Randomized, Double Blind, Cross Over Study Comparing Effectiveness of Traditional Opioids Versus Opioids in Admixture With Bupivacaine Upon Self-administration of Boluses Via a Personal Therapy Manager (PTM) in Intrathecal Pumps
Phase: PHASE4
Conditions: Pain, Intractable, Breakthrough Pain, Chronic Pain
Sponsor: University Hospitals Cleveland Medical Center

Study title: “Effectiveness of Self-Administered Boluses of Intrathecal Bupivacaine in 
Patients with Chronic Non-Cancer Pain Implanted with IDDS: A Double Blind 
Randomized Study”
Cover Page
NCT02886286
Document Date: January 29, 2016

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Study title: “Effectiveness of Self-Administered Boluses of Intrathecal Bupivacaine in 
Patients with Chronic Non-Cancer Pain Implanted with IDDS: A Double Blind 
Randomized Study”
Principal Investigator: Salim Hayek MD, PhD 
Protocol Title:  
“Randomized, double blind, cross over study comparing effectiveness of traditional 
opioids versus opioids in admixture with bupivacaine upon self-administration of boluses 
via a Personal Therapy Manager (PTM) in Intrathecal pump”.  
ABSTRACT 
2.1 Purpose:  
To determine whether the local anesthetic bupivacaine delivered intrathecally in small 
doses via PTM self-administered boluses significantly improves the breakthrough pain and 
functional status of patients with chronic intractable pain who are managed with an 
intrathecal drug delivery system.  
2.2 Research Design:  
Randomized, double-blind cross over effectiveness study. 
2.3 Methodology /Technical Approach:   
Seventeen patients who are already using SynchroMed II pump containing an admixture 
of bupivacaine and an opioid and using PTM doses will be randomized into two groups: 
  Group I:  Will have the intrathecal pumps refilled with 10 milliliters of a solution 
containing their usual intrathecal opioid with bupivacaine.  
  Group II:  IT pump will be filled with 10 ml of intrathecal opioid without bupivacaine. 
Both patients and the evaluating physician will be blinded. 
In order to accomplish this, only the central compounding (investigational) pharmacy at 
University Hospitals Case Medical Center would make two solutions labeled: A or B 
respectively.  Study subjects will be randomized and randomization order will be held at 
the pharmacy that will supply the medication.  Patients will be kept on each solution for 
one week.  Data will be collected daily.    
3. OBJECTIVESAND RATIONALE
The objective of this project is to conduct a randomized, double-blind, effectiveness study 
to determine whether intrathecal delivery of bupivacaine via self-administered boluses 
significantly improves breakthrough pain and functional status in patients with chronic, 
non-cancer pain who are managed with an implanted intrathecal drug delivery system 
(IDDS). This is important because some practitioners choose only a mono therapy (i.e. 
opioid) in the intrathecal solution without bupivacaine. This would delay pain relief 
without the near instant relief bupivacaine has been reported to provide after a PTM bolus. 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Study title: “Effectiveness of Self-Administered Boluses of Intrathecal Bupivacaine in 
Patients with Chronic Non-Cancer Pain Implanted with IDDS: A Double Blind 
Randomized Study”
Principal Investigator: Salim Hayek MD, PhD 
4. MEDICAL APPLICATION
Intrathecal drug delivery is an established interventional modality in managing different 
chronic pain conditions, especially post laminectomy syndrome, also known as failed 
