Clinical trial NCT01951105
Conditions: Sub-acute Back Pain
Keywords: Subacute Back Pain Brain MRI
Sponsor: Northwestern University
Start date: 2015-02-24; Completion date: 2017-09-25
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aims to determine if early treatment with Carbidopa/Levodopa and Naproxen in individuals with sub-acute back pain (SBP) is associated with changes in blocking transition to chronic back pain (CBP).

Detailed description:
The transition from acute low back pain to chronic low back pain has been shown to be a result of changes in brain circuitry. Learning mechanisms give rise to the transition from acute to chronic pain and render the pain to become more emotional. The aim of this study is to further explore the idea that persistent pain, following an inciting injury, leads to an aversive learning signal that reorganizes the brain into a chronic pain state. We hypothesize that blocking the emotional/motivational learning response triggered by peripheral nerve injury in a critical time window will decrease the probability of transition to chronic pain. The primary hypothesis to be tested in the study is that early treatment with Carbidopa/Levodopa and Naproxen in individuals with sub-acute back pain (SBP) should decrease related reorganization and block transition to chronic back pain (CBP). This will be done through a 6 month, double-blind, randomized, placebo-controlled, three-arm, parallel-group trial of the pharmacological treatment Carbidopa/Levodopa for individuals (N = 200) with sub-acute back pain (SBP). A baseline MRI scan will be used to determine each subject's pain type and group assignment. Individuals with recovering sub-acute back pain will be observed over 6 months. Individuals with a persisting sub-acute back pain will be randomized to receive either 12 weeks of Carbidopa/Levodopa plus naproxen or placebo plus naproxen. The main outcome measurements will be the results of MRI scans at the baseline and final visit, assessment of back pain by the NRS pain scale, as well as pain assessment through self-reported questionnaires.

Arms: arm 1: Individuals identified as having a recovering phenotype (SBPp) will be assigned to the observational arm and will be asked to continue his/her normal regime and return for the week 12 and week 24 visits for follow-up. arm 2: Individuals identified as having a persisting phenotype (SBPr) will be treated with Carbidopa/Levodopa on a flexible dose-titration designed intervention based on dose-response TID throughout the 12 week treatment period.

