A Randomized Double Blind Cross-over Trial of Continuous Intrathecal Infusion for Assessing Patients With Chronic Non-cancer Pain Who Would Benefit From Treatment With Intrathecal Drug Delivery System (IDDS) Implant
Phase: PHASE4
Conditions: Lumbar Post-Laminectomy Syndrome, Chronic Low Back Pain, Vertebral Compression Fracture, Failed Back Surgery Syndrome
Sponsor: University Hospitals Cleveland Medical Center

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
 
 
Protocol Title:  
“A randomized double blind cross-over trial of continuous intrathecal infusion for 
assessing patients with chronic non-cancer pain who would benefit from treatment with 
intrathecal drug delivery system (IDDS) implant” 
 
ABSTRACT 
2.1 Purpose:  
The purpose of this study will be to determine the efficacy and the prognostic value of a 
continuous intrathecal prognostic infusion test in an in-hospital setting for selecting 
patients who would have better long term outcomes for treatment with intrathecal 
implantable devices.  We will compare the primary outcomes [changes in pain intensity 
score (NRS), patient global impression of change (PGIC)] before and after intrathecal 
infusion of an admixture of bupivacaine and fentanyl versus normal saline. 
 
2.2 Research Design:  
Randomized, double blind placebo controlled cross over study 
 
2.3 Methodology /Technical Approach:   
The study will include 36 patients with intractable chronic low back pain in the setting of 
lumbar post-laminectomy syndrome or vertebral compression fracture who failed 
conservative management and are considered candidates for IDDS. 
 
As per usual clinical care prior to the implant, the patients will undergo an intrathecal 
prognostic infusion test with an externalized catheter.  An intrathecal catheter will be 
placed in the outpatient procedure suite and intrathecal infusion will be started using an 
external pump once patient is in the PACU.  The research component is to perform the 
intrathecal test with saline (inactive placebo solution) in addition to a test with fentanyl and 
bupivacaine (active solution).  Patients will be randomly assigned to two groups:  
Group I will be trialed with continuous infusion of intrathecal bupivacaine 0.625 mg/ml 
and fentanyl 1 mcg/ml at a rate of 0.5-1.0 ml/hr for approximately 14-18 hours followed 
by a washout period of 4-6 hours, before resuming intrathecal infusion for testing with 
continuous normal saline for another 14-18 hours.  
Group II will be trialed with intrathecal normal saline for approximately 14-18 hours 
followed by a washout period of 4-6 hours, before resuming intrathecal infusion with a 
solution of bupivacaine 0.625 mg/ml and fentanyl 1 mcg/ml for another 14-18 hours.  
Baseline numerical rating scale pain scores (NRS; an 11-point pain scale whereby 0 
signifies no pain and 10 the worse pain ever) will be assessed and documented on all 
patients upon admission to the preoperative area. Intrathecal catheters will be placed in the 
 
Protocol Version 4.0 Updated 15MAY2017 
Statistical Plan Version 3.0 Updated 13APR2018 
 
1 
 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
operating room as per usual clinical care at the appropriate level for target dermatomes.  
The needle entry point will occur in the upper lumbar spine and catheter tip will be placed 
in the lower thoracic spine (most commonly T7-T11), under local anesthesia with the 
patient awake and with minimal or no sedation. In PACU, patients will be started on an 
infusion rate of 0.5 ml/hr and titrated to pain relief greater than 50% of baseline or up to 
0.8-1.0 ml/hr within 6-8 hrs after start of the infusion on the day of the intrathecal 
prognostic infusion test.  
A clinician blinded to the treatment arm will assess NRS and PGIC on the patients after 
around 12 hours (around 6-7am/morning of the following day).  Assessment will include 
changes in pain intensity score at rest and upon ambulating or performing maneuvers that 
normally elicit patient’s low back pain. A 4-6-hour washout period will be allotted with 
infusion of preservative-free normal saline at a rate of 0.2 ml/hr, after which the physician 
will document a return of the NRS to baseline before switching therapies (cross over). 
 3. OBJECTIVES AND RATIONALE 
Continuous infusion intrathecal tests are prognostic clinical procedures routinely employed 
to select patients who would benefit from implantable intrathecal drug delivery systems.  
Intrathecal prognostic infusion tests are often criticized as subjective and proceeding with 
an implant after a questionable intrathecal test can only lead to frustration of both patient 
and provider.  Compared to normal saline, bupivacaine and fentanyl actively function as 
analgesics and therefore should reveal a difference compared to preservative-free normal 
saline. 
The objectives of this clinical trial would be: 
a) To determine the benefits of a continuous intrathecal prognostic infusion test with 
a mixture of fentanyl and bupivacaine for selecting patients that will benefit from 
an implantable therapy 
b) To examine the long-term effectiveness as determined by satisfaction and 
improvement in function of patients treated with IDDS and selected by a continuous 
infusion intrathecal prognostic test. 
4.  MEDICAL APPLICATION 
 
