way interaction in the primary analysis. 
 


 
3
Section 3: Trial Methods 
 
9. 
Trial design  
 
 
The trial is a two-center, randomized, double-blinded, parallel-group, placebo-controlled trial.  
Treatment allocation is a 1:1 ratio.  Patients are randomized to either gabapentin or placebo control. 
 
10. 
Randomization  
 
 
A computer-generated randomization using a 1:1 allocation ratio in permuted blocks of 8 will 
be developed by the study statistician uninvolved with data collection and administered by the 
research pharmacist at Wake Forest School of Medicine. The ‘blockrand’ package in R will be used 
by the study statistician. The randomization will be stratified based on study recruitment site, 
concurrent use of a serotonin-norepinephrine reuptake inhibitor, and chronic low- or high-dose opioid 
therapy. Allocation will be conducted by the research pharmacist and will occur after consent and 
completion of the first visit. At all times, the allocation assignment will be concealed from the study 
coordinator and other investigators who manage participant recruitment and follow-up. Allocation 
concealment is maintained using a centralized pharmacy administration of study drug. Both study 
agents are designed to look identical to each other to maintain blinding. 
 
11. 
Sample size  
 
 
To calculate the statistical power for our analytical strategies, we simulated scenarios for which 
we instilled known relationships between the random effects of change models as well as a range of 
predictors of those parameters that were 
themselves correlated. A sample size of 250 was 
to determine to provide substantial power (> 
90%) to detect clinically significant differences 
between a null model versus a 
demographic/perioperative + psychosocial 
predictors model using a likelihood ratio test. An 
example of the expected differences is displayed 
(left) that illustrates a three-way interaction 
between treatment (Placebo vs Gabapentin), 
cognitive-affective style (Optimist vs 
Catastrophizing), and pupil size (Low, Mid, 
High).   
 
12. 
Framework 
 
 
Superiority testing will be used to examine difference between the effect of treatment alone on 
the change process in pain after surgery and the effect of treatment as interacting with preferred 
cognitive style and pre-surgery pupil responses to painful stimuli. 
 
 
 
13a. Information on interim analyses 
 
 
There are no planned interim analyses.   
 
13b. Any planned adjustment of the significance level due to interim analysis 
 


 
4
 
None. 
 
13c. 
Details of guidelines for stopping a trial early 
 
 
There is no plan to stop the trial early aside from recommendations based on unanticipated 
serious adverse events by the DSMB. 
 
 
14. 
Timing of final analysis 
 
 
Final analysis of the gabapentin vs placebo comparison with and without inclusion of 
interactions with preferred cognitive style and pre-surgery pupil responses to pain will take place 
when all patients have completed the 12-month follow-up and data for the primary endpoint have 
been cleaned, which occurred in May 2022.  Results were anticipated to be posted by Jan, 2023, but 
complexities associated with generation of a novel psychologic construct from the final dataset and 
defining parameters for pupil assessment prevented completion of the primary analysis until Mar, 
2023. 
 
15. 
Timing of outcome assessments 
The schedule of study procedures is provided in the protocol and summarized in the table below. 
 
Section 4: Statistical Principles 
 
16. 
Level of statistical significance 
 
 
All applicable statistical tests will be 2-sided and will be performed using a 5% significance level. 
 


 
5
 
17. 
Adjusting for multiplicity 
 
 
The primary analysis involves a single model-based inference that will be interpreted at the 5% 
threshold of statistical significance. If the primary analysis is significant, each main factor, all two way 
interactions, and the three way interactions will be evaluated and each will be interpreted at the 5% 
level of significance with no adjustments made for multiplicity. 
 
18. 
Confidence intervals 
 
 
All confidence intervals presented will be 95% and two-sided. 
 
19a. Definition of adherence to the intervention and how it is assessed 
 
Compliance is assessed based on the number of daily diary entries after hospital discharge. It 
is defined as: 
 
 
% compliance = (number of entries/number of days entries were to be completed)*100% 
 
19b. How adherence will be presented 
 
 
The number and % of participants completing more than 80% of the daily diaries after surgery 
will be provided by treatment group in a table. All available data will be included in the analysis from 
the intention to treat sample. 
 
19c. 
Definition of protocol deviation 
 
 
The following are pre-defined major protocol violations with a direct bearing on the primary 
outcome: 
 
1)  Surgery during the primary outcome assessment period (first 8 weeks after surgery) 
 
19d. Description of which protocol deviations will be summarized 
 
 
Protocol deviations are classified prior to unblinding of treatment. The number (and 
percentage) of patients with major and minor protocol deviations will be summarized by treatment 
group with details of type of deviation provided. The patients that are included in the ITT analysis data 
set will be used as the denominator to calculate the percentages. No formal statistical testing will be 
undertaken. 
 
20. 
Analysis population 
 
 
The intention-to-treat population will include all randomized patients who received study drug 
and provided at least one pain score after the day of surgery. 
 
 
Section 5. Trial Population 
 
21. 
Screening data 
 


 
6
 
Enrollment: The dates of recruitment, the number of patients screened, the number of patients 
recruited, the number of screened patients not recruited, and the reason for non-recruitment will be 
reported as part of the CONSORT diagram. 
 
22. 
Eligibility criteria 
 
 
Inclusion and exclusion criteria are provided in the protocol. The number of ineligible patients 
randomized, if any, will be reported, with reasons for ineligibility 
  
 
23. 
Information to be reported in the CONSORT flow diagram 
 
 
A CONSORT flow diagram (appendix A) will be used to summarize the 
number of patients who were: 
• assessed for eligibility at screening 
• eligible at screening 
• ineligible at screening* 
• eligible and randomized 
• eligible but not randomized* 
• received the randomized allocation 
• did not receive the randomized allocation* 
• lost to follow-up* 
• discontinued the intervention* 
• randomized and included in the primary analysis 
 
*reasons will be provided for post randomization exclusions. 
 
24a. Description of level of withdrawal 
 
 
The level of consent withdrawal will be tabulated (classified as “consent to continue follow-up 
and data collection” “consent to continue data collection only”, “complete – no further follow-up or 
data collection”). 
 
24b. Timing of withdrawal/lost to follow up data 
 
 
This will be presented in CONSORT diagram format rather than as a table, with numbers and 
reasons for withdrawal and/or exclusion from analysis given at each stage 
 
24c. 
Reasons for withdrawal/lost to follow up data 
 
 
The numbers (with reasons, if available) of losses to follow-up (drop-outs and withdrawals) 
over the course of the trial will be summarized by treatment arm. 
 
25a. List of baseline characteristics to be summarized 
 
 
Patients will be described with respect to age, sex, race, ethnicity, medications, number of 
painful conditions excepting the hip and their locations, cognitive – optimism cognitive construct 
generated from questionnaires, baseline pain from the daily diaries prior to surgery, and surgical 
approach (anterior vs posterior). 
 
25b. How baseline characteristics will be described 
 


 
7
 
Categorical data will be summarized by numbers and percentages. Continuous data will be 
summarized by mean, SD and range if data are normal and median, IQR and range if data are 
skewed. Minimum and maximum values will also be presented for continuous data. Tests of statistical 
significance will not be undertaken for baseline characteristics; rather the clinical importance of any 
imbalance will be noted. 
 
Section 6: Analysis 
 
26. 
Outcomes and timings  
 
 
Primary outcome:  Worst pain intensity measured using a 0 to 10 numerical rating scale on a 
daily diary. Measurements will be obtained each evening from day 0 (surgery) to day 56 after surgery. 
The pain measurements will be evaluated in a statistical model using an intercept (i.e., immediate 
pain after surgery) and slope (i.e., rate of change of pain during the observation period).      
 
 
Secondary outcomes:  Daily measurements such as physical activity, as measured via 
actigraphy, disability, as measured by daily diaries and weekly WHODAS 2.0 scores, and opioid self-
administration, as measured by daily diaries will be collected from day 0 (surgery) to day 56 after 
surgery.  Questionnaire and cognitive game data will be assessed at baseline and follow-up. 
Validated scoring systems from the individual items will be used to score each questionnaire or 
measure.  These outcomes will not be used in the primary analysis. 
 