Naproxen (250mg) capsules will be administered orally, one capsule TID, throughout the 12 week treatment period. arm 3: Individuals identified as having a persisting phenotype (SBPr) will be treated with placebo capsule plus 250mg naproxen tablet three times a day for 12 weeks.
Interventions: intervention 1: Naproxen intervention 2: Carbidopa/Levodopa intervention 3: Placebo
Intervention descriptions: intervention 1: Take one 250mg naproxen tablet three times a day for 12 weeks. intervention 2: 12.5mg/50mg Carbidopa/Levodopa, administered orally as capsules, will be titrated up to TID over one week and then continued at that level for 4 weeks. If at the end of this initial 4 week period the participant has "responded," the subject will be maintained on that dose for the duration of the treatment period (12 weeks total). If there has not been a response, the dose will be increased to 25mg/100mg Carbidopa/Levodopa TID for the following 4 weeks at which time the pain status will be re-evaluated. If a response has occurred, that dose will be maintained in a blinded manner for the following 4 weeks of treatment; if not, further dose-titration will occur to 50mg/200mg Carbidopa/Levodopa TID for the final 4 weeks. If a subject experiences an AE at higher doses, then the subject will be given the next lower dose that s/he was able to tolerate and then be maintained on that dose for the remainder of the 12 week dosing period. intervention 3: Take two placebo capsules three times a day for 12 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
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Corticostriatal plasticity in the transition to 
chronic pain: Effect of Levodopa
NIDCR Protocol Number: 14-025-E
NIDCR Grant Number: 5R01DE022746-02
Principal Investigator: Apkar Vania Apkarian, PhD
NIDCR Program Official: John Kusiak, PhD
NIDCR Medical Monitor: Jane Atkinson, DDS
Independent On-Site Medical Monitor: Tanya Simuni, MD
Version Number: 1.20
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STATEMENT OF COMPLIANCE
The study will be conducted in accordance with the International Conference on 
Harmonisation guidelines for Good Clinical Practice (ICH E6), the Code of Federal 
Regulations on the Protection of Human Participants (45 CFR Part 46), and the NIDCR 
Clinical Terms of Award. All personnel involved in the conduct of this study have 
completed human subjects protection training.
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SIGNATURE PAGE
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines.
Principal Investigator:
Signed:
Date:
Name: A. Vania Apkarian, PhD
Title: Professor of Physiology
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TABLE OF CONTENTS
PAGE
STATEMENT OF COMPLIANCE
TABLE OF CONTENTS
LIST OF ABBREVIATIONS
PROTOCOL SUMMARY
SCHEMATIC OF STUDY DESIGN:
1
KEY ROLES AND CONTACT INFORMATION
2
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE
2.1
Background Information
2.1.1 Health problem
2.1.2 Study intervention
2.1.3 Research background discussion and scientific justification
2.1.4 Importance of study
2.2
Rationale
2.3
Potential Risks and Benefits
2.3.1 Potential Risks
2.3.2 Potential Benefits
3
OBJECTIVES
3.1
Study Objectives
3.1.1 The primary objective of this study is:
3.1.2 Key secondary objectives include:
3.2
Study Outcome Measures
3.2.1 Primary
3.2.2 Secondary
4
STUDY DESIGN
4.1
Substudy
5
STUDY ENROLLMENT AND WITHDRAWAL
5.1
Participant Inclusion Criteria
5.2
Participant Exclusion Criteria
5.3
Strategies for Recruitment and Retention
5.3.1 Recruitment: Media Advertising
5.3.2 Recruitment: Online Advertising
5.3.3 Recruitment: Community Advertising
5.3.4 Retention
5.4
Treatment Assignment Procedures
5.4.1 Randomization Procedures
5.4.2 Masking Procedures
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5.5
Participant Withdrawal
5.5.1 Reasons for Withdrawal
5.5.2 Handling of Participant Withdrawals or Participant Discontinuation 
of Study Intervention
5.6
Premature Termination or Suspension of Study
6
STUDY INTERVENTION
6.1
Carbidopa/Levodopa 25-100
6.1.1 Study Product Description
6.1.2 Acquisition
6.1.3 Formulation, Packaging, and Labeling
6.1.4 Product Storage and Stability
6.1.5 Dosage, Preparation and Administration of Study Product
6.1.6 Modification of Study Product Administration for a Subject
6.1.7 Accountability Procedures for the Study Product
6.1.8 Assessment of Participant Compliance with Study Product 
Administration
6.1.9 Concomitant Medications/Treatments
6.2
Placebo
6.2.1 Study Product Description
6.2.2 Acquisition
6.2.3 Formulation, Packaging, and Labeling
6.2.4 Product Storage and Stability
6.2.5 Dosage, Preparation and Administration of Study Product
6.2.6 Modification of Study Product Administration for a Subject
6.2.7 Accountability Procedures for the Study Product
6.2.8 Assessment of Participant Compliance with Study Product 
Administration
6.2.9 Concomitant Medications/Treatments
6.3
Naproxen 250 mg
6.3.1 Study Product Description
6.3.2 Acquisition
6.3.3 Formulation, Packaging, and Labeling
6.3.4 Product Storage and Stability
6.3.5 Dosage, Preparation and Administration of Study Product
6.3.6 Modification of Study Product Administration for a Subject
6.3.7 Accountability Procedures for the Study Product
6.3.8 Assessment of Participant Compliance with Study Product 
Administration
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6.3.9 Concomitant Medications/Treatments
7
STUDY SCHEDULE
7.1
Screening – Visit 1, Week -4
7.2
Baseline Scan – Visit 2, Week -2
7.3
Enrollment – Visit 3, Week 0
7.4
Intermediate Visit – Visit 4, Week 1 ± 3 Days
7.5
Intermediate Visit – Visit 5, Week 4 ± 7 Days
7.6
Intermediate Visit – Visit 6, Week 8 ± 7 Days
7.7
Intermediate Visit – Visit 7, Week 12 ± 7 Days
7.8
Follow-up Phone Call – Week 16 ± 7 Days
7.9
Follow-up Phone Call – Week 20 ± 7 Days
7.10
Final Study Visit – Visit 8, Week 24 ± 7 Days
7.11
Interim Electronic Contact
7.12
Withdrawal Visit
8
STUDY PROCEDURES/EVALUATIONS
8.1
Study Procedures/Evaluations
8.2
Laboratory Procedures/Evaluations
8.2.1 Clinical Laboratory Evaluations
8.2.2 Special Assays or Procedures
8.2.3 Specimen Preparation, Handling, and Storage
8.2.4 Specimen Shipment
9
ASSESSMENT OF SAFETY
9.1
Specification of Safety Parameters
9.1.1 Unanticipated Problems
9.1.2 Adverse Events (AE)
9.1.3 Serious Adverse Events (SAE)
9.2
Time Period and Frequency for Event Assessment and Follow-Up
9.3
Characteristics of an Adverse Event
9.3.1 Relationship to Study Intervention
9.3.2 Expectedness of SAEs
9.3.3 Severity of Event
9.4
Reporting Procedures
9.4.1 Unanticipated Problem Reporting to IRB and NIDCR
9.4.2 Serious Adverse Event Reporting to NIDCR
9.4.3 Reporting of SAEs and AEs to FDA
9.4.4 Events of Special Interest
9.4.5 Reporting of Pregnancy
9.5
Halting Rules
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STUDY OVERSIGHT
11
CLINICAL SITE MONITORING
12
STATISTICAL CONSIDERATIONS
12.1
Study Hypotheses
12.2
Sample Size Considerations
12.3
Planned Interim Analyses (if applicable)
12.3.1 Safety Review
12.3.2 Efficacy Review
12.4
Final Analysis Plan
12.5
Sensitivity analyses
13
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS
14
QUALITY CONTROL AND QUALITY ASSURANCE
15
ETHICS/PROTECTION OF HUMAN PARTICIPANTS
15.1
Ethical Standard
15.2
Institutional Review Board
15.3
Informed Consent Process
15.4
Exclusion of Women, Minorities, and Children (Special Populations)
15.5
Participant Confidentiality
15.6
Future Use of Stored Specimens and Other Identifiable Data
16
DATA HANDLING AND RECORD KEEPING
16.1
Data Management Responsibilities
16.2
Data Capture Methods
16.3
Types of Data
16.4
Schedule and Content of Reports
16.5
Study Records Retention
16.6
Protocol Deviations
17
PUBLICATION/DATA SHARING POLICY
18
LITERATURE REFERENCES
SUPPLEMENTAL MATERIALS
APPENDICES
APPENDIX A: SCHEDULE OF EVENTS
APPENDIX B: CONSENT FORM
APPENDIX C: SMARTPHONE APP USAGE MANUAL
APPENDIX D: CHART DOCUMENTS
APPENDIX E: KEY PROS
APPENDIX F: PROCEDURE FOR DETERMINING HIGH-RISK SUBACUTE BACK PAIN 
PATIENTS (HIGH-RISK SBP)
APPENDIX G: CASE REPORT FORM FOR PHENOTYPING
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LIST OF ABBREVIATIONS
ADL
Activities Of Daily Living
AE
Adverse Event/Adverse Experience
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BDI
Beck Depression Inventory
BID
Twice Daily
BP
Blood Pressure
BSE
Bovine Spongiform Encephalopathy
BUN
Blood Urine Nitrogen
CBC
Complete Blood Count
CBP
Chronic Back Pain
CFR
Code Of Federal Regulations
CNS
Central Nervous System
CONSORT
Consolidated Standards Of Reporting Trials
CRF
Case Report Form
DHHS
Department Of Health And Human Services
DTI
Diffusion Tensor Imaging
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
FDA
Food And Drug Administration
FFR
Federal Financial Report
FL
Fluid
fMRI
Functional Magnetic Resonance Imaging
g/dL
Gram Per Deciliter
GI
Gastrointestinal
HCT
Hematocrit
Hgb
Hemoglobin
HIPAA
Health Insurance Portability And Accountability Act
ICF
Informed Consent Form
ICH
International Conference On Harmonisation
ICMJE
International Committee Of Medical Journal Editors
IND
Investigational New Drug Application
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IP
Investigational Product
IRB
Institutional Review Board
ISM
Independent Safety Monitor
IUD
Intrauterine Device
K/uL
Thousands Per Cubic Milliliter
m/uL
Thousands Per Cubic Milliliter
MAOI
Monoamine Oxidase Inhibitor
MCH
Mean Corpuscular Hemoglobin
MCV
Mean Corpuscular Volume
mEq/L
Milliequivalents Of Solute Per Litre Of Solvent
Mg
Milligram
mg/dL
Milligram Per Deciliter
mL
Milliliter
MMRM
Mixed Model Repeated Measure
mPFC
Medial Prefrontal Cortex
MPQ 
Mcgill Pain Questionnaire
MRI
Magnetic Resonance Imaging
N
Number (Typically Refers To Participants)
NAc
Nucleus Accumbens
NIDCR
National Institute Of Dental And Craniofacial Research, Nih, Dhhs
NIH
National Institutes Of Health
NMFF
Northwestern Medical Faculty Foundation
NMH
Northwestern Memorial Hospital
NMPG
Northwestern Memorial Physicians Group
NRS
Numerical Rating Scale
NSAID
Non-Steroidal Anti-Inflammatory Drug
NU
Northwestern University
NUCATS
Northwestern University Clinical And Translational Science
OHRP
Office For Human Research Protections
PANAS
Positive And Negative Affect Schedule
PASS
Pain Anxiety Symptoms Scale
PCS
Pain Catastrophizing Scale
PDI
Pain Disability Index
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PFc
Prefrontal Cortex
pg
Picogram
PHH
Personal Health History
PHI
Protected Health Information
PI
Principal Investigator
PRO
Patient Reported Outcome
PSQ
Pain Sensitivity Questionnaire
QA
Quality Assurance
QC
Quality Control
QD
Once Daily
RDW
Red Cell Distribution Width
RN
Registered Nurse
SAE
Serious Adverse Event/Serious Adverse Experience
SBP
Subacute Back Pain
SBPp
Subacute Back Pain – Persisting Phenotype
SBPr
Subacute Back Pain – Recovering Phenotype
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SNRI
Serotonin-Norepinephrine Reuptake Inhibitor
SOP
Standard Operating Procedure
SSRI
Selective Serotonin Reuptake Inhibitor
TID
Thrice Daily
Unit/L
Unit Per Liter
UP
Unanticipated Problem
US
United States
WOCBP
Women Of Childbearing Potential
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PROTOCOL SUMMARY
Title:
Corticostriatal plasticity in the transition to chronic pain: Effect of 
Levodopa
Summary:
This study is a 28-week, double-blind, randomized, placebo-
controlled two-arm, flexible dose-escalation, parallel-group trial 
of a pharmacological treatment (Carbidopa/Levodopa and 
Naproxen), selected based on positive results from previous 
preclinical studies, for the treatment of subacute back pain 
(SBP). After a 2-week screening period, individuals deemed at 
high risk of developing chronic back pain (CBP) will be 
randomized to receive either 12 weeks of Carbidopa/Levodopa 
plus Naproxen or placebo plus Naproxen and then followed for 
an additional 12 weeks to evaluate persistence of benefit at 
study endpoint, 24 weeks after randomization. During the 12-
week treatment period, participants will undergo evaluation at 
Baseline and at clinic visits on weeks 1, 4, 8, and 12 after 
randomization to assess pain, proper treatment use and side 
effects. During the subsequent 12-week follow-up period, pain 
and safety will continue to be assessed monthly by phone 
calls. All patients will also be assessed daily by a smartphone 
app regarding pain and mood. T1-MRI, resting state, fMRI, and 
DTI-MRI will be performed at Baseline and at the end of 24 
weeks for individuals completing MRI, except for a subset of 
individuals not receiving MRI, who will be directly put on 
treatment. Individuals identified as recovering subacute back 
pain (SBPr), will not be treated. However, they have the 
choice to participate in an optional substudy where their pain 
and mood will be assessed daily for 24 weeks using the 
smartphone app.
Objectives:
Primary: To determine if treatment with Carbidopa/Levodopa 
and Naproxen in individuals with subacute back pain (SBP), 
who are at high-risk for developing chronic pain, will diminish 
their rate of transition to chronic back pain (CBP) compared to 
individuals with SBP treated with Naproxen alone.
Secondary: To determine whether treatment efficacy is gender 
dependent.
Secondary: To determine the brain reorganization with 
treatment response
Population:
Sample size: 126
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Gender: Male and Female
Age: 18 years and older
Demographic group: No racial/ethnic restrictions
General health status: History of low back pain for a minimum 
of 4 weeks and a maximum of 12 weeks; no other source of 
pain and good general health.
Phase:
2
Number of Sites:
One
Northwestern University
Chicago, IL 60611
Description of 
Intervention:
A flexible dose-titration designed intervention based on dose-
response: Initially, Carbidopa/Levodopa (12.5mg/50mg), or 
matching placebo, administered orally as capsules, will be 
titrated up to TID over one week and then continued at that 
level for 4 weeks. If at the end of this initial 4 week period the 
participant has “responded” (had a reduction in pain from 
baseline of ≥20%), the participant will be maintained on that 
dose for the duration of the treatment period (12 weeks total).  
If there has not been a response, the dose will be increased to 
Carbidopa/Levodopa (25mg/100mg) TID for the following 4 
weeks at which time the pain status will be re-evaluated.  
Again, if a response has occurred, that dose will be maintained 
in a blinded manner for the following 4 weeks of treatment; if 
not, further dose-titration will occur to Carbidopa/Levodopa 
(50mg/200mg) TID for the final 4 weeks. If a participant 
experiences an AE at higher doses, then the participant will be 
given the next lower dose that s/he was able to tolerate and 
then be maintained on that dose for the remainder of the 12 
week dosing period.
Naproxen (250mg) capsules will be administered orally, one 
capsule TID, throughout the 12 week treatment period.
Study Duration:
36 months
Participant 
Participation 
Duration:
28 weeks
Estimated Time to 
Complete 
Enrollment:
24 months
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SCHEMATIC OF STUDY DESIGN:
Visit 1(Week -4)
Visit 2*
(Week -2)
Visit 3*
(Week 0)
Visit 4**
(Week 1)
Visit 5*
(Week 4)
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Visit 6*
(Week 8)
Visit 7*
(Week 12)
(Week 16)*
(Week 20)*
Visit 8*
(Week 24)
*visit window = 1 week
**visit window = 3 days
(See Appendix A for a detailed schedule of events table)
1
k
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1.
KEY ROLES AND CONTACT INFORMATION
Principal 
Investigator: 
Apkar Vania Apkarian, PhD, Professor
Department of Physiology
300 E. Superior Street, Room 7-705
Chicago, Illinois 60611
Phone: (312) 503-0404 
Fax: (312) 503-5101
Email: a-apkarian@northwestern.edu 
Medical Monitor:
Dr. Tanya Simuni
NIDCR Program 
Official: 
Dr. John Kusiak
Clinical Site 
Investigator:
Thomas J. Schnitzer, MD, PhD, Professor
Department of Physical Medicine & Rehabilitation
710 N. Lake Shore Drive, Suite 1020
Chicago, IL 60611
Phone: (312) 503-2315
Fax: (312) 503-1505
Email: tjs@northwestern.edu 
Institutions:
Northwestern University
Chicago, IL 60611
Other Key 
Personnel
Data Analyst:
James Griffith
Northwestern University
633 N. St. Clair, 19th floor
Phone: (312) 503-5345 
Fax: (312) 503-4800
Email: j-griffith@northwestern.edu 
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2          INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
      RATIONALE 
2.1
Background Information
2.11 Health problem
When pain becomes chronic, it dramatically decreases quality of life and imparts a huge 
healthcare cost (more than $500 billion annually in the USA). Its prevalence is on the 
increase worldwide (back pain has become the number one leading cause in the USA, 
and number six cause worldwide, for days lost to disability). Even though there is 
extensive evidence for a long list of peripheral and central adaptations that are 
observed in humans’ pain conditions, and in animal models for neuropathic or 
inflammatory pain, there is minimal understanding of critical mechanisms that control 
the transition from an acute injury to persistent/chronic pain. Perhaps more importantly, 
there are no scientifically validated clinical intervention strategies to abrogate the 
transition from acute to chronic pain. The present clinical trial will test a potential 
strategy for this. 
Acute back pain is highly prevalent, and about 85% of the population suffers from 
back pain throughout life. The large majority of such participants properly recover from 
the condition within a few weeks and lead a healthy life. Although only approximately 5-
10% of people with acute back pain progress to develop chronic back pain, this number 
is large given the almost universal incidence of back pain, and it has enormous 
economic consequences. Furthermore, the current treatments for low back pain are 
largely ineffective, providing at best modest pain relief, and often with unacceptable and 
even dangerous side effects (e.g., opioids are widely used and lead to the death of 
>15,000 people per year). Therefore, reducing the incidence of transition to CBP would 
have major health, economic and societal benefits. Until recently there were no 
predictive mechanisms as to who transitions to chronic pain. In a series of studies we 
have identified brain parameters that put participants at risk for developing chronic pain 
from subacute back pain. Based on these results we have tested in animal models a 
novel drug combination therapy, with highly successful results. Here we will test 
translation of the animal study into a clinical trial. The study will test whether clinical 
acute back pain patients who are at high risk of transitioning to chronic pain can be 
properly treated to abrogate this transition. 
2.1.2 Study intervention
Carbidopa/Levodopa (12.5mg/50mg – 25mg/100mg – 50mg/200mg) and Naproxen 
(250mg). Carbidopa/Levodopa is a medication approved by the FDA for the treatment of 
Parkinson’s disease and has been used for many years. Levodopa is metabolized to 
dopamine, which is a known central neurotransmitter. Carbidopa prevents the 
degradation of Levodopa to permit higher levels of Levodopa to be biologically active.
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Naproxen is a non-steroidal anti-inflammatory drug (NSAID) used to treat mild-moderate 
pain. Its mode of action is via non-selective inhibition of the cyclooxygenase enzymes.
U-shaped dose response
The inverted u-shape hypothesis of dopamine refers to the finding whereby too little or 
too much dopamine can be disadvantageous for certain neural processes, suggesting 
that the best range of doses for dopamine treatment is somewhere in between these 
two extremes (i.e., located at the peak of the inverted u-curve). This phenomenon has 
been documented particularly well in literature investigating working memory and other 
functions related to the prefrontal cortex (PFC); in many of these studies, a moderate 
concentration of increased dopamine enhanced performance on cognitive tasks, 
whereas doses close to either endpoint of the curve proved detrimental.(Stewart 2006, 
Williams 1995, Arnsten 1998)  It is still being debated as to which dopamine receptor 
subtype is primarily involved in this curve, with D1-receptor activation being the most 
cited (Stewart 2006, Monte-Silva 2009), although D2-receptor activation has also been 
shown to produce this inverted curve in other areas, including the motor cortex (Monte-
Silva 2009) and the striatum (Gjedde 2010). This is most likely due to the complicated 
push-and-pull mechanisms of dopaminergic circuitry throughout the brain, such that one 
region’s concentration may have an antagonistic relationship with another’s levels (for 
example, PFC with striatum (Fallon 2013, Cools 2011)). It has also been shown that the 
effects of dopamine stimulation on a given cognitive phenomenon is inversely correlated 
to a participant’s baseline dopamine levels in target circuitry, which is also important to 
this curve (Gjedde 2010, Cools 2011, Costa 2014). Thus a participant with decreased 
dopamine transmission would be hypothesized to benefit from dopamine replacement 
whereas in a healthy participant or a person with higher levels of baseline dopamine, 
the same treatment might be detrimental due to this inverse relationship. Although some 
studies looking at dopaminergic treatment in pain models have suggested that 
increasing dopamine levels dose-dependently decreased pain (Park 2013) and that due 
to biphasic dopamine responses, smaller doses of dopamine can facilitate pain whereas 
larger doses can cause antinociception (Paalzow 1992), our own experiments do not 
support these findings.  In both rats and mice with chronic pain (spared nerve injury, 
SNI), smaller doses of Carbidopa/Levodopa (in combination with Naproxen) resulted in 
both acute (1 hour) and long-term (10 days) relief of tactile allodynia induced by the 
injury; in contrast, doubling this dose resulted in zero change from baseline pain levels 
(acutely) and did not produce results significantly different from those at the lower dose 
(chronically).
Four points can be made from this knowledge of the inverted-U curve.  First, dopamine 
treatment appears to have non-linear effects in both humans and animals. Therefore, a 
simple upward titration that continues to increase in time does not necessarily result in a 
simple increase in reported levels of pain relief.  Second, given that chronic pain 
patients are hypothesized to have less dopamine than healthy controls (one extreme of 
the curve) and more dopamine than individuals with mid-to-late stage Parkinson’s 
Disease (the other extreme), we would hypothesize that targeted dopamine levels 
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should be in between these two ends of the spectrum (again, residing at the peak of the 
curve).  Third and related, continuing to increase dopaminergic levels after initial 
efficacy is found does not guarantee increased efficacy results and may even cause 
additional or worsening levels of pain, as well as increased side effects. Fourth, it is 
clear that baseline levels of dopamine affect dopaminergic treatment efficacy and 
behavior, and as such, the starting and stopping of titration must be based on an 
individual’s perception of analgesia in order to indirectly account for this. All of these 
points would suggest that we therefore titrate the dopaminergic treatment upward until 
an individual’s efficacy is found and then cease increasing the dose in order to remain 
within this optimum middle range.  This would provide us with a tightly-controlled, data-
driven, and patient-centered approach to the proposed study.
2.1.3 Research background discussion and scientific justification
Over the last 10 years, the Apkarian group has pioneered the development of brain 
imaging methods that can be specifically used to study brain properties of chronic pain. 
A large portion of this work targets the CBP brain. A new mechanistic model for 
transition of acute to chronic pain was proposed and expounded in three review articles 
(Apkarian 2008a, Apkarian et al 2009, Apkarian et al 2010). It proposes that learning 
mechanisms within the limbic circuitry give rise to the transition from acute to chronic 
pain and cause the pain to become more emotional. Within the context of this model we 
undertook a longitudinal observational brain imaging study, where SBP patients1 are 
tracked over a year as they transition to either persistent pain (SBPp; chronicity) or into 
recovery (SBPr), enabling comparisons of brain parameters in this time window and in 
contrast to healthy and CBP patients.2 We observe that functional corticostriatal 
connectivity (a dopaminergic circuit), the size of limbic nuclei, and white matter 
anisotropy PREDICT participants at high risk for transition to chronic pain, with about 
90% accuracy. Most of these results are now published.
Given that the human longitudinal study directly implicates brain dopaminergic limbic 
circuitry in transition to chronic pain, we recently began mouse electrophysiological 
studies (patch clamp) where we could identify cellular excitability and morphological 
changes in nucleus accumbens D2 spiny neurons, 5 days after a peripheral nerve 
injury. When such animals were treated with a combination of Carbidopa/Levodopa and 
Naproxen (a combination treatment designed to decrease the peripheral nociceptive 
load as well as the central dopamine deficit), we were able to block the transition to 
persistent pain (note that the use of either drug alone had little efficacy in diminishing 
1 Subacute back pain (SBP) patients are defined as individuals still experiencing back pain during a 
window of 4-12 weeks after the onset of this new acute back pain episode 
2 SBPr denoted individuals seen during the subacute phase of their pain who, at some time after 12 
weeks, have demonstrated a reduction in pain from their baseline of ≥ 20%; SBPp individuals are those 
who do not demonstrate this reduction from their baseline pain over a one year observation period; CBP 
(chronic back pain) individuals are those who have a history of back pain that has persisted for more than 
6 months (in the study these were subjects with back pain of at least 5 year duration) but who have not 
been followed at earlier time points and for whom there is no “baseline” pain level available.
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persistence of pain behavior), and also we could show that accumbens D2 spiny 
neuronal excitability and morphological adaptations were blocked. Therefore, we think 
we have identified both a critical site of action and a combination treatment that should 
diminish transition to chronic pain. The current trial tests this idea in humans at high risk 
to transition to chronic back pain.
2.1.4 Importance of study
CBP is the single largest cause of loss of work and has major personal and societal 
consequences. The ability to reduce the number of people who develop CBP after an 
acute back pain episode would reduce health care expenditures, increase overall 
productivity and improve quality of life. Up to this point in time, no treatment has been 
shown to be effective at altering what is described as the natural history of low back 
pain; therefore, if successful, this study would be the first to demonstrate that it is 
possible to identify individuals who will progress and to interfere medically in order to 
prevent that progression.
2.2
Rationale
Based on our results demonstrating the importance of dopaminergic pathways in the 
modulation of chronic pain response, and the additive effect of Naproxen on the 
response, this study will attempt to affect brain pathways by the administration of 
Carbidopa/Levodopa and Naproxen. 
Our main hypothesis is: SBP patients treated with Carbidopa/Levodopa and Naproxen 
will show a statistically significant decrease in rate of transition to chronic pain.
Our secondary hypothesis is: The rate of response to Carbidopa/Levodopa and 
Naproxen is gender dependent.
Our other secondary hypothesis is: Of the three brain biomarkers that define SBP at 
high risk for chronification, only the extent of corticostriatal information sharing (mPFC-
NAc) will show statistically significant reduction in SBP treated with 
Carbidopa/Levodopa and Naproxen. 
Carbidopa/Levodopa will be administered orally as this has been shown to result in 
increased dopaminergic brain activity, and also because our rodent studies were also 
done with oral administration of Carbidopa/Levodopa and Naproxen. The dosage 
chosen is based on obtaining a clinically meaningful dose without resulting in an 
unacceptably high rate of side effects, which would limit the utility of this approach. The 
dosage is also derived from our rodent studies, where standard clinical doses were 
tested, and with such doses neither Carbidopa/Levodopa alone nor Naproxen alone 
showed any efficacy on pain related outcomes. By dosing three times per day (TID), it is 
anticipated that stable elevated drug levels can be maintained (this is the regimen we 
used in rodents as well). It is anticipated, from our animal studies, that 12 weeks of 
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treatment will be sufficient to alter the course of the transition from subacute to chronic 
pain. To evaluate whether this intervention has a long-lasting effect, participants will be 
followed for an additional 12 weeks after treatment has been stopped, to evaluate their 
pain response and assess whether the treatment benefits are sustained. 
This study specifically focuses on people with subacute low back pain because these 
individuals have a high likelihood of progressing to chronic pain; as our previous work 
has shown that ~50% of this group develops CBP. Furthermore, we have extensive 
experience with this population of people, and have shown that we can identify those 
individuals who will develop persistent pain and those who will recover, based on MRI 
findings when first seen with SBP. 
2.3
Potential Risks and Benefits
Potential Risks
The risks from the study procedures may include possible side effects from the study 
medications, the MRI procedure, completion of PROs and the blood draw. (See 
Supplemental Materials for package inserts.)
Study medications
Carbidopa/Levodopa
Carbidopa/Levodopa is a therapy that combines the dopamine agonists Levodopa and 
Carbidopa. The combination aims at increasing the levels of dopamine in the brain while 
preventing any similar increase in the rest of the body, hence minimizing side effects. 
To reduce the incidence of side effects, the dose of medication will be increased slowly, 
and subject’s health will be monitored closely. After completing 12 weeks of treatment, 
the participant will slowly taper off the study drug. 
The list of adverse events noted below derives from the package insert for 
Carbidopa/Levodopa and was a consequence of AEs reported in clinical trials of 
individuals with Parkinson’s disease who have depleted brain dopamine levels. The 