Targeted 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) and vertebral compression fractures.  Intrathecal 
delivery of pharmacological agents reduces systemic side effects and the potential for 
aberrant medication use (1). 
  
The success of the treatment with an implantable device is strictly dependent on patient 
selection.  Currently, there are no unified standard protocols for intrathecal tests which are 
 
Protocol Version 4.0 Updated 15MAY2017 
Statistical Plan Version 3.0 Updated 13APR2018 
 
2 
 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
considered prognostic procedures for future implants (2).  Previous clinical studies, but 
also guidelines, consider acceptable single intrathecal bolus placebo controlled injection or 
continuous infusion intrathecal test which mimic somewhat closely the continuous 
intrathecal infusion from an implantable device.  The proposed study will clearly address 
the question of placebo controlled continuous infusion tests’ utility in prognosis and 
effectiveness of intrathecal drug delivery systems. 
 
5.  BACKGROUND AND SIGNIFICANCE 
  
Chronic low back is a major socioeconomic burden.  Despite numerous treatment strategies 
including rehabilitation, medications, injections, minimally invasive procedures and 
surgeries, chronic back pain remains a challenge. In particular, patients with back pain 
persisting after previous lumbar spine surgery (often referred to as post-laminectomy 
syndrome or failed back surgery syndrome-FBSS) appear to be most resistant to traditional 
treatment strategies. Neuromodulation in the form of spinal cord stimulation or intrathecal 
drug delivery, represents the best option at providing effective pain relief in this 
challenging chronic pain population. While spinal cord stimulation has traditionally been 
more effective for persistent leg pain, intrathecal drug delivery is more effective in 
refractory low back pain.  Refractory back pain following remote vertebral compression 
fracture(s) is another clinical entity whereby intrathecal therapy is particularly effective in 
the absence of alternatives. Prior to implanting an intrathecal drug delivery system, an 
intrathecal prognostic test is performed.  Despite the agreement on the importance of 
intrathecal testing before the implant, there has been no consensus on the method of testing 
due to lack of high-quality data. While some clinicians utilize single intrathecal bolus doses 
of morphine or other opioids, others use continuous infusions especially in the setting of 
combination therapies (2). Both modalities have been employed with the use of placebo (3, 
4).  The value of intrathecal testing has been questioned, as it is unclear if it really predicts 
the long-term success or failure of IDDS. However, it is still advocated as an important 
initial step before the implant in chronic non-cancer pain (5).  
Most of the current data available are derived from prognostic testing with opioids; no 
prospective randomized trials assessed the effectiveness of bupivacaine combined with an 
opioid.  Our published studies have shown that combination of bupivacaine with intrathecal 
opioids results in sustained pain relief and blunting of opioid dose escalation (6, 7). 
However, no studies have been published on the efficacy of prognostic intrathecal infusion 
testing with a combination of bupivacaine and an opioid.  While two studies used placebo 
saline injections during intrathecal prognostic testing, both involved only opioid boluses 
(mostly morphine), one in the setting of repeat lumbar puncture(3) and the other with repeat 
injections through an intrathecal catheter (4). 
6.  PLAN 
6.1 New Investigational Drugs/ Investigational Devices Exemption Status:  N/A 
 
Protocol Version 4.0 Updated 15MAY2017 
Statistical Plan Version 3.0 Updated 13APR2018 
 
3 
 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
 
6.2 Selection of Subjects 
 
6.2.1 Type of the Subject Population 
Patients with refractory chronic low back pain and previous back surgeries or remote 
compression fractures who are referred to the Division of Pain Medicine at UHCMC for pain 
management and who failed previous conservative management such as physical therapy, 
spinal injections and medication therapy with membrane stabilizers. 
 