back surgery syndrome (FBSS).  Intrathecal delivery of pharmacological agents reduces 
systemic side effects and the potential for aberrant medication use1. 
Previous publications from our center have demonstrated that bupivacaine in combination 
with intrathecal opioids results in long term relief and reduces opioid dose escalation2—
an important problem in intrathecal drug delivery Particularly, the PTM dosing function 
with bupivacaine has rapid onset of action3 (given bupivacaine site of action 
preferentially on nerve rootlets) which significantly improves patient satisfaction4. 
5. BACKGROUND AND SIGNIFICANCE
Treatment of chronic pain is a challenging endeavor and intrathecal drug delivery is an 
important tool in the armamentarium of Pain Medicine specialists. 
Continuous intrathecal drug delivery is an interventional modality often applied in 
refractory chronic pain of cancer or non-cancer etiology. Intrathecal drug delivery 
systems (IDDS’s) involve programmable pumps that constantly deliver the medication 
into the spinal canal but also may allow the patients to self-administer a dosage of 
medication that is pre-determined by the clinician in terms of dose and frequency. The 
use of this latter feature helps control emergent (breakthrough) pain and/or preempts 
predictable mechanical pain. The patient is provided with a remote control device (called 
Personal Therapy Manager—PTM) that is easy to use and allows self-administration of 
boluses3,4. 
Standard of care medications used in IDDS include opioids such as morphine or 
hydromorphone and the local anesthetic bupivacaine. A combination of an opioid with 
bupivacaine is used in the vast majority of patients implanted at University Hospitals 
Case Medical Center.  
Opioid medications work by binding to opioid receptors in the substantia gelatinosa in 
the dorsal horn of the spinal cord. Hence, the opioid would have to diffuse 1-2 mm below 
the surface of the spinal cord in order to reach its target and effect pain relief. Similar to 
other local anesthetics, bupivacaine works by blocking sodium channels. While these are 
distributed ubiquitously in the nervous system, it is much more efficient for bupivacaine 
to bind to sodium channels on nerve rootlets (fila radicularia or small branches that divide 
off each nerve root before it plugs into the cord). This may explain why many patients 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Study title: “Effectiveness of Self-Administered Boluses of Intrathecal Bupivacaine in 
Patients with Chronic Non-Cancer Pain Implanted with IDDS: A Double Blind 
Randomized Study”
Principal Investigator: Salim Hayek MD, PhD 
who use a PTM to self-administer boluses report instant pain relief when bupivacaine is 
present in the intrathecal pump solution1.   
The effective analgesic PTM dose of bupivacaine is 0.4-1.5 mg and is self-administered 
with a lock-out interval of 15-120 minutes as needed for pain control. The dose is titrated 
for analgesic effectiveness without causing motor impairment. 
6. PLAN
6.1 New Investigational Drugs/ Investigational Devices Exemption Status:  N/A 
6.2 Selection of Subjects 
6.2.1 Type of the Subject Population 
Patients with intractable chronic pain being managed with an intrathecal drug delivery 
system programmed with a continuous infusion as well as a self-administered bolus (PTM) 
for breakthrough pain who have an opioid as well as bupivacaine in the intrathecal solution 
and have been stable on their current settings for at least 3 months.      
6.2.2 Inclusion and Exclusion Criteria 
a. Inclusion Criteria