incidence and type of AEs occurring in people in this study with normal dopamine levels 
is not known but may be lower, particularly as the dose of Carbidopa/Levodopa used is 
at the low end of the therapeutic range.
The most common side effects (prevalence ≥ 1.5%) of Carbidopa/Levodopa are shown 
below and information from the package insert which lists all reported side effects, 
regardless of prevalence, follows (Sinemet CR, 2011).
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Adverse Experience
Carbidopa/Levodop
a (n = 524)
Dyskinesia
12.2%
Nausea
5.7%
Hallucinations
3.2%
Confusion
2.3%
Dizziness
2.3%
Urinary Tract Infection
2.3%
Headache
1.9%
Vomiting
1.9%
Constipation
1.5%
As noted, the most common adverse reactions reported with Carbidopa/Levodopa have 
included dyskinesias, such as choreiform, dystonic and other involuntary movements, 
and nausea.
The following other adverse reactions have been reported with Carbidopa/Levodopa:
Body as a Whole: chest pain, asthenia.
Cardiovascular: cardiac irregularities, hypotension, orthostatic effects including 
orthostatic hypotension, hypertension, syncope, phlebitis, palpitation.
Gastrointestinal: dark saliva, gastrointestinal bleeding, development of duodenal ulcer, 
anorexia, vomiting, diarrhea, constipation, dyspepsia, dry mouth, taste alterations.
Hematologic: agranulocytosis, hemolytic and non-hemolytic anemia, thrombocytopenia, 
leukopenia.
Hypersensitivity: angioedema, urticaria, pruritus, Henoch-Schonlein purpura, bullous 
lesions (including pemphigus-like reactions).
Musculoskeletal: back pain, shoulder pain, muscle cramps.
Nervous System/Psychiatric: psychotic episodes including delusions, hallucinations, 
and paranoid ideation, neuroleptic malignant syndrome, bradykinetic episodes ("on-off" 
phenomenon), confusion, agitation, dizziness, somnolence, dream abnormalities 
including nightmares, insomnia, paresthesia, headache, depression with or without 
development of suicidal tendencies, dementia, pathological gambling, increased libido 
including hypersexuality, impulse control symptoms. Convulsions also have occurred; 
however, a causal relationship with Carbidopa/Levodopa has not been established.
Respiratory: dyspnea, upper respiratory infection.
Skin: rash, increased sweating, alopecia, dark sweat.
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Urogenital: urinary tract infection, urinary frequency, dark urine.
Laboratory Tests: decreased hemoglobin and hematocrit; abnormalities in alkaline 
phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, bilirubin, blood urea 
nitrogen (BUN), Coombs test; elevated serum glucose; white blood cells, bacteria, and 
blood in the urine.
Other adverse reactions that have been reported with Levodopa alone and with various 
Carbidopa/Levodopa formulations, are:
Body as a Whole: abdominal pain and distress, fatigue.
Cardiovascular: myocardial infarction.
Gastrointestinal: gastrointestinal pain, dysphagia, sialorrhea, flatulence, bruxism, 
burning sensation of the tongue, heartburn, hiccups.
Metabolic: edema, weight gain, weight loss.
Musculoskeletal: leg pain.
Nervous System/Psychiatric: ataxia, extrapyramidal disorder, falling, anxiety, gait 
abnormalities, nervousness, decreased mental acuity, memory impairment, 
disorientation, euphoria, blepharospasm (which may be taken as an early sign of 
excess dosage; consideration of dosage reduction may be made at this time), trismus, 
increased tremor, numbness, muscle twitching, activation of latent Horner's syndrome, 
peripheral neuropathy.
Respiratory: pharyngeal pain, cough.
Skin: malignant melanoma, flushing.
Special Senses: oculogyric crises, diplopia, blurred vision, dilated pupils.
Urogenital: urinary retention, urinary incontinence, priapism.
Miscellaneous: bizarre breathing patterns, faintness, hoarseness, malaise, hot flashes, 
sense of stimulation.
Laboratory Tests: decreased white blood cell count and serum potassium; increased 
serum creatinine and uric acid; protein and glucose in urine.
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Naproxen
A dose of Naproxen 250mg TID will be administered. Participants with uncontrolled 
hypertension, history of recent myocardial infarction, peptic ulcer disease, renal disease 
or history of allergies to NSAID medication will be excluded. 
Adverse reactions reported in controlled clinical trials in 960 patients treated for 
rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients 
treated chronically were reported 2 to 10 times more frequently than they were in short-
term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. 
The most frequent complaints reported related to the gastrointestinal tract.
A clinical study found gastrointestinal reactions to be more frequent and more severe in 
rheumatoid arthritis patients taking daily doses of 1500 mg Naproxen compared to 
those taking 750 mg Naproxen. 
In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-
label studies with about 400 pediatric patients with juvenile arthritis treated with 
Naproxen, the incidence of rash and prolonged bleeding times were increased, the 
incidence of gastrointestinal and central nervous system reactions were about the 
same, and the incidence of other reactions were lower in pediatric patients than in 
adults.
In patients taking Naproxen in clinical trials, the most frequently reported adverse 
experiences in approximately 1 to 10% of patients are:
Gastrointestinal (GI) Experiences, including: heartburn*, abdominal pain*, nausea*, 
constipation*, diarrhea, dyspepsia, stomatitis
Central Nervous System: headache*, dizziness*, drowsiness*, lightheadedness, vertigo
Dermatologic: pruritus (itching)*, skin eruptions*, ecchymoses*, sweating, purpura
Special Senses: tinnitus*, visual disturbances, hearing disturbances
Cardiovascular: edema*, palpitations
General: dyspnea*, thirst
*Incidence of reported reaction between 3% and 9%. Those reactions occurring in less 
than 3% of the patients are unmarked.
In patients taking NSAIDs, the following adverse experiences have also been reported 
in approximately 1 to 10% of patients.
Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI 
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ulcers (gastric/duodenal), vomiting
General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding 
time, rashes
The following are additional adverse experiences reported in <1% of patients taking 
Naproxen during clinical trials and through post-marketing reports. Those adverse 
reactions observed through post-marketing reports are italicized.
Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, 
pyrexia (chills and fever)
Cardiovascular: congestive heart failure, vasculitis
Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, jaundice, 
pancreatitis, vomiting, colitis, abnormal liver function tests, nonpeptic gastrointestinal 
ulceration, ulcerative stomatitis
Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, 
agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia
Metabolic and Nutritional: hyperglycemia, hypoglycemia
Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, 
malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction
Respiratory: eosinophilic pneumonitis
Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema 
multiforme, Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity 
reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) 
or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of 
pseudoporphyria occur, treatment should be discontinued and the patient monitored.
Special Senses: hearing impairment
Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic 
syndrome, renal disease, renal failure, renal papillary necrosis
In patients taking NSAIDs, the following adverse experiences have also been reported 
in <1% of patients.
Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, 
death
Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, 
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myocardial infarction
Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, 
hepatitis, eructation, liver failure
Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia
Metabolic and Nutritional: weight changes
Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, 
tremors, convulsions, coma, hallucinations
Respiratory: asthma, respiratory depression, pneumonia
Dermatologic: exfoliative dermatisis
Special Senses: blurred vision, conjunctivitis 
Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria
Omeprazole
A dose of Omeprazole 40mg QD will be administered. Participants with known 
hypersensitivity to any component of the formulation or substituted benzimidazoles are 
not required to take the medication for participation in the study. 
PPI therapy may be associated with increased risk of Clostridium difficile associated 
diarrhea 
Concomitant use of Omeprazole Delayed-Release Capsules with clopidogrel should be 
avoided.
Use of Omeprazole Delayed-Release Capsules concomitant with St. John's Wort or 
rifampin should be avoided due to the potential reduction in omeprazole concentrations. 
Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like 
cell hyperplasia and increased Chromogranin A levels, which may interfere with 
diagnostic investigations for neuroendocrine tumors
In patients taking Omeprazole the most frequently reported adverse experiences in 
approximately 1 to 10% of patients are:
Gastrointestinal (GI) Headache, abdominal pain, nausea, diarrhea, vomiting, and 
flatulence
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Interactions with this drug include:
Combination with atazanavir, nelfinavir, saquinavir: not recommended to be taken 
concomitantly with omeprazole. 
May interfere with ketoconazole, iron salts, erlotinib, ampicillin esters, digoxin, and 
mycophenolate mofetil, clopidogrel, and cilostazol. 
Diazepam, warfarin, phenytoin, cyclosporine, disulfiram, benzodiazepines can be 
prolonged in their elimination when taking in conjunction with omeprazole; monitor and 
determine need for dose adjustments. 
Patients treated with omeprazole and voriconazole may have raised omeprazole levels.
Drug status regarding interactions will be reviewed by the study clinician and the NU 
pharmacy. Based on this review, participants may be excluded if there may be a drug-
drug interaction that would be clinically significant and affecting subject safety (See 
Section 5.2. Exclusion criteria).
Acetaminophen
The rescue medication for this study, acetaminophen, may cause liver damage and 
rarely death due to overdosing and/or mixing with alcohol. Early symptoms of liver 
damage include, but are not limited to, nausea, vomiting, sweating, and general malaise 
(not feeling well). Participants should not take more than four 500 mg tablets during a 
24-hour period. If a participant drinks 3 or more alcoholic beverages per day, then he or 
she should tell the study doctor. Regular use of acetaminophen and NSAIDS in general 
may increase the risk of chronic kidney failure, but only in those individuals with pre-
existing kidney disease. Acetaminophen has no significant side effects on the kidney if 
subject’s kidney function is normal and the dosing instructions are followed. Prior to 
receiving study treatment, blood will be tested to see if kidneys and liver are functioning 
as they should.
Placebo
There is the risk that participants will not get the study drug or normal medication, so 
they may see no improvement in their condition or symptoms may get worse.
Magnetic Resonance Imaging (MRI)
For the MRI test, participants will lie in a small closed area inside a large magnetic tube 
for up to 60 minutes at a time. In our previous experience with MR imaging of 
individuals with chronic and subacute back pain, almost all are able to tolerate periods 
of testing up to 60 minutes.  Some people are scared or anxious in small places 
(claustrophobic). Because the test requires that participants lay as still as possible with 
only minimal movements, back pain may worsen during the test. During the test, 
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personnel will continuously ask participants about their level of pain, and will discontinue 
the scan at any time requested. Participants will be asked about any concerns they may 
have prior to testing. 
Blood Draw
The risks of taking blood include pain, a bruise at the point where the blood is taken, 
redness and swelling of the vein and infection, and a rare risk of fainting.
Patient Reported Outcomes (PROs)
Some of the questions asked may be upsetting, or may cause the participant to feel 
uncomfortable answering them. If a participant does not wish to answer a question, he 
or she may skip it and go to the next question. 
Potential Benefits
The possible benefits from this study include decreased low back pain and the potential 
to avoid being in a chronic pain state. It is possible that participants will receive no 
benefit from taking part in this study.
Taking part in this study may help scientists to better understand how chemical 
interactions in the brain determine the type of pain, chronic or acute, in an individual 
following an injury. It will also help scientists to determine if early treatment with 
Levodopa and/or NSAID may benefit patients with low back pain. This study may also 
help inform future research studies involving individuals with subacute low back pain.
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3
OBJECTIVES
3.1
Study Objectives
The conceptual basis of this study is that persistent pain, following an inciting injury, 
leads to an aversive learning signal that the corticostriatal system hijacks to reorganize 
the brain into a chronic pain state. We hypothesize that blocking the 
emotional/motivational learning response triggered by peripheral nerve injury and 
integrated within the corticostriatal circuitry, in a critical time window, will decrease the 
probability of transition to chronic pain. Specifically, the primary hypothesis to be tested 
in the study is that early treatment with Levodopa and Naproxen in individuals with SBP 
will block transition to CBP.
3.1.1 The primary objective of this study is:
To compare the efficacy and safety of Carbidopa/Levodopa (12.5mg/50mg – 
25mg/100mg – 50mg/200mg) plus Naproxen 250 mg administered TID compared to 
placebo plus Naproxen 250mg administered TID in people with subacute low back pain 
in reducing the risk of transitioning to persistent low back pain. 
3.1.2 Key secondary objectives include:
●
To evaluate if an interaction exists between change in pain condition and gender
●
To examine the correlation of corticostriatal reorganization with change in pain 
condition
3.2
Study Outcome Measures
3.2.1 Primary
The primary outcome measure for efficacy is the percent of participants who have 
developed chronic back pain. Mean pain levels will be assessed at study baseline 
(mean pain over the 5 days prior to randomization) and compared to mean pain levels 
for the 5 days prior to the visit at week 24 (study endpoint). Pain will be assessed using 
an 11-point NRS scale. Chronic pain is defined as an improvement in mean pain level at 
study endpoint of <20% compared to the mean pain level at randomization. 
Improvements of ≥ 20% reflect “recovery” of pain from the baseline values. 
3.2.2 Secondary
A number of secondary outcome measures will be evaluated (see below). Many of 
these will add information regarding the response to treatment in this study. Specifically, 
analyses will be done utilizing not only endpoint data but pain (and other) data collected 
at each of the clinic visits. This will permit further analyses of the pain data which will 
complement and extend the responder analysis that is the primary endpoint. Other pain-
associated parameters will also be evaluated as covariates in regard to the basic pain 
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outcome. Additionally, brain parameters obtained by fMRI will be assessed and 
correlated with the clinical outcome measures. Safety will also be assessed as a 
secondary outcome measure. 
A list of major secondary outcome measures includes:
1. Effect of gender on incidence of transition to chronic back pain
2. Brain biomarkers (obtained at scanning visits) 
3. NRS pain score (obtained at each study visit, and daily by smartphone app)
4. McGill Pain Questionnaire (obtained at each study visit)
5. painDETECT instrument (obtained at each study visit)
6. Pain Disability Inventory (obtained at scanning and intermediate visits)
7. Daily NRS mood score (by smartphone app)
8. Beck Depression Inventory – Second version (obtained at each study visit)
9. Positive and Negative Affect Schedule (obtained at scanning and 
intermediate visits)
10.Pain Catastrophizing Scale (obtained at screening visit)
11.Pain Anxiety Symptoms Scale (obtained at screening visit)
12.Pain Sensitivity Questionnaire (obtained at screening visit)
13.Personal Health History (obtained at screening visit)
Measure 1 will assess the interaction between the primary endpoint and gender. 
Measure 2 will evaluate the interaction between the primary endpoint and specified 
brain biomarkers with particular attention to corticostriatal connectivity.  In addition, 
brain biomarker measures will be used initially to identify SBP patients at high risk for 
pain chronification, that is, identify the study cohort. They are then measured again at 
end of treatment. There are four predefined measures extracted from these scans: right 
amygdala volume, white matter fractional anisotropy, mPFC-NAc functional connectivity 
and mPFC/somatosensory link ratio. Only mPFC-NAc and mPFC/somatosensory link 
ratio values are expected to reflect treatment effects.   Whole-brain exploratory analyses 
will be used to identify both brain predictors of treatment response and brain 
reorganization (consequences) in response to treatment. 
Measures 3-12 are validated instruments that have been successfully applied to the 
back pain population.  Measure 3 utilizes the same instrument as the primary outcome 
measure but at different points of time during the trial to permit a more detailed 
evaluation of overall change in pain with time.  Measures 4-6 are expected to reflect the 
change observed in measure 3, and are thus primarily confirmatory for the main 
outcome. They will also be used to examine characteristics of the pain that differentiate 
between treatment responders and non-responders, and this information can be used in 
future response prediction based studies and in clinical decision making.  Measure 7 
should generally reflect measures 3 and 8, as well as contribute to treatment response. 
It should also capture brain properties reflecting treatment response. 
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Measures 8-12 are expected to contribute to prediction of treatment response. They will 
be used as covariates in logistic multiple regression exploratory models where brain 
parameters, pain parameters and personality values are combined to predict treatment 
effect.
Measures from 13 include age, gender, smoking, past history of comorbidities, and 
medication use. We will use gender to test its effect on treatment outcome. We use age, 
education and behavioral outcomes (measures 8-12) as covariates. Demographic 
outcomes are also used as covariates in the brain outcome comparisons.
Measures 8 and 9 are collected repeatedly, similarly to measures 3-6, as we expect 
them to change in parallel with treatment. 
Interaction of this primary outcome measure with gender will be assessed (key 
secondary objective of the study).
Interaction of the primary outcome measure with brain biomarker measures will be 
assessed (the other key secondary objective of the study). 
Correcting for covariates of no interest will strengthen our conclusions. In addition, 
incorporating covariates of interest into our models provide additional explanations for 
observed results.
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4
STUDY DESIGN
This study is a 24-week, flexible dose escalation, double-blind, randomized, placebo-
controlled two-arm, parallel-group trial of a pharmacological treatment 
(Carbidopa/Levodopa plus Naproxen), selected based on positive results from previous 
preclinical studies, for people with SBP who are at high risk of progressing to CBP.
Individuals with subacute low back pain (new onset back pain that has been present for 
4-20 weeks) will be identified and screened. Individuals having a mean pain level over 
the 5 days prior to baseline of at least 4 (on a 0-10 NRS) and deemed to be at high risk 
of developing chronic persistent low back pain (based on brain MRI and fMRI 
parameters – see Appendix F & Appendix G) will be entered into the study in order to 
increase study sensitivity. In addition, individuals who have diabetes, who are not safe 
to undergo MRI, , who are claustrophic, or who are unwilling to undergo an MRI, will not 
undergo brain imaging but will be directly entered into the treatment phase of the study 
and informed that they are assumed to be at risk for chronification. Participants will then 
be randomized to receive either 12 weeks of Carbidopa/Levodopa plus naproxen and 
omeprazole, or placebo plus naproxen and omeprazole; acetaminophen will be 
available as a rescue medication. Omeprazole is prescribed QD as a preventative 
measure against possible gastric adverse effects of naproxen. All participants will also 
use a smartphone app to log their back pain intensity, mood, proper medication use, 
and other information that they may wish to report. The smartphone data are entered 
every time participants ingest their medication (up to TID) and after termination of 
treatment (up to TID) until the final study visit. 
Mean pain levels will be assessed at study baseline (mean pain over the 5 days prior to 
randomization) and compared to mean pain levels for the 5 days prior to the 
randomization study visit. Pain will be assessed using an 11-point (NRS) scale. Chronic 
pain is defined as an improvement in mean pain level <20% compared to the mean pain 
level at randomization. Improvements of ≥ 20% reflect “recovery” of pain from the 
baseline values.
Treatment with Carbidopa/Levodopa will be titrated up to 12.5mg/50mg TID over one 
week and then continued at that level for 4 weeks. If at the end of the initial 4-week 
period the participant has “responded or recovered” (had a reduction in pain from 
baseline of ≥20%), the participant will be maintained on that dose for the duration of the 
treatment period (12 weeks total).  If there has not been a response, the dose will be 
increased to Carbidopa/Levodopa (25mg/100mg) TID for the following 4 weeks at which 
time the pain status will be re-evaluated.  Again, if a response has occurred, that dose 
will be maintained in a blinded manner for the following 4 weeks of treatment; if not, 
further dose-titration will occur to Carbidopa/Levodopa (50mg/200mg) TID for the final 4 
weeks. If a participant experiences an AE at higher doses, then the participant will be 
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given the next lower dose that s/he was able to tolerate and then be maintained on that 
dose for the remainder of the 12 week dosing period.  Study drug will be tapered off 
over a one-week period starting after their week 12 clinic visit, and participants will 
continue to be evaluated to determine persistence of response for another 12 weeks, at 
which point they will have a final MRI and fMRI scan session. (See Appendix A for a 
detailed schedule of events table)
Individuals with subacute low back pain will be studied as they have a higher likelihood 
of progressing to chronic low back pain than the entire acute pain population. 
Furthermore, the initial MRI screening will further identify a subset of the subacute low 
back pain population who has a brain phenotype that, from results of our previous work, 
makes it highly likely (~90%) that they will develop persistent low back pain with 
standard treatment. (See Appendix F & Appendix G for further phenotyping 
information.) In addition, those participants (defined above) who are eligible but do not 
undergo brain imaging will also be treated with study medication. It is anticipated that it 
will require approximately 200 to be enrolled over 20-24 months in order to identify and 
randomize 126 with a persistent pain to randomize at baseline and have 100 complete 
the study at week 24. During the treatment period, participants will return to the clinic at 
Weeks 1, 4, 8 and 12 after randomization to assess pain, proper treatment use and side 
effects. After 12 weeks, pain will continue to be assessed monthly through PROs, and 
daily through smartphone app. MRI scans will be conducted at the end of 24 weeks. 
4.1
Substudy
Some individuals with subacute back pain who undergo screening for this study will not 
meet the inclusion criterion of high-risk phenotype for chronification of back pain.  These 
individuals will be offered the opportunity to participate in a substudy under a separate 
protocol.  The substudy will be an observational study designed to follow these back 
pain participants over time to collect information on pain levels and other subject-
reported outcomes.  Data from this study could be used to help evaluate the model 
proposed in the main study.  
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5
STUDY ENROLLMENT AND WITHDRAWAL
It is anticipated that to obtain 100 evaluable participants at the final study visit we will 
need to enroll 126 participants to allow for individuals that discontinue participation 
prematurely. This will require screening approximately 200 participants during the 
course of the trial. We anticipate telephone screening in the range of 600-700 
individuals.
In our prior study of SBP patients, recruitment of an equivalent number of participants 
resulted in 50% female representation. We will again ensure in this trial that gender is 
equally represented, as influence of gender on treatment effect is a major secondary 
aim.
Based on our previous results, we expect 30% minority representation in our sample.
Children are not included in this study because etiology of pain chronification is likely 
different from adults. Brain anatomical and functional properties in children are also 
different from adults. Thus, our brain biomarker based predictive model is most likely 
invalid in children.
5.1
Participant Inclusion Criteria
In order to be eligible to participate in this study, an individual must meet all of the 
following criteria:
●
Male or female, over the age of 18 years, (no racial/ethnic restrictions)
●
Must have an average pain score of ≥ 4 (on a 0-10 NRS) over a 5 day period 
(average of ~15 measures on smartphone app) immediately preceding the 
baseline visit (visit 2) and also ≥ 4 between the baseline and enrollment visits 
(visit 2 and visit 3, respectively).
●
Must be willing to read and able to understand instructions as well as PROs
●
Must be in generally stable health
●
Must sign an informed consent document after complete explanation of the study 
documenting that they understand the purpose of the study, procedures to be 
undertaken, possible benefits, potential risks, and are willing to participate (See 
Appendix B for an example of the ICF)
●
Must have a history of low back pain for a minimum of 4 weeks and a maximum 
of 20 weeks with signs and symptoms of radiculopathy: positive straight leg 
raising test with dermatomal radiation and/or myotomal weakness and/or reflex 
asymmetry; pain must radiate into buttock or below. Individuals undergoing MRI 
must have a high risk phenotype for chronification of back pain (evaluated at 
baseline T1-MRI, DTI-MRI, and fMRI scans)
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5.2
Participant Exclusion Criteria
An individual who meets any of the following criteria will be excluded from participation 
in this study:
●
Previous (distinct) episodes of back pain onset (more than 3 distinct episodes of 
back pain lasting for a total of more than 4 weeks) in the previous year
●
Evidence of acute vertebral fracture
●
Low back pain associated with any systemic signs or symptoms, e.g., fever, chills
●
Symptoms of neuropathy due to diabetes Type I or Type II 
●
Chronic neurologic conditions, including Parkinson’s disease, Alzheimer’s 
disease, and other conditions associated with dementia
●
Significant other medical disease such as congestive heart failure, coronary or 
peripheral vascular disease, chronic obstructive lung disease, or malignancy
●
History of glaucoma or narrow angle glaucoma
●
Presence of undiagnosed skin lesions or history of melanoma
●
Presence of severe cardiovascular or pulmonary disease, bronchial asthma, 
renal, hepatic or endocrine disease 
●
History of myocardial infarction with residual cardiac arrhythmia
●
History of gastrointestinal bleeding or peptic ulcer
●
Diagnosis of current depression (assessed via BDI, total > 28 are excluded) or 
psychiatric disorder requiring treatment, or such a diagnosis in the previous 6 
months
●
Use of therapeutic doses of antidepressant medications (i.e., tricyclic 
antidepressants, SSRIs, SNRIs; low doses used only in the evening for sleep will 
be allowed if dose is not changed
●
Current use of recreational drugs or recent history of alcohol abuse (pattern of 
drinking having social, financial or physical consequences) or drug abuse
●
Current use of medical marijuana
●
High dose opioid prophylaxis, defined as > 50mg morphine equivalent/day
●
Use of MAOIs, currently or within the past 2 weeks
●
Prior use of Levodopa
●
Use of any of the following drugs: bromocryptine, linezolid, metoclopramide, 
phenothiazines, promethazine/codeine, isoniazid, rifampin, pyrazinamide
●
Oral iron supplementation
●
Contraindications to use of study product, based on any of the following:
o
Hypersensitivity to Carbidopa/Levodopa or other constituents of the 
Carbidopa/Levodopa capsules
o
Hypersensitivity to lactose or other constituents of the placebo capsules
o
Hypersensitivity to Naproxen or other constituents of the Naproxen 
capsules
o
Hypersensitivity to Acetaminophen or other constituents of the 
Acetaminophen tablets
o
Taking concomitant medication which may be adversely affected by 
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omeprazole to a degree that alters subject’s safety
●
Currently taking Levodopa or dopaminergic drugs
●
In the judgment of the investigator, unable or unwilling to follow protocol and 
instructions
●
For those receiving MRI: Intra-axial implants (e.g. spinal cord stimulators or 
pumps, All exclusion criteria for MR safety: any metallic implants, pacemaker, 
brain or skull abnormalities, tattoos on large body parts, and claustrophobia
●
Pregnancy or inability to use an effective method of birth control in sexually 
active men and women while taking the study drug and for one week thereafter. 
Barrier contraceptives (condoms or diaphragm) with spermicide, intrauterine 
devices (IUD’s), hormonal contraceptives, oral contraceptive pills, surgical 
sterilization, and complete abstinence are examples of effective methods of 
contraception.