27a. Analysis methods to be used 
 
 
and 
27b. Adjustments for covariates 
 
 
Primary analysis:  
 
Overview 
 
The primary analysis will model trajectory of recovery of daily worst pain ratings and examine 
several sources of influence on this recovery. Sometimes referred to as mixed-effects models, or 
hierarchical linear models, growth curve modeling allows specification of a change trajectory that is 
unique to each individual. The nature of the common form of changes in daily pain will be modeled 
using a curvilinear form (e.g., polynomial regression). Through the use of fixed and random effects, 
variations in intercepts (i.e., levels of pain on day of discharge) and slopes (i.e., change in daily pain 
over time) can be examined using the pre-specified influences outlined below.  To model individual 
pain trajectories, several model form candidates will be examined with the best fit determined using a 
Bayesian Information Criterion.  These model forms will include linear, quadratic, cubic, and log(time), 
and each of these model candidates will be employed that reflect a fundamental change in trajectory 
that occurs during the observation period. Based on preliminary data it is highly likely that a log(time) 
form will be chosen.1,2  
 
 
To examine the proposed hypotheses, several key sets of predictors will be specified including 
patient characteristics, operative characteristics, cognitive style, randomized treatment assignment, 
and pre-operative pupil diameter response. Each of these predictors are described below: 
 
   Patient characteristics: To adjust the associations for individual age and sex will be entered into the 
model. 
 
 
   Operative characteristics: To adjust the associations for any subtle differences in medical care, 
study site,  and surgery type (hip or knee arthroplasty) will be entered into the model. 


 
8
 
 
   Cognitive style:  Multidimensional scaling of the pre-operative questionnaires will be conducted to 
create a unidimensional scale that represents a broader spectrum of cognitive style that ranges from 
optimism/acceptance of pain to catastrophizing. This novel predictor will be examined for reliability 
and correlations with the original scales. If insufficient reliability ( < 0.70) or construct validity (r < 
|0.40|) with the original scales cannot be obtained, the analysis will proceed using the originally 
scaled catastrophizing predictor.    
 
   Pupil diameter: Pupil recordings will be conditioned to remove artifacts (e.g., blinks), saccades, and 
deviations from central gaze that might bias recordings.  A response window with appropriate lag 
reflecting delayed onset of pupil response due to physiological delays will be used to define change in 
diameter to each stimulus as previously reported.17 Two pupil measurements will be estimated from 
the session data, the mean pupil diameter during baseline (i.e., pre-stimulus) and the modeled 
response to pupil to 50-degree stimulus.   
 
 
   Gabapentin:  Randomized treatment assignment of either gabapentin or placebo will be a 
fundamental predictor of trajectory. 
 
 
These individual predictors sets will then be used to test the primary hypothesis that 
gabapentin alters time course of recovery after arthroplasty in a manner dependent on its interaction 
with preferred cognitive style and pre-surgery pupil diameter. The primary statistical inference will be 
the difference in the likelihood ratio between two nested models using a chi-square test with K 
degrees of freedom (i.e., K being the difference in the number of parameters between the two 
models). The first model (i.e., null model) will consist of the pain trajectory model with the addition of 
patient characteristics and operative characteristics. The second nested model will add medication 
assignment (gabapentin versus placebo), cognitive style (catastrophizing ↔ optimism latent score), 
and resting pupil diameter, and all two-way interactions and three-way interaction between these 3 
predictors (i.e., 3 two-way, and 1 three-way interaction for both intercept and slope parameters) from 
the first nested model. This approach allows a single likelihood ratio test of the primary hypothesis 
and will be interpreted using a two-tailed hypothesis test using p < 0.05.  A statistically significant 
difference in the likelihood ratio test will be interpreted as evidence to support the primary hypothesis 
in that the interaction of these predictors impacts some aspect of the change process beyond that of 
the basic model. We have planned several sensitivity analyses using multiple imputation to account 
for missing data. 
 
 
Several exploratory secondary analyses of the data set: 
 
 
1.  Trajectories for daily activity, as measured via actigraphy, disability, as measured by daily 
diaries and weekly WHODAS 2.0 scores, and opioid self-administration, as measured by daily diaries, 
will be analyzed using a similar approach. As noted, other questionnaire and cognitive game scores 
will be described for the two groups but not analyzed or entered as covariates for the purpose of the 
primary analysis and publication. Changes in questionnaire data will be evaluated using the 
generalized linear model regressing follow-up score on baseline score and medication group 
assignment.   
 
 
2.  The contribution of pupil diameter change in response to acute preoperative pain testing to 
prediction of trajectory of change in postoperative pain intensity rating will be assessed.  This will be 
performed in the same manner as the primary analysis.  In addition, a 4 way-interaction test using the 
same approach as in the primary analysis will be used by included both pupil diameter at rest and its 
response to preoperative acute pain stimuli.  
 
 


 
9
 
3.  Development and internally validation a predictive model for recovery from pain from the full 
battery of preoperative questionnaires and application of item response theory to create a much 
smaller set of questions with retained predictive value for subsequent testing as a practical tool. 
 
 
4.  Modeling recovery of function from the World Health Organization Disability Assessment 
Score 2.0 (WHODAS 2.0), Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC) and daily activity level as assessed using actigraphy in order to assess their relationships 
and those between these functional measures and daily pain, including lead-lag and influence of days 
of physical therapy, during recovery from physical therapy after lower extremity major total joint 
arthroplasty. 
 
   
5.  Examining the influence of anesthetic technique (general anesthesia, regional anesthesia 
via single injection regional anesthesia with sustained catheter infusion) on perioperative acute pain 
and pain and functional recovery over the subsequent two months. 
 
 
6.  Exploring biomarkers for stress and noradrenergic functioning by exploring the relationship 
between preoperative patient characteristics, including psychophysical responses to pain processing 
and CSF concentrations of norepinephrine and markers associated with stress. 
 
27c. 
Methods to be used for assumptions to be checked for statistical methods for primary and 
secondary analyses 
 
 
The assumptions underlying parametric modeling will be evaluated using regression diagnostic 
procedures and histograms of residuals.  
 
27d. Alternative methods to be used if distributional assumptions do not hold for primary and 
secondary analyses 
 
 
If necessary, the primary outcome distribution will be log transformed to satisfy assumptions. 
For secondary outcomes, the generalized linear model allows the specification of an array of 
distributions (e.g., normal, binomial, gamma) with corresponding link functions (e.g., log).   
 
27e. Planned sensitivity analyses 
 
 
Four sensitivity analyses will be performed to evaluate the robustness of the trajectory analysis 
to the primary and secondary analyses.  These are to include multiple imputation for missing data, to 
include baseline measures of primary and secondary outcomes as predictors in the trajectory models,  
to include monthly through 6 months and the 12-month daily diary data and to include patient race 
and surgeon as other causes of variability in trajectory in the primary analysis. 
 
27f. 
Planned subgroup analyses 
 
 
No subgroup analyses are planned. 
 
28. 
Missing data – reporting and assumptions/statistical methods to handle missing data 
 
 
Multiple imputation will be used to account for embedded missing data in daily diary entries. 
The autocorrelation of each time-series for each individual along with baseline predictors will be used 
in conjunction with the MICE algorithm to estimate m = 20 imputations. These imputations will then be 
re-analyzed using the primary model with Rubin’s rules used to pool the estimates of model 
parameters.     