6.2.2 Inclusion and Exclusion Criteria 
 
a. Inclusion Criteria 
• Age 30 years or greater 
• Previous lumbar or thoracic spine surgery or lower thoracic/lumbar vertebral 
compression fracture 
• Intractable pain of trunk (more than limbs)  
• Patient who passed psychological evaluations as part of the usual clinical care 
prior to consideration of IDDS and are stable with current pain condition and 
medications 
• Failed more conservative management. 
 
b.  Exclusion Criteria 
• Untreated coagulopathy or infection. 
• Immune compromised state precluding having an implant. 
• Allergic reactions to bupivacaine or fentanyl. 
• Pregnancy 
• Patients using more than 30 mg oral equivalents of morphine daily or who are 
unable to wean down below that dosage for more than 4 weeks before the 
prognostic intrathecal infusion test. 
• Neurological deficits characterized as weakness in lower extremities with evidence 
of nerve damage 
• Patients with cognitive disorders who would not be able to provide meaningful 
outcome responses 
 
6.2.3 Recruitment 
Subjects will be recruited from patients seen at the University Hospitals Pain Medicine 
clinics by attending physicians.  Screening will be done before obtaining consent by an 
investigator.   If patients are deemed appropriate for an intrathecal device they will undergo 
normal procedures and guidelines in place prior to being considered candidates for an 
implantable device.  No subject will be compensated for participation.  
 
 
Protocol Version 4.0 Updated 15MAY2017 
Statistical Plan Version 3.0 Updated 13APR2018 
 
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University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
6.2.4 Consent Process   
Subjects will be consented by one of the investigators.  An explanation in lay terms for the 
reasons of the study and the proposed prognostic benefits will be used to promote patient 
understanding.  
  
If interested, eligible individuals will be given the opportunity to ask and have all 
questions addressed before signing the informed consent document.  The procedure will 
occur at their next visit, and continued consent of study participation will be confirmed.  
 
 
6.3 Study Design and Methodology   
 
6.3.1 Study Design 
This is a randomized, double-blind, placebo controlled cross over study comparing prognostic 
intrathecal testing with an admixture of bupivacaine and fentanyl versus saline.  None of the 
procedures in this study deviate from usual clinical care that patients receive at UHCMC or 
nationally.  Baseline scores using the numerical rating scale (NRS) for pain (a scale form 0-
10, where 0 signifies no pain at all, and 10 the worst possible pain) will be recorded, both in 
the sitting or supine position (least pain) and with ambulation or standing (worst pain).  Patients 
will be given weight based cefazolin (or vancomycin if indicated) prior to placing the 
externalized intrathecal catheter.  Placement of the percutaneous intrathecal catheter will be 
done in the operating room with minimal or no sedation in the prone or lateral decubitus 
position under fluoroscopic guidance. Needle entry will occur in the mid-upper lumbar spine 
and through the needle an intrathecal catheter will be advanced until its tip is positioned in the 
posterior intrathecal space in the lower thoracic spine.  The needle is then removed and the 
catheter is secured in place with steri-strips and a clear sterile bio-occlusive dressing will be 
placed.  Patients will then be transferred to the PACU where they will be initiated on one of 
two solutions that will be prepared for each patient by the investigational pharmacy staff at 
UHCMC.  The solutions will be labeled as “Intrathecal solution 1” and “Intrathecal solution 
2” and will be contained in a sterile 50 ml bag.  Solution 1 and 2 may contain either: 
 
a) Preservative-free normal saline 
b) Fentanyl 1 mcg/ml and bupivacaine 0.625 mg/ml 
 
The content of Intrathecal solution 1 and 2 will be unknown to all investigators and participants 
in the study with the exception of the investigational pharmacy.  The order of the Intrathecal 
solution (1 or 2) will be determined by pharmacy using a computer generated random sequence 
allocation.  The intrathecal catheter will be attached to a pump delivering solution 1 or 2 at 
around noon time, in the recovery area on the day the catheter is placed. A bolus of 1cc will be 
given through the infusion pump at initiation of therapy and the patient will then be started on 
an infusion rate of 0.5 ml/hr. After 3-4 hours (around 3-4 pm) hours and similarly around 6-7 
pm the rate will be titrated depending on patient’s response up to a maximum of 0.8-1.0 ml/hr.  
 