Following laboratory abnormalities: liver function tests (SGOT/SGPT) greater 
than twice the upper limit of normal; unexplained anemia (Hgb  13.5 to 17.5
g/dL for men, 12.0 to 15.5g/dL for women); evidence of renal insufficiency 
(creatinine >upper limit of normal) or any other abnormality that the principal 
investigator feels puts the participant at risk during the study. A blood re-test will 
occur for all enrolled subjects within one month of the first blood draw due to 
potential risk for renal impairment with NSAIDs at this dosage. 
●
History of chronic opioid use for pain management. 
●
Any medical condition that in the investigator’s judgment may prevent the 
individual from completing the study or put the individual at undue risk
5.3
Strategies for Recruitment and Retention
Participants for the study will be recruited from the following sources: (1) advertising in 
the local newspapers and radio, (2) online advertising (e.g., craiglist.com, social media 
like Facebook and Twitter; ResearchMathc.org; (3) professionals who see patients with 
low back pain or related conditions and/or people with low back pain or related 
conditions, and (4) community advertising (i.e., coffee shops, libraries, train stations and 
buses). Research Match is a secure online, national recruitment tool that is maintained 
by Vanderbilt University. ResearchMatch.org allows researchers to conduct feasibility or 
recruit potential study participants. These recruitment sources have resulted in a steady 
flow of patients, given that many individuals with SBP have not yet sought medical 
treatment. 
Potential subjects and data may also be identified through reports generated by the 
Northwestern Medicine Enterprise Data Warehouse (NMEDW), a joint initiative across 
the Northwestern University Feinberg School of Medicine and Northwestern Memorial 
HealthCare (NMHC), a corporate parent of Northwestern Memorial Hospital, 
Northwestern Medical Group, and Northwestern Medicine Lake Forest Hospital.  
NMEDW data sources include Cerner PowerChart, PRIMES, Epic, IDX, eNOTIS, and 
50+ other systems from the campus. Once approved by the treating provider, potential 
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subjects reported by NMEDW to a study Research Coordinator/Assistant may then be 
contacted with an opt-out letter followed by telephone calls, and provided detailed study 
information and encouraged to complete a screening questionnaire.
We anticipate needing to telephone screen 600-700 individuals to identify approximately 
300 who may be eligible for the study.  Of these, we estimate that 200-225 will actually 
show for their scheduled screening visit.  These estimates are based on our prior 
experience screening back pain participants for clinical trials. 
If potential subjects are interested in the study, they will be able to contact the research 
staff via the telephone number given on the website or click on a link to complete a brief 
online screener. To facilitate the recruitment of similar studies on low back pain 
conducted by Dr. Apkarian’s lab at Northwestern, participants who are screened for the 
current study will be asked if they are interested in learning about other studies on low 
back pain. If participants agree, they will be referred to and pre-screened for the other 
low back pain studies.      
It is anticipated that, to obtain 100 evaluable participants at the final study visit, we will 
need to enroll approximately 126 participants to allow for individuals who discontinue 
participation prematurely. This will mean screening approximately 200 participants 
during the course of the trial. These ratios are also derived from our previous 
experience with the SBP trial that has been completed recently, where in the range of 
60% of individuals who were screened were eligible. The completion of the clinical 
enrollment portion of this project in 24 months will therefore require an overall screening 
rate of 8-9 participants/month (~2 participants/week) from all recruitment sources. 
Based on our previous experience with longitudinal studies in this population, this is a 
highly realistic and achievable rate of enrollment from these sources. We have 
attempted to recruit participants from pain clinics, both in the community and at 
Northwestern, and have found this not to be a productive means of identifying the 
subacute back pain population needed for this study.
5.3.1 Recruitment: Media Advertising
Advertising in the media (newspaper and radio) has proven to be extremely effective in 
identifying people with subacute low back pain in our previous longitudinal study. 
Expertise in media placement as well as use of an experienced call center will be made 
available through the recruitment division of the NUCATS Institute. This recruitment 
service is a core facility for the medical school that provides assistance in recruitment of 
study participants. A recruitment plan specific for this study will be developed and 
implemented by the recruitment division staff, working in close conjunction with the 
investigators and other study personnel. This methodology in the past has yielded 30-
40% of participants for trials of this sort.
5.3.2 Recruitment: Online Advertising
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Advertisements using online resources (including but not limited to www.craigslist.com, 
online newspaper classifieds, social media, e.g., Facebook and Twitter, websites for 
people who work with or have low back pain or related conditions; ResearchMatch.org; 
and Apkarian laboratory website) has been a fruitful source of SBP patients in our 
previous work. As with traditional media advertising, we are able to control when and 
how often we place these advertisements to make maximum use of our staff’s time. 
This approach has generated 20-30% of participants for trials of this sort in the past.
5.3.3 Recruitment: Community Advertising
Given the high reliance on public transportation in the Chicago area, advertising in bus, 
train, and rail stations/facilities reaches a large number of citizens from broad 
socioeconomic backgrounds. Ridership reports indicate the Chicago Transit Authority 
ridership exceeds 2 million bus, train, and rail rides each day. Even short-term 
advertising in these venues has repeatedly resulted in large numbers of calls that 
continue to come in over long periods of time. In addition, coffee shops and libraries are 
opportunities to tap into diverse communities. As with the above approaches, this 
methodology will be expected to yield approximately 30-40% of the participants for this 
trial.
5.3.4 Retention
As this is a longitudinal study, the ability to have participants return to collect data at 
multiple time points is crucial to the success of the research. In our previous longitudinal 
study, an individualized retention program was developed to ensure optimal 
maintenance of participants throughout the trial. Specific branding of the study (specific 
name with associated letterhead, literature, etc.), use of low cost, IRB-approved 
mementos (e.g., calendars, tote bags, etc.), regular communication via email and/or 
telephone, and recognition of special events (e.g., birthdays, holidays) will be employed 
to make participants feel engaged. In our experience, the optimal means to enhance 
retention is repeated contact with the participants, via telephone or mail service or 
electronically. Our retention rates have also benefited from the maximum flexibility in the 
availability of scanning times. We can routinely scan or interview participants any time 
between 8:00am-9:00pm to accommodate difficult schedules (including weekends), and 
missed appointments are typically re-booked within 24 hours. Additionally, the 
frequency of visits and interactions during the initial 6 weeks of the study when 
participants come in to obtain their study medication (visits 3-6) will also serve to keep 
the participants invested in the study and enhance treatment adherence. These 
methodologies have been shown to be effective in other longer-term trials and are an 
important aspect to ensure participants’ continued interest and involvement.
5.4
Treatment Assignment Procedures
5.4.1 Randomization Procedures
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Participants will be assigned to treatment arms (Carbidopa/Levodopa plus Naproxen vs 
placebo plus Naproxen) based on a computer generated permuted block randomization 
with block size randomly varied and an allocation ratio of 1:1. Allocation concealment 
will be ensured by utilization of sequentially numbered containers. An unblinded 
individual from NUCATS with no other role in the study will be responsible for assuring 
proper medication assignment to each container. The randomization code will be 
maintained by NUCATS and will be available in cases of emergency or clinical 
situations in which knowing the treatment allocation would make a difference in the 
safety or management of a subject. In such a circumstance, the allocation assignment 
will be made available after consultation with the site investigator and the principal 
investigator. At study conclusion, after database lock, the randomization code will be 
made available to the study statistician and other personnel analyzing the data.
5.4.2 Masking Procedures
Masking will be achieved by over-encapsulation of the Carbidopa/Levodopa capsules 
as well as Naproxen capsules utilizing larger capsules that will be identical to those to 
be filled with lactose to be used as placebo. The only person who will know which 
capsules contain active vs placebo will be the unblinded NUCATS individual responsible 
for filling the numbered medication vials with the appropriate kind and number of 
capsules. This person will have no other involvement with study staff or be involved with 
any study procedures. Naproxen to be provided to both groups will also be masked in 
order that participants not be aware of which medication is active that they are taking. 
Unmasking should not be required during the study. If allocation assignment needs to 
be made available, this will be done based on the circumstances outlined above. If there 
should be a question regarding proper allocation of treatment product, it would be 
possible to ascertain placebo from active drug product by opening the treatment 
capsules and determining if there were an enclosed tablet present. This will be 
prevented by sealing of all capsules prior to their being placed in treatment vials for 
dispensing.
Participants will take 2 capsules on a TID schedule and one capsule will be taken QD. 
TID medications include one capsule of Naproxen and one capsule of  either placebo or 
some dose of Carbidopa/Levodopa. Omeprazole will be taken QD in the morning. In 
order to assure that participants take their study medication as designed, the Naproxen 
and omeprazole will be placed in a separate colored capsule from the 
Carbidopa/Levodopa. Each colored capsule will be dispensed in separate containers 
and participants will be asked to take one capsule from each container.  As they will be 
differently colored, this should reduce the possibility of error.
5.5
Participant Withdrawal
Participants have the right to withdraw fully or partially from the study at any time and 
for any reason without prejudice to his or her future medical care by the physician or at 
the institution. Withdrawal of full consent for a study means that the participant does not 
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wish to receive further investigational treatment and does not wish to or is unable to 
continue further study participation; participant data up to withdrawal of consent will be 
included in the analysis of the study. Any participant may withdraw full consent to 
participate in the study at any time during the study. The investigator will discuss with 
the participant appropriate procedures for withdrawal from the study.
5.5.1 Reasons for Withdrawal
Reasons for removal from protocol-required product(s) or observation might include:
●
Partial withdrawal of consent
●
Withdrawal of full consent
●
Administrative decision by the investigator
●
Pregnancy in a female subject
●
Pregnancy in female partner of a male participant if he is unwilling to use a 
condom during treatment and for 7 drug half-lives after the end of treatment
●
Ineligibility
●
Significant protocol deviation
●
Patient noncompliance
●
Study drug compliance <80%
●
AE / SAE
●
Disease progression
●
Other safety concern by the investigator
●
Death
●
Lost to follow-up
5.5.2 Handling of Participant Withdrawals or Participant Discontinuation of Study 
Intervention
Withdrawal of partial consent for a study means that the participant does not wish to 
take IP(s) or other protocol-required therapies any longer but is still willing to collaborate 
in providing further data by continuing on study (e.g., participate in all subsequent study 
visits or procedures). Participants may decline to continue receiving IP(s) or other 
protocol-required therapies at any time during the study. If this occurs, the investigator 
will discuss with the participant appropriate procedures for withdrawal from IP(s) or 
other protocol-required therapies. These participants, as well as those who have 
stopped receiving IP(s) or other protocol-required therapies for other reasons (e.g., 
investigator or sponsor concern) should continue the schedule of study observations. 
Should a participant (or a legally acceptable representative) request or decide to 
withdraw from the study, all efforts will be made to complete and report the observations 
as thoroughly as possible up to the date of withdrawal.
5.6
Premature Termination or Suspension of Study
This study may be suspended or prematurely terminated if there is sufficient reasonable 
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cause. Written notification, documenting the reason for study suspension or termination, 
will be provided by the suspending or terminating party to the NIDCR. If the study is 
prematurely terminated or suspended, the principal investigator will promptly inform the 
IRB and will provide the reason(s) for the termination or suspension.
Circumstances that may warrant termination include, but are not limited to:
●
Determination of unexpected, significant, or unacceptable risk to participants.
●
Insufficient adherence to protocol requirements.
●
Data that are not sufficiently complete and/or evaluable. 
●
Inadequate retention and/or recruitment. 
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6
STUDY INTERVENTION
6.1
Carbidopa/Levodopa 25-100
6.1.1 Study Product Description
Carbidopa/Levodopa is a combination of Carbidopa and Levodopa for the treatment of 
Parkinson's disease and syndrome.
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline 
compound, slightly soluble in water, with a molecular weight of 244.3. It is designated 
chemically as (—)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid 
monohydrate. Its empirical formula is C10H14N2O4•H2O, and its structural formula is:
Capsule content is expressed in terms of anhydrous Carbidopa which has a molecular 
weight of 226.3.
Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in 
water, with a molecular weight of 197.2. It is designated chemically as (—)-L-α-amino-β-
(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C9H11NO4, and its 
structural formula is:
Carbidopa/Levodopa is supplied as tablets containing 25 mg of Carbidopa and 100 mg 
of Levodopa.
For blinding, the Carbidopa/Levodopa tablets supplied by the manufacturer are over-
encapsulated at the clinical site investigational pharmacy, by putting the supplied tablet 
inside another capsule and filling the remaining space with excipient. The excipient for 
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the capsules will be Lactose NF. The manufacturer is Humco in Texarkana, Texas. 
NDC 0395-1501-01. The active ingredient would be the Carbidopa/Levodopa tablets 
distributed by Caraco and manufactured by Sun Pharmaceutical Industries Ltd., Acme 
Plaza, Andheri-Kurla Road,Andheri (East), Mumbai-400 059, India. 
The capsule shells (hard gelatin) will be manufactured by Capsugel (Coni Snap Size 1). 
Capsugel provides a certificate of analysis with each capsule batch ordered. Capsugel 
manufactures gelatin capsules from gelatin that complies with bovine spongiform 
encephalopathy (BSE) requirements. Capsugel provides confidential detailed 
information about facilities, processes, articles used in manufacturing, processing, 
packaging, and storing of empty capsules through Type IV (Excipient) Drug Master Files 
submitted to the FDA. 
Inactive ingredients are lactose NF and gelatin. Carbidopa/Levodopa capsules also 
contain FD&C Blue #1.
6.1.2 Acquisition
The blinded Carbidopa/Levodopa capsules will be manufactured by the Investigational 
Pharmacy at NMH, 251 E. Huron St. LC700, Chicago, IL 60611.
6.1.3 Formulation, Packaging, and Labeling
Over-encapsulation is conducted in the Investigational Pharmacy on a segregated and 
cleaned countertop. Active capsules are prepared by putting the active drug inside an 
empty gel cap and further filling it with lactose. For the lowest dose of 
Carbidopa/Levodopa (12.5mg/50mg), the scored tablet will be cut in half by the 
pharmacy technician. For the highest dose, two tablets will be put into one capsule.  A 
manufacturing record is kept with a listing of all the ingredients, manufacturer, lot 
numbers and expiration dates of the components used.
6.1.4 Product Storage and Stability
Carbidopa/Levodopa will be stored at 25°C (77°F), excursions permitted to 15-30°C (59-
86°F) in a locked cabinet protected from light in a locked room. Carbidopa/Levodopa 
has a 6-month shelf-life.
6.1.5 Dosage, Preparation and Administration of Study Product
Carbidopa/Levodopa will be administered in this study as an oral capsule. Participants 
will be titrated up to the therapeutic dose at the beginning of treatment and tapered off 
at the end of treatment. Participants will always take one capsule TID except during the 
first week of titration.  Both schedules are detailed as follows:
●
At treatment initiation, Carbidopa/Levodopa (12.5mg/50mg) QD for 3 days, 
Carbidopa/Levodopa (12.5mg/50mg) BID for 3 days, and then 
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Carbidopa/Levodopa (12.5mg/50mg) TID over one week and then continued at 
that level until 4 weeks is completed (+/- visit window). If at the end of the initial 4 
week period the participant has “responded or recovered” (i.e., had a reduction in 
pain from baseline of ≥20%), the participant will be maintained on that dose for 
the duration of the treatment period (12 weeks total).  If there has not been a 
response, the dose will be increased to Carbidopa/Levodopa (25mg/100mg) TID 
for 4 weeks, after which the pain status will be re-evaluated.  Again, if a response 
has occurred, that dose will be maintained in a blinded manner for the following 4 
weeks of treatment; if not, further dose-titration will occur to Carbidopa/Levodopa 
(50mg/200mg) TID for the final 4 weeks. If a participant experiences an AE at 
higher doses, then the participant will be given the next lower dose that s/he was 
able to tolerate and then be maintained on that dose for the remainder of the 12 
week dosing period. 
●
At treatment discontinuation, participants will begin tapering off the medication 
based on their highest treatment dose. If a participant ended the treatment period 
on Carbidopa/Levodopa (12.5mg/50mg) TID, then s/he will start with 
Carbidopa/Levodopa (12.5mg/50mg) BID for 3 days and then 
Carbidopa/Levodopa (12.5mg/50mg) QD for 3 days before discontinuing it 
completely. If a participant ended the treatment period on Carbidopa/Levodopa 
(25mg/100mg) TID or Carbidopa/Levodopa (50mg/200mg) TID, then s/he will 
start at Carbidopa/Levodopa (25mg/100mg) BID for 3 days and then 
Carbidopa/Levodopa (25mg/100mg) QD for 3 days before discontinuing it 
completely.
6.1.6 Modification of Study Product Administration for a Subject
N/A
6.1.7 Accountability Procedures for the Study Product
Study product will be purchased by Northwestern Memorial Hospital Investigational 
Pharmacy for over-encapsulation. A defined quantity of capsules of 
Carbidopa/Levodopa, Naproxen and placebo will be supplied by NMH Investigational 
Pharmacy for distribution to participants. Each of the 126 participants will be provided 
with vials containing 15, 84, 105, 105, and 9 capsules of Carbidopa/Levodopa or 
placebo at Visits 3, 4, 5, 6, and 7, respectively. Each of the 126 participants will be 
provided with vials containing 27, 84, 105, and 105 capsules of Naproxen at Visits 3, 4, 
5, and 6, respectively. Participants will be required to record all medication usage using 
the smartphone app. These data are immediately logged into our server, which provides 
us routine overview of participants’ participation and compliance, and further enhances 
retention of participants. If participants repeatedly miss entering these values, they are 
contacted by phone and instructed for compliance. (See Appendix C for smartphone 
app usage manual.) Participants will be asked to return all unused study medication at 
each visit. Unused study medication will be collected at Visits 4, 5, 6, and 7 and counted 
by the study coordinator. Accountability for study medication will be confirmed at each 
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participant visit and for each participant at the conclusion of his/her involvement in the 
study. An overall compliance of 80% is required to remain in the study. A final inventory 
at study conclusion will be compared with drug supplied, drug participant recorded 
taking, drug participants actually took, and drug returned. Returned medication will be 
destroyed through NMH pharmacy drug disposal services after final accountability is 
determined. 
6.1.8 Assessment of Participant Compliance with Study Product Administration
Participants are required to return study medication bottles and any unused medication 
to the study coordinator at each study visit. Participants will be asked if they missed any 
days of study medication and if so, how and why. Participant will also be asked if they 
exceeded taking six capsules per day. The coordinator is responsible for conducting pill 
counts at each study visit.
6.1.9 Concomitant Medications/Treatments
Participants are asked to discontinue all concomitant pain medications prior to starting 
study treatment. Participants who refuse to cease pain medication usage between 
screening and first treatment visit will continue with screening and be asked to rate their 
pain 15 times (the same as for those who will be scanned with MRI) while they are on 
their pain medications. If pain is >4, they will undero an MRI, and if deemed to be part of 
treatment arm will discontinue their pain medication upon starting the study medication.. 
Participants will be required to restrict all medications for relief of pain to only those 
provided during the course of this study (i.e., rescue medication, acetaminophen). 
Participants will be allowed to continue their existing non-pain medications as long as 
they are not exclusionary for study enrollment. Concomitant medications not permitted 
in this study are therapeutic doses of antidepressant medications (i.e., tricyclic 
antidepressants, SSRIs, SNRIs; low doses used for sleep may be allowed), opioids, 
MAOIs, dopamine D2 receptor antagonists, and NSAIDs (acetaminophen is allowed).
6.2
Placebo
6.2.1 Study Product Description
The content of the capsules will be Lactose NF. The manufacturer is Humco in 
Texarkana, Texas. NDC 0395-1501-01. The capsule shells (hard gelatin) will be 
manufactured by Capsugel (Coni Snap Size 0), which have a volume of 0.5 cc and will 
hold 300 mg of powder.. Capsugel provides a certificate of analysis with each capsule 
batch ordered. Capsugel manufactures gelatin capsules from gelatin that complies with 
BSE requirements. Capsugel provides confidential detailed information about facilities, 
processes, articles used in manufacturing, processing, packaging, and storing of empty 
capsules through Type IV (Excipient) Drug Master Files submitted to the FDA.
Inactive ingredients are cellulose and gelatin. Placebo capsules also contain FDC Blue 
#1.
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6.2.2 Acquisition
The blinded placebo capsules will be manufactured by the Investigational Pharmacy at 
Northwestern Memorial Hospital, 251 E. Huron St. LC700, Chicago, IL 60611.
6.2.3 Formulation, Packaging, and Labeling
Capsule manufacturing is conducted in the Investigational Pharmacy on a segregated 
and cleaned countertop. Placebo capsules are completely filled with lactose using a 
capsule maker. A manufacturing record is kept with a listing of all the ingredients, 
manufacturer, lot numbers and expiration dates of the components used.
6.2.4 Product Storage and Stability
Placebo capsules will be stored at 25°C (77°F), excursions permitted to 15-30°C (59-
86°F) in a locked cabinet protect from light in a locked room. Placebo capsules have a 
6-month shelf-life.
6.2.5 Dosage, Preparation and Administration of Study Product
The placebo capsule is an oral capsule. 
6.2.6 Modification of Study Product Administration for a Subject
N/A
6.2.7 Accountability Procedures for the Study Product
See Section 6.1.7.
6.2.8 Assessment of Participant Compliance with Study Product Administration
See Section 6.1.8.
6.2.9 Concomitant Medications/Treatments