 
10 
 
29. 
Details of any additional statistical analyses required e.g., complier-average causal effect 
analysis. 
 
 
None 
 
30. 
Harms 
 
 
The number (and percentage) of patients experiencing each AE/SAE will be presented 
for each treatment arm categorized by severity. For each patient, only the maximum severity 
experienced of each type of AE will be displayed. The number (and percentage) of occurrences of 
each AE/SAE will also be presented for each treatment arm. No formal statistical testing will be 
undertaken 
 
31. 
Statistical Software 
 
 
The analysis will be carried out using R version 4.1.2 
 
32.   References 
 
 
There are no non-standard statistical methods used, but references to methods used are listed 
below.  As regards the Data Management Plan, data handling and cleaning were provided at Wake 
Forest School of Medicine and Massachusetts General Hospital, where data are secured.  The Trial 
Master File is included in Investigator New Drug (IND) 107166, Food and Drug Administration. The 
Statistical Master File materials are housed at Wake Forest School of Medicine.  Standard Operating 
Procedures followed when writing the SAP are from the guidelines published in JAMA in 2017.3 
 
 
Cited References 
 
1. 
Houle TT, Miller S, Lang JE, Booth JL, Curry RS, Harris L, Aschenbrenner CA, Eisenach JC: 
Day-to-day experience in resolution of pain after surgery. Pain 2017; 158: 2147-2154 
2. 
Booth JL, Sharpe EE, Houle TT, Harris L, Curry RS, Aschenbrenner CA, Eisenach JC: 
Patterns of recovery from pain after cesarean delivery. Pain 2018; 159: 2088-2096 
3. 
Gamble C, Krishan A, Stocken D, Lewis S, Juszczak E, Doré C, Williamson PR, Altman DG, 
Montgomery A, Lim P, Berlin J, Senn S, Day S, Barbachano Y, Loder E: Guidelines for the Content of 
Statistical Analysis Plans in Clinical Trials. Jama 2017; 318: 2337-2343 
 
 
 


 
11 
Appendix 
 
SAP 2.1 
 
 
The SAP was amended on Feb 6, 2023 to correct an error in the primary analysis in SAP 2.0 
which stated that pre-surgery pupil response to acute experimental pain would be entered into a three 
way interaction with study drug and preferred cognitive style to predict modeled recovery from pain 
after lower extremity total joint arthroplasty.  As stated in the NIH application which funded the 
research, the IRB approved protocol for the study and its analysis, and the ClinicalTrials.gov 
registration, the primary analysis was stated to use pre-operative resting pupil diameter rather than its 
response to pain.  The error in the SAP was observed prior to performing the primary analysis and is 
described in this amendment.   
 
Addition of pre-surgery pupil response to acute experimental pain as a 4th interacting factor 
was inferred in the grant application and protocol and the SAP is amended to include this as a pre-
planned secondary analyses from this extensive dataset, in addition to creating a unique subset of 
questionnaire questions to predict postoperative pain intensity trajectory, assessing the day to day 
time relationship  between pain and disability during recovery, the role of anesthetic technique in long 
term recovery, and interrogating various biomarkers for speed of trajectory of recovery after surgery. 
 
SAP 2.2 
 
 
The SAP was amended a second time on April 26, 2023 to correct an error in the primary and 
secondary analyses to remove the statements that modeled trajectory of change in outcome 
measures for each analysis (pain in the primary; daily steps, disability scores, and opioid use in the 
secondaries) would be adjusted for preoperative values of these measures.  Such adjustments were 
not included in either the IRB approved protocol nor the NIH application which funded the study and 
its analysis. 
 
There is a large literature demonstrating a positive correlation between the extent of pain 
catastrophizing with pain, disability, and opioid use and a negative correlation with activity.  Since the 
cognitive construct to be used in both the primary analysis and the secondary analyses is derived 
from the pain catastrophizing instrument, adjustment of modeled trajectories by preoperative pain, 
activity disability, and opioid use would be expected to diminish the independent effect of the 
cognitive construct in these analyses.  The adjustments in modeling using these preoperative 
variables were intended as sensitivity analyses rather than testing the primary and secondary 
hypotheses.  This mistake was identified and this amendment was prepared and submitted prior to 
performing analyses using these adjustments. 

Prot_004.pdf: 
Official Title:  A Multi-Center Study: Predicting, Understanding and Speeding Recovery after Total Joint 
Replacement
NCT02685735 
Date:  03/05/2020


Protocol version: 3/5/2020
1 
Study Title: Predicting, Understanding, and Speeding Recovery after Total Joint Replacement 
Principal Investigator; Co-investigator(s): James C. Eisenach, M.D.; Timothy T. Houle, Ph.D., Jason 
Lang, M.D., Scott Miller, M.D.  
Sponsor or funding source: NIH 
Background, Rationale and Context 
Chronic pain after surgery is typically defined as pain outlasting the normal healing process from 
uncomplicated surgery, usually 2-6 months.  Given over 250 million major surgical procedures performed 
annually on a global basis and an incidence of chronic pain after surgery of 10-50% (Kehlet, 2006), the 
problem of chronic pain after surgery is clearly a major public health problem. Major surgery also results 
in acute physical disability which is especially important after procedures for which the primary 
indication is to improve or remove disability, exemplified by major total joint replacement surgery. We 
chose to study total knee arthroplasty (TKA) and total hip arthroplasty (THA) in this NIH grant 
application for two reasons.  First, TKA is a commonly performed surgery to reduce pain and improve 
function,  and 3.5 million TKAs are predicted to be performed each year in the US by 2030 (Kurtz, 2007).  
Second, although most patients show improved joint range of motion from this surgery, approximately 
40% of patients fail to improve function after TKA as assessed by validated measures of minimally 
clinical important improvement (MCII), and 10-20% are left with chronic, moderate to severe pain 
(Maxwell, 2014; Singh, 2014a).  
Critical barriers to progress addressed by this study. These are fourfold: 
1. Focus on dichotomous outcomes. Clinical and preclinical
studies on recovery from surgery utilize dichotomous outcomes, 
which makes no biological sense.  Recovery after injury is a dynamic 
process, and the very few longitudinal, prospective studies in this area 
show that the incidence of this dichotomous outcome continues to 
decline for years following surgery (Kaasa, 2010).Thus, choosing an 
arbitrary time to define chronic pain or disability after surgery tells us 
little about the path upon which patient are recovering and when they 
will recover.  The cartoon in Figure 1 depicts the problem.  The 
incidence of “chronic” pain or disability changes over time and 
predictive models based on disparate times are likely to be 
inconsistent and potentially misleading.  The subject in orange in 
Figure 1, for example, experienced considerably more pain, disability, 
and possible risk for opioid misuse, than the one in blue, but both are 
lumped as “no chronic pain” at 12 months. We do not argue that
dichotomous outcomes at fixed times after surgery are worthless as 
primary outcome measures for interventional trials, but beyond this 
we believe they represent barriers to understanding and progress.   
Clearer definition of normal time course of improvement in 
pain and other patient-centered aspects of recovery could significantly 
impact surgical decisions regarding candidates for surgery and 
managing expectations (Losina, 2012).  Previous efforts to define 
trajectory of recovery from pain and disability were limited to a few 
days after surgery (Brewer, 2007; Chapman, 2011; Althaus, 2014), 
although one study recently extended this to 45 days (Gaudilliere, 
2014).  To demonstrate feasibility of high density time sampling for 
Figure 1: Time course of recovery 
from pain or disability in 5 
hypothetical patients after surgery 
Figure 2: A) Modeled time course of 
recovery from pain, B) latent classes 
of recovery, C) and time course for 
recovery in activity 


Protocol version: 3/5/2020 
2 
months after surgery we recorded frequent pain assessments in 31 patients after lower extremity total joint 
arthroplasty and 155 women after cesarean delivery. The time course of daily pain intensity was best 
modeled to a log of time function in both cases and, as expected, worst daily pain was initially slightly 
less intense and resolved considerably more rapidly after cesarean delivery than arthroplasty (Figure 2A).  
Latent class analysis of the cesarean delivery group yielded 3 distinct patterns of recovery (Figure 2B), 
although this is an ongoing study and 550 total subjects will be required to allow adequate power for a 
stable latent class analysis.   
 
 
2. Focus on pain in isolation.  Major surgery induces dysfunction in many patient centered 
domains, including pain, physical disability, cognitive dysfunction, and risk of prescription opioid misuse, 
which has been linked to impulsivity (Marino, 2013).  For many surgical procedures, and certainly for 
TKA, patients choose surgery in the hope of less pain and better quality of life.  Yet most studies focus on 
one or at most two outcomes, most commonly components rather than integrated patient centered 
outcomes.  We will repeatedly apply the simple, 12-question World Health Organization Disability 
Assessment (WHODAS) 2.0, recently validated in postoperative patients to define disability-free survival 
(Shulman, 2015) in order to define the trajectory of this patient-centered, integrated outcome.  We will 
also frequently quantify the important components of pain (feasibility shown in Figure 2A and B) and 
physical activity using Fitbit™ accelerometers (feasibility shown in Figure 2C) in order to define 
trajectory of recovery in these domains. We will also repeatedly assess executive function and impulsivity 
(along with daily opioid use) to test novel hypotheses in parallel with lab projects in this NIH Program 
Project (P01) application which assess these constructs.  Finally, we will examine the associations 
previously shown using dichotomous outcomes between known risk factors for individuals with chronic 
pain and dysfunction after surgery (Scott, 2010; Wylde, 2011; Rakel, 2012; Singh, 2014b) but applying 
growth curve analysis of recovery in pain, physical activity, and disability free survival.  
 