Age more than 30 years implanted with an intrathecal drug delivery device.

Intrathecal pump patients on stable dose for the last 3 months.

Using on average more than 2 and less than 10 PTM  doses per day

Intrathecal medication admixture consisting of bupivacaine and another opioid
(fentanyl or hydromorphone or morphine)
b. Exclusion Criteria

Using 10 or more PTM bolus doses per day or 2 or less PTM bolus doses per day

Pending litigation or worker compensation claim

Any recent (less than 3 month) procedures in spine (surgeries) or catheter
adjustments.

Recent pump dose adjustment within the past 3 months

Pumps with medications other than bupivacaine opioid combination.
6.2.3 Recruitment 
Subjects will be recruited from among patients seen at the University Hospitals pain clinic 
at UHCMC by attending physicians.  Screening will be done before obtaining consent by 
an investigator.  Screening for stable programmed mode and dose of medication for at least 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Study title: “Effectiveness of Self-Administered Boluses of Intrathecal Bupivacaine in 
Patients with Chronic Non-Cancer Pain Implanted with IDDS: A Double Blind 
Randomized Study”
Principal Investigator: Salim Hayek MD, PhD 
three months.  Except for parking pass and meal pass, no subject will be compensated for 
participation.  
6.2.4 Consent Process  
The Principal Investigator and/ or associate investigators will present and explain in detail 
the consent and HIPAA authorization forms to potential participants.  If interested, eligible 
individuals will be given the opportunity to ask and have all questions answered before 
signing the informed consent document and HIPAA authorization form.  
Subjects will be consented by one of the investigators after they are screened by a pain 
clinic attending for eligibility, before having their intrathecal drug delivery system refilled.  
In subjects who elect to participate, the consent form will be taken home to be examined 
and after a detailed explanation is given, will be signed in the clinic during the next visit 
for the refill.  An explanation in lay terms for the reason of the study and the proposed 
effectiveness bupivacaine has on near immediate relief of breakthrough pain will be used 
to promote patient understanding.   
6.3 Study Design and Methodology  
6.3.1 Study Design 
This is a randomized, double-blind, effectiveness study looking at self-administered 
boluses of an opioid with and without bupivacaine via a Personal Therapy Manager (PTM) 
in patients with an intrathecal drug delivery system to assess the effect of bupivacaine 
administered by PTM on pain scores and functional status in patients with breakthrough 
pain.  Patients in group I will receive a refill of a 10 mL solution “A” containing their usual 
intrathecal opioid and including bupivacaine.  Patients in group II will receive a refill of a 
10 mL solution “B” containing their usual intrathecal opioid without bupivacaine.  Both 
groups will be kept on solution A and on solution B for a maximum of one week each after 
which they will cross over to the other solution for one week and then exit the study.  The 
patients will then be returned to their baseline programming.  Potential changes in 
programming to benefit patients may be undertaken as necessary—if existent--after 
unblinding.  Primary outcome measures will include 0-10 numerical rating scale (NRS) or 
Visual Analogue Scale (VAS) both immediately before and within 30 minutes after a PTM 
bolus.  Patients will be provided with a diary to record pain scores just before a PTM bolus 
and the lowest pain score within half an hour after a PTM bolus. Only 5 recording per day 
will be available on the diary—thus patients would record pain scores only before and after 
the first 5 PTM boluses.  However, the scores before and after the first 3 successful PTM 
boluses would be the only ones considered.  Successful PTM activations would be 
determined by review of the patient PTM diary and the internal log from the intrathecal 
drug delivery system.  Each recording on the PTM diary would be time matched to the 
successful PTM activation code in the internal log.  This will obviate any potential mis-
administered bolus whereby the patient does not activate the bolus device appropriately.  

