Efficacy of Intrathecal Oxytocin to Speed Recovery After Hip Surgery
Phase: PHASE2
Conditions: Postoperative Pain
Sponsor: Wake Forest University Health Sciences

 
 
Unique Protocol ID: IRB00036246 
Title: Efficacy of Intrathecal Oxytocin to Speed Recovery After Hip 
Surgery 
NCT03011307 
Document Date: 12/13/2016 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
1a 
12/13/2016 
BACKGROUND 
 
There is a strong experimental basis to support the study of oxytocin by the spinal route 
for analgesia and to speed recovery from pain after injury in humans.  Oxytocin containing cells 
in the dorsal parvocellular division of the paraventricular nucleus (PVN) project to the spinal 
cord (1).  Noxious stimulation activates these cells via the A1 noradrenergic relay in the pons (2) 
and produces analgesia by spinal release of oxytocin, since intrathecal injection of an oxytocin 
receptor antagonist worsens pain behaviors from peripheral inflammation (3).  Direct electrical 
stimulation of the PVN reduces dorsal horn neuronal responses to noxious stimulation, and this 
is blocked by administration of sequestering antibody for oxytocin (4).  Similarly, direct 
electrical stimulation of the PVN reduces behavioral sensitivity in a model of chronic 
neuropathic pain, and this effect is blocked by an 
oxytocin receptor antagonist (5).  Intrathecal injection of 
oxytocin in normal rats reduces dorsal horn neuronal 
responses to noxious stimuli (6) as well as behavioral 
responses to noxious thermal (3), mechanical (3), and 
chemical (7) stimuli.  Finally, intrathecal injection of 
oxytocin in rat models of chronic pain also reduces 
dorsal horn neuronal responses to sensory stimulation 
(6) as well as behavioral responses to thermal (5) and 
mechanical (7) stimuli.   
 
Many compounds and manipulations produce 
evidence of analgesia in rodents, but most studies, 
including the ones cited for oxytocin above, rely on 
reflex withdrawal responses to simulation or 
electrophysiologic responses in individual cells.  As such, the relevance of these observations to 
spontaneous pain in humans is far from certain.  Two observations, however, strongly suggest 
that intrathecal oxytocin would be analgesic in humans and would speed recovery from pain after 
surgery. 
 
The first, most direct evidence, is a report from China of 608 patients with chronic low 
back pain and 369 patients with acute low back pain who received single intrathecal injections of 
oxytocin (8). Intrathecal oxytocin produced acute analgesia in both settings, with nearly 
Figure 1.  Percentage of patients 
with complete pain relief from 
intrathecal injection of oxytocin. 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
2a 
12/13/2016 
universal complete pain relief reported at doses of approximately 30 μg per injection for chronic 
low back pain and 60 μg per injection for acute low back pain (Figure 1).  Duration of analgesia 
was dose dependent, with < 1 hr analgesia from approximately 7 μg per injection and > 5 hr 
analgesia from approximately 60 μg per injection. 
The second line of evidence comes from our clinical observations in obstetric patients.  
Physical injury, whether from trauma or surgery, is recognized as an important cause of chronic 
pain, and the incidence of chronic pain after surgery ranges from 10 to 40%, depending on the 
procedure (9).  We recently completed a clinical trial of over 1200 women examining the 
incidence of chronic pain after vaginal and cesarean delivery.  Although approximately 10% of 
women had pain 2 months after delivery (10), the incidence of pain one year after delivery was 
remarkably low (95% confidence limit for pain at one year of 0.7%).  This is at least an order of 
magnitude lower than that reported from any other abdominal surgery, including superficial 
surgery like inguinal herniorrhaphy (9).  We hypothesized, based on these studies, that a factor 
which is present during pregnancy may be protective of chronic pain.  We therefore examined 
hypersensitivity in rats following a surgery (spinal nerve ligation) which is commonly used as a 
model of neuropathic pain.  To our surprise, this surgery produced similar degrees of 
hypersensitivity when performed during pregnancy than in nonpregnant animals (Figure 2).  In 
contrast to this lack of effect of pregnancy, the degree of hypersensitivity significantly 
diminished for several weeks after delivery, abruptly returning when the pups were weaned from 
Figure 2.  Withdrawal threshold drops 
similarly after spinal nerve ligation 
(SNL, a model of neuropathic pain) in 
pregnant and nonpregnant animals, but 
this hypersensitivity is alleviated after 
delivery.  Colored areas are 95% CIs. 
Figure 3.  In animals with SNL 
performed during pregnancy, withdrawal 
threshold drops abruptly when pups are 
weaned at 17 days, but when SNL is 
done on the day of delivery, withdrawal 
threshold never changes from control.   