 
3. Lack of unifying testable hypothesis. Most critically, the field lacks a testable, mechanistic and 
actionable hypothesis of mechanisms of recovery from these impairments after surgery.  We provide one: 
 
 
The LC provides exclusive or near-exclusive innervation to the cortex, spinal cord, and several 
midbrain regions, where it provides important 
moderating input to areas involved in (among 
other things) pain, fear, attention, and 
impulsivity. LC neurons exhibit two modes of 
activity: spontaneous, tonic, low frequency firing 
(0.1-5 Hz) and phasic bursts (10-25 Hz) in 
response to external, sensory or cortical network 
stimuli.   
 
 
Two aspects of LC function determine its 
widespread modulatory effects. First, the 
interplay between tonic and phasic LC activity 
determines how the LC molds responses to the 
environment (Figure 3).  At low to moderate 
levels of tonic norepinephrine (NE) release from 
LC afferents, stimulation of α2-adrenoceptors 
increases gain across cortical circuits.  As 
opposed to amplification, which results in 
increased signals from all components of a 
Central hypothesis: Activity of the locus coeruleus (LC) at the time of and in response to surgical injury is 
a key determinant of speed of recovery across pain and other patient-centered domains. 
Figure 3: Conceptual relationship between tonic activity and 
level of arousal, attention, application of preferred cognitive 
style, and phasic response to stimuli. For domains 1-3 the 
curved text is meant to show an inverted U effect on these 
aspects of cognition. Drugs which increase tonic LC activity 
may exert opposite effects, depending on level of tonic 
activity (↑ if in  a  and ↓ if in  b ). 


Protocol version: 3/5/2020 
3 
complex circuit, increasing gain results in increased dominance of strong signals at the expense of weak 
signals, as recently demonstrated by fMRI in humans engaged in learning tasks (Eldar, 2013).  As tonic 
LC activity increases, so does level of alertness and the ability to focus on task (Figure 3, domains 1 and 
2) accompanied by the tendency to exploit the environment, which is viewed as predictable.  With higher 
tonic NE release, such as occurs under acute stress, these effects are degraded by activation of lower 
affinity α1- and β-adrenoceptors, resulting in hypervigilance, distraction (Suto, 2014), and tendency to 
explore the environment which is viewed as surprising / unpredictable (Gilzenrat, 2010; Jepma, 2011).  
Project 2 (a laboratory project in the P01 application) induces high tonic LC activity to test whether this 
results in beneficial effects to reduce impulsivity or detrimental effects to exaggerate attention deficits, 
and we will assess in humans the effect of tonic LC activity on these parameters following TKA. 
Impulsivity and attention are specifically regulated by the locus coeruleus, are relevant to 
postoperative cognitive dysfunction and potential opioid misuse, and are being studied in the 
preclinical arms of this NIH program project grant.   
 
 
Domains 3 and 4 are particularly relevant to pain.  For all but the lowest range of frequencies, 
increases in tonic LC neural firing frequency are accompanied by decreases in phasic bursts in response to 
salient stimuli (Figure 4A). Project 1 (a 
laboratory project in the P01 application) 
shows in rats that a manipulation which 
increases tonic LC activity reduces release 
of NE in the spinal cord in response to a 
noxious stimulus and reduces Conditioned 
Pain Modulation (CPM), a form of 
endogenous analgesia (Figure 4B).  In 
preliminary data, we observed that 
strength of CPM in 7 healthy volunteers 
(conditioning stimulus of foot in cool 
water with test stimulus of 5 sec 49⁰C 
stimulus to forearm (Nahman-Averbuch, 
2013)) was inversely related to resting 
pupil diameter in a constant luminosity, 
darkened environment as a proxy for tonic 
LC activity (Figure 4C). In animals, CPM 
is dependent on LC→spinal noradrenergic 
signaling, and in both animals and 
humans, low CPM is associated with a greater risk of chronic pain after surgery (Yarnitsky, 2008; Peters, 
2015).  We will therefore test the hypothesis that resting pupil diameter, a stable trait in humans for long 
periods of time (Alnaes, 2014), predicts the strength of CPM and partially regulates the speed of recovery 
from pain after surgery.   
 
 
According to our central hypothesis, LC activity does not just regulate the time course of spinal 
sensitization and ascending nociceptive input, it also alters the pain experience, which results from 
supraspinal processing of this bottom-up signal (Figure 3, domain 3).  In humans, increased tonic LC 
activity results in stronger reliance on an individual’s preferred visual or semantic learning style  (Eldar, 
2013). To test whether a similar relationship exists in response to pain, 16 individuals with osteoarthritis 
of the hip or knee answered a series of questionnaires to place them on a catastrophizing↔optimism 
(C↔O) cognitive continuum, and resting pupil diameter was measured to infer tonic LC activity.  
Noxious heat stimuli were applied to the forearm using a Peltier-controlled thermode in 5-sec pulses, 
ranging from innocuous (41⁰C) to mildly or moderately noxious (47⁰C and 50⁰C, respectively).  A 
generalized estimating equation (GEE) analysis was applied to examine the repeated measurements of 
Figure 4: A) In this example an individual with higher tonic LC activity 
(Red) has less phasic response to a noxious stimulus than one with 
lower tonic activity (Green).  B) This yields fewer noxious stimulus-
induced action potentials (APs) of LC neurons with spinal projections 
(orange bars) resulting in lower CPM. C) As predicted by this 
hypothesis, CPM strength in 7 subjects was inversely related to 
resting pupil diameter, a validated measure of tonic LC activity in 
humans. 


Protocol version: 3/5/2020 
4 
temperature condition on C↔O dimension, and resting pupil diameter on pain reporting.  We anticipated 
that pain report would be affected by preferred style on the C↔O dimension, and this was observed at 
both 50⁰ and 47⁰ stimuli (Figure 5A; p=0.0007).  We anticipated that additional variance in pain report 
could be identified by the interaction between C↔O style and resting pupil diameter, and this was also 
observed (Figure 5B) although not significant in this underpowered small pilot sample.  As resting pupil 
diameter increased, pain report tended to increase or decrease depending on preferred style in the C↔O 
dimension. These data are consistent with tonic LC activity in this population residing in area b of Figure 
3, since increased tonic activity increased rigidity to apply the preferred style.  Tonic LC activity and 
hence this relationship may differ in the surgical population. 
 
 
This complex interaction between tonic LC activity and C↔O style on recovery from pain after 
surgery is important because its determinants (resting pupil diameter and cognitive assessment) can be 
easily measured and because it provides novel and testable predictions in the laboratory and clinic.  These 
preliminary data strongly support the use of pupillometry to infer tonic LC activity, as they also support 
the central hypothesis and the feasibility of testing it.  
 
 
4. Inability to target treatment to responders.  There are two critical barriers to identifying and 
targeting treatments to speed recovery from surgical injury.  First, surgical procedures utilized to study 
pain in rodents result in recovery within a few days (incision model of (Brennan, 1996)), or no recovery 
over many months (e.g., spinal nerve ligation (SNL) model of (Kim, 1992)). This P01 application utilizes 
partial SNL (Guan, 2010), a surgical procedure which resolves over 2 months, with recovery delayed if a 
negative affective phenotype is induced prior to injury.  Second, treatments based on theory or studies in 
rodents have been largely negative in the clinic, including prolonged regional blockade, gabapentinoids, 
clonidine, ketamine, and serotonin-NE reuptake inhibitors (SNRIs).  
This may reflect inability to identify responders. 
 