See Section 6.1.9.
6.3
Naproxen 250 mg
6.3.1 Study Product Description
Naproxen is a proprionic acid derivative related to the arylacetic acid group of NSAIDs.
The chemical name for Naproxen is (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid. 
Naproxen has the following structure:
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Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3.
Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble, 
practically insoluble in water at low pH and freely soluble in water at high pH. The 
octanol/water partition coefficient of Naproxen at pH 7.4 is 1.6 to 1.8.
Naproxen tablets are available as white tablets containing 250 mg of Naproxen for oral 
administration. 
For blinding, the Naproxen tablets supplied by the manufacturer are over-encapsulated 
at the clinical site investigational pharmacy, by putting the supplied tablet inside another 
capsule and filling the remaining space with excipient. The excipient for the capsules 
will be Lactose NF. The manufacturer is Humco in Texarkana, Texas. NDC 0395-1501-
01. The active ingredient would be the Naproxen tablets manufactured by Amneal 
Pharmaceuticals. 
The capsule shells (hard gelatin) will be manufactured by Capsugel (Coni Snap Size 1). 
Capsugel provides a certificate of analysis with each capsule batch ordered. Capsugel 
manufactures gelatin capsules from gelatin that complies with BSE requirements. 
Capsugel provides confidential detailed information about facilities, processes, articles 
used in manufacturing, processing, packaging, and storing of empty capsules through 
Type IV (Excipient) Drug Master Files submitted to the FDA. 
The inactive ingredients are Croscarmellose Sodium, Povidone, Magnesium Stearate, 
lactose NF, and gelatin. Naproxen capsules also contain TiO2 to make them white in 
appearance.  
6.3.2 Acquisition
The blinded Naproxen capsules will be manufactured by the Investigational Pharmacy 
at NMH, 251 E. Huron St. LC700, Chicago, IL 60611.
6.3.3 Formulation, Packaging, and Labeling
See Section 6.1.3. 
6.3.4 Product Storage and Stability
Naproxen will be stored at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) in a 
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locked cabinet protected from light in a locked room. Naproxen has a 4-year shelf-life.
6.3.5 Dosage, Preparation and Administration of Study Product
Naproxen is an oral capsule. All participants in both arms will be given a therapeutic 
dose of one 250mg capsule TID during the treatment period (but not during the tapering 
down at the end of the study).
6.4    Omeprazole 40mg
6.4.1 Study Product Description
Omeprazole is a proton pump inhibitor that is prescribed to prevent any gastrointestinal 
upset due to intake of naproxen.   
The chemical name for omeprazole is a substituted benzimidazole, 5-
methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, a 
compound that inhibits gastric acid secretion.The structural formula is:
Its empirical formula is C H N O S, with a molecular weight of 345.42.
Omeprazole Delayed-Release Capsules, 40 mg, are opaque gold cap and opaque gold 
body capsules imprinted with "KU" and "136" in black ink.
Inactive ingredients are crospovidone, glyceryl dibehenate, hypromellose, lactose 
monohydrate, methacrylic acid copolymer dispersion, silicon dioxide, talc, titanium 
dioxide and triethyl citrate. 
Manufactured by: Kremers Urban Pharmaceuticals Inc.,a subsidiary of Lannett Company, 
Inc.
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The side effects for omeprazole (given with a capsule of naproxen) include common and 
less serious symptoms such as headache, diarrhea, nausea, stomach pain, vomiting, and 
gas.  Less common but serious side effects include: rash, face swelling, throat tightness, 
and difficulty breathing.
6.4.2 Acquisition
The omeprazole capsules will be distributed by the Investigational Pharmacy at NMH, 
251 E. Huron St. LC700, Chicago, IL 60611.
Formulation, Packaging, and Labeling
See Section 6.1.3. 
Product Storage and Stability
Omeprazole will be stored at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) in 
a locked cabinet protected from light in a locked room. Omeprazole has a 3-year shelf-
life.
Modification of Study Product Administration for a Subject
N/A
Accountability Procedures for the Study Product
See Section 6.1.7.
Assessment of Participant Compliance with Study Product Administration
See Section 6.1.8.
Concomitant Medications/Treatments
See Section 6.1.9.
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7
STUDY SCHEDULE
The study duration is 28 weeks, which includes an initial screening period of up to 4 
weeks. There will be 8 visits during this time: a Screening Visit, Baseline Visit, and 6 
Study Visits. The schedule for the 6 Study Visits after the Baseline Visit will be: Week 0, 
Week 1, Week 4, Week 8, Week 12, and Week 24. Treatment with study medication will 
be terminated after Week 12. Follow-up telephone calls at Week 16 and Week 20 will 
be made to continue evaluation of participants’ back pain through PROs to the study 
end (Week 24). All participants will also use a smartphone app to log their back pain 
intensity, their mood, proper medication use, and other information that they may wish 
to report. The smartphone data are entered every time participants ingest their 
medication (up to TID) and after termination of treatment (up to TID) until the final study 
visit. Smartphone entries are immediately transmitted through Wi-Fi to a secure web 
site, downloaded daily to assess compliance, and stored in a second secure server (we 
have been using such apps for about 6 months and they have been very effective). 
Windows for all visits will be ± 1 week except for Visit 4 which will have a 3-day window.
7.1
Screening – Visit 1, Week -4
Screening visit (90 min): Participants will have been prescreened over the telephone 
prior to being invited to attend this screening visit.  Those invited will complete the 
informed consent process and evaluated with full inclusion/exclusion criteria. Once 
consented, a medical/pain history and physical examination, including orthostatic BP 
measurements for participants taking anti-hypertensive medications, will be completed. 
Urine will be collected for drug screening after participants have signed their consent 
forms. Blood will be drawn to screen individuals before starting treatment; blood draw 
will include a CBC, chemistry panel, alcohol levels, and liver function tests. Participants 
will be asked to assess current back pain intensity on a NRS scale (0-10, no pain to 
worst possible pain; ≥ 4 required to qualify for study). Participants will complete all 
PROs electronically and be instructed on the use of smartphone app (if participants do 
not have a smartphone, they will be given one for the duration of the study) (See 
Section 16.2: Data Capture Methods) and return in 1-2 weeks for baseline MR 
imaging scans (this length of time is adequate to allow scheduling and permit flexibility 
for participants’ preferences). Study staff will ask the participant to discontinue all pain 
medications (14 days prior to Visit 2). Staff will explain to the participant that s/he can 
take only the rescue medication provided for pain during this time.
7.2
Baseline Scan – Visit 2, Week -2 
Baseline imaging visit (2-2.5 hours): Participants will complete the NRS pain scale, and 
if score ≥ 4 and their average back pain on the smartphone over the last 5 days is also 
≥ 4, and no changes in clinical status are reported, participant will complete PROs 
electronically and undergo MRI and fMRI brain scans. This scan data will be used to 
derive brain biomarkers to determine risk for chronic pain. Only SBP assessed at high 
risk for chronic pain enter the study. 
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7.3
Enrollment – Visit 3, Week 0
Randomization and treatment administration (60-90 min). Those participants who meet 
all entry criteria (except for the first 12 participants, who will be included in the study if 
they fulfill all entry criteria except for being classified as high risk, as brain parameters 
derived from these subjects will be used to hone the model predicting risk for chronic 
pain) will return to the clinic to be randomized to receive either active treatment or 
placebo in a double-blind fashion, with medication dispensed sufficient until the next 
visit. For WOCBP, a urinary pregnancy test will be done prior to receiving study 
medication.  Participants will complete the NRS pain scale, pledge to continue to use 
smartphone app, complete PROs, and have AEs assessed by an unstructured interview 
of interval medical history since last visit. BP and heart rate will be determined for all 
participants. Orthostatic BP measurements will be obtained for all participants taking 
anti-hypertensive medications.
7.4
Intermediate Visit – Visit 4, Week 1 ± 3 Days 
Treatment administration (60-90 min). All procedures will be performed as described for 
Visit 3. Adherence will be assessed by pill counts (participants must take a minimum of 
80% of the expected study medication to be considered adherent to study protocol) and 
participant will be queried about any side effects experienced. Study medication will be 
dispensed.
7.5
Intermediate Visit – Visit 5, Week 4 ± 7 Days
Treatment administration (60-90 min). All procedures will be performed as described for 
Visit 3. Adherence will be assessed by pill counts (participants must take a minimum of 
80% of the expected study medication) and participant will be queried about any side 
effects experienced. Study medication will be dispensed.
7.6
Intermediate Visit – Visit 6, Week 8 ± 7 Days
Treatment administration (60-90 min). All procedures will be performed as described for 
Visit 3. Adherence will be assessed by pill counts (participants must take a minimum of 
80% of the expected study medication) and participant will be queried about any side 
effects experienced. Study medication will be dispensed.
7.7
Intermediate Visit – Visit 7, Week 12 ± 7 Days
End-of-treatment visit (60-90 min). All procedures will be performed as described for 
Visit 3. Adherence will be assessed by pill counts (participants must take a minimum of 
80% of the expected study medication) and participants will be queried about any side 
effects experienced. Study medication to permit taper and discontinuation of study 
product will be dispensed. Participants will be allowed to resume former pain therapies 
for the follow-up period only after IP taper and discontinuation.
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7.8
Follow-up Phone Call – Week 16 ± 7 Days
Follow-up phone call (15 min). Participants will be asked if they have had any changes 
to health/condition and concomitant medications. AEs will be assessed by an 
unstructured interview of interval medical history since their last visit. Participant also be 
queried on successful discontinuation of study product and their current pain level using 
the NRS.
7.9
Follow-up Phone Call – Week 20 ± 7 Days
Follow-up phone call (15 min). All procedures will be performed as described for Week 
16 phone call.
7.10 Final Study Visit – Visit 8, Week 24 ± 7 Days 
Final visit (1.5-2 hours). All procedures will be performed as described for Visit 2 except 
for blood draw, with the addition of post-treatment imaging scans. Participants will be 
queried about any side effects experienced.
The participant will be debriefed once the researchers are unblinded. They will receive 
communication from the research coordinator by letter, text as follows:
“Dear Participant:
Thank you for agreeing to participate in this important research. The purpose of this study was to see how 
sub-acute back pain is represented in the brain, and to understand the effects of a new treatment on the 
body and on the brain. 
At the beginning of the study, we took images of your brain (using Magnetic Resonance Imaging, MRI) 
and identified findings that makes us believe that it was possible that you would continue to have low 
back pain and therefore you were entered into the studyYou participated in a double-blinded study, 
meaning that neither you nor the study staff knew which treatment you received until the end of the study. 
Participants were randomized into one of 2 groups: a placebo group or an active treatment group (with 
naproxen and Levodopa/Carbidopa). In this study, you (did/did not) receive the active treatment. We will 
only know if the treatment was helpful when all the information from the study has been analyzed. 
Results of this study will be available for viewing in approximately fall of 2016 at 
http://clinicaltrial.gov (study number NCT01951105) 
We greatly appreciate your involvement in making this study possible. If you have further questions about 
the study, please contact the clinical research coordinator, Elizabeth Hunt, at 312-503-6475.  In addition, 
if you have any concerns about any aspect of the study, you may contact the Office for the Protection of 
Research Subjects at (312) 503-9338.”
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7.11 Interim Electronic Contact
In order to enhance retention of participants in the study and to obtain additional data 
regarding the course of the participants, participants will be in contact with the site by 
cell phone on a daily basis. At each of these interactions, the participants will provide an 
assessment of their level of pain utilizing an 11-point NRS scale.
All participants will also be using a smartphone app to log pain, mood, and medication 
use daily. These data are immediately logged into the study server, which provides 
routine overview of participants’ participation and compliance and further enhances 
retention of participants. If participants repeatedly miss entering these values, they are 
contacted by phone and instructed for compliance. (See Appendix C for smartphone 
app usage manual) 
7.12 Withdrawal Visit
Early termination visit (1.5-2 hours). If a participant withdraws early or the PI terminates 
the subject’s participation, an early termination visit will be conducted. All procedures 
will be performed as described for Final Study Visit. All dispensed study medication will 
be collected and counted. If necessary, study medication to permit taper and 
discontinuation of study product will be dispensed.
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8
STUDY PROCEDURES/EVALUATIONS
8.1
Study Procedures/Evaluations
●
Medical history will be obtained through interview. All past medical history will be 
included. (See Appendix D for example chart document)
●
Medications history will be obtained through interview. Both prescription and 
over-the-counter medications from the previous two weeks to currently taking will 
be recorded. (See Appendix D for example chart document)
●
AEs and SAEs will be obtained at each study visit to assess participant safety. 
(See Section 9.1 Specification of Safety Parameters for further details) (See 
Appendix D for example chart document)
●
Physical examination will be obtained during the screening visit with the study 
doctor. Organ systems assessed will be HEENT (Head, Ears, Eyes, Nose, 
Throat), Chest, Heart, Lungs, Abdomen, Extremities, Skin, Neurological, and 
Musculoskeletal. (See Appendix D for example chart document)
●
Vital signs obtained by the study coordinator at the beginning of each visit 
include height (only at screening visit), weight (only at screening visit), BP 
(orthostatic BP measured for participants taking anti-hypertensive medications), 
heart rate, and temperature. (See Appendix D for example chart document)
●
Daily subject-reported outcomes: Smartphone app will be used to collect pain, 
mood, and medication use on a daily basis for the duration of the study. (See 
Appendix C for smartphone app usage manual)
●
T1-MRI, DTI-MRI, resting state, fMRI scans will be performed as described 
(Baliki M, 2012) (Mansour A, 2013) twice: baseline (Week -2) and at final study 
visit (Week 24). 
o
All brain imaging is done on two 3.0 T Siemens Trio whole-body MRI 
scanner with echo-planar imaging (EPI) capability and using a 32 
channels head-coil. Both scanners are dedicated for research and shared 
between 15 NIH funded research groups. The university has guaranteed 
us access to these magnets for the next 5 years. The magnets are 
managed by Radiology Department and are fully staffed and equipped. 
They are core human imaging facilities of NU. Their signal-to-noise ratio is 
excellent and they have produced very nice results over the last 5 years of 
operation, and >100 publications.
o
We will acquire four different types of brain images: 
▪
Anatomical T1-MRI (high resolution anatomical magnetic 
resonance imaging): voxel size = 1 × 1 × 1 mm, repetition time = 
2,500 ms, echo time = 3.36 ms, flip angle = 9°, in-plane matrix 
resolution = 256 × 256; 160 slices, field of view = 256 mm.
▪
Resting state fMRI (functional MRI): multi-slice T2*-weighted echo-
planar images with repetition time = 2.5 s, echo time = 30 ms, flip 
angle = 90°, number of volumes = 244, slice thickness = 3 mm, in-
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plane resolution = 64 × 64. The 36 slices are covering the whole 
brain from the cerebellum to the vertex.
▪
fMRI (functional MRI): multi-slice T2*-weighted echo-planar images 
with repetition time = 2.5 s, echo time = 30 ms, flip angle = 90°, 
number of volumes = 244, slice thickness = 3 mm, in-plane 
resolution = 64 × 64. The 36 slices are covering the whole brain 
from the cerebellum to the vertex.
▪
DTI-MRI (diffusion tensor imaging): 72 × 2-mm-thick axial slices; 
matrix size=128 × 128; field of view=256 × 256mm2, resulting in a 
voxel size of 2 × 2 × 2mm). Images have an isotropic distribution 
along 60 directions using a b value of 1000 s × mm-2.
o
Brain imaging data analysis is done on free-share software including FSL, 
SPM, FreeSurfer, Caret, MRIcron as well as ad-hoc routines written in 
Matlab, C++, Pearl, Awk. The university maintains a user contract for 
Matlab and other software that we use routinely.
o
We have a dedicated server for brain imaging data analysis. This is a 23 
TByte data management system and with large number of processors, 
which runs on Linux. This server is our main brain imaging data storage 
and processing system. It is accessible through Internet, and all data 
processing is performed on it, mainly by remote access.
●
Blood samples will be collected from all participants at baseline scan. Urine 
samples will only be collected from WOCBP at the first dosing visit. 
●
Administration of PROs (See Section 16.2 for a comprehensive list)
8.2
Laboratory Procedures/Evaluations
8.2.1 Clinical Laboratory Evaluations
Baseline laboratory values will be collected for determination of inclusion/exclusion 
criteria and to assess safety and also will be entered into the study database. Repeat 
laboratory testing will only be done if there is a clinical basis for further testing. Blood 
and urine samples will be collected at the MRI scanning facility by a RN. Urine 
pregnancy tests will be processed before starting any study medication. Blood samples 
will be processed through Pathology Laboratory at NMH, 251 E. Huron St. LC700, 
Chicago, IL 60611. All results will be faxed to the study doctor for review before 
participants begin study medications. Samples will not be frozen nor stored for long-
term or future use. 
Screening Laboratory Evaluations
Hematology - Complete Blood Count (CBC) 
(This evaluation will be re-conducted among elderly participants for monitoring at 1 month after 
beginning treatment)
9 tests will be performed.
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●
White cell count [3.5-10.5 K/UL, normal reference range]
●
Red cell count [3.80-5.20 M/UL]
●
Hemoglobin [11.6-15.4 g/dL]
●
Hematocrit HCT [34.0-45.0%]
●
MCV [80-99 FL]
●
MCH [27.0-34.0 pg]
●
MCHC [32.0-35.5%]
●
RDW [11.0-15.0%]
Hematology - Differential
10 tests will be performed. 
●
Neutrophils [34-73%]
●
Lymphocytes [15-50%]
●
Monocytes [5-15%]
●
Eosinophils [0-8%]
●
Basophils [0-2%]
●
Absolute neutrophils [1.5-8.0 K/UL]
●
Absolute lymphocytes [1.0-4.0 K/UL]
●
Absolute monocytes [0.2-1.0 K/UL]
●
Absolute eosinophils [0.0-0.6 K/UL]
●
Absolute basophils [0.0-0.3 K/UL]
Chemistry Panel
16 tests will be performed. (This evaluation will be re-conducted among elderly participants 
for monitoring at 1 month after beginning treatment)
●
Sodium [134-142 mEq/L]
●
Potassium [3.5-5.1 mEq/L]
●
Chloride [98-109 mEq/L]
●
Bicarbonate [21-31 mEq/L]
●
Blood urea nitrogen [2-25 mg/dL]
●
Creatinine [0.00-1.30 mg/dL]
●
eGFR – African Am [>=60 mL/min/1.73m2]
●
eGFR – Non African Am [>=60 mL/min/1.73m2]
●
Glucose level [65-100 mg/dL]
●
Calcium [8.3-10.5 mg/dL]
●
Albumin [3.5-5.7 g/dL]
●
Total protein [6.4-8.9 g/dL]
●
ALT [0-52 Unit/L]
●
AST [0-39 Unit/L]
●
Total bilirubin [0.0-1.0 mg/dL]
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●
Alkaline phosphatase [34-104 Unit/L]
●
Alcohol levels
Vital signs
●
Blood Pressure – diastolic [60-90 mm Hg]
●
Blood Pressure – systolic [100-130 mm Hg]
●
Pulse [60-100 beats/minutes]
●
Respirations  [10-16 breaths/minute]
●
Temperature [36-37.5oC]
Urine Tests
●
A urine test for drug use will be performed on all participants during screening 
after study consent has been obtained. A negative test result will be required 
prior to consenting to participate in the study.
●
A urine pregnancy test will be performed on all WOCBP prior to starting 
treatment. A negative test result will be required before receiving study 
medication.
8.2.2 Special Assays or Procedures
N/A
8.2.3 Specimen Preparation, Handling, and Storage
N/A
8.2.4 Specimen Shipment
N/A
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9
ASSESSMENT OF SAFETY
This study will evaluate the efficacy and safety of the combination of two treatments, the 
fixed dose combination of Carbidopa/Levodopa and Naproxen in people with subacute 
low back pain. Naproxen is a drug that has an FDA-approved indication for the 
treatment of pain. Carbidopa/Levodopa is primarily used to treat the symptoms of 
Parkinson’s disease, and is being investigated in this study for off-label central CNS 
affects that could influence mechanisms associated with chronification of pain. An IND 
application (IND 118758) for this study has been filed and the study has been 
determined by the FDA to be exempt. 
Both Carbidopa/Levodopa and Naproxen are associated with potential side effects, 
which have been well known for more than 30 years. In order to reduce the incidence 
and severity of side effects in this study, doses of both drugs well below the maximum 
suggested dosage for usual treatment are being utilized: a total maximum daily dose of 
150mg/600mg of Carbidopa/Levodopa and 750mg of Naproxen, both given in three 
divided doses. Additionally, it should be noted that the population being studied is 
expected to be significantly younger than the typical population of people with 
Parkinson’s disease, and therefore may have a lower incidence of some of the reported 
side effects which are thought to be at least to some extent age-dependent and disease 
dependent. Similarly, the GI safety of Naproxen is well recognized to be a function of 
age.
The only special safety consideration is the development of orthostatic hypotension due 
to the possible interaction of Carbidopa/Levodopa with antihypertensive medications. In 
order to assess this potential interaction, orthostatic blood pressure measurements will 
be done at each visit while participants are receiving study medication. No other special 
safety considerations appear applicable and further details are provided below. 
9.1
Specification of Safety Parameters
In addition to reporting of AEs (see below), BP and pulse rate will be collected at each 
study visit and entered into the study database for safety evaluation. As noted above, 
orthostatic blood pressure measurements will be obtained on all participants on 
antihypertensive medications. Baseline physical examination will be documented, and 
any interim change reported by the participant will also be entered into the database. 
Baseline laboratory values will be collected for determination of inclusion/exclusion 
criteria and will be entered into the study database. Repeat laboratory testing will only 
be done if there is a clinical basis for further testing. Reporting requirements are 
detailed below.
9.1.1 Unanticipated Problems
A UP includes any AE, incident, experience, or outcome that meets all of the following 
criteria:
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1. Unexpected (in terms of nature, severity, or frequency) given:
a. the research procedures that are described in the protocol-related 
documents, such as the IRB approved research protocol and informed 
consent document; and
b. Characteristics of the participant population being studied.
i. The known or foreseeable risk of adverse events associated with 
the procedures involved in the research that are described in: a) the 
protocol-related documents, such as the IRB-approved research 
protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document; and b) other relevant 
sources of information, such as product labeling and package 
inserts; or
ii. The expected natural progression of any underlying disease, 
disorder, or condition of the subject(s) experiencing the adverse 
event and the subject's predisposing risk factor profile for the AE.
2. Related or possibly related to a subject's participation in the research; and
 
