Clinical trial NCT03523000
Conditions: Lumbar Post-Laminectomy Syndrome Chronic Low Back Pain Vertebral Compression Fracture Failed Back Surgery Syndrome
Keywords: intractable chronic low back pain lumbar post-laminectomy syndrome vertebral compression fracture intrathecal drug delivery system
Sponsor: University Hospitals Cleveland Medical Center
Start date: 2017-10-18; Completion date: 2021-10-12
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
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. The investigators 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 0.625 mg/ml and fentanyl 1 mcg/ml versus normal saline.

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.

Prior to the implant, the patients will undergo an intrathecal prognostic infusion test with an externalized catheter. Baseline NRS pain scores will be assessed and documented on all patients upon admission to the preoperative area. An intrathecal catheter will be placed in the outpatient procedure suite 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, under local anesthesia with the patient awake and with minimal or no sedation. The 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 normal saline (inactive placebo solution) in addition to a test with fentanyl and bupivacaine (active solution). Patients will be randomly assigned to either Group I (continuous infusion of bupivacaine and fentanyl followed by saline) or Group II (continuous infusion of saline followed by bupivacaine and fentanyl).

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. A clinician blinded to the treatment arm will assess NRS and PGIC on the patients after approximately 12 hours. 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.

Detailed description:
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.

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.

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:

1. Preservative-free normal saline
2. 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) 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. 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.

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 two groups.

Group I 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 II 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.

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.

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.

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.

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.

Arms: arm 1: Continuous intrathecal prognostic infusion test of active solution: intrathecal bupivacaine 0.625 mg/ml and fentanyl 1 mcg/ml

6 hour washout followed by

Continuous intrathecal prognostic infusion test of inactive placebo solution: preservative-free normal saline arm 2: Continuous intrathecal prognostic infusion test of inactive placebo solution: preservative-free normal saline

6 hour washout followed by

Continuous intrathecal prognostic infusion test of active solution: intrathecal bupivacaine 0.625 mg/ml and fentanyl 1 mcg/ml
Interventions: intervention 1: Continuous intrathecal prognostic infusion test intervention 2: Bupivacaine intervention 3: Fentanyl intervention 4: Placebo intervention 5: Intrathecal Drug Delivery System (IDDS)
Intervention descriptions: intervention 1: The patient is infused with solution through the percutaneous intrathecal catheter at a rate of 0.5-1.0 ml/hr for approximately 14-18 hours intervention 2: Bupivacaine 0.625 mg/ml and fentanyl 1 mcg/ml continuous infusion at a rate of 0.5-1.0 ml/hr for approximately 14-18 hours intervention 3: Bupivacaine 0.625 mg/ml and fentanyl 1 mcg/ml continuous infusion at a rate of 0.5-1.0 ml/hr for approximately 14-18 hours intervention 4: Intrathecal infusion of normal saline at a rate of 0.5-1.0 ml/hr for approximately 14-18 hours intervention 5: 40-mL IDDS containing a solution of fentanyl 50 mcg/mL with bupivacaine 30 mg/mL

Protocol documents:
Prot_SAP_001.pdf: 
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 
 
4 
 


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 
Statistical Plan Version 3.0 Updated 13APR2018 
 
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 
Statistical Plan Version 3.0 Updated 13APR2018 
 
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 
Statistical Plan Version 3.0 Updated 13APR2018 
 
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 
Statistical Plan Version 3.0 Updated 13APR2018 
 
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 
Statistical Plan Version 3.0 Updated 13APR2018 
 
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 
 
15 
 

ICF_000.pdf: 
UNIVERSITY HOSPITALS  
CLEVELAND MEDICAL CENTER 
CONSENT FOR INVESTIGATIONAL STUDIES 
(v. 11.2012) 
 
 
 
 
 
 
Project Title: A randomized double blind cross-over trial of continuous intrathecal infusion for 
assessing patients with chronic noncancer pain who would benefit from treatment with intrathecal 
drug delivery system (IDDS) implant 
 
Principal Investigator:  Salim Hayek, MD, Ph.D. 
                    
Version 3.0 
 15May2017 
Page 1 of 9 
Introduction/Purpose 
You are being invited to take part in a research study because you are going to be scheduled for a 
test of a continuous “intrathecal infusion” for relief of your back pain.  By “intrathecal infusion” 
we mean putting medicine (or other treatments) directly into the spinal fluid that is around your 
spinal cord and nerves. 
 