 
Without a testable and mechanistic rationale for treatment, 
understanding treatment failure and prospectively identifying responders 
are difficult.  This proposal will build on our central hypothesis, that the 
interaction between tonic LC activity and C↔O style regulates speed of 
recovery, to test whether responders to a drug which increases tonic LC 
activity can be predicted.  We chose gabapentin as that drug, based on 
animal and novel preliminary data in humans.  The osteoarthritis 
subjects described in Figure 4 were randomized to receive oral 
Figure 5. Ascending input from the spinal cord is conceptually filtered through a cognitive dimension which 
disperses pain experience, as supported by A) an observed relationship between predicted pain and 
preferred style on this C↔O dimension.  We hypothesize that further dispersion of pain occurs through 
filtering depending on degree of tonic LC activity, as supported by B) Spread of pain dependent on C↔O 
dimension increases as tonic LC activity (inferred by pupil diameter) increases (n=16 osteoarthritis 
patients).   
Figure 6: Change in pupil diameter 2 hr 
after oral treatment (bars are median) 


Protocol version: 3/5/2020 
5 
modafinil, a drug known to increase tonic LC activity and pupil 
diameter (Minzenberg, 2008), gabapentin, 1200 mg, or placebo.  Two 
hr later, pupil diameter increased after gabapentin and modafinil in 
comparison to placebo (Figure 6), consistent with an increase in LC 
activity from gabapentin in rodents (Hayashida, 2008) and in CSF NE 
in patients receiving gabapentin (Hayashida, 2007).  The proposed 
clinical study will test high-order interactions between pupil diameter, 
C↔O dimension and drug on speed of recovery from pain after TKA.  
If positive, this would explain the failure of gabapentin to exert large 
effects to reduce pain presence months after surgery in a general 
population and provide a testable algorithm to use simple patient 
characteristics – resting tonic LC activity as measured by pupillometry 
and C↔O style as measured by simple questionnaires – to those who 
may be most helped or most harmed by this drug.  An example of a tool using minimum effect sizes 
observable in the proposed clinical study is available at https://pain.shinyapps.io/clinicalPredictions/ 
(adjacent screenshot).  This tool assumes an inverted U effect of resting pupil diameter on speed of 
decline in noxious ascending input from the spinal cord and that of reliance on preferred style in the 
C↔O dimension.  The effect of gabapentin, which increases tonic LC activity, on speed of recovery will 
depend on both pre-drug pupil size and cognitive style in the C↔O dimension.  
 
 
In summary, the significance of the proposed work lies in 1) shifting dichotomous, static 
measures to continuous primary outcomes in recovery from surgery; 2) investigating several key, patient-
centered domains rather than just pain intensity in recovery; 3) providing a mechanistic hypothesis linking 
tonic LC activity and its interaction with C↔O style to speed of recovery across these domains; and 4) 
testing this hypothesis using a commonly applied therapeutic intervention to generate novel, clinically 
actionable results.   
 
 
Objectives 
 
We propose a two-site, longitudinal, randomized clinical intervention study to examine three 
specific aims: 
 
Aim 1: Characterize the dynamic pain experience, activity, and cognitive response after TKA or 
THA  and determine patterns of recovery in these domains 
 
Aim 2: Test whether gabapentin alters time course of recovery after TKA or THA in a manner 
dependent on its interaction with pre-drug pupil diameter and preferred style in the C↔O 
dimension  
 
 
Primary Hypothesis: Novel variance beyond established associations in recovery from pain following 
TKA or THA surgery is accounted for by the interaction between pupil diameter and C-A state, and this 
interaction predicts efficacy of gabapentin to speed recovery. 
 
Key secondary hypotheses: Disability, impulsivity, and attentional deficits recover after TKA or THA 
surgery follow a log of time pattern, and are predicted by C-A state and its interaction with pupil 
diameter. Gabapentin increases resting pupil diameter in patients scheduled for TKA or THA who are 
receiving high doses of opioids 
 
 
 


Protocol version: 3/5/2020 
6 
Methods and Measures 
 
Primary analysis: Three way Resting Pupil Diameter*C-A State*Drug treatment in the 250 subjects not 
on high dose opioids. 
 
Setting 
Subjects recruited at Wake Forest Baptist Medical Center will be identified by research personnel 
in the Departments of Anesthesiology and Orthopaedics. Research personnel will approach the 
subjects while they are in a private exam room, the study will be explained to the subject and the 
subject will be given a copy of the study consent form to read. Informed consent may be obtained 
at this time or the subject may choose to take the informed consent home and call the study 
personnel to schedule an appointment to come to the Headache and Pain Research Unit (HPRU) 
for consent and their initial study visit. Subjects will be seen in the HPRU (subjects may choose 
to have their 2 month and 6 month postoperative study visit occur in conjunction with their 
postoperative visit to their surgeon at Davie Medical Center) for 3 study visits; approximately 2 
weeks prior to surgery, approximately 8 weeks after surgery and 6 months after surgery. 
 
Subjects will also be recruited at the Cleveland Clinic in Cleveland, Ohio under the direction of 
Dr. Daniel Sessler, Professor and Chair, Cleveland Clinic Lerner College of Medicine. 
 
Subjects selection criteria 
We will recruit patients having primary, unilateral total knee arthroplasty (TKA) or unilateral 
total hip arthroplasty (THA). 
We will recruit  300 subjects in primary analysis - taking < 100 mg morphine equivalents/day 
(low dose opioid)  to test gabapentin’s effect on pupil diameter – taking >100 mg morphine 
equivalents/day (high dose opioid). 
 
• 
Inclusion Criteria 
Adult, non-pregnant adults scheduled for elective total knee replacement, American Society 
of Anesthesiologists physical status 1-3, able and willing to perform the study procedures. 
Individuals must be able to read and write English and have a stable residence. 
 
• 
Exclusion Criteria 
      (1) Inability to complete questionnaires; (2) Pregnancy; (3) Litigation or workers   
compensation related to their joint surgery;  (4) history of Raynaud’s disease of the feet; (5) 
suffering from a psychotic disorder or a recent psychiatric hospitalization; (6) history of eye 
surgery or topical eye medications that would render pupillometry unreliable or would directly 
affect pupil diameter; (7) any disorder that would affect pupil responsivity or prevent accuracy of 
pupillometry such as movement disorders. (8) Exclusion for preoperative calculated GFR <30 
ml/min, hold of study med if postop GFR<30 ml/min. (9) severe Chronic Obstructive Pulmonary 
Disease (COPD) requiring home oxygen. (10) Obstructive Sleep Apnea (OSA) with daily use of 
CPAP at home. 
 
• 
Sample Size 
Two-center interventional study of 300 evaluable patients having primary, unilateral TKA or 
unilateral THA at Wake Forest School of Medicine and Cleveland Clinic. Patients will be 
stratified by norepinephrine serotonin reuptake inhibitor (NSRI) use, 300 subjects not on high 
dose opioids will be included in the primary analysis to test the effect of gabapentin on 
resting pupil diameter. 
 


Protocol version: 3/5/2020 
7 
Interventions and Interactions 
Preoperative procedures. Eligible subjects will be identified at least 3 weeks prior to surgery, informed 
consent obtained, and a ~ 2hr preoperative assessment will be performed, consisting of 3 parts. We will 
record demographic and history information, including pre-existing pain elsewhere, female subjects of 
child-bearing potential will have a urine pregnancy test performed. 
In the first part we will administer thermal heat temperatures ranging from warm but not 
painful to painfully hot. We will ask subjects to indicate when they feel warmth or pain, and to 
rate the pain using a scale from 0-10.  
The second part will consist of subjects to completing a series of 3 questionnaires on the 
computer, 2 questionnaires on paper, and play 2 simple card games.  
The third part will consist of the subject experiencing the warm and hot temperatures again 
while we make a recording of their pupils.  
We will administer questionnaire-based measures of psychological state, physical function, and pain 
(Table 1). Questionnaire responses will be entered via a custom designed REDCap data entry form and 
checked for completeness by the data coordinating center. We will have the subjects complete 2 of the 
questionnaires (PLOC and PSE) on paper the evening before the visit as well as the PAS and DSI. 
The LOT-R, PCS, and WOMAC will be completed on the computer   during the first visit. The remaining 
questionnaires will be completed at home and returned to the study team on the day of surgery (Stanford 
Expectations of Therapy Scale, PROMIS-Depression, PROMIS-Anxiety, PMAQ, Barratt Impulsivity, 
Fear of Pain, TSK, WHODAS 2.0, BRS)From these questionnaires, we will place each participant on a  
dimensional continuum that describes their 
general cognitive style. We will use 
multidimensional scaling (MDS) to force 
catastrophizing and optimism as 2 ends of 
this continuum (Figure 7). These 
questionnaires will assess activities of daily 
living and associated disabilities. 
Upon review of the questionnaire data, the 
study staff will notify the primary attending 
surgeon for any subject showing suicidal 
ideation as well as the study staff will call 
the subject and inform them. 
 