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Study title: “Effectiveness of Self-Administered Boluses of Intrathecal Bupivacaine in 
Patients with Chronic Non-Cancer Pain Implanted with IDDS: A Double Blind 
Randomized Study”
Principal Investigator: Salim Hayek MD, PhD 
Secondary outcome measures will include average NRS pain scores for the day, functional 
capacity as evaluated by the Oswestry disability index (ODI) scores, number of boluses 
used, paresthetic sensation post bolus, and Global Perceived Effect.  
6.3.2 Study Methodology/Procedures 
Seventeen patients who are already using Intrathecal therapy and PTM dose will be 
randomized in a 1:1 ratio by a computer generated randomization table to receive one of 
two treatments.  At patient’s regular scheduled appointment for pump refill, the residual
intrathecal medication volume will be removed from the pump and half of the patients 
will be allocated to receive the opioid alone whereas the other half will receive the same 
solution containing the opioid with bupivacaine. 
At each of the first two visits following signing of informed consent Patient should be 
refilled in the IDD pumps with a 10 mL solution containing either the usual intrathecal 
medications (solution A or Solution B–coded by pharmacy) including bupivacaine with 
the opioid (same intrathecal solution) or their usual intrathecal solution with the same 
opioid concentration but without bupivacaine. Taking away bupivacaine from the 
intrathecal solution does not result in withdrawal. The investigational pharmacy at 
UHCMC would be the only party who knows whether the patients are receiving solution 
A or solution B. No changes will be recorded in pump programming with respect to the 
opioid.  However, upon each of the two first visits after consent, when the patients are 
refilled with 10 ml of solution A or solution B, the pump will be programmed with the 
same concentration of the opioid and bupivacaine labeled at 29 mg/ml at the first visit 
and 30 mg/ml at the second visit.  Changing the solution at the first visit to a label of 
bupivacaine 29 mg/ml will not affect the delivery of the opioid or bupivacaine (if the 
solution has bupivacaine) as the only (and primary) driver for amount delivered is the 
opioid which will not change in concentration or dose throughout the study. However, 
labeling the bupivacaine with 29 mg/ml (a concentration not used and different from 
previous bupivacaine concentration) will prompt the decision algorithm to request a 
“bridge bolus”—namely, a calculation of how long it would take for the new solution to 
get through the dead space in the pump and catheter to get to the catheter tip. Upon 
changing the solution in the pump, it may take about a day or so for the new medication 
to enter the intrathecal space because of dead space.  The exact duration is dependent on 
the patient’s initial rate (ml/day) the length of the catheter in the patient; thus would vary 
from patient to patient.  The dead space in the Medtronic SynchroMed II pump is 
comprised of the internal tubing within the pump (0.199 ml) + external catheter tubing 
extending from the pump to the Intrathecal space (usually about 0.1 to 0.15 ml). This 
amount is calculated at pump change and is usually on the order of one day, but varies 
and the pump programmer will calculate the exact date when the bridge bolus is 
completely delivered.  Importantly, during the bridge bolus, the patients will not be able 
to self-administer PTM boluses.  Many patients may be used to this with solution 
changes.  When the bridge bolus is completely administered, usually after a day or so, the 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Study title: “Effectiveness of Self-Administered Boluses of Intrathecal Bupivacaine in 
Patients with Chronic Non-Cancer Pain Implanted with IDDS: A Double Blind 
Randomized Study”
Principal Investigator: Salim Hayek MD, PhD 
patient will be able to self0-administer PTM doses.  When doing so, the patients will be 
receiving either opioid + bupivacaine (exactly similar to baseline) or opioid alone (similar 
to baseline but without bupivacaine).  Hence, patients will continue to have access to 
PRN (as necessary) analgesia with self-administered PTM doses.  As patients will be kept 
on solution A or solution B for a maximum of one week each, the maximal duration 
without bupivacaine in the intrathecal bolus would be one week. 
The patients will be provided with a paper diary that will be attached by Velcro to the 
PTM remote device which will act as a reminder for patients to record pain scores prior 
to the PTM bolus. The patients will also record the lowest pain scores within the first 30 
minutes after a PTM bolus.  Only the first 3 successful PTM boluses per day will be 
recorded and tracked by the study.  The patients will also record the average NRS score 
and GPE score daily.  Reminders to complete the diary will also be provided to patients 
via phone, email or text message.   
6.3.3 Collection of the Human Biological Specimens:   N/A6.3.4 Data Collection 
Randomization will be performed, patients will be recording data and baseline data will be 
collected during the first day or so after refilling with the study solution and the study data 
over the ensuing few days.  No programming changes will be made during the study period.  
All participants will be kept on solution “A” and solution “B” for a maximum of one week 
each.  All data will be obtained by a physician or member of the research staff.  
 6.3.5 Study Time Line 
Assessment 
4-8 wks
before rx 
1-2wks
before
1st refill 
Time 0 
1 week later 
2nd refill 
 2 weeks
Screening and Informed conse
x 
Randomization/data collection
Questionnaire administration 
x 
Initial study visit 
x 
1st follow-up Data collection 
Including questionnaires 
x 
 2nd follow up 
Data collection for 2nd week 
 x 
6.4.1 The primary endpoints (i.e., primary outcome variables) and the secondary 
endpoints, if any.   