The usual procedure is to see if giving medicine through a catheter directly into the intrathecal 
space in your spine where there are nerves is helpful in relieving your pain. If the test shows that 
this is effective, your doctor may recommend that you have a permanent catheter and pump 
implanted to give you the medicine continuously.  
 
Although this kind of test is commonly done, there are a number of different ways it can be done, 
with different medicines and for different lengths of time. The purpose of our research study is to 
learn more about how accurate the test is in predicting who will benefit from an implanted pump 
when the test is done using an active medication combination compared to an inactive substance 
(saline solution without medicine). The “extra” or research part of the procedure is testing how 
much pain relief you get when the active medicines (the usual approach) are given, compared to 
your reaction to the inactive saline. All patients will receive both solutions at different times. The 
detailed procedures are described below. 
 
This study is being conducted at University Hospitals Cleveland Medical Center.  We hope that 36 
patients will take part in the study. 
 
Study Procedures 
If your doctor believes you are eligible to be in this study and you decide to participate, you will be 
asked to read and sign this consent form.  You may take this consent form home with you prior to 
making your decision.  You will then be scheduled for the following. 
 
All patients who take part in this study will be admitted to the hospital and stay for 3 days (two 
nights). As is usually done for any patient being tested for use of an implanted device for pain, you 
will have already received instruction by video and discussion with your physician about the 
procedure and the implanted pump.  
 
IRB NUMBER: 08-16-09
IRB APPROVAL DATE: 06/30/2017
IRB EXPIRATION DATE: 06/12/2018


UNIVERSITY HOSPITALS  
CLEVELAND MEDICAL CENTER 
CONSENT FOR INVESTIGATIONAL STUDIES 
(v. 11.2012) 
 
 
 
 
 
 
Project Title: A randomized double blind cross-over trial of continuous intrathecal infusion for 
assessing patients with chronic noncancer pain who would benefit from treatment with intrathecal 
drug delivery system (IDDS) implant 
 
Principal Investigator:  Salim Hayek, MD, Ph.D. 
                    
Version 3.0 
 15May2017 
Page 2 of 9 
All patients will go to the Operating Room to have a temporary catheter inserted in to their back, 
using x-rays to place the catheter in the exact spot needed. Once you are back in your hospital 
room, a solution (either the active medicines, Fentanyl and bupivacaine, or the inactive solution, 
the saline) will be given through the catheter, into the space on your spine where there are nerves. 
The next morning (Day 2) the solution will be stopped for 6 hours. After this, the other solution 
will be started. That is, if you received fentanyl and bupivacaine during the first infusion, you will 
then be given the saline solution. If you received saline in the first solution, you will then be given 
the fentanyl/bupivacaine solution. 
 
Neither you nor your doctors will know which solution is being given first and which is being 
given second. The order in which the solutions are given will be determined by a process similar to 
a flip of a coin - -this is called ‘randomization.’ All patients will receive both solutions, just in a 
different order. The section below explains more about what happens on each day. 
 
Hospital Day 1  
After you have been admitted to the hospital, before you go to the operating room to have the 
catheter placed, you will be asked to complete some research questionnaires about your pain. The 
questionnaires will take approximately 10-15 minutes to complete.  Once all the questionnaires 
and other pre-procedure activities are completed, you will have your temporary catheter implant 
procedure. 
  
Once the temporary catheter implant procedure is finished, you will be taken to the Recovery 
Room. That is where the first infusion (fentanyl with bupivacaine, or normal saline) will be started. 
Once you are assigned a bed, you will be transferred to a regular hospital room. The medication 
infusion will be adjusted periodically by a pain management physician based on how you are 
feeling and how your pain is. 
  
Throughout the post procedure period, you are encouraged to get up in a chair as well as walk 
around the hospital ward. This will help the doctors assess how well each infusion helps your back 
pain.  
 