Protocol Version 4.0 Updated 15MAY2017 
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5 
 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
If the patient has achieved > 50% pain relief compared to baseline, no up-titration will occur; 
i.e. the rate will be increased only if the patient has not had 50% or more reduction in baseline 
pain on the NRS.  The intrathecal rate will be kept the same provided the patient had 50% or 
greater decrease in pain scores or has reached the 1.0 ml/hr rate (whichever comes first).  The 
rate will be unchanged from 6-7 pm until around 6-7 am the next morning when the infusion 
will be stopped and the patient will be assessed for pain relief.  In the morning, the patient will 
be asked to rate the pain score at rest (in bed or chair) and with ambulation/standing. The pain 
scores will be recorded and the catheter will be aspirated at the hub to ensure continued 
cerebrospinal fluid flow and the patient will be started on a solution of preservative-free normal 
saline at 0.2 ml/hr to keep the catheter patent.  After 6 hours, around noon time, the patient will 
be crossed over to Intrathecal solution 1 or 2, depending on what she/he had the day before, 
given 1.0 ml of that solution as a bolus and then infusion will be started at 0.5 ml/hr and the 
same protocol as the day before will be repeated with the patient discharged the next morning.  
Patients who experience greater than 50% pain relief (relative to baseline) with either 
intrathecal solution will be offered the implant of a permanent IDDS that will deliver a 
combination of bupivacaine and low-dose fentanyl.  Patients not responding to both solutions 
with greater than 50% pain relief will be considered to have failed the intrathecal test and 
would not proceed to implant.  The patients will be asked to pick which solution provided 
better pain relief: solution 1 or solution 2 and responses will be recorded.   Additionally, pain 
scores obtained periodically as part of patients’ usual clinical care vital signs and recorded by 
the nursing staff on the hospital ward will be collected throughout the study.  Un-blinding for 
patients who had a successful intrathecal prognostic infusion test with greater than 50% pain 
relief will not occur until 12 months have elapsed since the pump implant. 
 
Outcome measures will include: 
1- Baseline prior to commencement of the prognostic infusion test:  Pain intensity using 
the Numerical Rating Scale [NRS], patient global impression of change [PGIC], 
Oswestry disability index [ODI] and painDETECT. 
2- At 14-18 hours: Pain intensity in Numerical Rating Scale [NRS], patient global 
impression of change [PGIC], complications and side effects. 
3- Prior to second infusion: Pain intensity in Numerical Rating Scale [NRS], patient global 
impression of change [PGIC], complications and side effects. 
4- At prognostic infusion test completion: Pain intensity in Numerical Rating Scale 
[NRS], patient global impression of change [PGIC], complications and side effects, 
Oswestry disability index [ODI] and painDETECT. 
5- At 6 and 12 months post-implant for implanted patients Pain intensity in Numerical 
Rating Scale [NRS], patient global impression of change [PGIC], Oswestry disability 
index [ODI] and painDETECT. 
 
 
 
 
 
Protocol Version 4.0 Updated 15MAY2017 
Statistical Plan Version 3.0 Updated 13APR2018 
 
6 
 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
6.3.2 Study Methodology/Procedures 
The study will include 36 patients with intractable chronic low or mid back pain due to 
failed back surgery syndrome or vertebral fracture who failed conservative management 
including epidural steroid injection and medical therapy and were referred to our practice 
for pain management. 
 
Patient will undergo the usual psychological and medical evaluations before the initiation 
of the prognostic infusion test. 
  
Patients who are considered candidates for intrathecal pump implant fulfilling the 
inclusion/exclusion criteria above and who elect to participate in the study will be randomly 
assigned to receive treatment in one of two counterbalanced conditions. 
  
Group A tested with continuous infusion of intrathecal bupivacaine 0.625 mg/ml and 
fentanyl 1 mcg/ml for 14-18 hours followed by a trial with normal saline for another 14-
18 hours.  
Group B tested with intrathecal normal saline for 14-18 hours followed by intrathecal 
Bupivacaine 0.625 mg/ml and fentanyl 1 mcg/ml for another 14-18 hours. 
  
Note that drugs will be delivered by the pharmacy to a blinded physician and labeled as 
Intrathecal solution 1 and Intrathecal solution 2 to be administered sequentially, separated 
by a 4-6-hr infusion of preservative-free saline. 
 