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
3a 
12/13/2016 
the dams (Figure 3).  When nerve injury surgery was performed on the same day as delivery, 
hypersensitivity never developed, mimicking the clinical trial results of a lack of chronic pain 
from surgical or vaginal delivery (Figure 3). 
We subsequently performed several studies which suggest that spinal release of oxytocin 
represents the protective factor against chronic pain after childbirth.  Intrathecal injection of the 
specific oxytocin receptor antagonist, atosiban, temporarily reverses the blockade of nerve injury 
induced hypersensitivity in the postpartum period in rats.  Similarly, intracerebroventricular 
administration of the α-adrenoceptor antagonist, phentolamine, which is known to block the 
effects of lactation on activation of oxytocin-containing neurons in the paraventricular nucleus 
(PVN) of the hypothalamus, also temporarily reverses the blockade of nerve injury induced 
hypersensitivity in the postpartum period in rats.  Finally, protection against hypersensitivity 
from nerve injury is abruptly reversed when pups are separated from dams for 24 hr, and this is 
accompanied by a large decrease in oxytocin concentration in cerebrospinal fluid.  Although we 
are currently performing more laboratory studies to further define this mechanism, these data 
suggest that spinal oxytocin receptor stimulation in the period immediately following delivery 
speeds recovery from injury-induced hypersensitivity and subsequent chronic pain. 
We recently completed a Phase 1 safety study of intrathecal oxytocin and observed no 
serious adverse events over the dose range studied (5-150 μg).  One subject at the 150 μg dose 
had transient subjective numbness in sacral dermatomes, but this was preceded by a vasovagal 
episode beginning just prior to spinal injection, and this did not occur in other subjects at this 
dose.  There were no objective signs of motor or sensory dysfunction in any volunteer, and blood 
pressure, heart rate, sensorium, corrected QT interval and serum sodium were unaffected. 
In addition, we are progressing on two other Phase 2 studies, one in healthy volunteers 
and another in patients with chronic neuropathic pain, and have observed no serious adverse 
events in these subjects. 
We anticipate that intrathecal oxytocin will speed recovery from pain after major surgery 
(hip arthroplasty).  For these future studies, we will use a randomized, controlled and blinded 
study of intrathecal oxytocin in patients scheduled for hip arthroplasty, with primary outcome 
being the slope of change in pain over the first 60 days following surgery, using growth curve 
modeling and a ln(time) function.  

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
4a 
12/13/2016 
References 
 
1.  Hallbeck M, Larhammar D, Blomqvist A. Neuropeptide expression in rat paraventricular 
hypothalamic neurons that project to the spinal cord. J Comp Neurol 2001;433:222-38. 
 
2.  Pan B, Castro-Lopes JM, Coimbra A. Central afferent pathways conveying nociceptive 
input to the hypothalamic paraventricular nucleus as revealed by a combination of 
retrograde labeling and c-fos activation. J Comp Neurol 1999;413:129-45. 
 
3.  Yu SQ, Lundeberg T, Yu LC. Involvement of oxytocin in spinal antinociception in rats 
with inflammation. Brain Res 2003;983:13-22. 
 
4.  Rojas-Piloni G, Lopez-Hidalgo M, Martinez-Lorenzana G, Rodriguez-Jimenez J, 
Condes-Lara M. GABA-mediated oxytocinergic inhibition in dorsal horn neurons by 
hypothalamic paraventricular nucleus stimulation. Brain Res 2007;1137:69-77. 
 
5.  Miranda-Cardenas Y, Rojas-Piloni G, Martínez-Lorenzana G, Rodríguez-Jiménez J, 
López-Hidalgo M, Freund-Mercier MJ, Condés-Lara M. Oxytocin and electrical 
stimulation of the paraventricular hypothalamic nucleus produce antinociceptive effects 
that are reversed by an oxytocin antagonist. Pain 2006;122:182-9. 
 
6.  Condes-Lara M, Maie IA, Dickenson AH. Oxytocin actions on afferent evoked spinal 
cord neuronal activities in neuropathic but not in normal rats. Brain Res 2005;1045:124-
33. 
 
7.  Yang J, Yang Y, Chen JM, Liu WY, Wang CH, Lin BC. Central oxytocin enhances 
antinociception in the rat. Peptides 2007;28:1113-9. 
 
8.  Yang J. Intrathecal administration of oxytocin induces analgesia in low back pain 
involving the endogenous opiate peptide system. Spine 1994;19:867-71. 
 