Hospital Day 2   
Infusion #1 will be stopped around 6-7am. One of the pain management doctors will assess you 
and your pain and make sure your intrathecal catheter is working properly. You will be asked to 
complete some questionnaires about your pain and the treatment.  The questionnaires will take 
approximately 10-15 minutes to complete. 
IRB NUMBER: 08-16-09
IRB APPROVAL DATE: 06/30/2017
IRB EXPIRATION DATE: 06/12/2018


UNIVERSITY HOSPITALS  
CLEVELAND MEDICAL CENTER 
CONSENT FOR INVESTIGATIONAL STUDIES 
(v. 11.2012) 
 
 
 
 
 
 
Project Title: A randomized double blind cross-over trial of continuous intrathecal infusion for 
assessing patients with chronic noncancer pain who would benefit from treatment with intrathecal 
drug delivery system (IDDS) implant 
 
Principal Investigator:  Salim Hayek, MD, Ph.D. 
                    
Version 3.0 
 15May2017 
Page 3 of 9 
After Infusion #1 finishes, you will have a four to six hour washout period. The washout period 
gives your body the chance to get rid of the effects of the first infusion. During the washout period, 
normal saline will infuse through your temporary catheter to make sure your temporary catheter 
continues to function. You are encouraged to get up in a chair and walk around during the wash 
out period. You will answer more questionnaires at the end of the wash out period which will only 
take a couple minutes. 
  
Around noon, at the end of the washout period, you will be started on Infusion #2 (whichever 
solution you did not receive the first time). A similar pattern to day 1 will take place.  
 
Throughout the post procedure period, you are encouraged to get up in a chair as well as walk 
around the hospital ward.  This will help the doctors assess how well each infusion helps your back 
pain. 
 
Hospital Day 3/Discharge 
Infusion #2 will finish around 6am. One of the pain management doctors will assess you and your 
pain, and will remove the temporary catheter. You will be asked to complete some questionnaires 
about your pain and the treatment. The questionnaires will take approximately 10-15 minutes to 
complete.  Once all this is done, if you are having no problems, you may be discharged from the 
hospital. 
 
Follow-up  
If you did not receive at least 50% pain relief with either of the solutions, you will not be offered a 
permanent intrathecal pump. We would still like to contact you at 6 and again at 12 months to ask 
you how your pain is. We will do this by calling you on the telephone. 
 
If you did have at least 50% pain relief with one or both solutions, you will be offered a permanent 
implanted intrathecal pump. Regardless of which solution you responded to, the permanent pump 
would be filled with active medicine. The decision to proceed with having the pump inserted is up 
to you. Regardless of whether you decide to have the permanent pump implanted, we would like to 
ask to complete pain related questionnaires around 6 and 12 months. This can be done over the 
phone, or if you do decide to have the pump implanted, we can ask you the questions when you 
come back for a scheduled pump refill visit.  The questionnaires will take approximately 10-15 
minutes to complete.    
 
 
 
IRB NUMBER: 08-16-09
IRB APPROVAL DATE: 06/30/2017
IRB EXPIRATION DATE: 06/12/2018


UNIVERSITY HOSPITALS  
CLEVELAND MEDICAL CENTER 
CONSENT FOR INVESTIGATIONAL STUDIES 
(v. 11.2012) 
 
 
 
 
 
 
Project Title: A randomized double blind cross-over trial of continuous intrathecal infusion for 
assessing patients with chronic noncancer pain who would benefit from treatment with intrathecal 
drug delivery system (IDDS) implant 
 
Principal Investigator:  Salim Hayek, MD, Ph.D. 
                    
Version 3.0 
 15May2017 
Page 4 of 9 
Risks 
Doing a test of your response to intrathecal medicine is the usual procedure for evaluating whether 
you might benefit from a permanent implanted pump. Therefore, risks of having a catheter inserted 
in your back and receiving pain medication through the catheter are all risks that you would 
experience even if you do not take part in the research. 
 
Comparing these specific active medicines (fentanyl and bupivacaine) to the inactive solution 
(saline) is part of the research. There is an added risk of you experiencing increased back pain with 
the normal saline solution because it does not contain the pain medication. You also will be in the 
hospital an extra day in order to complete the full test. 
 
It is unlikely, but possible that some patients may respond to the saline infusion during the test, but 
then would receive the active medicine in their permanent pump. This may also be associated with 
less pain relief or no pain relief over time. 
  