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Study title: “Effectiveness of Self-Administered Boluses of Intrathecal Bupivacaine in 
Patients with Chronic Non-Cancer Pain Implanted with IDDS: A Double Blind 
Randomized Study”
Principal Investigator: Salim Hayek MD, PhD 
The primary outcome variable will be the average change in the NRS for back pain scores 
between NRS scores before PTM bolus and NRS scores within 30 minutes after PTM bolus.  
Secondary outcome variables will be Oswestry disability score, satisfaction (categorical 
“positive” or negative”), the Global Perceived Effect score and side effects (medications).  
These variables will be recorded at baseline and during each follow-up visit. Global Perceived 
Effect and Oswestry questionnaires (as well as adverse effects) will be collected at baseline 
and at the end of each one-week study period. 
6.4.2-3 Data analysis, interim analysis and stopping rules 
Baseline data will be compared using analysis of variance (parametric or Kruskal Wallis 
ANOVA) for continuous or ordinal data and the chi square test for categorical data. 
 6.4.4 Sample Size Estimation 
To estimate the sample size we based our calculation on the primary outcome which would 
be: 
A. The difference of the average of the change in pain intensity score [Avg D NRS] of the
first 3 successful PTM daily for 5 days [maximum 15 PTM boluses] between the Group I
and Group II.
Specifically, from the literature and previous experience usually a change of 2 points in 
absolute pain score is considered minimally clinically significant. The provided parameters 
were: significance level (adjusted for sidedness) = 0.05, standard deviation within patients 
= 2, standard deviation of the difference = undefined, number of patients = undefined, 
power = 0.8, difference in means = 2. 
The variable calculated was the total number of patients. 
A total of 14 patients will enter this two-treatment crossover study. The probability is 80 
percent that the study will detect a treatment difference at a two-sided 0.1 significance 
level, if the true difference between treatments is 2 points [NRS]. This is based on the 
assumption that the within-patient standard deviation of the response variable is 2. 
Another 10-20% (or up to 3 patients should be factored in the sample size to account for 
normal withdrawals from the study.  The final number of patient to be recruited for this 
study would be 17. These calculations were made using the sample size software. 
6.5 Reporting Adverse Events 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Study title: “Effectiveness of Self-Administered Boluses of Intrathecal Bupivacaine in 
Patients with Chronic Non-Cancer Pain Implanted with IDDS: A Double Blind 
Randomized Study”
Principal Investigator: Salim Hayek MD, PhD 
6.5.1 Expected Adverse Events from Research Risks and Reporting 
Adverse effects are not expected from this minimal intervention. All precautions would be 
taken to do the pump refills in the aseptic manner. Other possible side effect would be poor 
pain control. 
All investigators will take the same steps normally taken to minimize adverse events. 
6.5.2 Reporting Serious and Unexpected Adverse Events to the IRB 
Serious Adverse Events: The PI, within one working day, will report all serious adverse 
events (SAE) occurring in any subject.  This will be accomplished by submitting an adverse 
event report memorandum to the IRB.   
Unexpected (but not serious) adverse events which, in the opinion of the PI, are possibly 
related to participation in the protocol will be reported by the PI within 10 (ten) working 
days to the IRB using the same procedure. 
For all serious and/or unexpected adverse events, the PI will examine the adverse event for 
relation to the study (unlikely given the study is examining the effect of removing the local 
anesthetic from the intrathecal solution—not adding any new drugs) and report if needed 
to the IRB. 
6.6 Banking of Human Biological Specimens/Tissue (HBS/tissue):   N/A 
*6.7 Subject Confidentiality Protection:  All treatments received in this study are
standard of care.  No data will be collected that is not relevant to patient care (e.g. treatment,
analgesic usage, numerical rating scale pain scores and disability scores), and no data will
be shared with any non-investigator.  In addition to name and date of birth, patients will
also identified by their place on the randomization table (e.g. RT 2, PT 3).  This “code” 
will enable the transfer of study information without mentioning patients’ names 
6.7.1 Certificate of Confidentiality:  N/A 
*6.7.2 HIPAA Authorization
i. Are you intending to collect subject’s Protected Health Information (PHI) and
any of the following 18 personal identifiers? 
___ No – HIPAA does not apply – go to question #iv 
_x__ Yes – please check which ones: 
___ 1. Names 
___ 2. Street address, city, county, 5-digit zip code 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Study title: “Effectiveness of Self-Administered Boluses of Intrathecal Bupivacaine in 
Patients with Chronic Non-Cancer Pain Implanted with IDDS: A Double Blind 
Randomized Study”
Principal Investigator: Salim Hayek MD, PhD 
_x__ 3. Months and dates (years are OK) and ages >89 (unless all persons over 89 
years are aggregated into a single category) 
_x__ 4. Telephone numbers 
_x__ 5. Fax numbers 
_x__ 6. E-mail addresses 
___ 7. Social security number 
___ 8. Medical record number 
___ 9. Health plan beneficiary number 
___ 10. Account number 
___ 11. Certificate/license number 
___ 12. Vehicle identification number (VIN) and/or license plate number 
___ 13. Device identifiers and serial numbers 
___ 14. URLs (Uniform Resource Locators) 
___ 15. Internet protocol address number 
___ 16. Biometric identifiers, such as finger and voice prints 
___ 17. Full face photographic images or any comparable images 
___ 18. Any other unique identifying number, characteristic, or code such as patient 
initials 
ii. Can you limit your collection of personal identifiers to just dates, city/state/zip,
and/or “other unique identifier” (#18 of the above)?
___ Yes – then your dataset may qualify as a Limited Data Set – please complete a
Data Use Agreement and attach to your protocol. Then go to question #iv.
_x__ No – Go to question #iii.
iii. Is obtaining patient Authorization “impracticable”?
___ Yes – Authorization may qualify to be waived by the IRB. Go to Section 6.7.3
HIPAA Authorization Waiver for the application.
_x__ No – Research subjects will need to sign a HIPAA Authorization. Complete
the HIPAA Authorization and attach to this protocol.
iv. What precautions will you take to protect the confidentiality of research source
documents (Case Report Forms, questionnaires, etc.), the research data file, and the
master code (if any)?
A randomization table will be developed by a computer generated random 
number sequence.  This “code” and a copy of all data collection sheets will be
kept by our research staff in a locked office and protected by computer 
passwords as well as the UHCMC compounding pharmacy that will prepare the 
solutions labeled as described.    
v. When will you destroy the research source documents, data file, and the master