9.  Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. 
Lancet 2006;367:1618-25. 
 10.  Eisenach JC, Pan PH, Smiley R, Lavand'homme P, Landau R, Houle TT. Severity of 
acute pain after childbirth, but not type of delivery, predicts persistent pain and 
postpartum depression. Pain 2008;140:87-94. 
 
 
 
 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
5a 
12/13/2016 
Protocol 
Efficacy of Intrathecal Oxytocin to 
Speed Recovery after Hip Surgery 
 
GOAL:  Determine the effect of intrathecal oxytocin on speed of reduction in pain for the first 
60 days after hip surgery. 
 
METHODS: 
 
Primary analysis: Slope of modeled change in daily worst pain intensity scores from the first 60 
days after surgery. 
 
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    
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 at 
Piedmont Plaza 2 (HPRU) for consent and their initial study visit. Subjects will be seen in the 
HPRU twice; within 2 weeks prior to surgery, and approximately 2 months after surgery. 
Subjects selection criteria:  We will recruit patients having primary, unilateral hip 
arthroplasty (HA). 
 
Inclusion criteria:  Adult, non-pregnant adults scheduled for elective HA, 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) taking  > 100 mg morphine 
equivalents/day; (5) suffering from a psychotic disorder or a recent psychiatric hospitalization. 
 
Sample size:  Single-center interventional study of 120 evaluable patients having primary 
HA.  
 
 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
6a 
12/13/2016 
Interventions and interactions:   
Preoperative procedures. Eligible subjects will be identified at least 2 weeks prior to 
surgery, informed consent obtained, and 
a ~ 1.5-hr preoperative assessment will 
be performed, consisting of 3 parts. 
First, we will record demographic and 
history information, including pre-
existing pain elsewhere.  Second, we 
will administer the 9CH iPad game.  
Third, 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 research personnel. 
From these questionnaires, 
we will place each 
participant, as on another 
protocol approved by this 
IRB, on a 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 4).  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) 
Figure 4: The dimensional structure of the continuum of cognitive 
style to be used, including psychosocial constructs associated with 
each end. 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
7a 
12/13/2016 
 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 
approximately  2 weeks prior to surgery so that they will become familiar with the devices to 
increase compliance and adherence to the protocol after surgery. 
 
 
We will 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, Wisconsin card sorting task to assess executive function, and the TSK 
to assess kinesiophobia. Participants will complete these tasks at baseline and again when 
returning to the HPRU 2 months after surgery, when they will return the electronic tablet and the 
accelerometer. 
 
Drug treatment. Patients will be randomized to equal numbers in one of two groups to 
receive either 1) intrathecal oxytocin, 100 μg or 2) intrathecal saline. Once the spinal needle is 
inserted, 2 ml of cerebrospinal fluid will be withdrawn for subsequent measurement of 
neurotransmitters and other non-genomic modulators of pain responses, then the study solution 
in a 2 ml volume will be administered, followed by injection of local anesthetic with adjuvants as 
chosen by the anesthesiologist.  Intrathecal study drug solutions will be provided by the research 
pharmacy and the investigators and patients will be blinded to treatment group.  
 
Intraoperative and in-hospital care. We will not limit intraoperative surgical management or in-
hospital analgesic management. Subjects will receive anesthesia and postoperative analgesia per 
the standard of care that is utilized by the Regional Anesthesia and Pain Management (RAAPM) 
team. A study team member will record  a verbal pain score 24 hours after the administration of 
the peripheral nerve blocks, potential confounds including surgical complications, in-hospital 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
8a 
12/13/2016 
physical therapy, intraoperative and postoperative opioid, gabapentin, ketamine, and regional 
anesthesia administration, and days from surgery to discharge. Subjects will also play the 9CH 
iPad game that they were introduced to in the preoperative visit 24 hours after surgery. 
 
Post-hospital discharge measures. Patients will begin daily evening electronic diary 
entries on the day of hospital discharge for 60 days. 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 a customized, secure database. Several tablets equipped with pre-
paid 4G wireless access will be available to ensure that participants without home internet 
connections can participate. The diaries will be monitored and maintained by research personnel 
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 60 days after discharge.  Participants will also complete the cognitive tasks (Iowa 
gambling task, Wisconsin card sort, TSK) that they were introduced to at the baseline session at 
2 months after hospital discharge. These tasks will again be administered via the PEBL software. 
Questionnaires done at pre-randomization will be repeated at 2 months after surgery. We will 
also record objective assessments of joint function at the times when the subjects return to clinic 
for their postoperative visits.  Finally, we will contact each participant by telephone monthly 
until 6 months after surgery and at one year after surgery with a brief (<10 min) series of 
questions regarding their pain, physical function, and disability (12 item WHODAS 2.0) 
following surgery. 
 