Questionnaires/Research:  The questionnaires will be used to compare the outcomes of each 
infusion treatment. The only risks of the questionnaires include potential breach of confidentiality 
of your medical record information and associated privacy. This risk will be minimized by 
assigning you a unique study number and only attaching your questionnaire answers to the study 
number, not your name. This number will be kept in a locked area with only the study team having 
access. 
 
 
Benefits 
You may or may not benefit from participating in this study. By comparing active medicine with 
saline during the test, we hope we will have an accurate way to predict if a permanent pump will 
help your pain, but this cannot be guaranteed. We hope that the information we gain from the study 
will be useful in the care of those who suffer from the disease.  
 
Alternatives to Study Participation 
If you choose not to take part in the study, you will continue with your current treatment for your 
back pain. This includes having the test of the intrathecal done using the usual protocol, which 
only includes testing the active medicine.  
You may choose to withdraw from the study at any time.  
IRB NUMBER: 08-16-09
IRB APPROVAL DATE: 06/30/2017
IRB EXPIRATION DATE: 06/12/2018


UNIVERSITY HOSPITALS  
CLEVELAND MEDICAL CENTER 
CONSENT FOR INVESTIGATIONAL STUDIES 
(v. 11.2012) 
 
 
 
 
 
 
Project Title: A randomized double blind cross-over trial of continuous intrathecal infusion for 
assessing patients with chronic noncancer pain who would benefit from treatment with intrathecal 
drug delivery system (IDDS) implant 
 
Principal Investigator:  Salim Hayek, MD, Ph.D. 
                    
Version 3.0 
 15May2017 
Page 5 of 9 
 
Consequences of Withdrawing or being discontinued from the Research 
There is no penalty to you if you would like to withdraw your participation from this study.  
Normal standard of care procedures will be discussed and offered by your doctor.   
 
You may be discontinued from the research study if you do not follow your doctor’s advice or if 
we are unable to reach you for follow up visits.  It is also possible that your study doctor may stop 
your participation in the research study if he/she feels it is in the best interest of your health. 
 
Financial Information 
All procedures involved in the study for diagnosis and treatment are considered “standard of care”. 
Standard of care are procedures that you would normally undergo whether you choose to 
participate in the study or not.  For study purposes, standard of care applies to the costs of the 
procedure, medications and hospitalization, and you/your insurance will be billed.   
 
You will receive no monetary compensation for taking part in the study.   
 
Research-Related Injury 
If injury occurs as a result of your involvement in this research, medical treatment is available 
from University Hospitals or another medical facility but you/your medical insurance will be 
responsible for the cost of this treatment.  A research injury is an injury that happens as a result of 
taking part in this research study.  If you are injured by a medical treatment or procedure that you 
would have received even if you weren’t in the study, that is not considered a “research injury”. 
There are no plans for payment of medical expenses or other payments, including lost wages, for 
any research related injury.  To help avoid injury, it is very important to follow all study directions. 
 
Confidentiality 
Results of this research study will be treated as confidential information and the results will not be 
included in your medical record.  Similarly, your medical history will also be treated as 
confidential with no identifiable information released or shared with anyone outside the study 
team.  If the study results are published, your name will not be used.  Once all your results are 
collected, any identifiers will be removed and the information assigned a code.  The data will be 
identified by a study number and not by your name or identifying information.  The code 
assignment key will be maintained by the Principal Investigator, Salim Hayek, MD and his 
research staff on a password protected computer kept in a locked area.  Access to the code key will 
be limited to the Principal Investigator and study personnel. 
 
IRB NUMBER: 08-16-09
IRB APPROVAL DATE: 06/30/2017
IRB EXPIRATION DATE: 06/12/2018


UNIVERSITY HOSPITALS  
CLEVELAND MEDICAL CENTER 
CONSENT FOR INVESTIGATIONAL STUDIES 
(v. 11.2012) 
 
 
 
 
 
 
Project Title: A randomized double blind cross-over trial of continuous intrathecal infusion for 
assessing patients with chronic noncancer pain who would benefit from treatment with intrathecal 
drug delivery system (IDDS) implant 
 
Principal Investigator:  Salim Hayek, MD, Ph.D. 
                    