The Daily Stress Inventory (DSI) 
and the Perceived Arousal Scale (PAS) will 
be completed the night before the scheduled 
appointment and the PAS will be completed 
once during the scheduled appointment. The 
Modified Pain DETECT will also be 
completed during visit 1.  
 
These two constructs describe cognitive styles that are strongly inversely associated with each 
other; MDS will provide the optimal weights to best order individuals on this latent scale. Studies have 
examined the interplay of these constructs with other psychological concepts such as acceptance, pain-
related disability and psychosocial adjustment and have found that both are reliably associated with the 
positive and negative aspects of the adjustment to pain.                                             
 
 
 
 
Table 1.  Preoperative Questionnaire 
Stanford Expectations of Therapy Scale 
WOMAC- Osteoarthritis Index 
Life Orientation Test-Revised (LOT-R) 
PROMIS- Depression 
PROMIS- Anxiety 
Pain Medication Attitudes Questionnaire (PMAQ) 
Pain Locus of Control Scale (PLOC) 
Pain Self-Efficacy Scale (PSE) 
Barratt Impulsivity Test 
Fear of Pain Questionnaire 
Pain Catastrophizing Scale (PCS) 
Tampa Scale of Kinesiophobia (TSK) 
WHO Disability Assessment (WHODAS 2.0) 
Brief Resiliency Scale (BRS)  
Modified Pain DETECT 
Daily Stress Inventory (DSI) 
Perceived Arousal Scale (PAS) 


Protocol version: 3/5/2020 
8 
We will perform pupillometry during presentation of calibrated noxious stimuli. Subjects will 
report pain and unpleasantness using mechanical 10 cm visual analog scales (VAS) to 5 sec duration heat 
stimuli (37⁰ to 50⁰ C in 2⁰ increments) applied to a 2 cm2 area of skin on the forearm using Peltier-
controlled thermode (TSA-II®, 
Medoc, Ramat Yishai, Israel). 
Stimuli will be separated by 30 
sec and the all temperatures 
will be presented in an 
ascending series for training 
followed by a random series to 
generate a stimulus response as 
previously described (Hood, 
1995; Eisenach, 2010). We will 
deliver 3 blocks of thermal 
stimuli to each subject for the 
pupillometry session. The blocks will include the same temperatures (37⁰C; warm threshold, 46⁰C; pain 
threshold and 50⁰C; painful stimuli) delivered 3 times each per block. Each block will consist of a 
random presentation of these temperatures. We will provide verbal instructions to the subjects 
immediately prior to the block: block 1 will be labeled as ½ of the stimuli will be painful and ½ of the 
stimuli will not be painful, block 2 will be labeled as 80% of the stimuli will be painful and block 3 will 
be labeled as 20% of the stimuli will be painful.   The thermal probe will be moved to a different area of 
skin on the forearm for each testing sequence. The debriefing statement is included in Appendix 3. 
We will then test CPM as previously described (Nahman-Averbuch, 2013) by recording VAS 
pain and unpleasantness from a 5 sec, 49⁰C stimulus on the volar forearm before, 30 sec after insertion of 
the foot of the extremity not planned for operation in 10⁰C water, the foot will remain in the water for a 
total of 90 seconds.   During pain testing, study subjects will sit in a comfortable chair in a low-ambient 
light room with their head positioned on a chinrest for continuous recording of pupil diameter using a 
near infrared recording system as described in preliminary data. Pupil diameter and probe temperature 
will be passed through an analog to digital and acquired at 60Hz for subsequent analysis.  
We will have the subjects wear a portable heart monitor during the study visit so that the 
researchers can record the heart rate to assess the state of arousal to coincide with the PAS questionnaire 
that will be completed. The heart rate monitor will be a non-invasive monitor. 
 
Subjects will be trained and provided with a tablet device for daily diary entries and the 
accelerometer. The accelerometer has wireless connectivity such that daily diary and activity will be time 
stamped and can be easily uploaded by the patient to the data coordinating center on a regular basis. We 
will utilize a password protected web based database tool for near real-time access to facilitate adherence 
(e.g., phone calls or emails when participants fail to wear the device during regularly scheduled time 
points). 
 
We will have subjects begin using the tablet and wearing the accelerometer 2 weeks prior to 
surgery so that they will become familiar with the devices to increase compliance and adherence to the 
protocol after surgery. 
 
 
The tablet will also have the capabilities to access PEBL software for cognitive assessment. This 
open-source software employs several cognitive tasks that look and feel like challenging games that allow 
the assessment of different areas of cognitive function. The specific tasks will be the Iowa Gambling Task 
to assess impulsivity. The Wisconsin Card Sorting Task will be utilized to assess executive function. 
Participants will complete these tasks at baseline and again at several times after hospital discharge 
(Figure 8). 
 
Figure 7: The dimensional structure of the 
continuum of cognitive style to be used, 
including psychosocial constructs associated 
with each end 


Protocol version: 3/5/2020 
9 
 
 
 
Drug treatment. Patients will be randomized, stratifying for NSRI use, to equal number to receive 
gabapentin of placebo pills formulated by the research pharmacy at the institutions. Drug treatment will 
begin 2 weeks prior to surgery and continue 3 weeks afterwards. To reduce treatment-limiting side effects 
subjects randomized to gabapentin will receive 900 mg/day for the first week, 1800 mg/day for the next 3 
weeks, and 900 mg/day for the last week (Figure 8). Subjects will be contacted 5 days after beginning the 
1800 mg dose and assessed for bothersome side effects (sleepiness, dizziness, confusion) that are 
interfering with normal activities of daily living(ADL’s). If bothersome side effects are present at this 
time dose will be decreased back to 900mg/day. Subjects’ will receive a weekly phone call while on study 
drug treatment and assessed for side effects, difficulty breathing or falls that have occurred.  
 
Intraoperative and in-hospital care. We will not limit intraoperative surgical or anesthetic management 
or in-hospital analgesic management. A study team member will record potential confounds including 
surgical complications, in-hospital physical therapy, intraoperative and postoperative opioid, gabapentin, 
ketamine, and regional anesthesia administration, and days from surgery to discharge. For patients 
receiving a spinal injection as part of clinical care, we will collect a 2 ml CSF sample for planned 
exploratory analyses for measures of noradrenergic activity (norepinephrine) and chronic stress state 
(NPY, cortisol, IL-1β). Research staff will see the subject daily in the hospital to have them complete the 
daily diary questions. Study medication will be held during hospitalization if postoperatively the 
calculated GFR<30 ml/min until resolution of lab abnormality. 
 
Post-hospital discharge measures. Patients will begin daily evening electronic diary entries on the day of 
hospital discharge for 8 weeks then once monthly (beginning 3 months after surgery) study staff will call 
the subject to collect the diary questions until 6 months after surgery. Patients will also answer a weekly 
WHODAS 2.0 (12 questions) on the electronic diary and will complete this monthly during their phone 
call as well.  These assessments will typically take less than 2 minutes and assess IMMPACT 
recommended domains (Turk, 2006): pain intensity, physical functioning, emotional functioning, and 
participant ratings of global improvement and associated symptoms. Electronic diary entries are captured 
wirelessly using the participant’s home wireless connection via the customized secure electronic, 
password protected database. Both sites will be provided with several tablets that are equipped with pre-
paid 4G wireless access to ensure that participants without home Internet connections can participate. The 
diaries will be monitored and maintained by the data coordinating center in real-time; if a participant 
misses a diary entry, they will be emailed or called (their preference) to ensure maximal adherence to the 
protocol. Using these procedures we have been able to obtain > 95% adherence in our previous diary 
studies. Participants will also wear the accelerometer for the first 8 weeks after discharge. Participants 
will also complete the cognitive tasks (Iowa Gambling Task, Wisconsin Card Sort,) that they were 
introduced to at the baseline session at, 2 months, and 6 months after hospital discharge. The Iowa 
Gambling Task will again be administered via the PEBL software. Questionnaires done at pre-
randomization (Table 2) will be repeated at 2 and 6 months after surgery. Finally, we will also record 
objective assessments of joint function at the times when the subjects return to clinic for their 
postoperative visits. 
 