Subject payment: Subjects will be paid $700 with pro-rated payment steps (listed below) 
to study completion. The tablet devices will be returned to each study center for re-use. 
Pro-rated payment will be made as follows:  
• $100 for completion of the first HPRU study visit 
• $100 for completion of the second HPRU study visit 
• $100 for return of study supplies (electronic tablet, accelerometer and chargers) 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
9a 
12/13/2016 
• $200 for completing at least 90% of the daily diary entries on the electronic tablet and 
wearing the accelerometer through 8 weeks after surgery at least 90% of required time 
• $200 for completion of all the scheduled study visits and telephone questionnaires 
 
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.   
 
Analytical plan:   
Data analysis. We will examine the daily frequently obtained pain scores and the total daily 
(i.e., non-sleep) movement score. One growth curve model will be created for each outcome 
(pain, movement). 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?). 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) as an 
additional, novel predictor. 
Growth curve modeling, sometimes referred to as mixed-effects modeling, or hierarchical 
linear modeling, will allow us to specify a change trajectory (i.e., healing) that is unique to each 
individual/animal. The nature of the common form of changes in pain/behavior will be modeled 
using curvilinear forms (e.g., polynomial regression). Through the use of fixed and random 
effects, we will then be able to examine the influences on the changes in pain and activity 
measurements. In this way, we can examine the predictors immediately after surgery, the factors 
that predict delayed/absent recovery, patterns in these changes across individuals, examine the 
relationships between initial measurements and expected change, and test efficacy of the test 
intervention, intrathecal oxytocin.   
To examine how the subjects in these studies recover over the repeated measurement 
occasions, we will employ hierarchical linear modeling (HLM: Raudenbush & Bryk, 2002).  The 
application of HLM to individual change data is well suited for the expected changes that occur 
after surgical injury.  HLM is a polynomial regression with random effects where interaction 
terms are used to examine impacts on the change parameters.  Because of the nature of the 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
10a 
12/13/2016 
expected change, the trajectories will be modeled using parameters consisting of an intercept and 
some form of change parameter(s).  Where appropriate, the slope and quadratic parameter will be 
estimated using the natural log of time (change in recovery). The intercept is coded to represent 
the initial level (first day after hospital discharge) of the outcome variable.  The slope estimates 
the linear change over time (or ln of time) and represents the increase or decrease in the variable. 
Measurements taken before discharge (i.e., pain reporting immediately after surgery, analgesic 
use), demographic predictors (e.g., age, sex, previous history of chronic pain), and operative 
characteristics (e.g., surgery type, anesthesia regimen) will be used as predictors in a basic 
trajectory model. Variability between surgeons will be modeled using random effects by surgeon 
(with individual patients viewed as nested within surgeon). We will add additional predictors that 
measure baseline levels of affective distress, fear of pain, etc. We will utilize model fit indices 
(e.g., Bayesian Information Criterion (BIC)) to best characterize the change process using the 
most parsimonious model. Separate models will be conducted for pain reporting and physical 
activity. 
Based on analysis of over three dozen subjects after total hip or knee arthroplasty and over 
500 subjects after cesarean delivery using the methods in the current protocol, we anticipate that 
the ln (time) model will best fit the population and will be used as the primary outcome measure 
for the primary and secondary analyses involving recovery from pain and inactivity. 
All analyses will be conducted with the most recent versions of SAS (SAS, Inc., Cary, NC), 
The R Project for Statistical Computing (R Foundation for Statistical Computing, Vienna, 
Austria) or SPSS (IBM Corp., Chicago, IL). Where appropriate, all analyses will be two-tailed 
with statistical significance interpreted at p < 0.05. 
 
Statistical Power Considerations. Enrolling N = 120 participants (n = 60 per study arm) 
provides sufficient power to examine the study’s primary hypothesis. Assuming that each 
individual contributes ~ 60 daily measurements, with alpha = 0.05, power = .80, a modest level 
of within-subject correlation, and adequate model fits (SD of the residuals < 2.0), we will be able 
to detect difference in slopes of d = 0.09 units. Thus, if the saline group exhibited a mean pain 
score of 8.0 VAS units after surgery and decreased on average 0.38 points each day (i.e., 
expected full recovery at 21 days), sufficient power exists to detect an enhanced slope of 0.47 in 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
11a 
12/13/2016 
the oxytocin group (i.e., expected full recovery in ~17 days). This difference is a clinically 
meaningful effect size that could substantially improve the life of patients.  
 