Version 3.0 
 15May2017 
Page 6 of 9 
Disclosure of your study records 
Efforts will be made to keep the personal information in your research record private and 
confidential, but absolute confidentiality cannot be guaranteed.  The University Hospitals 
Cleveland Medical Center Institutional Review Board may review your study records.  If this study 
is regulated by the Food and Drug Administration (FDA), there is a possibility that the FDA might 
inspect your records. If your records are reviewed your identity could become known. 
 
Privacy of Protected Health Information 
The Health Insurance Portability & Accountability Act (HIPAA) is a Federal law that helps to 
protect the privacy of your health information and to whom this information may be shared within 
and outside of University Hospitals.  This Authorization form is specifically for a research study 
entitled “A randomized double blind cross-over trial of continuous intrathecal infusion for 
assessing patients with chronic noncancer pain who would benefit from treatment with intrathecal 
drug delivery system (IDDS) implant” and will tell you what health information (called Protected 
Health Information or PHI) will be collected for this research study, who will see your PHI and in 
what ways they can use the information.  In order for the Principal Investigator, Salim Hayek, MD, 
and the research study staff to collect and use your PHI, you must sign this authorization form.  
You will receive a copy of this signed Authorization for your records.  If you do not sign this form, 
you may not join this study.  Your decision to allow the use and disclosure of your PHI is 
voluntary and will have no impact on your treatment at University Hospitals. By signing this form, 
you are allowing the researchers for this study to use and disclose your PHI in the manner 
described below.   
 
Generally the Principal Investigator and study staff at University Hospitals and Cleveland Western 
Reserve University who are working on this research project will know that you are in a research 
study and will see and use your PHI.  The researchers working on this study will collect the 
following PHI about you:  
 Name, initials, address, telephone number, age and other demographic information 
 Your medical history, past medical records (including history and diagnosis of your disease 
and your family medical history. 
 Medical data, including your research evaluation findings. 
 Records about your study visits and information obtained during this research. 
 
This PHI will be used to assess whether receiving bupivacaine via your pain pump in small doses 
with your opioid pain medicine significantly improves your back pain and ability to function.  
Your access to your PHI may be limited during the study to protect the study results.   
 
IRB NUMBER: 08-16-09
IRB APPROVAL DATE: 06/30/2017
IRB EXPIRATION DATE: 06/12/2018


UNIVERSITY HOSPITALS  
CLEVELAND MEDICAL CENTER 
CONSENT FOR INVESTIGATIONAL STUDIES 
(v. 11.2012) 
 
 
 
 
 
 
Project Title: A randomized double blind cross-over trial of continuous intrathecal infusion for 
assessing patients with chronic noncancer pain who would benefit from treatment with intrathecal 
drug delivery system (IDDS) implant 
 
Principal Investigator:  Salim Hayek, MD, Ph.D. 
                    
Version 3.0 
 15May2017 
Page 7 of 9 
Your PHI may also be shared with the following groups/persons associated with this research 
study or involved in the review of research:  
 Staff from the principal investigator’s medical practice at UHCMC 
 Staff at University Hospitals Cleveland Medical Center, including the Center for Clinical 
Research and the Law Department, Institutional Review Board, Federal agencies or any 
agency when required by law.  
 
Your permission to use and disclose your PHI does not expire.  However, you have the right to 
change your mind at any time and revoke your authorization.  If you revoke your authorization, the 
researchers will continue to use the information that they previously collected, but they will not 
collect any additional information.  Also, if you revoke your authorization you may no longer be 
able to participate in the research study.  To revoke your permission, you must do so in writing by 
sending a letter to: 
Salim Hayek, MD, Ph.D 
University Hospitals Cleveland Medical Center 
Department of Anesthesiology/Division of Pain Management 
11100 Euclid Ave., Mather Pavilion B270 
Cleveland, OH  44106 
 
If you have a complaint or concerns about the privacy of your health information, you may also 
write to the UH Privacy Officer, Management Service Center, 3605 Warrensville Center, MSC 
9105, Shaker Heights, OH 44122 or to the Federal Department of Health and Human Services 
(DHHS) at DHHS Regional Manager, Office of Civil Rights, US Department of Health and 
Human Services Government Center, JF Kennedy Federal Building, Room 1875, Boston, MA 
02203.  Complaints should be sent within 180 days of finding out about the problem.    
 