Figure 8: 
Timeline of 
study.  
Cognitive tasks 
are performed at 
circled times. 


Protocol version: 3/5/2020 
10 
Subject payment: Subjects will be paid $1000 with pro-rated payment steps (listed below) to study 
completion. An additional incentive will be provided in the form of the Fitbit at the end of the subject’s 
use in the study. The tablet devices will be returned to each study center for re-use. 
Pro-rated payment will be made as follows:  
 
• 
$300 for completion of the  preoperative HPRU study visit, 
• 
$50 for completion of questionnaires 2 months after surgery (HPRU or Davie Medical Center) 
• 
$50 for completion of questionnaires 6 months after surgery and return of study supplies 
(electronic tablet, charge, wireless internet card) completed in the HPRU or Davie Medical 
Center 
• 
$200 for completing at least 90% of the daily diary entries on the electronic tablet and wearing 
the accelerometer weeks 1 through 8 at least 90% of required time 
• 
$400 for completion of all the scheduled study visits and postoperative assessment/questionnaires 
(At the end of the 6 month assessment: the electronic diary must be returned (including the 
charger) and the wireless card for compensation to be processed) 
 
 
If a subject withdraws for any reason from the study before completion they will be paid according to the 
schedule of payment above.  The accelerometer and the tablet must be returned if a subject withdraws 
from the study prior to completion for payment to be processed for the portion of the study completed. 
 
To encourage good effort on the Iowa Gambling Task (IGT), a yearly raffle (after 40 completed subjects) 
of $500 will be held.  All subjects who complete the IGT will have one raffle ticket entered into the 
drawing, regardless of net earnings.  In addition, each $100 of net earnings will earn the participant an 
additional raffle ticket.   For example, if a subject completes the IGT and has net earnings of $300, he/she 
will have four tickets entered in the raffle.  Prior research suggests that providing monetary reinforcement 
on the IGT improves overall performance and reduces performance variability. (Fernie G, Tunney RJ. 
Some decks are better than others: The effect of reinforcer type and task instructions on learning in the 
Iowa Gambling Task. Brain and Cognition. 2006;60:94–102.)  
 
 
Analytical Plan 
Data analysis. The plan of analysis and sample size estimation for the primary analysis is presented in 
full detail in the Bioinformatics Core (Appendix). Briefly, we will examine the frequently obtained (i.e., 
daily, then monthly) worst daily pain intensity score and the total daily (i.e., non-sleep) accelerometer 
movement score. One growth curve model will be created for each outcome (pain, movement) using all of 
the predictors in Table 2, strength of conditioned pain modulation (CPM) from the laboratory session. 
Additionally, one model that combines both outcomes will examine for lagged and synchronous 
relationships between the two outcomes (i.e., do changes in one outcome predate changes in the other?). 
See the Bioinformatics Core for details about the handling of nuisance variables (e.g., site effects, 
surgeon), missing data, and sensitivity analyses. Pupil diameter data will be conditioned to remove blink 
and saccade artifacts and smoothed using an autoregressive filter. The local resting diameter will be 
determined representing the average smoothed value for the 500 msec preceding the stimulus onset. The 
pupil response to each stimulus is calculated as the mean pupil diameter during the 5 sec stimulus after 
accounting for lag time from onset of stimulus to onset of pupil response and is expressed as a % change 
from the local resting diameter (see our preliminary data for examples). Multidimensional Scaling (MDS) 
will be used to create a single dimensional scale from the catastrophizing and optimism scores (i.e., 
responses from these two questionnaires will be weighted and scaled to create a single-dimensional 
construct) to determine the interaction among the factors of interest, and to accommodate the many 
repeated measures within each participant, we will utilize Generalized Estimating Equations. In our 


Protocol version: 3/5/2020 
11 
experience, the pupil response to painful stimuli is well modeled by a normal distribution with an identity 
link and an AR1 repeated measures covariance structure. To examine our hypotheses, we will model 
percent pupil change (the DV) using fixed effects for stimulus temperature, catastrophizing-optimism 
score (i.e., C-A state), and pre-stimulus baseline pupil diameter (i.e., LC activity). The association 
between C-A state and pain reporting will first be examined, and in a later block the moderating effect of 
baseline pupil size will be entered. Statistically significant interaction between baseline pupil diameter 
and the relationship between C-A state and pain reporting will be interpreted as support for the primary 
hypothesis (1). Primary hypothesis (2) will be tested by comparing placebo to gabapentin resting pupil 
diameter after controlling for condition and stimulus intensity. Secondary analyses will include the effect 
of drug and C-A state on condition. Please see the Bioinformatics Core for more details as well as for 
statistical power considerations. 
We assume that the mechanisms underlying this association are the same in total knee 
arthroplasty and total hip arthroplasty patients, but that the two groups will have different 
intercepts (pain at discharge) and slopes (recovery times after surgery). These surgical 
differences will be modeled using an additional fixed effect for intercept and slope in our 
primary model. We do not expect these additional fixed effects to be correlated with the 
predictors used in the primary hypothesis, so the original statistical power calculation is 
unchanged. We will modify the statistical analysis plan to reflect these changes in the expected 
statistical model.     
 
Outcome Measure(s) 
Primary outcome measure: Modeled trajectory of recovery from pain using a log of time form. 
 
Several secondary analyses are planned that examine changes in cognition (e.g., impulsivity, attention) as 
well as kinesiophobia. The cognition measures (Iowa Gambling Task, Wisconsin Card Sort, TSK) 
collected at baseline, , 2 months and 6 months after discharge will be examined using generalized linear 
model with Time (BL, , 2mo, 6mo) as a fixed factor. Please see the Bioinformatics Core for complete 
details. Finally, we will collect and secondarily examine biomarkers for stress and noradrenergic 
functioning by exploring the relationship between preoperative patient characteristics, including 
psychophysical responses to pain processing and CSF concentrations of norepinephrine and markers 
associated with stress. 
 
Human Subjects Protection 
Subject Recruitment Methods 
Appropriate subjects will be identified and approached in the Department of Orthopedics during their 
regular scheduled appointment, by research personnel. Research personnel will utilize a private exam 
room to talk with subjects. Subjects will be given the study details and the opportunity to read the 
informed consent. The subject may take the informed consent home and make their decision regarding 
study participation.  Contact information for the research staff will be provided to the subject so that they 
may call for questions or to participate.  Study personnel will make every effort to approach any subject 
that will be scheduled for primary TKA or THA.  
 
Informed Consent 
Signed informed consent will be obtained from each subject. Research personnel will obtain informed 
consent, the subject may sign the informed consent during their appointment time in the Orthopedic 
Clinic or the informed consent may be reviewed and signed during their first scheduled visit to the 
Headache and Pain Research Unit (HPRU). If the subject has signed the informed consent prior to their 
first HPRU visit, consent will be confirmed and all questions answered prior to any study procedures.  No 
study information or procedures will be performed prior to the subject signing the informed consent. 
All subjects will be given a copy of the signed, informed consent.   


Protocol version: 3/5/2020 
12 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner.  To help ensure subject privacy 
and confidentiality, only a unique study identifier will appear on the data collection form.  Any 
collected patient identifying information corresponding to the unique study identifier will be 
maintained on a linkage file, store separately from the data.  The linkage file will be kept secure, with 
access limited to designated study personnel.  Data access will be limited to study staff.  Data and 
records will be kept locked and secured, with any computer data password protected.  No reference to 
any individual participant will appear in reports, presentations, or publications that may arise from the 
study. 
 
 
Risks.  
 
The thermal heat testing may be discomforting (however, subjects are not exposed to 
temperatures greater than they would experience in everyday life.) The heat probe can cause a temporary 
redness of the skin for several hours.  The risk of burn is very remote.  We will remove the probe any 
time the subject requests. The subject may also move their extremity away from the thermal heat probe at 
any time. The device is a computer controlled, water cooled device that has safety mechanisms in place to 
prevent extreme temperatures from being utilized. Additionally, we have used this device for > 10 years 
and have not had any reported burns.  
 