Outcomes will be assessed and documented on all patients upon admission to the 
preoperative area.  
The patients will be taken then to the procedure room and a standardized intrathecal 
catheter will be placed under fluoroscopic guidance where the tip of the catheter will be 
placed at the T7-T11 posterior intrathecal interspace. Patients will be discharged to the 
PACU where they will be started on a rate of 0.5 ml/hr. 
Six to eight hours following initiation of the infusion, all the patients will be titrated to 0.8-
1.0 ml/hr, provided less < 50% improvement in pain scores occurs.  A physician who is 
blinded to the treatment will assess NRS after approximately 12 hrs (around 6-7 am of the 
following day).  A 4-6 hours washout period will ensue with infusion of preservative-free 
normal saline at a rate of 0.2 ml/hr after which the physician will document a return of the 
NRS to baseline before switching therapies or record the value at 6 hrs after infusing 
normal saline and switch then to solution 2. NRS will be reassessed around 6 am the 
following morning.  Additionally, pain scores documented with usual clinical care vital 
signs will be captured. 
All reported adverse events will be recorded. 
 
Protocol Version 4.0 Updated 15MAY2017 
Statistical Plan Version 3.0 Updated 13APR2018 
 
7 
 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
No pain medications will be prescribed during the admission.  If such medications are 
needed, the patient will be excluded from continuing on with the study and will be recorded 
as a prognostic-infusion-test failure. 
The intrathecal catheter will be aspirated for confirmation of free cerebrospinal fluid flow 
(about 1 ml) between all solution changes and at the end of the prognostic infusion test . 
After the completion of the prognostic infusion test, the catheter will be removed and 
patients will be discharged home. 
Only patients who report >50% reduction from baseline NRS while receiving either 
intrathecal solution will be considered for intrathecal drug delivery system implant.  It is 
conceivable that some patients may get >50% reduction in pain scores with both the active 
solution and saline or have better outcome with the saline solution.  The patients will be 
asked to answer a binary question rating preference to solution 1 vs. solution 2.  Patients 
with pain relief greater than 50% will be implanted with an IDDS and will receive an 
intrathecal solution of fentanyl and bupivacaine. All subjects with >50% pain relief with 
either or both intrathecal solutions will be implanted. Even if the patient gets >50% pain 
relief only from the saline solution, or the patient chooses the saline solution over the active 
solution  (when asked if #1 vs. #2 was better relief) each patient will receive active drug 
after being implanted. All patients will be compared in long-term outcome (secondary 
outcome measures) at 6 months and 12 months versus the response to the prognostic test 
solutions.  Unblinding of solution 1 and 2 will not occur until 12 months have elapsed since 
pump implant.  The six and twelve month visits will be coordinated with a pump refill visit. 
6.3.3 Collection of the Human Biological Specimens:   N/A 
6.3.4 Data Collection  
Randomization will be performed, and baseline data will collect on admission to the 
preoperative area. A physician or physician assistant will obtain all data.  
Baseline data collected will include name, last 4 digits of social security number, age, sex, 
race, duration of pain, treatment group, average 0-10 low back numerical rating scale (NRS) 
pain scores over the past week and analgesic medication consumption.   
 
NRS scores will be collected again around 6am, noon and 6am of the following day, as well 
as per regular nursing routine on the medical floor. Medication side effects, satisfaction [patient 
global impression of change-PGIC], complications will also be documented at the completion 
of each infusion. 
 
At the end of the prognostic infusion test, patients will be asked to specify which infusion they 
preferred:  Intrathecal solution 1 or Intrathecal solution 2.  An “assessment of blinding” 
questionnaire will also be administered.  When the data is recorded on the Excel spreadsheet 
 
Protocol Version 4.0 Updated 15MAY2017 
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8 
 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
for statistical analysis, identifying information will be deleted.   
 
6.3.5 Study Time Line  
 
Assessment 
Before 
testing 
procedure 
Testing 
Procedure; 
Intrathecal 
Catheter 
Placement 
Infusion 
1           
 
14-18 
hours 
Wash
out  
          
4-6 
hours 
Infusion 
2  
 
14-18 
hours        
Follow 
Up          
 
6- 
months 
Follow 
Up        
 
12- 
months 
Screening 
Informed Consent 
 
X 
Randomization; 
Questionnaires; 
Data Collection; 
Medication Dose 
Titration 
 
X 
X 
X 
X 
Data Collection; 
Questionnaires; 
Adverse Events 
 
X 
X 
X 
Long Term 
Outcomes; 
Questionnaires; IT 
Medication Use; 
Adverse Events 
 