3. Suggests that the research places participants or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized.
9.1.2 Adverse Events (AE)
An AE is any untoward or unfavorable medical occurrence in a human subject, including 
any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the 
research, whether or not considered related to the subject’s participation in the 
research.
9.1.3 Serious Adverse Events (SAE)
The following events are considered a SAE and would place participants at a greater 
risk of harm: 
●
Results in death;
●
Is life-threatening (places the participant at immediate risk of death from the 
event as it occurred);
●
Results in inpatient hospitalization or prolongation of existing hospitalization
●
Results in a persistent or significant disability/incapacity;
●
Results in a congenital anomaly/birth defect; or
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●
Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition (examples of such events include allergic 
bronchospasm requiring intensive treatment in the emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse).
9.2
Time Period and Frequency for Event Assessment and Follow-Up
UPs will be recorded in the data collection system throughout the study. 
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day 
of study participation. At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit. Events will be followed for outcome 
information until resolution or stabilization.
9.3
Characteristics of an Adverse Event
9.3.1 Relationship to Study Intervention
To assess relationship of an event to study intervention, the following guidelines are 
used:
1. Related (Possible, Probable, Definite)
a. The event is known to occur with the study intervention.
b. There is a temporal relationship between the intervention and event onset.
c. The event abates when the intervention is discontinued.
d. The event reappears upon a re-challenge with the intervention. 
e. No compelling alternative etiology is discernible.
2. Not Related (Unlikely, Not Related)
a. There is no temporal relationship between the intervention and event 
onset.
b. An alternate etiology has been established.
9.3.2 Expectedness of SAEs
The NIDCR Medical Monitor and the Study PI will be responsible for determining 
whether an SAE is expected or unexpected. An AE will be considered unexpected if the 
nature, severity, or frequency of the event is not consistent with the risk information 
previously described for the intervention on the product label. 
9.3.3 Severity of Event
The following scale will be used to grade adverse events:
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1. Mild: no intervention required; no impact on activities of daily living (ADL)
2. Moderate: minimal, local, or non-invasive intervention indicated; moderate impact 
on ADL
3. Severe: significant symptoms requiring invasive intervention; participant seeks 
medical attention, needs major assistance with ADL
4. Life-Threatening: An experience that in the opinion of the Investigator places the 
subject at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have 
caused death.
5. Death 
9.4
Reporting Procedures
The reporting of AEs, SAEs and UPs will be completed according to the guidelines of 
the NU IRB. 
As of August 20, 2007, NU IRB requires filing of internal or external AEs reports, or 
safety reports only if they have been determined by the PI to contain a report of UPs 
involving risks to participants or others.
UPs involving risks to participants or others should be reported to the IRB within 10 
working days (unanticipated deaths of participants enrolled at NU or Affiliates need to 
be reported within 24 hours). 
All AEs deemed to be serious, both unexpected and expected, will be reported to the 
independent safety monitor.
The independent safety monitor is required to review all UPs involving risk to volunteers 
or others, SAEs and all volunteer deaths associated with the protocol and provide an 
unbiased written report of the event.  The monitor will comment on the outcomes of the 
event or problem and in the case of a SAE or death comment on the relationship to 
participation in the study. The monitor will also indicate whether he/she concurs with the 
details of the report provided by the study investigator. 
9.4.1 Unanticipated Problem Reporting to IRB and NIDCR
Incidents or events that meet the OHRP criteria for UPs require the creation and 
completion of an unanticipated problem report form. OHRP recommends that 
investigators include the following information when reporting an AE, or any other 
incident, experience, or outcome as an UP to the IRB:
●
Appropriate identifying information for the research protocol, such as the title, 
PI’s name, and the IRB project number;
●
A detailed description of the AE, incident, experience, or outcome; 
●
An explanation of the basis for determining that the AE, incident, experience, or 
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outcome represents an UP; 
●
A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UP.
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
●
UPs that are SAEs will be reported to the IRB and to NIDCR within 1 week of the 
PI becoming aware of the event. 
●
Any other UP will be reported to the IRB and to NIDCR within 2 weeks of the PI 
becoming aware of the problem. 
●
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or 
designee), and OHRP within one month of the IRB’s receipt of the report of the 
problem from the PI.
All UPs will be reported to NIDCR’s centralized reporting system via Rho Product 
Safety:
●
Product Safety Fax Line (US): 1-888-746-3293
●
Product Safety Fax Line (International): 919-287-3998
●
Product Safety Email: rho_productsafety@rhoworld.com 
General questions about SAE reporting can be directed to the Rho Product Safety Help 
Line (available 8:00AM – 5:00PM Eastern Time): 
●
US: 1-888-746-7231
●
International: 919-595-6486
9.4.2 Serious Adverse Event Reporting to NIDCR
Any AE meeting the specified SAE criteria will be submitted on an SAE form to NIDCR’s 
centralized safety system via Rho Product Safety. This report may be sent by fax or 
email. Once submitted, Rho Product Safety will send a confirmation email to the 
investigator within 1 business day. The PI should contact Rho Product Safety if this 
confirmation is not received. This process applies to both initial and follow-up SAE 
reports.
SAE Reporting Contact Information:
●
Product Safety Fax Line (US): 1-888-746-3293
●
Product Safety Fax Line (International): 919-287-3998
●
Product Safety Email: rho_productsafety@rhoworld.com 
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Line (available 8:00AM – 5:00PM Eastern Time): 
●
US: 1-888-746-7231
●
International: 919-595-6486
The study clinician will complete a SAE Form and submit via fax or email within the 
following timelines: 
●
All deaths and immediately life-threatening events, whether related or unrelated, 
will be recorded on the SAE Form and submitted to Product Safety within 24 
hours of site awareness. 
●
SAEs other than death and immediately life-threatening events, regardless of 
relationship, will be reported by fax within 72 hours of site awareness. 
All SAEs will be followed until resolution or stabilization. 
9.4.4 Events of Special Interest 
Special attention will be directed toward the possible interaction of Carbidopa/Levodopa 
and antihypertensive medications in causing postural hypotension.  Orthostatic blood 
pressure measurements will be made at all visits for participants receiving 
antihypertensive medications and adverse effects closely monitored to evaluate any 
signs or symptoms of postural hypotension.
9.4.5 Reporting of Pregnancy
The study will follow our institution’s procedure regarding pregnancy during a clinical 
trial. Female patients will have to have a negative pregnancy test. Both male and female 
participants agree in their written consent to use double-barrier contraception during the 
course of the study. If a female participant or partner of a male participant becomes 
pregnant while taking part in this study, the participant will be instructed to discontinue 
the study drug and will be withdrawn from the study. Permission of the participant will be 
requested to notify their  physician of pregnancy during participation in this trial and to 
follow the participant or partner of the participant closely through delivery or termination 
of pregnancy. Unblinding may occur by a member of the research staff if requested by 
the subject’s physician and/or obstetrician. All pregnancies occurring during the course 
of the study will be reported to the FDA, NIDCR and the NU IRB.
9.5 Halting Rules
As both treatments being evaluated in this study are medications that have been widely 
utilized, mainly in Parkinson’s patients, for many years, often at dosages considerably 
higher than will be used in this study, it is not anticipated that discontinuation of the 
study due to safety concerns will occur. However, a safety review will be triggered if 
there is the occurrence of any serious, unexpected, and related AEs by the Medical 
Monitor. Additionally, a safety review will be triggered by finding an increase in the 
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number of occurrences of expected AEs or SAEs (e.g., GI bleeding, dyskinesia) overall. 
If the safety review demonstrates evidence of concern, the FDA, NIDCR and the NU 
IRB will be notified and corrective action will be taken which could include actions such 
as reduction of the dosage of a given intervention, a reduction in the frequency of 
administration or possibly a suspension of further administration of study product.
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STUDY OVERSIGHT
In addition to the PI’s responsibility for oversight, study oversight will be under the 
direction of an Independent Safety Monitor (ISM), who has expertise in clinical trials and 
in the pharmacology of treatments for Parkinson’s disease, particularly Levodopa and 
Carbidopa/Levodopa.  The ISM is independent of the study and will be available in real 
time to review and recommend appropriate action regarding adverse events and other 
safety issues.  We anticipate safety concerns to be relatively limited due to the fact that 
(1) the safety profiles of both study medications have been well described over long 
periods of time, (2) the doses that are being used are at the lower end of the therapeutic 
range for both Carbidopa/Levodopa and Naproxen, (3) treatment is for a limited period 
of time (12 weeks) and (4) careful monitoring of safety will be undertaken by the study 
team with regular oversight by the clinical investigator and the principal investigator.  
In addition, a DSMB will be assembled by NIDCR.  Its meetings and calendar will 
operate under a charter that will be approved by the DSMB.  The DSMB will meet at 
least annually.
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CLINICAL SITE MONITORING
Site monitoring is conducted to ensure that the rights of human participants are 
protected, that the study is implemented in accordance with the protocol and/or other 
operating procedures, and that the study uses high quality data collection processes.  
NIDCR or its contractor will conduct clinical site monitoring for this study.  The monitor 
will evaluate study processes based on NIDCR standards and ICH E6 Good Clinical 
Practice guidelines.  NIDCR will receive monitoring reports from the contractor that 
performs monitoring visits, and reserves the right to conduct independent audits as 
necessary. 
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12
STATISTICAL CONSIDERATIONS
12.1 Study Hypotheses
The basis of this study is the notion that persistent pain, following an inciting injury, 
leads to an aversive learning signal that the corticostriatal system hijacks to reorganize 
the brain into a chronic pain state. We hypothesize that blocking the 
emotional/motivational learning response triggered by peripheral nerve injury and 
integrated within the corticostriatal circuitry, in a critical time window, will decrease the 
probability of transition to chronic pain. 
The primary hypothesis to be tested in the study, for which we have supporting 
preclinical data, is that early treatment with Levodopa (in the form of 
Carbidopa/Levodopa) and Naproxen in individuals with SBP will block transition to CBP.
This will be tested by undertaking a parallel-group double-blind study comparing 
Carbidopa/Levodopa plus Naproxen to Naproxen alone in individuals with SBP. It is 
anticipated that there will be a lower number of individuals progressing to CBP in the 
Carbidopa/Levodopa plus Naproxen group than in the Naproxen treatment alone group. 
Key secondary objectives are to evaluate the interaction with gender of the response to 
pain and to evaluate the correlation between pain response and corticostriatal 
reorganization.
Our main hypothesis is: High-risk SBP patients treated with Carbidopa/Levodopa and 
Naproxen will show statistically significant decrease in rate of transition to chronic pain. 
The null hypothesis is that SBP patients treated with Carbidopa/Levodopa and 
Naproxen and those treated with placebo and Naproxen show equal efficacy for 
blocking transition to chronic pain.
Our secondary hypothesis is: Rate of response of high risk SBP to Carbidopa/Levodopa 
and Naproxen is gender dependent.
Our other secondary hypothesis is: Of the three brain biomarkers that define SBP at 
high risk for chronification, only the extent of corticostriatal information sharing (mPFC-
NAc) will show statistically significant reduction in SBP treated with 
Carbidopa/Levodopa and Naproxen.
12.2 Sample Size Considerations
We plan to recruit approximately 200 individuals with SBP. During screening, 126 
participants will be recruited that are at high risk for developing chronic pain based on 
brain-based biomarkers. These 126 participants will be randomized to the active 
treatment arm (Carbidopa/Levodopa and Naproxen) or the placebo treatment arm 
(placebo and Naproxen). As a conservative estimate, we presume that 100 participants 
will complete the study. The clinical trial is a two-group design examining the effects of 
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predicted response on type of treatment. Because our dependent variable is binary 
(recovered from back pain or not; more than 20% decrease in back pain magnitude 
between entry and 24 weeks after treatment is classified as recovering from back pain) 
and we wish to have sufficient power to detect treatment effect, we conducted power 
analysis based on comparison of independent proportions. Our preliminary data shows 
that in high-risk SBP ~90% will persist with back pain if treated with standard of care 
(mostly occasional use of anti-inflammatories). Thus, for power calculations, we assume 
that 90% of participants that receive placebo will have persisting pain at study end. 
Calculations in G*Power 3.1.2 9.2 indicated that we will detect significant differences 
with 80% power if the probability of pain persistence is reduced to .67 or smaller (Type I 
error rate assumed at .05, two-tailed, n = 50 per group). Again, this is a conservative 
scenario given that our team has extensive experience with participant retention, and 
we assumed a two-tailed comparison, even though there is no a priori reason for the 
placebo to outperform the active drug. We are planning to enter 126 participants, so we 
will have adequate power, accounting attrition. As a supplemental data analysis 
strategy, Dr. Griffith can model pain trajectory as a continuous variable using mixed 
modeling approaches, which potentially has more power, but at some cost of model 
complexity. All effects will be estimated with 95% confidence intervals, consistent with 
CONSORT guidelines.
Our secondary aim is to determine if there is a gender by treatment interaction effect. 
Specifically, we want to test the influence of gender on response to active treatment 
with Carbidopa/Levodopa and Naproxen. Assuming no gender effect on the placebo 
treatment response rate, then we are left with the active treatment arm. Calculations in 
G*Power 3.1.9.2 indicated that we will detect an odds ratio of greater than 2.7 (2.5-3.0) 
with ≥ 80% power with an overall sample size of 50 (assuming n = ~25 per gender). We 
assumed a two-tailed comparison because there is no a priori reason for a given gender 
to respond better to the active drug. Although power will be adequate with this 
conservative scenario, we will be able to strengthen the analyses, if needed, by 
removing variance due to nuisance covariates and using longitudinal modeling, as 
described above. All binary outcomes will be reported based using absolute and relative 
descriptive statistics, consistent with CONSORT guidelines.
Our other secondary aim is to determine if prevention of chronification of pain is 
correlated with inhibition of corticostriatal reorganization. These are planned 
comparisons for brain regional gray matter density and brain functional connectivity 
strengths, as determined in fMRI, DTI, and T1 scans, collected at time of entry into the 
study and at 24 weeks after treatment. Our previous published studies indicate that n = 
~20 per group would be sufficient to show medium size effects of recovery from back 
pain on these pre-specified brain parameters; above calculations indicate that we will 
have an adequate sample size. If we observe a gender by treatment interaction, then 
we can also test whether the interaction can also be detected for the pre-specified brain 
regions.
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Additional exploratory analyses will also be conducted in which we examine whole-brain 
contrasts and whole-brain correlations for parameters of interest. One such analysis 
entails examining brain parameters that distinguish between treatment responders and 
non-responders. A second would be to test for treatment by response interaction effect 
on the whole brain, contrasting anatomical and functional brain states between before 
and after treatment. We expect to have adequate number of participants per group to 
detect medium-sized such effects. All whole-brain statistical results will be based on 
proper correction for multiple comparisons. Post-hoc analyses are then performed for 
specific brain regions or networks identified from whole-brain analyses.
As it stands, our analysis will have sufficient power, but we will achieve even greater 
power by including covariates that are associated with pain recovery/persistence in our 
preliminary data. For example, we have identified extent of radiculopathy as a 
significant contributor with odds ratio of 2.0. We expect to replicate this finding in this 
treatment study.
12.3 Planned Interim Analyses (if applicable)
There are no planned interim analyses for efficacy or safety endpoints. It is anticipated 
that by the time a sufficient number of participants have completed the trial to provide 
an adequate data set to permit interim assessment of efficacy, all or almost all the 
participants will have already been recruited. Therefore, no planned interim analysis has 
been considered. Interim analysis for safety will be undertaken if there is evidence of a 
concern regarding safety generated from consideration of AE and SAE reporting.
Safety Review
Participants’ safety will be closely monitored by the site investigator and the principal 
investigator in conjunction with the proposed Independent Safety Monitor, who will be 
available in real time for participant assessment should the need arise. Careful, periodic 
assessment of all safety data will be undertaken. An inclusion/exclusion criteria check-
list will be reviewed for each participant enrolled to ensure that only appropriate 
participants are included. AEs will be collected at each visit and tabulated by the 
coordinator during the trial. The site and principal investigator will meet on a monthly 
basis to review these data and be joined on a quarterly basis by a biostatistician. There 
will be regular meetings with the Independent Safety Monitor every 6 months, and more 
frequently if requested.  All SAEs will be collected separately and reviewed as such. 
Those that are unexpected and considered related will be reported to the IRB 
immediately. An annual report of study progress and adverse effects will be made. 
MRI safety is routinely implemented at Northwestern University Center for Translational 
Imaging, and participants are carefully screened for contraindications at entry and prior 
to entering the scanner suite. Participants are screened for iron or steel implants or clips 
from surgery, or metallic objects, such as shrapnel or metal sliver in their bodies, are 
excluded from the study if present. Dental fillings do not present a hazard.
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Efficacy Review
There are currently no plans to perform an interim efficacy analysis or review (please 
see 12.3 above for rationale).  
12.4 Final Analysis Plan
SBP participants who qualify to participate in the study are first instructed to rate their 
back pain for a week on the smartphone Pain App. If their average back pain over the 
last 5 days (~15 measures) is >4/10, they undergo brain resting state, fMRI, DTI, and 
T1 scans. The outcome of these scans determine if they are at high risk for transitioning 
to chronic pain, in which case they are randomized to active or placebo treatment for 12 
weeks; followed for another 12 weeks; and then undergo repeat brain scans.
From our previous longitudinal observational study (n = 68 SBP patients followed over 
one year), we have built a statistical model for identifying high risk SBP. The model 
uses a Naïve Bayes Classifier where 3 independent brain biomarkers are used to 
predict risk. The three parameters are: from resting state fMRI the strength of functional 
connectivity between two brain regions, of predefined coordinates (6 mm3 regions) (right 
medial prefrontal cortex and right nucleus accumbens, mPFC-NAc); from DTI we derive 
mean fractional anisotropy for a predefined white matter track (superior longitudinal 
fasciculus); from T1 we measure the volume of the right amygdala. We have shown that 
specific ranges of these 3 values, when used in our model, can identify high risk SBP at 
greater than 90% accuracy. 
At termination of study, participants are classified into recovering (r), based on individual 
back pain (5 day average) decrease >20%, from entry to 24 weeks later. Otherwise they 
are labeled persisting (p). Therefore, our main outcome is a 2x2 frequency table for 
treatment type and ratio of p/(p+r). As the total n = ~ 100 for this table, we will use a chi-
squared test to identify effect of active treatment on risk of pain chronification.
Our secondary aim is to test for an interaction effect between gender and treatment 
outcome, which we will evaluate within a multiple logistic regression model. Our other 
secondary aim is to relate brain parameters to treatment outcome. We expect that DTI 
fractional anisotropy and T1 right amygdala volume will not change with treatment, 
whereas resting state functional connectivity and fMRI mPFC/somatosensory link ratio 
will decrease in time in treatment responders. The four brain biomarkers are treated as 
continuous outcome measures, and tested within a three-way mixed-design ANOVA 
with factors of treatment type, response type, and time (repeated measure).
All brain imaging data undergo a routine pipeline for quality assessment and 
standardized preprocessing. Fixed coordinate values are then extracted from each 
participant and for each modality. These analyses are all performed blinded. Once all 
data are available and the study is closed, we use appropriate groupings to perform the 
ANOVA tests.
Whole-brain exploratory analyses will contrast between groups, and correlate pain, 
anxiety, depression (and other behavioral outcomes) with brain anatomy and function. 
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All initial preprocessing of these comparisons are also done blinded. All whole-brain 
comparisons properly correct for multiple comparisons. The design of the contrasts will 
be repeated measure ANOVA applied over the whole brain, or applied to specific brain 
structures, or functional network measures. Single parameter whole-brain correlates, 
with correction for covariates of no interest will also be performed, across the modalities 
and for multiple behavioral measures.
We will also perform exploratory analyses regarding the contribution of demographics 
and pain-related behavioral measures to the treatment outcome, as well as to their 
influence on outcomes as a covariate when combined with brain biomarkers. These 
would be based on building logistic multivariate regression models.
12.5 Sensitivity analyses
Although our primary analyses will be on N = 100 completers, we will also 
conduct sensitivity analyses on all enrolled participants (N = 126) assuming a worst-
case scenario by imputing baseline-observation-carried-forward for missing data. 
Because we have a two-group design with a binary outcome, it is possible to visualize 
how all possible imputation strategies would influence the outcome of the trial 
(Liublinska 2014). We will calculate propensity scores using logistic regression on 
participation (1 = included/0 = not included) with other study variables as covariates. We 
will then compare the treated versus untreated groups on propensity scores, as well as 
reanalyze the data weighting cases on the basis of propensity scores.
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13
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS
Study staff will maintain appropriate medical and research records for this study, in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for 
the protection of confidentiality of participants. All source documents pertaining to an 
individual participant is compiled into a participant folder. Each participant folder 
includes, but is not limited to, records on personal contact information, demographic 
information, physical exam, vital signs, personal health history, researcher comments 
from each visit, PROs, concomitant medication logs, study medication logs, indications 
of any AEs experienced, clinical laboratory results, and ICFs. PROs will be collected 
directly into REDCap (REDCap is the source document), but will be printed and 
maintained with the participant folder. All folders are kept in a locked cabinet, located in 
a locked room away from all participant activity. Only study coordinators have access to 
the locked room and cabinet. These paper charts are also kept separate from any 
hospital records acquired through NMH or the NMFF. Study staff will permit authorized 
representatives of NIDCR, the NU IRB and defined regulatory agencies to examine (and 
when required by applicable law, to copy) research records for the purposes of quality 
assurance reviews, audits, and evaluation of the study safety, progress and data 
validity. 
All brain imaging data are maintained on a secure server, stored under lock at the NMH 
hospital server banks. Access to these data are password protected, and all brain scan 
data are anonymized and coded prior to being available on the server. Only NUCATS 
will maintain the lock for the specific subject-to-data correspondence, and this 
information is not anticipated to be used, except in some unusual emergency situation 
(such an event has not arisen in the past >15 years).
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QUALITY CONTROL AND QUALITY ASSURANCE
NUCATS Institute maintains SOPs that deal with quality control and quality assurance 
activities related to clinical trials. In brief, data are evaluated for compliance with the 
protocol and for accuracy in relation to source documents by regular audits from 
NUCATS staff. All study documents may be reviewed. Ultimate responsibility for QA 
and QC resides with the site investigator and PI. These responsibilities can be 
delegated to designated study staff. Staff training is made available by both on-line and 
live educational forums. All training is tracked by a university employee database. 
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15
ETHICS/PROTECTION OF HUMAN PARTICIPANTS
15.1 Ethical Standard
The investigator will ensure that this study is conducted in full conformity with the 
principles set forth in The Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Participants of Research, as drafted by the US National 
Commission for the Protection of Human Participants of Biomedical and Behavioral 
Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6. 
15.2 Institutional Review Board
The protocol, ICF(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the ICF 
must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented in the 
study. 
15.3 Informed Consent Process
Informed consent is a process that is initiated prior to the individual agreeing to 
participate in the study and continues throughout study participation. Extensive 
discussion of risks and possible benefits of study participation will be provided to 
participants and their families, if applicable. A consent form describing in detail the study 
procedures and risks will be given to the subject. Consent forms will be IRB-approved, 
and the participant is required to read and review the document or have the document 
read to him or her. The investigator or designee will explain the research study to the 
participant and answer any questions that may arise. The participant will sign the 
informed consent document prior to any study-related assessments or procedures. 
Participants will be given the opportunity to discuss the study with their surrogates or 
think about it prior to agreeing to participate. They may withdraw consent at any time 
throughout the course of the study. A copy of the signed informed consent document 
will be given to participants for their records. The rights and welfare of the participants 
will be protected by emphasizing to them that the quality of their clinical care will not be 
adversely affected if they decline to participate in this study.
The consent process will be documented in the participant folder. (See Appendix B for 
an example of the ICF)
15.4 Exclusion of Women, Minorities, and Children (Special Populations)
N/A
15.5 Participant Confidentiality
We are committed to respect participant privacy and to keep personal information 
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confidential. When choosing to take part in this study, participants are giving us the 
permission to use their PHI that includes health information in their medical records and 
information that can identify them. For example, PHI may include name, address, phone 
number or social security number. Health information that we may collect and use for 
this research includes: 
●
All information in a medical record 
●
Results of physical examinations
●
Medical history including back pain history and family history of back pain
●
Lab tests, or certain health information indicating or relating to a particular 
condition as well as information collected by cellphone apps and PROs
●
Records about study medication or drugs
●
Records about MRI scans
●
Substance abuse information: current recreational drug use or history of alcohol 
or drug abuse 
The following groups of people may give the researchers information about 
research participants: 
●
All current and previous health care providers, including but not limited to the 
NMFF, NMPG, NMH. 
Once we have the health information listed above, we may share some of this 
information with the following people. Please note that any research information shared 
with people outside of NU and its clinical partners (or affiliates) will not contain subject’s 
name, address, telephone or social security number or any other direct personal 
identifier unless disclosure of the direct identifier is required by law [except that such 
information may be viewed by the Study sponsor and its partners or contractors at the 
PI’s office] 
●
Authorized members of the NU workforce, who may need to see information, 
such as administrative staff members from the Office for Research, Office for 
Research Integrity and members of the Institutional Review Board (a committee 
which is responsible for the ethical oversight of the study), 
●
Clinical affiliates, including but not limited the NMFF, NMH, and NMPG. 
Individuals’ participation in this clinical trial will be tracked in an electronic 
database and may be seen by investigators running other trials and by other 
healthcare providers having access to this database. 
●
Other University research centers and University contractors who are also 
working on the study,
●
Study monitors and auditors who make sure that the study is being done 
properly, 
●
Government agencies and public health authorities, such as the FDA and the 
DHHS.
The results of this study may also be used for teaching, publications, or presentation at 
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scientific meetings. However, the individual’s name and personal information will not be 
used.
15.6 Future Use of Stored Specimens and Other Identifiable Data
We foresee that the brain imaging data and related PROs may be used in future 
studies, either by us or when we make this data available on OpenPain for use by other 
researchers (Apkarian, 2014). In all such cases all data will be fully anonymized prior to 
their availability for future use by investigators outside of Apkarian’s lab.
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16
DATA HANDLING AND RECORD KEEPING
The investigators are responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. All source documents should be completed in a 
neat, legible manner to ensure accurate interpretation of data. The investigators will 
maintain adequate case histories of study participants, including accurate CRFs, and 
source documentation.
16.1 Data Management Responsibilities
Data collection and accurate documentation are the responsibility of the study staff 
under the supervision of the investigator. All source documents and laboratory reports 
must be reviewed by the study team and data entry staff, who will ensure that they are 
accurate and complete. UPs and AEs must be reviewed by the investigator or designee. 
16.2 Data Capture Methods
We plan to use REDCap (http://www.project-redcap.org/) as our data management tool. 
Participant-entered data will be collected directly into the REDCap application as source 
documents and subsequently printed out for participant files. PROs,will not contain any 
PHI and will be stored in participant’s folder(See Appendix E for examples of PROs). 
Clinical (e.g., medical history and physical examination, pain evaluations) and functional 
(e.g., brain phenotype) status assessments will be entered on paper as source 
documentation and subsequently entered into REDCap as confirmation of a 
participant’s passing or failing inclusion/exclusion criteria, Other data collected by study 
staff pertaining to the study visit will be entered on paper and subsequently entered into 
REDCap. 
Instruments used for assessing characteristics of back pain:
Numerical Rating Scale (NRS) (Farrar et al, 2001): is an 11-point numerical rating scale 
used to measure pain intensity, where 0 corresponds to no pain and 10 indicates worst 
possible pain. The timeframe in question is concerned with the average pain 
experienced in the past 48 hours. This questionnaire has been extensively used across 
pain management studies.
McGill Pain Questionnaire - Short Form (sf-MPQ) (Melzack, 1987): is a well-validated 
pain measure, which permits separation of sensory and affective components of pain, 
as well as a total score. It also includes a numeric/descriptor scale, a visual analog pain 
scale (VAS), and a body map to localize the pain. This instrument is very well validated 
and often used in pharmacological research (Caraceni et al. 2002). However its 
affective subscale is thought to be relatively rudimentary. 
Beck Depression Inventory, second version (BDI-II) (Beck et al., 1996): A 21-item self-
report instrument for measuring the severity of depression in adults (and adolescents 13 
and up). It is well validated in pain populations, and has been extensively used in 
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pharmacological research (Rowbotham et al. 1998) and in chronic back pain (Harris & 
D’Eon, 2008).
Pain DETECT (PD-Q) (Freynhagen et al., 2006): A 12-item self-report instrument that 
assesses neuropathic pain properties and was originally developed in a sample of 8,000 
low back pain suffers in Germany. The PD-Q demonstrates high sensitivity (80%) and 
specificity (85%), and has since been validated in other clinical pain populations.
Personal Health History (PHH): This general questionnaire will assess demographic 
information (gender, age, marital/relationship status, race/ethnicity, and education), pain 
history (descriptions, diagnostic testing history, and treatment history), general health 
history (other medical/surgical history, concurrent medications, health behaviors, a 
general symptom checklist, and health-care utilization), and work history. The entire 
questionnaire will be completed at the baseline visit. Participants will be asked about 
any changes to concurrent medications at subsequent visits. History and physical 
examination will be done to confirm diagnosis, inclusion and exclusion criteria and 
assess overall safety.
Positive and Negative Affect Schedule (PANAS)(Watson et al., 1988): is a 20-item self-
report instrument that measures the general distress and dysfunction, depression, and 
state anxiety and more of an individual. The PANAS was developed with a sample of 
undergraduate students and validated with adult populations. It is comprised of two 
mood scales, one measuring positive affect and the other measuring negative affect. 
Each item is rated on a 5-point scale ranging from 1 = very slightly or not at all to 5 = 
extremely to indicate the extent to which the respondent has felt this way in the 
indicated time frame. 
Pain Catastrophizing Scale (PCS) (Sullivan et al., 1995): The PCS is a 13-item 
instrument derived from definitions of catastrophizing described in the literature (Chaves 
& Brown, 1987; Spanos et al., 1979) as well as items from the catastrophizing subscale 
of the CSQ (Rosenstiel & Keefe, 1983). The PCS instructions ask participants to reflect 
on past painful experiences, and to indicate the degree to which they experienced each 
of 13 thoughts or feelings when experiencing pain, on 5-point scales with the end points 
(0) not at all and (4) all the time. The PCS yields a total score and three subscale scores 
assessing rumination, magnification and helplessness. The PCS has been shown to 
have adequate to excellent internal consistency (coefficient alphas: total PCS = .87, 
rumination = .87, magnification = .66, and helplessness = .78; Sullivan et al., 1995). 
Pain Anxiety Symptoms Scale (PASS-20) (Author et al., year): is a 20-item instrument 
used to measure the relationship between fear and avoidance of pain, and the suffering 
and disability of chronic pain. The PASS-20 is designed to assess four aspects of pain-
related anxiety: cognitive anxiety, escape-avoidance behaviors, fear of pain, and 
physiological symptoms of anxiety.
Pain Sensitivity Questionnaire (PSQ) (Ruscheweyh et al., 2009): is a 17-item, self-rated 
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instrument used to assess individual pain sensitivity. This questionnaire is based on 
pain intensity ratings of daily life situations, which include various modalities (heat, cold, 
pressure, pinprick) and measures (pain threshold, intensity ratings). Participants are 
asked to rate pain intensities from a 0-10 scale pertaining to hypothetical situations.
Pain Disability Inventory (PDI) (Tait et. al., 1987): a brief 7 item instrument that was 
developed to assess pain-related disability, providing information that complements 
assessment of physical impairment. This self-reported index is based off an 11-point 
scale ranging from no disability (0) to total disability (10). The PDI is a measure of social 
participation in relation to pain, which corresponds to C (achievements) and E 
(subjective evaluations and reactions) of Dijker’s Model (Dijkers, 2005).
Daily NRS Mood Score: is a 21-point numerical rating scale used to measure mood 
intensity, where 0 corresponds to a neutral mood, -10 indicates sadness, and 10 
indicates happiness. The timeframe in question is concerned with mood experienced 
currently.
16.3 Types of Data
Our research staff will be collecting multiple types of data pertaining to the participants, 
such as those dealing with safety, imaging, and behavioral and medical participant 
domains. The safety of the participant will be initially assessed through obtaining a 
thorough history and assuring that participants meet all the criteria of the 
inclusion/exclusion checklist, which reviews comorbid illnesses and contraindicated 
medications. Safety data will continue to be collected at each contact with participants 
and recorded in the source documents. There will not be a separate safety database. 
Imaging data will be collected during each of the scanning visits and will be collected 
based on well-documented protocols. Behavioral data will be provided through selected 
patient PROs that assess various aspects of pain and overall quality of life. Medical 
data will be collected primarily during physical examinations and from a baseline blood 
draw, in addition to follow-up visits throughout the study. These measurements include 
BP, heart rate, chemistry panel, CBC, drug urine screening, and urine pregnancy 
screening.
16.4 Schedule and Content of Reports
In order to monitor the progress of the study and to provide quality control, a number of 
reports will be regularly generated throughout the course of the study. The clinical 
investigator will have a weekly meeting with all study staff to review the status of the 
study and address issues that have arisen during the week. At this meeting, a 
recruitment and retention report will be presented and discussed. Dates of important 
summary reports (e.g., annual IND report, report to clinical committee, IRB annual 
renewal, etc.) will be highlighted. In general, a draft of any report to be circulated 
outside the study team will be prepared at least one week prior to the deadline for the 
report needing to be sent in order to provide adequate time for review and discussion. It 
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is anticipated that there will be a data review regarding safety done at least quarterly or 
more often as requested by the study oversight committee. Outcome data will not be 
reviewed until after database lock, though the integrity and completeness of data will be 
assessed on a quarterly basis as part of quality assurance activities. The database will 
not be locked until all data fields have been checked and any remaining discrepancies 
dealt with. Once the database has been locked, no further changes will be made and 
the randomization code can be provided to the study statistician.
16.5 Study Records Retention
Study records will be maintained for at least five years from the date that the grant FFR 
is submitted to the NIH. No records will be destroyed for up to 3 years after the study 
has completed. There is no anticipation of a marketing application.
16.6 Protocol Deviations
A protocol deviation is any noncompliance with the clinical study protocol or Good 
Clinical Practice requirements. The noncompliance may be on the part of the subject, 
the investigator, or study staff. As a result of deviations, corrective actions will be 
developed by the study staff and implemented promptly.
These practices are consistent with investigator and sponsor obligations in ICH E6:
•
Compliance with Protocol, Sections 4.5.1, 4.5.2, 4.5.3, and 4.5.4.
•
Quality Assurance and Quality Control, Section 5.1.1
•
Noncompliance, Sections 5.20.1 and 5.20.2.
All serious and significant deviations from the protocol will be documented in the study 
participant source documents and promptly reported to NIDCR and the local IRB, 
according to their requirements. 
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17
PUBLICATION/DATA SHARING POLICY
This study will comply with the NIH Public Access Policy, which ensures that the public 
has access to the published results of NIH funded research. It requires scientists to 
submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital 
archive PubMed Central upon acceptance for publication.
The International Committee of Medical Journal Editors (ICMJE) member journals have 
adopted a clinical trials registration policy as a condition for publication. The ICMJE 
defines a clinical trial as any research project that prospectively assigns human 
participants to intervention or concurrent comparison or control groups to study the 
cause-and-effect relationship between a medical intervention and a health outcome. 
Medical interventions include drugs, surgical procedures, devices, behavioral 
treatments, process-of-care changes, and the like. Health outcomes include any 
biomedical or health-related measures obtained in patients or participants, including 
pharmacokinetic measures and adverse events. The ICMJE policy requires that all 
clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is 
sponsored by the National Library of Medicine. Other biomedical journals are 
considering adopting similar policies. For interventional clinical trials performed under 
NIDCR grants and cooperative agreements, it is the grantee’s responsibility to register 
the trial in an acceptable registry, so the research results may be considered for 
publication in ICMJE member journals. The ICMJE does not review specific studies to 
determine whether registration is necessary; instead, the committee recommends that 
researchers who have questions about the need to register err on the side of 
registration or consult the editorial office of the journal in which they wish to publish.
U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 or 
FDAAA), Title VIII, Section 801 mandates that a "responsible party" (i.e., the sponsor or 
designated principal investigator) register and report results of certain "applicable 
clinical trials:" 
Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I 
investigations, of a product participant to FDA regulation; 
Trials of Devices: Controlled trials with health outcomes of a product participant to FDA 
regulation (other than small feasibility studies) and pediatric postmarket surveillance 
studies.
NIH grantees must take specific steps to ensure compliance with NIH implementation of 
FDAAA.
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18
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SUPPLEMENTAL MATERIALS
Supplemental materials provided are: 
●
Package insert for Carbidopa/Levodopa (Double-click to open)
●
Package insert for Naproxen (Double-click to open)
●
Package insert for Acetaminophen (Double-click to open)
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APPENDICES
APPENDIX A: SCHEDULE OF EVENTS
APPENDIX B: CONSENT FORM
APPENDIX C: SMARTPHONE APP USAGE MANUAL
APPENDIX D: CHART DOCUMENTS
APPENDIX E: KEY PROs
APPENDIX F: PROCEDURE FOR DETERMINING HIGH-RISK SUBACUTE BACK 
PAIN PATIENTS (HIGH-RISK SBP)
APPENDIX G: CASE REPORT FORM FOR PHENOTYPING
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APPENDIX A: SCHEDULE OF EVENTS
 