 Pulmonary 
                Gabapentin has been associated with serious breathing difficulties in patients taking opioids and 
those with diseases that reduce lung function including chronic obstructive pulmonary disease (COPD).  
Symptoms include confusion, unusual dizziness or lightheadedness, extreme sleepiness, slowed, shallow 
or difficult breathing, unresponsiveness, and bluish colored or tinted skin, especially on the lips, fingers, 
or toes. 
 
The most common side effects (greater than 2%) of gabapentin are listed in the table below: 
 
Body System/Preferred Term  
  
 
 
Neurontin
®   
Placebo  
 
 
 
 
 
 
 
 
N=336  
N=227 % %  
Body as a Whole  
Asthenia  
 
 
 
 
 
 
5.7  
 
4.8  
Infection  
 
 
 
 
 
 
5.1  
 
3.5  
Headache  
 
 
 
 
 
 
3.3  
 
3.1  
Accidental injury  
 
 
 
 
 
3.3  
 
1.3  
Abdominal pain  
 
 
 
 
 
2.7  
 
2.6  
 
Digestive System  
Diarrhea  
 
 
 
 
 
 
5.7  
 
3.1  
Dry mouth  
 
 
 
 
 
 
4.8  
 
1.3  
Constipation   
 
 
 
 
 
3.9  
 
1.8  
Nausea  
 
 
 
 
 
 
3.9  
 
3.1  
Vomiting  
 
 
 
 
 
 
3.3  
 
1.8  
Flatulence  
 
 
 
 
 
 
2.1  
 
1.8  
 
 


Protocol version: 3/5/2020 
13 
Metabolic and Nutritional Disorders  
Peripheral edema  
 
 
 
 
 
8.3  
 
2.2  
 
Nervous System  
Dizziness  
 
 
 
 
 
 
28.0  
 
7.5  
Somnolence  
 
 
 
 
 
 
21.4  
 
5.3  
Ataxia   
 
 
 
 
 
 
3.3  
 
0.0  
Thinking abnormal  
 
 
 
 
 
2.7  
 
0.0  
 
Special Senses  
Amblyopia
a  
 
 
 
 
 
 
2.7  
 
0.9  
 
a Reported as blurred vision  
Other events in more than 1% of patients but equally or more frequent in the placebo group included 
pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome.  
 
The incidence of depression and confusion were reported as frequent (defined as occurring in at 
least 1/100 patients).   
 
 
Safe chronic ocular exposure values to Infrared, Range A (IR-A), are in the range of 10mW/cm2 
or below.   The largest eye irradiance noted with the near infrared recording system that will be utilized for 
this protocol is between 0.75 - 0.80 mW/cm2 at the plane of the eye. Under normal use, eye irradiance is 
between 0.1 – 0.3 mW/cm2. 
 
 
Protections Against Risk From Providing Data. 
• 
Data security: Electronic data will be maintained in a password protected database, on password 
protected servers, to which only the study team has access. Daily hand-held data is de-identified, 
and is transferred to lab computers via a secure connection. REDCap is a HIPAA compliant, 
secure database system. Data validity will be maintained by validity criterion in the database, and 
errorchecking procedures. Study staff will complete training in HIPAA regulations, and will be 
clearly instructed not to divulge confidential information regarding subjects. The system will also 
be developed in accordance with FDA Part 11 [21CFR11] guidelines. Participant records are kept 
confidential, with paper records in a secure location and computer records password protected, 
available only to study staff. 
• 
CSF will be obtained by a board certified anesthesiologist during the course of routine care in 
providing spinal anesthesia. 
• 
Symptoms of depression, anxiety, and other forms of psychological distress symptoms are to be 
measured upon enrollment. Because many patients will endorse some level of distress, and it is 
impossible to know for each individual when they require or are even open to mental health 
assistance. Therefore, and because our questions may focus patients attention on these sources of 
significant distress, we will offer a referral to a mental health professional to ALL patients. To be 
specific, we will provide all patients with telephone numbers and addresses of at least three local 
mental health resources. We will not explicitly seek suicidal ideation. Patients spontaneously 
endorsing thoughts of harming themselves or others will have their treating physician informed 
for an assessment if they need to be guided to the emergency room, or other care pathway. 
 
 


Protocol version: 3/5/2020 
14 
Data and Safety Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study staff. 
 
The DSMP outlined below will provide appropriate oversight and monitoring to ensure the safety of 
participants, the validity of the data, and make intermittent recommendations whether to continue, modify 
or stop the study. The DSMP will utilize an independent DSMB to ensure the effective institution of the 
DSMP. 
 
This DSMB will have discretion to unblind any results, or conduct any inquiry needed to ensure the 
safety and efficacy of the trial at the request of the DSMB chair. The committee will maintain a written 
record of its meetings. 
 
Scope of Data Monitoring 
The primary source of the data will be the entered questionnaire data and adverse event reporting. 
 
Study admission data 
Monitoring of admission data will include the number of subjects requesting participation in the study, 
number of subjects screened and number of subjects admitted to the study. The DSMB may request a 
report of the reason why subjects were disqualified from participating in the study. For subjects admitted 
to the study, the DSMB will review eligibility criteria for admitted subject, any protocol deviations and/or 
violations, and the demographic distribution of the subjects by group. 
 
Protocol Compliance 
The DSMB will monitor the data to assess compliance with the protocol including the adherence to the 
randomization schedule. The DSMB will also monitor the quality and completeness of the data being 
collected, including the frequency of missing or erroneous data, and presence and frequency of outliers. 
 
Safety Data 
Monitoring of safety data will include review of Adverse Events (AEs) and Serious Adverse Events 
(SAEs), trial retention, and reason for drop out. Safety information will be reported to the DSMB in an 
unblinded manner. Formal statistical analyses of the safety data may be requested by the DSMB. For 
SAEs, data will include all the adverse event data meeting the FDA definition of serious adverse events. 
In the assessment of SAEs, the DSMB will review each individual case including treatment group 
assignment. After each meeting of the DSMB, the secretary will forward a summary report of all serious 
and unexpected adverse experiences to the principal investigator to summarize the DSMB's review of the 
serious and unexpected adverse events reported. Furthermore, the DSMB will make a recommendation to 
continue, modify or halt the study protocol. This report will be transmitted to the Wake Forest University 
IRB and NIH. Safety data will be prepared for review following the enrollment of each 40 subjects. 
 
Establishing a DSMB Board membership 
The DSMB will be appointed by Dr. Eisenach and Dr. Houle with the purpose of reviewing, approval, 
and monitoring the implementation of the DSMP. The DSMB will have three members encompassing 
multidisciplinary expertise who are not involved in the study protocol. Board members will have no 
financial and/or scientific ties to the outcome of the clinical trial to avoid any real or perceived conflict of 
interest. At the start of each new member's term, the individual will sign a confidentiality statement 
promising not to disclose any proprietary and nonproprietary data. The DSMB will include the following 
physicians; Peter Pan, M.D., Professor of Anesthesiology, Robert Weller, M.D., Professor of 
Anesthesiology and Dennis Ang, M.D., Associate Professor of Rheumatology and Immunology. 
 
 


Protocol version: 3/5/2020 
15 
Board meeting schedule 
The board will have scheduled meetings twice a year and expedited meetings to review unexpected SAEs 
or other urgent issues that may arise during the trial. Unscheduled meetings may be initiated by the 
DSMB chair, Dr. Eisenach, or Dr. Houle. The data to be reviewed by the DSMB will be available to the 
Board members. 
 
DSMB Recommendations: 
DSMB recommendations will be made in writing by The DSMB chair to Dr. Eisenach. The secretary will 
prepare meeting minutes for inclusion in the DSMB report. The draft report will be reviewed by all Board 
members prior to issuance of the final report. DSMB recommendations will then be forwarded to the 
NIGMS program officer and Wake Forest University IRB. 
 
 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes 
will be promptly reported by the principal investigator or designated member of the research team to 
the IRB and sponsor or appropriate government agency if appropriate. 
 
 
Appendix 
1. Bioinformatics Core 
2. Copies of each questionnaires or surveys that will be used 
3. Debriefing statement 
 
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