The researchers and staff agree to protect your health information by using and disclosing it only 
as permitted by you in this Authorization and as directed by state and Federal law. University 
Hospitals is committed to protecting your confidentiality.  Please understand that once your PHI 
has been disclosed to anyone outside of University Hospitals, there is a risk that your PHI may no 
longer be protected; however other Federal and State laws may provide continued protection of 
your information.  
 
IRB NUMBER: 08-16-09
IRB APPROVAL DATE: 06/30/2017
IRB EXPIRATION DATE: 06/12/2018


UNIVERSITY HOSPITALS  
CLEVELAND MEDICAL CENTER 
CONSENT FOR INVESTIGATIONAL STUDIES 
(v. 11.2012) 
 
 
 
 
 
 
Project Title: A randomized double blind cross-over trial of continuous intrathecal infusion for 
assessing patients with chronic noncancer pain who would benefit from treatment with intrathecal 
drug delivery system (IDDS) implant 
 
Principal Investigator:  Salim Hayek, MD, Ph.D. 
                    
Version 3.0 
 15May2017 
Page 8 of 9 
Summary of your rights as a participant in a research study 
Your participation in this research study is voluntary.  Refusing to participate will not alter your 
usual health care or involve any penalty or loss of benefits to which you are otherwise entitled.  If 
you decide to join the study, you may withdraw at any time and for any reason without penalty or 
loss of benefits.  If information generated from this study is published or presented, your identity 
will not be revealed.  In the event new information becomes available that may affect the risks or 
benefits associated with this study or your willingness to participate in it, you will be notified so 
that you can decide whether or not to continue participating.  If you experience physical injury or 
illness as a result of participating in this research study, medical care is available at University 
Hospitals Cleveland Medical Center (UHCMC) or elsewhere; however, UHCMC has no plans to 
provide free care or compensation for lost wages. 
 
Contact information 
 
________________________________________ has described to you what is going to be done, 
the risks, hazards, and benefits involved. The Principal Investigator, Salim Hayek, MD, can also be 
contacted at 216-844-3771. If you have any questions, concerns or complaints about the study in 
the future, you may also contact them later. 
 
 
If the researchers cannot be reached, or if you would like to talk to someone other than the 
researcher(s) about; concerns regarding the study; research participant’s rights; research- related 
injury; or other human subject issues, please call the University Hospitals Cleveland Medical 
Center’s Research Subject Rights phone line at (216) 983-4979 or write to: The Chief Medical 
Officer, The Center for Clinical Research, University Hospitals Cleveland Medical Center, 11100 
Euclid Avenue, Lakeside 1400, Cleveland, Ohio, 44106-7061. 
 
 
Signature 
Signing below indicates that you have been informed about the research study in which you 
voluntarily agree to participate; that you have asked any questions about the study that you may 
have; and that the information given to you has permitted you to make a fully informed and free 
decision about your participation in the study.  By signing this consent form, you do not waive any 
legal rights, and the investigator(s) or sponsor(s) are not relieved of any liability they may have.  A 
copy of this consent form will be provided to you. 
 
 
IRB NUMBER: 08-16-09
IRB APPROVAL DATE: 06/30/2017
IRB EXPIRATION DATE: 06/12/2018


UNIVERSITY HOSPITALS  
CLEVELAND MEDICAL CENTER 
CONSENT FOR INVESTIGATIONAL STUDIES 
(v. 11.2012) 
 
 
 
 
 
 
Project Title: A randomized double blind cross-over trial of continuous intrathecal infusion for 
assessing patients with chronic noncancer pain who would benefit from treatment with intrathecal 
drug delivery system (IDDS) implant 
 
Principal Investigator:  Salim Hayek, MD, Ph.D. 
                    
Version 3.0 
 15May2017 
Page 9 of 9 
x  
Signature of Participant                                                                                           Date 
x  
Printed Name of Participant 
 
 
x  
Signature of Witness (if applicable)                                                                        Date 
x  
Printed Name of Witness  
 
 
x 
 
 
Signature of person obtaining informed consent                                                    Date 
x 
 
Printed name of person obtaining informed consent  
 
 
 
 
IRB NUMBER: 08-16-09
IRB APPROVAL DATE: 06/30/2017
IRB EXPIRATION DATE: 06/12/2018