S
cr
e
e
ni
n
g
B
a
s
el
in
e 
S
c
a
n
R
a
n
d
o
m
iz
at
io
n
Double-blind 
Treatment
Follow
-Up 
Phone 
Call
Fi
n
al 
S
c
a
n
E
ar
ly 
T
er
m
.
Visit Number
1
2
3
4
5
6
7
8
--
Telephone Contact
X
X
Week
-4
-2
0
1
4
8
12
1
6
2
0
2
4
--
Visit Window (Days)
--
7
7
3
7
7
7
7
7
7
--
Study informed consent
X
Eligibility criteria
X
Demographic information
X
Medical/surgical history
X
Vital signs
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
Physical Examination
X
Prior / Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Washout instructions
X
Provide daily pain diary
X
X
X
X
X
X
X
X
X
MRI scan
X
X
X
Review / collect daily pain diary
X
X
X
X
X
X
X
X
Hematology - CBCa
X
Hematology - Differentialb
X
Chemistry Panelc
X
Clinical 
Labora
tory 
Tests
Urined
X
Rescue medication
X
X
X
X
X
X
X
X
Investigational drug dispensinge, f
 
 
X
X
X
X
X
 
 
 
X
Study drug compliance
 
 
 
X
X
X
X
X
 
 
X
AE / SAE reporting
 
 
X
X
X
X
X
X
X
X
X
NRS
X
X
X
X
X
X
X
X
X
X
X
painDETECT
X
X
X
X
X
X
X
 
 
X
X
MPQ
X
X
X
X
X
X
X
 
 
X
X
BDI
X
X
X
X
X
X
X
 
 
X
X
PHH
X
 
 
 
 
 
 
 
 
 
PANAS
 
X
X
X
X
X
X
 
 
X
X
Pain 
Assess
ment
PCS
X
 
 
 
 
 
 
 
 
 
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PASS
X
 
 
 
 
 
 
 
 
 
PSQ
X
 
 
 
 
 
 
 
 
 
PDI
 
X
X
X
X
X
X
 
 
X
X
a Hematology – CBC: White cell count, Red cell count, Hemoglobin, Hematocrit HCT, 
MCV, MCH, MCHC, RDW, Platelet count.
b Hematology – Differential: Neutrophils, Lymphocytes, Monocytes, Eosinophils, 
Basophils, Absolute neutrophils, Absolute lymphocytes, Absolute monocytes, Absolute 
eosinophils, Absolute basophils.
c Chemistry Panel: Sodium, Potassium, Chloride, Bicarbonate, Blood urea nitrogen, 
Creatinine, eGFR – African Am, eGFR – Non African Am, Glucose level, Calcium, 
Albumin, Total protein, ALT, AST, Total bilirubin, Alkaline phosphatase.
d Urinalysis – Alcohol and pregnancy (pregnancy collected before any procedures from 
WOCBP only).
e At Visit 3, Carbidopa/Levodopa (12.5mg/50mg) QD for 3 days, Carbidopa/Levodopa 
(12.5mg/50mg) BID for 3 days, and then Carbidopa/Levodopa (12.5mg/50mg) TID over 
one week and then continued at that level at Visit 4 for 4 weeks. If at the end of the 
initial 4 week period the participant has “responded or recovered” (had a reduction in 
pain from baseline of ≥ 20%), the participant will be maintained on that dose for the 
duration of the treatment period (12 weeks total).  If there has not been a response, the 
dose will be increased to Carbidopa/Levodopa (25mg/100mg) TID at Visit 5 for the 
following 4 weeks at which time the pain status will be re-evaluated.  Again, if a 
response has occurred, that dose will be maintained in a blinded manner for the 
following 4 weeks of treatment; if not, further dose-titration will occur to 
Carbidopa/Levodopa (50mg/200mg) TID at Visit 6 for the final 4 weeks. If a participant 
experiences an AE at higher doses, then the participant will be given the next lower 
dose that s/he was able to tolerate and then be maintained on that dose for the 
remainder of the 12 week dosing period. At Visit 7, participants will begin tapering off 
the medication based on their highest treatment dose. If a participant ended the 
treatment period on Carbidopa/Levodopa (12.5mg/50mg) TID, then s/he will start with 
Carbidopa/Levodopa (12.5mg/50mg) BID for 3 days and then Carbidopa/Levodopa 
(12.5mg/50mg) QD for 3 days before discontinuing it completely. If a participant ended 
the treatment period with Carbidopa/Levodopa (25mg/100mg) TID or 
Carbidopa/Levodopa (50mg/200mg) TID, then s/he will start with Carbidopa/Levodopa 
(25mg/100mg) BID for 3 days and then Carbidopa/Levodopa (25mg/100mg) QD for 3 
days before discontinuing it completely. 
f All participants in both arms will be given a therapeutic dose of one 250mg capsule TID 
during the treatment period (but not during the tapering down at the end of the study).
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APPENDIX B: CONSENT FORM
The following document titled “Consent Form and HIPAA Authorization for Research” is 
an example of the ICF used by NU’s IRB for this study. (Double-click to open)
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APPENDIX C: SMARTPHONE APP USAGE MANUAL
The following document is the usage manual for the smartphone app. (Double-click to 
open)
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APPENDIX D: CHART DOCUMENTS
The following are chart documents used in this study:
●
Medical History Form (Double-click to open)
●
Concomitant Medications (Double-click to open)
●
Physical Examination Form (Double-click to open)
●
Vital Signs Form (Double-click to open)
●
Adverse Event Form (individual) (Double-click to open)
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Confidential
AdverseEvents
(con_1)RecordID
Effe
Pag
AdverseEvents
Were anyadverse
e
v
e
n
t
s
e
x
p
e
r
i
e
n
c
e
d
?
N
o
Y
e
s
AdverseEvent1
(pleasetypeAEname)
AdverseEvent1-AdditionalComments/Description
Was theAEexpected?
Yes
N
o
StartDate
StopDate
Severity
Mild
M
o
d
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●
AE/SAE/UAP Tracking Master Log
●
AE/SAE Log (Double click to open)
●
Unanticipated Problem Form (UP)
●
Serious Adverse Event (SAE) Report Form
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●
SAEs Cumulative Tracking Log
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APPENDIX E: KEY PROS
The following documents are the PROs used in this study:
●
Numerical Rating Scale (NRS) (Double-click to open)
●
McGill Pain Questionnaire - Short Form (sf-MPQ) (Double-click to open)
●
Beck Depression Inventory, second version (BDI-II) (Double-click to open)
●
Pain DETECT (PD-Q) (Double-click to open)
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●
Personal Health History (PHH) (Double-click to open)
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Positive and Negative Affect Schedule (PANAS) (Double-click to open)
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Pain Catastrophizing Scale (PCS) (Double-click to open)
●
Pain Anxiety Symptoms Scale (PASS-20) (Double-click to open)
●
Pain Sensitivity Questionnaire (PSQ) (Double-click to open)
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●
Pain Disability Inventory (PDI) (Double-click to open)
●
MRI Screening Form (Double-click to open)
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APPENDIX F: PROCEDURE FOR DETERMINING HIGH-RISK 
SUBACUTE BACK PAIN PATIENTS (HIGH-RISK SBP)
This step is necessary to identify who of the recruited subacute back pain patients fulfills 
the criteria for high risk SBP, as the latter are entered into the clinical trial while others 
are excluded. Given MRI/fMRI brain scans are collected, as explained in the section 8.1 
study procedures/evaluations, we perform several analyses to obtain brain parameters 
that define which patients are high risk SBP/non high risk SBP. Following are the 
specific steps: 
Brain parameters validation:
The MRI facility at Northwestern University recently updated one of their MRI scanners. 
To be able to use the prediction model that we have developed on the previous 
scanner, we need to validate the brain parameters obtained on this new scanner. To do 
so, we will enroll in this study the first 12 eligible participants to gather brain data and 
update our model. Based on our prediction model, that is designed to maximize 
participant to be included in the treatment arm, the likelihood of exclusion from this 
study is 20%. This exclusion rate leads to a maximum of 2-3 participants, out of these 
first 12, that could be excluded from this study. Once the updated prediction model will 
be finalized with the data from the first 12 participants, we will use this model to 
retrospectively stratify them into high-risk or low-risk SBP and take the appropriate 
decision regarding study continuation. 
Quality control pipeline:
A robust quality control pipeline has been established in the Apkarian’s lab and is 
detailed in the publication (Huang et al., 2012). Briefly, each imaging modality (fMRI, T1, 
DTI) is assessed for excessive motion or bad signal to noise ratio. Four different metrics 
are evaluated for each subject: for T1, the volume of seven ROIs and the stretch factor 
(transformation required to move the native-space brain to template space) is obtained. 
For fMRI, the temporal signal to noise ratio is calculated. For DTI, the mean FA and 
mean diffusivity is obtained for specific ROIs and for white matter. These metrics must 
be met for the obtained scans to be accepted and to start the analysis for each 
modality. 
Anatomical parameter:
Subject’s structural T1 images are analyzed with FSL subcortical segmentation tool 
“FIRST” (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FIRST). From the FIRST result that includes 
14 subcortical regions, we extract the volume of the right amygdala, which is our main 
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structural parameter of interest. This parameter is established from patients in our 
longitudinal study of SBP (amygdala results are in a manuscript currently in preparation; 
the study details are described by Baliki (Baliki et al., 2012). We have shown that 
chronic back pain (CBP of duration > 5 years) and persisting SBP patients have a lower 
right amygdala volume. The latter data provides us with the normative distribution of 
amygdala volumes. If the obtained result is within this distribution then the value is used 
with no further manipulation. However, occasionally FIRST segmentation may fail, in 
which case the obtained volume would underestimate amygdala volume. In such cases 
the volume measure need to be checked manually, and might be further augmented 
manually.
Functional parameters:
Subject’s T2* resting state functional images are analyzed with FSL tools. First, we use 
“FEAT” (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FEAT) to pre-process the data and correct 
resting images for motion. To produce the final filtered functional data that we use for 
analysis, we use “MELODIC” toolbox (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/MELODIC) to 
regress-out any signal found in ventricles and in white matter as this is considered 
artifacts. We also remove the whole brain global signal. To allow comparison between 
participants, these filtered functional data are finally registered to a standard brain and 
down-sampled to a 6x6x6 mm voxel size. A c program produced in house called 
“ABLM” (for Apkarian Brain Linkage Map), described and results reported by Baria 
(Baria et al., 2013), is used to provide the number of functional connectivity link of each 
brain voxels. We then extract the average number of links from the nucleus accumbens 
(NAc) and the medial prefrontal cortex (mPFC) and also from sensory regions 
(somatosensory cortex S1 and anterior cingulate cortex). The link ratio of mPFC-
NAc/sensory is then calculated (link ratio). We also extract mPFC-NAc correlation 
coefficient based on coordinates reported by Baliki (Baliki et al., 2012). 
White matter parameter:
Subject’s diffusion tensor images (DTI) are analyzed with FSL tools. We use the 
diffusion toolbox “FDT” (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FDT) to pre-process the DTI 
images. First, we correct each participant DTI images for “Eddy current” 
(http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FDT/UserGuide#Eddy_Current_Correction) and then 
apply a “dtifit” algorithm (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FDT/UserGuide#DTIFIT) to 
obtain a diffusion tensor model value at each white matter voxel. We further extract the 
mean FA value of a group of voxels that were identified in our previous publication 
(Mansour et al., 2013).
Bayesian Model for identifying high risk SBP:
For predicting high-risk/non-high-risk SBP at 6 months from brain parameters collected 
at entry time, assuming that the a priori incidence of high-risk SBP 0.6, we construct the 
following model:
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We want to identify participants, with high specificity, to be non-high risk SBP (non-HR 
SBP), exclude them from the trial and assume all others are high-risk SBP. Each 
individual participant parameter is first tested for being in the range of already existing 
data, otherwise we manually review data extraction steps.
For amygdala volume (Amyg), although alone has a ROC D of 0.77 for predicting high-
risk SBP, its Bayesian prediction curve is bimodal: for volumes > 1600 mm3 P(non-HR 
SBP/Amyg) > 0.7; while for volumes > 900 and < 1200 mm3 P(non-HR SBP/Amyg) < 
0.35. In other ranges prediction is less certain.
For DTI group mean fractional anisotropy (gFA), ROC D is 0.95 for predicting high-risk 
SBP. Bayesian prediction curve is unimodal: for gFA < 0.53 P(non-HR SBP/gFA) < 0.2; 
while for gFA values > 0.57 P(non-HR SBP/gFA) > 0.8.
For fMRI mPFC-NAc correlation coefficient(mPFC-NAc r), ROC D is 0.8 for predicting 
high-risk SBP. Bayesian prediction curve is unimodal: for correlation coefficients > 0.3 
P(non-HR SBP/mPFC-NAc r) < 0.35; while for values < -0.1 P(non-HR SBP/mPFC-NAc 
r) > 0.9.
For fMRI mPFC/somatosensory link ratio (mPFC-S1 LR) ROC D is 0.78 for predicting 
high-risk SBP. Bayesian prediction curve is unimodal but only predictive for high values: 
for LR > 1.2 P(non-HR SBP/mPFC-S1 LR)<0.1; while for LR values <0.7 P(non-HR 
SBP/mPFC-S1 LR) = 0.6.
For all unspecified values we assign a P=0.5. 
Best prediction of non-HR SBP would be (1-0.7)*(1-0.8)*(1-0.9)*(1-0.6)=0.0024
Participants with P-values < 0.05 are designated non-HR SBP. The model is slightly 
inflated, as these parameters are not fully independent of each other. However, the 
procedure provides with a robust decision making algorithm, where specificity of non-
HR SBP participants is emphasized.
We assess performance of this classification based on the 69 SBP participants where 
we know their classification as persisting (=high-risk) or recovering (=non-high risk) SBP 
at 6 months from entry into the study. In this data set, the model shows that only 26% 
are assessed as non-HR SBP, which is 65% of recovering SBP (% with high specificity) 
and only 7% of persisting SBP (% false). Thus, we expect >90% of those classified as 
non-HR SBP to recover from back pain without treatment. More importantly, we expect 
to exclude only 26% of SBP from entering into the clinical trial.
Table below is an excel sheet that calculates and classifies SBP into non-HR SBP. Data 
are shown for 5 participants.
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Non-High Risk SBP Classifier
Amyg
MPFC -
NAC
FA
link ratio
P(nonHR 
amyg)
P(non
HR 
mPFC-
Nac)
P(nonHR 
FA)
P(nonHR 
link 
ratio)
total 
1-p
non 
HR 
SBP
1787
0.100659
0.568133
0.507062392
0.7
0.5
0.5
0.6
0.03
1
1453
0.072483
2
0.574221
0.331351597
0.5
0.5
0.8
0.6
0.02
1
1189
0.136514
0.535257
0.459744165
0.35
0.5
0.5
0.6
0.06
5
0
1648
0.095017
7
0.548217
0.405086864
0.7
0.5
0.5
0.6
0.03
1
1235
0.132299
0.546297
0.699325003
0.5
0.5
0.5
0.6
0.05
0
It is important and clinically highly significant to validate this model as for the first time it 
provides a means of identifying back pain patients that do not need treatment. The latter 
can be achieved by simply following the non-HR SBP that were not included in the 
treatment trial. Therefore, we would like to add this as another secondary aim of the 
study.
References:
Baliki MN, Petre B, Torbey S, Herrmann KM, Huang L, Schnitzer TJ, Fields HL, 
Apkarian AV (2012) Corticostriatal functional connectivity predicts transition to chronic 
back pain. Nature neuroscience 15:1117-1119.
Baria AT, Mansour A, Huang L, Baliki MN, Cecchi GA, Mesulam MM, Apkarian AV 
(2013) Linking human brain local activity fluctuations to structural and functional network 
architectures. NeuroImage 73:144-155.
Huang L, Wang X, Baliki MN, Wang L, Apkarian AV, Parrish TB (2012) Reproducibility 
of Structural, Resting-State BOLD and DTI Data between Identical Scanners. PloS one 
7:e47684.
Mansour AR, Baliki MN, Huang L, Torbey S, Herrmann KM, Schnitzer TJ, Apkarian AV 
(2013) Brain white matter structural properties predict transition to chronic pain. Pain 
154:2160-2168.
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APPENDIX G: CASE REPORT FORM FOR PHENOTYPING
The following document is a case report form used to phenotype participants into high-
risk and not high-risk SBP groups. (Double-click to open)
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ICF_001.pdf: 
Version Date: 13Apr2017                                                                                                 Main
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1
Northwestern University
Physical Medicine & Rehabilitation and Internal Medicine
Consent Form and HIPAA Authorization for Research
TITLE OF RESEARCH STUDY:  
Corticostriatal plasticity in the transition to chronic pain: Effect of L-dopa 
INVESTIGATORS: 
A. Vania Apkarian, PhD
Thomas J. Schnitzer, MD, PhD
Department of Physiology
Department of Physical Medicine & 
300 E. Superior Street, Room 7-705
 