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Study title: “Effectiveness of Self-Administered Boluses of Intrathecal Bupivacaine in 
Patients with Chronic Non-Cancer Pain Implanted with IDDS: A Double Blind 
Randomized Study”
Principal Investigator: Salim Hayek MD, PhD 
code? 
The UHCMC research team in the Pain Medicine Clinic will keep the research 
data for up to six years after the end of the study. Then all the information will 
be destroyed. The master code will be destroyed as soon as all data collection is 
completed. 
vi. Will research data including Identifiable Protected Health Information be sent
outside of UHCMC?  No
6.7.3 HIPAA Authorization Waiver:  N/A- We will obtain signed HIPAA authorization 
from each patient.  
6.8 Reporting Protocol Deviations 
Minor protocol deviations (e.g. minor changes in the consent process, prolonged 
completion time due to deployments) will be discussed with the investigative team on a 
standard protocol deviation sheet.   
1.
Hayek SM, Hanes MC. Intrathecal therapy for chronic pain: current trends and
future needs. Current pain and headache reports. Jan 2014;18(1):388.
2.
Veizi IE, Hayek SM, Narouze S, Pope JE, Mekhail N. Combination of intrathecal
opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer
pain patients. Pain Med. Oct 2011;12(10):1481-1489.
3.
Hayek SM, Veizi E, Hanes M. Intrathecal Hydromorphone and Bupivacaine
Combination Therapy for Post-Laminectomy Syndrome Optimized with Patient-
Activated Bolus Device. Pain Med. Dec 14 2015.
4.
Ilias W, le Polain B, Buchser E, Demartini L. Patient-controlled analgesia in
chronic pain patients: experience with a new device designed to be used with
implanted programmable pumps. Pain practice : the official journal of World
Institute of Pain. May-Jun 2008;8(3):164-170.