X 
X 
 
6.4.1 Data Analysis 
For this study, there will be two within-patient experimental groups in a counterbalanced 
crossover design, such that all patients will receive both treatments. An equal number of 
patients will be randomly assigned to receive the intrathecal solutions in the order of 
Treatment 1 followed by Treatment 2, or Treatment 2 followed by Treatment 1.  
The primary outcome variable will be the change in pain intensity score [NRS] 0-10 numerical 
rating scale back pain score at the end of the intrathecal prognostic infusion testing period 
around 6am between Intrathecal solution 1 and Intrathecal solution 2. That is, the primary 
outcome will report the degree of change in NRS pain scores between baseline (pre-treatment) 
and the end of receiving that treatment (post-treatment; approximately 18 hours after treatment 
initiation), separately for Treatment 1 and for Treatment 2. Changes in NRS pain scores will 
be considered clinically significant if they result in ≥ 50% pre-treatment/post-treatment NRS 
scores for pail relief compared to baseline, in either intrathecal solution   
 
Protocol Version 4.0 Updated 15MAY2017 
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9 
 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
Secondary outcome variables will be Oswestry disability score, changes in painDETECT, 
Patient Global Impression of Change (PGIC) and side effects (medications) and complications 
(injections).  These variables will be recorded at baseline, at the completion of each phase of 
the prognostic infusion test, and at 6 and 12 months post-implant.  
 
6.4.2-3 Data Analysis and Statistical Plan 
 
Continuous or ordinal data for two groups or conditions will be analyzed using t-tests for 
paired or independent samples. If the data are non-normally distributed, variations of the t-
test for non-parametric distributions will be utilized: Mann-Whitney U test for independent 
samples. Comparisons of three or more groups will be conducted using a One-Way 
ANOVA with Bonferroni post-hoc tests to correct for multiple comparisons; alternatively 
if the data are non-normally distributed a Kruskal-Wallis test will be used. Categorical data 
will be analyzed using the chi-squared test for categorical data, or using Fisher’s exact test, 
a robust chi-square alternative that is valid for all sample sizes. 
 
 6.4.4 Sample Size Estimation  
 To estimate the sample size we based our calculation on the primary outcome which is 
change of NRS score from baseline and at 18 hrs and 36 hrs. From the literature we expect 
50% in absolute pain score changes with the treatment agent [∆ NRS 1] and that is 
considered clinically significant.  Placebo response is considered 20-30% [∆ NRS 2]. To 
identify a true effect of treatment, distinguishable from a placebo response, the power 
analysis should identify an absolute score change from baseline of ≥ 30%; to identify a 
clinically significant change this score should change by ≥ 50%. The power analysis is 
conducted to estimate the number of patients required to identify this clinically significant 
change as also statistically significant.  
  
Power analyses are performed on the primary outcome of interest, the change in NRS 
scores from baseline to post-treatment. The power analysis software G*Power was used to 
calculate the sample size for a two-tailed t-test for matched pairs, alpha 0.05, power = 0.8, 
difference in means = 30%, standard deviation of within-patient differences = 50%. Under 
these parameters a projected effect size of .5 (Cohen’s d, moderate effect size) was 
calculated, and 29 patients were required in total. Under the assumption of a 20% dropout 
rate, sample size was estimated at 36 patients.  
 
A total of 36 patients will enter this two-treatment crossover study. The probability is 80 
percent that the study will detect a treatment difference at 95% confidence that a 
statistically significant difference would reveal a true effect, if the true difference 
between treatments is 30 units. This is based on the assumption that the within-patient 
standard deviation of the response variable is 50. 
 
 
Protocol Version 4.0 Updated 15MAY2017 
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10 
 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
The final number of patient to be recruited for this study would be 36.  
 
6.5 Reporting Adverse Events  
 
6.5.1 Expected Adverse Events from Research Risks and Reporting 
Adverse effects are not expected from this minimal intervention. 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 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 usual 
clinical 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 
_x__ 3. Months and dates (years are OK) and ages >89 (unless all persons over 89 
years are aggregated into a single category) 
 
Protocol Version 4.0 Updated 15MAY2017 
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11 
 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
_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 nurse (Karen Arters) in a room in that is locked at night 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 
code?  
 