Outcome measures. 
Primary outcome measure: Modeled trajectory of recovery from pain (worst daily pain intensity) 
using a log of time form. 
 
Several secondary analyses are planned, including slope of modeled change in other pain 
intensity measures (daily average pain and pain right now), activity and cognitive function tests.  
Interaction between preoperative cognitive style and slope of modeled change in these measures. 
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 and 2 
months after discharge will be examined using generalized linear model with time as a fixed 
factor.  
 
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 HA.  
 
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 HPRU. If the subject has signed the informed consent 
prior to their first visit, consent will be confirmed and all questions answered prior to any study 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
12a 
12/13/2016 
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.   
 
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.  One patient receiving intrathecal oxytocin in previous and ongoing studies at this 
institution exhibited hypotension and bradycardia.  Although these symptoms were consistent 
with previous vaso-vagal episodes that the volunteer subsequently described with procedures, it 
is conceivable that this could be a drug effect. Blood pressure is monitored at frequent intervals 
(every 1-2 min) during the first 10 min after spinal injection for spinal anesthesia for HA, then 
every 2-5 min thereafter, and hypotension treated with intravenous fluid administration or 
vasopressors. 
 
Other risks of intrathecal oxytocin uterine contractions during the 3rd trimester of 
pregnancy, and unforeseen adverse events.  Animal studies have shown no histologic, 
behavioral, or neurochemical evidence of neurotoxicity with doses and concentrations several 
fold greater than those proposed in this study.   
 
In a previous application, the IRB noted that questionnaires of psychologic well being, 
including depression and catastrophizing cognition, could produce emotional distress in 
participants, and we included disclosure of this risk in the informed consent document and 
additional resources for counseling or treatment should this occur.  We will use the same 
approach in this protocol.  
 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
13a 
12/13/2016 
Protections against risk. 
• 
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 error checking 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. 
• 
Cerebrospinal fluid 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. 
 
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. 
 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
14a 
12/13/2016 
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 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
15a 
12/13/2016 
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, FDA, 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 two members 
encompassing multidisciplinary expertise who are not involved in the study protocol including 
an anesthesiologist and clinical researcher. Thus the DSMB will encompass expertise in clinical 
research design and methodology. 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. The 
chairperson of the DSMB, will have previous experience in monitoring clinical trials with 
administrative experience.  
 
The DSMB will also include a non-voting member as a secretary. DSMB members will disclose 
in writing to the irb conflict of interest representative any potential conflicts of interest, actual or 
implied by appearance. 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 data safety monitoring board physicians will be Dr. Francis Walker, Professor, Department 
of Neurology and Dr. Laura Dean, Associate Professor, Department of Anesthesiology at Wake 
Forest Baptist Medical Center. Drs. Walker and Dean currently serve as DSMB for 2 existing 
spinal oxytocin studies. 
 
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 

Efficacy of Intrathecal Oxytocin to  
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PI: James C. Eisenach, M.D. 
 
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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. 
 
Conduct of the meetings 
DSMB meetings will be divided into three sessions: open, closed and executive. Drs. Eisenach 
and/or Houle will attend the open session and present relevant information to the dsmb about the 
trial. The open session will focus on the status of the study, problems with accrual and follow-up, 
baseline demographic data, compliance issues, frequency of adverse events, data quality issues, 
flow of forms, and data based protocol modification issues. Following the open session, a closed 
session will be held. During the closed session, the dsmb chair will conduct the review of all 
issues and put each issue to a vote. Following the closed session, an executive meeting may be 
held to discuss any unmasked analysis of the trial and any sensitive issues surrounding the trial. 
 
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 report will outline 
and summarize all discussions during the open and closed sessions of the meeting. 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. 
 
 
References 
Raudenbush, S. W. and A. S. Bryk (2002). Hierarchical Linear Models: Applications and Data 
Analysis Methods. Thousand Oaks, CA, Sage Publications. 

Efficacy of Intrathecal Oxytocin to  
Speed Recovery after Hip Surgery  
 
 
 
PI: James C. Eisenach, M.D. 
 
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12/13/2016 
Turk, D. C., et al. (2006). "Developing patient-reported outcome measures for pain clinical trials: 
IMMPACT recommendations." Pain 125(3): 208-215. 
 
 
 
 
 
Appendix 
1. 
Copies of each questionnaires or surveys that will be used 
2. 
Consent form