 
Protocol Version 4.0 Updated 15MAY2017 
Statistical Plan Version 3.0 Updated 13APR2018 
 
12 
 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
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 and 
reported to the IRB on a standard protocol deviation sheet.  Any major deviations (e.g. 
unexpected findings necessitating a change in protocol) may require temporarily stopping 
the protocol until the steps needed to rectify the deviation are cleared with IRB (e.g. 
change in protocol). 
 
7.0 Risks, Benefits, Alternatives, Withdrawal 
 
7.1 Risks 
 
All of the medication and equipment being used for this study are considered usual 
clinical care treatment for back pain.  There is a risk for increase in back pain with the 
normal saline solution. 
 
Questionnaires/Subject Diaries/Research 
The questionnaires and subject diaries will be used to compare the outcomes of each 
week of treatment and pose no risk to the subject.  
 
Possible minimal risks include potential breach of confidentiality of the subject’s medical 
record information and associated privacy.  This risk will be minimized by assigning each 
subject a unique study number.  This number will be kept in a locked area with only the 
study team having access. 
 
Unforeseeable risks 
There may be risks or side effects related to the study procedures that are unknown at this 
time. Subjects will be notified of any significant new findings that become known that may 
affect their willingness to continue in the study. 
 
 
Protocol Version 4.0 Updated 15MAY2017 
Statistical Plan Version 3.0 Updated 13APR2018 
 
13 
 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
7.2 Benefits 
Subjects may not receive benefits from participating in this research study. The 
information that can potentially be gained from this study regarding their condition may 
be useful to those who suffer from the disease, including the participants.  
 
7.3 Alternatives 
 If a patient chooses not to participate, they will continue with their current treatment.  
Any patient may withdraw from the study at any time. 
 
7.4 Withdrawal from Study Participation 
Subjects may withdraw from the study at any time.  Upon withdrawal, they will return to 
their usual, usual clinical care treatment and have their IDDS prognostic infusion test and 
follow up per usual clinical care.  Follow up will be per usual clinical care per the 
investigator’s discretion.  Data prior to withdrawal may be used, but no further data will 
be collected.  Also, the investigator may choose to withdraw the subject if the 
investigator deems it is in the best interest of the subject's health and well-being. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Version 4.0 Updated 15MAY2017 
Statistical Plan Version 3.0 Updated 13APR2018 
 
14 
 

University Hospitals Case Medical Center 
Department of Anesthesiology  
Division of Pain Medicine 
Short Study title: “Determining the Prognostic Value of Continuous intrathecal infusion  prognostic 
infusion test” 
 
References: 
 
1. 
Hayek SM, Deer TR, Pope JE, Panchal SJ, Patel VB. Intrathecal therapy for cancer 
and non-cancer pain. Pain physician. 2011;14:219-48. 
2. 
Deer TR, Prager J, Levy R, Rathmell J, Buchser E, Burton A, et al. Polyanalgesic 
Consensus Conference 2012: recommendations for the management of pain by intrathecal 
(intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation : 
journal of the International Neuromodulation Society. 2012;15:436-64; discussion 64-6. 
3. 
Dominguez E, Sahinler B, Bassam D, Day M, Lou L, Racz G, et al. Predictive value 
of intrathecal narcotic trials for long-term therapy with implantable drug administration 
systems in chronic non-cancer pain patients. Pain practice : the official journal of World 
Institute of Pain. 2002;2:315-25. 
4. 
Hamza M, Doleys D, Wells M, Weisbein J, Hoff J, Martin M, et al. Prospective 
study of 3-year follow-up of low-dose intrathecal opioids in the management of chronic 
nonmalignant pain. Pain Med. 2012;13:1304-13. 
5. 
Deer TR, Prager J, Levy R, Burton A, Buchser E, Caraway D, et al. Polyanalgesic 
Consensus Conference--2012: recommendations on trialing for intrathecal (intraspinal) 
drug delivery: report of an interdisciplinary expert panel. Neuromodulation : journal of the 
International Neuromodulation Society. 2012;15:420-35; discussion 35. 
6. 
Hayek SM, Veizi E, Hanes M. Intrathecal Hydromorphone and Bupivacaine 
Combination Therapy for Post-Laminectomy Syndrome Optimized with Patient-Activated 
Bolus Device. Pain Med. 2015. 
7. 
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. 2011;12:1481-9. 
 
 
 
Protocol Version 4.0 Updated 15MAY2017 
Statistical Plan Version 3.0 Updated 13APR2018 
 
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