Rehabilitation
Chicago, Illinois 60611 
710 N. Lake Shore Drive,Room 1020
tel. (312) 503-0404 
Chicago, IL 60611
fax. (312) 503-5101
tel. (312) 503-2315
fax. (312) 503-1505
Introduction
You are being asked to take part in a research study. This document has important information 
about the reason for the study, what you will do if you choose to be in this research study, and the 
way we at Northwestern University would like to use information about you and your health.  
What should I know about a research study?
o
Someone will explain this research study to you.
o
Whether or not you take part is up to you.
o
You can choose not to take part in this study.
o
You can agree to take part in this study and later change your mind.
o
Your decision will not be held against you.
o
You can ask all the questions you want before you decide.
Conflict of Interest Disclosure
If your doctor is also a person involved in this research study, please note that he is interested in 
both your clinical care and the conduct of this research study. You have the right to discuss this 
study with another person who is not part of the research team before deciding whether or not to 
participate in the research.
Financial Interest Disclosure  
The following disclosures are made to give you an opportunity to decide if the following 
information will affect your willingness to participate in this research study: This research is being 
funded by The National Institute of Dental and Craniofacial Research (NIDCR) and The National 
Institute of Health (NIH).
Why am I being asked to take part in this research study?
You are being asked to participate because you currently have new lower back pain that began 4– 
20 weeks ago.
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Why is this research being done?
The transition from acute low back pain to chronic low back pain has been shown to be a result of 
changes in brain activity. Acute pain might be mild and last just a moment, or it might be severe and 
last for weeks or months. In most cases, acute pain does not last longer than six months, and it 
disappears when the underlying cause of pain has been treated or has healed. Unrelieved acute pain, 
however, might lead to chronic pain. Chronic pain persists despite the fact that the injury has 
healed. Pain signals remain active in the nervous system for weeks, months, or years. 
These pain signals can be directly affected by a chemical in the brain called dopamine. Dopamine 
helps control the brain's reward and pleasure centers; it enables us not only to see rewards, but to 
take action towards obtaining them. Dopamine also helps regulate movement and emotional 
responses. The purpose of this study is to assess the efficacy and safety of early treatment with the 
drug Carbidopa/Levodopa when used in combination with Naproxen in preventing chronic low 
back pain in individuals who have sub-acute low back pain following an injury, or new back pain, 
which has persisted for less than 20 weeks. 
The study drug, Carbidopa-Levodopa, is an FDA-approved medicine traditionally used for the 
treatment of Parkinson’s disease.  The study drug will be used for an un-approved or un-labeled use: 
potentially preventing chronic lower back pain in individuals who have acute back pain. 
Carbidopa/Levodopa is an artificially made version of a naturally occurring hormone that helps 
regulate brain activity (Levodopa), combined with an artificially made version of a naturally 
occurring molecule that inhibits the breakdown of Levodopa (Carbidopa).  
This study is a 24-week, two-armed, double-blind, randomized, placebo-controlled trial of the 
pharmacological treatment Carbidopa/Levodopa for individuals with sub-acute back pain (SBP). 
o
This is a two-armed study. If you qualify for the study you will receive either the study drug 
or placebo and Naproxen for your low back pain.  Naproxen is a non-steroidal anti-
inflammatory drug (NSAID) approved by the FDA for treatment of pain. The first 12 
participants who will be eligible and will agree to sign the consent form will enter this study 
in order to validate the brain parameters obtained with our updated MRI scanner. The 
participation of these subjects may be discontinued afterwards based on the MRI results.
o
This is a double-blind study. If you are in this study, you, the doctors, and the study staff 
will not know which treatment you will get. You will get the medicines in a way that will 
not make it possible for you, the doctor, or the study staff to know which treatment it is. 
However, in an emergency, doctors can get this information.
o
This is a randomized study. If you are in this study, you will either be given the study drug 
or an inactive substance (known as a placebo) by chance using a process similar to the flip 
of a coin. This process is called randomization. Neither you nor the study staff will know 
whether or not you are taking the study drug. However, if you have a medical emergency, 
we can get this information.
o
This is a placebo-controlled study. The study compares the study drug, 
Carbidopa/Levodopa, to a placebo. A placebo looks like the study drug, but is an inactive 
substance that has no medication. Researchers use a placebo to see if the study drug works 
better or is safer than not taking anything. Regardless of which treatment arm participants 
are in, everyone will receive Naproxen. 
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How many people will be studied?  
The study investigators hope to screen 200 individuals and enroll 126 participants at Northwestern 
University.  
How long will this research last?  
The study duration is approximately 28 weeks and will consist of 8 visits. There will be a Screening 
Visit, Baseline Visit, and 6 Study Visits, which are outlined below. The schedule for the 6 Study 
Visits after your Baseline Visit will be referred to as Week 0, Week 1, Week 4, Week 8, Week 12, 
and Week 24. If you receive the study drugs, treatment will be terminated after Week 12, but your 
back pain will continue to be evaluated by monthly questionnaires until the end of the study (Week 
24). Follow-up telephone calls at Week 16 and Week 20 will be made to continue evaluation of 
your back pain.
What happens if I say “Yes, I want to be in this research”? 
If you consent to participate, you will be asked to come to Abbott Hall located at 710 N. Lake Shore 
Drive, 10th floor, Chicago, IL 60611. Some of the study procedures will take place in nearby 
buildings and the study coordinator will direct you to those locations.
In this study, all subjects will continue their clinical care as needed with their primary care 
physician and/or specialist.  If you are taking medication for your back pain upon entry into this 
study, you will be asked to discontinue your current treatment and take only the study medication 
for the first 12 weeks of this study.  You will be allowed to take rescue pain medication 
(acetaminophen, up to 3 grams/day) as needed for the 12 week treatment period. You may not take 
other non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, or other 
acetaminophen-containing medications during the 12-week treatment period. Additionally, the use 
of opioids (such as tramadol, codeine, oxycodone, and methadone) and tricyclic antidepressants 
(such as, Elavil, Silenor, Afafranil) except in low doses for sleep are prohibited during the study 
period. At each visit, we will record all medications that you are taking or have taken since the last 
visit. You will be allowed to resume former pain therapies for the follow-up period (Weeks 12-24) 
only after proper study medication discontinuation. Additionally, if you are interested, you will 
have an option to participate in other low back pain studies at Northwestern University.
•
Screening Visit (Visit 1: Week -4)
The first visit will take 1.5 hours. You will be asked to complete the informed consent process and 
will be evaluated with inclusion/exclusion criteria.  A medical/pain history and physical 
examination will be completed. You will be asked to assess your current back pain intensity and 
complete self-report questionnaires. Urine will be obtained for screening of illicit drugs; 
additionally, blood will be drawn for screening purposes (40 mL or 8 teaspoons) to check your 
kidney and liver functions, alcohol level, and blood cell counts (for problems like anemia). For 
women of child-bearing potential, blood will be collected for a pregnancy test. Temperature, 
weight, blood pressure and heart rate will be assessed.  Orthostatic (standing) blood pressure 
measurements will be obtained if you are taking anti-hypertensive medications. You will return in 1 
– 2 weeks for baseline fMRI scans unless you are not able to have, or meet the requirements for, 
brain imaging. Additionally, you will be trained on how to use an electronic application for a smart 
phone that will allow you to rate your pain 3 times per day for the 24-week duration of the study. 
You will be compensated for your responses. Failure to use the application to rate your pain will 
result in being dropped from the study. 
•
Baseline Imaging Visit (Visit 2: Week -2) 
(Note: Those not eligible for brain imaging will go directly to Visit 3). 
If you qualify for the study (based on the initial screening visit and your pain ratings on the smart 
phone app between visits 1 and 2) and are eligible for brain imaging, you will return for the baseline 
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imaging visit. This visit will take approximately 2 – 2.5 hours. You will be asked to rate your back 
pain and complete questionnaires. You will also undergo fMRI procedures.  These scan data will be 
used to determine eligibility for entering the study. 
This study uses functional magnetic resonance imaging (fMRI) to look at the brain at both the 
Baseline and the Final Visit. An fMRI is a type of brain scan that uses magnetic fields and radio 
waves to make an image of changes in blood flow in your brain while you perform certain tasks.
In order to make sure the fMRI procedure will be safe, you will be asked to fill out a screening form 
before starting the study. It is important that you tell the researchers in this study if you have any 
history of:
•
Metal fragments in your eyes or face.
•
Implantation of any electronic devices such as (but not limited to) cardiac pacemakers, 
cardiac defibrillators, cochlea implants or nerve stimulators.
•
Surgery on the blood vessels of your brain or the valves of the heart
•
Claustrophobia (fear of enclosed places)
•
Body piercing or tattoos
•
Brain or skull abnormalities
You will be given instructions about the scanning prior to entering the MRI scanner. Next, you will 
be asked to lie still on the MRI patient table and your head will be placed in a specially-designed 
head holder. Your head will be cushioned by a firm foam pillow. The table will then slide into the 
enclosed space of the MRI scanner. Some people feel tired, uncomfortable or claustrophobic (afraid 
of small spaces) in the MRI scanner. The MRI scanning session will take about 50 minutes to an 
hour to complete once you are in the scanner. 
The information from the MRI scanner is only useful if you are able to complete the whole imaging 
session, and hold your head very still the whole time; therefore, you will be encouraged to hold as 
still as possible and let the investigators know if you are uncomfortable in any way as soon as 
possible after the imaging session begins.
The front of the head-holder will be open, which lets you look through a special mirror and see the 
open end or a projection screen near your head. You will be asked to hold your head as still as 
possible and to respond to visual cues by pushing a button or thinking quietly to yourself.
The MRI scanner makes loud banging noises while taking a measurement, so either ear plugs or 
specially designed headphones will be used to reduce the noise. The researchers will be in 
communication with you through an intercom system to tell you how the study is going. The 
earplugs or headphones should not get in the way of communicating with the researchers.
•
Randomization Visit (Visit 3; Week 0)
The randomization visit will take around 30 minutes. If you have not undergone a baseline MRI, 
you will receive treatment at this visit and you will be assumed to be at high risk for chronification 
of lower back pain. If you did receive  brain imaging, we will inform you (also known as 
“debriefing”) of the results from your first MRI screening that may indicate whether or not you are 
likely (~90%) to develop persistent low back pain with regular treatment (such as NSAIDs). If the 
results indicate that you are unlikely (~10%) to develop persistent low back pain, you will be given 
the option to participate in the observational substudy, which does not include medication. 
Participants receiving treatment will be put on active study medication (carbidopa/levodopa plus 
naproxen) or a placebo plus naproxen; regardless, both of these groups will receive omeprazole and 
the rescue medication (acetaminophen). Omeprazole is prescribed one time per day as a 
preventative measure against possible gastric adverse effects of naproxen. Both the study 
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medication and the placebo will be identical in appearance and are suggested to be taken with food 
or a meal. If you are randomized to the group that receives the active carbidopa/levodopa capsules, 
you will begin treatment with 12.5/50mg, and over time you may be increased from the initial dose 
up to a total daily dose of 50/200 mg of carbidopa/levodopa. After a total of 12 weeks, you will be 
tapered off of treatment. You will take 2 capsules (one containing naproxen, and the other 
containing either placebo or carbidopa/levodopa) 3 times per day after the first week. Neither you 
nor the research team will know what treatment you will be receiving.  You will be asked to report 
any changes in your health or medications, rate your current back pain, and complete the self-report 
questionnaires. Blood pressure and heart rate will be determined for all subjects.  Orthostatic 
(standing) blood pressure measurements will be obtained for if you are taking anti-hypertensive 
medications. If you are a woman of child-bearing potential, you will have a urine pregnancy test 
done prior to receiving study medication.
•
Interim Treatment Visits (Visit 4 – Visit 7: Weeks 1, 4, 8, and 12)
The interim treatment visits will take around 30 minutes.  You will come to the study location and 
be asked to report any changes in your health or medications, rate your current back pain, and 
complete the self-report questionnaires. Blood pressure and heart rate will be determined for all 
subjects.  Orthostatic (standing) blood pressure measurements will be obtained for all participants 
taking anti-hypertensive medications. You will be given enough medication at each visit to last until 
the next visit. You will also be asked to bring back your study medications in their vials so that we 
may count the number of pills remaining. You will also be asked about any side effects or adverse 
events experienced. During Visit 5, at which time you will have had 4 weeks of medication, blood 
will be obtained to determine that the medication is at safe levels in your body. 
If, at the end of the initial 4-week period, you have had a significant improvement in your pain, you 
will be maintained on that initial dose for the duration of the treatment period (12 weeks total).  If 
there has not been a response in your pain level, the dose of the active drug (if you have been 
randomized to this group) will be increased for 4 more weeks, after which the pain status will be re-
evaluated.  Again, if there has been significant improvement in your pain, that dose of study 
medication will be maintained for the following 4 weeks of treatment; if not, the dose will increase 
again for the final 4 weeks. If you experience any side effects at a higher dose, you will be given the 
next lower dose that you are able to tolerate and then be maintained on that dose for the remainder 
of the 12-week medication period. After completing 11 weeks of treatment, we will have you 
slowly reduce the dosage of the study drug over the course of one week, for a total of 12 weeks on 
study medication.
•
Final Visit (Visit 8: Week 24):  
The final visit will take about 2 – 2.5 hours. You will be asked to assess your current back pain 
intensity and complete self-report questionnaires. Blood pressure and heart rate will be determined 
for all subjects.  Orthostatic (standing) blood pressure measurements will be obtained for all 
participants taking anti-hypertensive medications.  If you attended the MRI scanning session at the 
baseline visit (Visit 2), you will also undergo fMRI procedures. A urine sample will be collected 
from female subjects that are of child-bearing potential. You will be asked to bring back the 
medication so that we may count the pills remaining. You will be asked about side effects 
experienced. 
•
Interim Electronic Contact
You will be contacted by telephone and/or internet access on a monthly basis for two months after 
you have completed 12 weeks of treatment.  At each of these interactions you will be asked about 
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your back pain, changes in health/medications, side effects, and will be able to share any other 
information. At the end of this clinical trial, we will be able to inform you which medication 
treatment you received while on study and the dosage of these medications.
What happens if I say “Yes”, but I change my mind later?
You can leave the research at any time and it will not be held against you. 
What are my responsibilities if I take part in this research?
If you take part in this research, you will be responsible for the following:
o
Attending all visits within the timeframe set by the study coordinator
o
Taking study medications as directed
o
Rating pain and mood on the study phone application (or computer)
Can I be removed from the research without my OK?
The person in charge of the research study or the sponsor can remove you from the research study 
without your approval. Possible reasons for removal include if you do not follow the directions of 
the study doctor, you do not provide responses on the smart phone app, you develop a serious 
illness that is not related to taking part in the study, or the study doctor decides that the study is not 
in your best interest. You could also be asked to stop taking part if the study sponsor, the 
responsible regulatory authority, or Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) decides to stop the study altogether. You may also be asked to stop taking part in the 
study if you become pregnant, intend to become pregnant or are nursing a child during the study 
period.
What do I need to know about reproductive health/sexual activity if I am in this study? 
The effects of the study drug, Carbidopa-Levodopa, on human sperm, human eggs, and the 
developing fetus have not been studied. The risk of birth defects is also unknown or may be 
unforeseeable. No effects on fertility were seen in rats receiving doses of approximately two times 
the maximum human dose and four times the maximum human dose of Carbidopa and Levodopa, 
respectively. No malformations of the embryo or fetus were seen in mice receiving up to 20 times 
the maximum recommended human dose of Carbidopa/Levodopa. 
The effects of Carbidopa-Levodopa in pregnant women have also not been adequately studied. 
However, it is known that Levodopa crosses the placental barrier, enters the fetus, is metabolized, 
and trace amounts can be seen in fetal tissue. Therefore, both men and women should not attempt 
pregnancy, and women should not be pregnant or breast-feeding while taking part in this study.
If sexually active, both men and women should use an effective method of birth control while 
taking the study drug. Barrier contraceptives (condoms or diaphragm) with spermicide, intrauterine 
devices (IUDs), hormonal contraceptives, oral contraceptive pills, surgical sterilization, and 
complete abstinence are examples of effective methods. If you or your partner become pregnant 
while taking the study drug, it is important that you tell your study doctor immediately. You will 
need to discontinue the study drug and will be withdrawn from the study.  Additionally, we will ask 
your permission to notify your physician of your participation in this clinical trial and will ask to 
monitor you or your partner throughout the pregnancy and delivery or termination of pregnancy. 
Unbinding may occur by a member of the research staff if requested by your physician and/or 
obstetrician. All pregnancies occurring during the course of the study will be reported to the FDA, 
our sponsor (NIDCR) and the Institutional Review Board at Northwestern University.
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Naproxen has been shown to be harmful to developing fetuses and should only be taken by pregnant 
women when there is no other alternative and their health care providers have determined that the 
benefits of naproxen outweigh the risks.  Other treatment options will be discussed with you if you 
stop the study drug.
If you are considered to be postmenopausal, you are not required to use contraception while in this 
study.  Rarely, women considered to be postmenopausal become pregnant.  If you suspect that you 
become pregnant while taking the study drug, it is important that you tell the study doctor 
immediately.  You may have to stop the study drug.  Other treatment options will be discussed with 
you if you stop the study drug.
Is there any way being in this study could be bad for me?
Risks from being in this study may include the following: possible side effects from the study 
medications or blood draw; feeling uncomfortable answering the questionnaires, participating in a 
MRI test. Here we describe some of these potential effects:
Study Medications
1) Carbidopa-Levodopa: A drug therapy that combines the dopamine agonists Levodopa and 
Carbidopa. The combination aims at increasing the levels of dopamine in the brain while preventing 
any similar increase in the rest of the body, hence minimizing side effects.  To reduce the incidence 
of side effects, the dose of medication will be increased slowly and your health will be monitored 
closely. After completing 12 weeks of treatment, we will have you slowly taper off of the study 
drug.  
The risks involved in using Carbidopa-Levodopa are as follows:

Dyskinesia (involuntary movements)

Nausea

Mental disturbances (hallucinations, depression)

Confusion

Dizziness

Urinary tract infection

Headache

Vomiting

Constipation

Impulse control symptoms (failure to resist a temptation, urge or impulse that may harm 
oneself or others such as excessive gambling, excessive shopping or binge eating)

Fatigue

Drowsiness

Abdominal pain and distress

Vivid dreams
2) Naproxen: All NSAIDs, including Naproxen, may cause serious cardiovascular side effects such 
as heart attack (myocardial infarction) or stroke (cerebrovascular accident), which may result in 
hospitalization and even death.  Although serious cardiovascular events can occur without warning 
symptoms, you should be alert for the signs and symptoms of chest pain, shortness of breath, 
weakness, or slurring of speech, and should ask for medical advice if you observe any of these signs 
or symptoms.
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Naproxen, as all other NSAIDs, can cause gastrointestinal (abdominal) discomfort, and, rarely, more 
serious side effects such as ulcers and bleeding, which may result in hospitalization and even death.  
Although serious gastrointestinal events can occur without warning symptoms, you should be alert for 
the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when you 
observe any signs or symptoms that are indicative of these disorders, including epigastric pain 
(stomach pain), dyspepsia (upset stomach), melena (black stools) and hematemesis (vomiting blood).  
Older people are at higher risk for ulcers caused by these medications.
Other side effects that you may have after taking Naproxen include: constipation, diarrhea, 
heartburn, abdominal pain, nausea, headache, feeling dizzy, itching, hives, rash, ringing in the ears, 
feeling sleepy, shortness of breath and swelling of hands, feet and/or face.
Long-term use of Naproxen may result in abnormal liver tests or impaired kidney function. The 
cardiovascular (heart and blood vessel) safety of Naproxen in comparison to placebo has not been 
studied in a long-term research study.
3) Acetaminophen: The rescue medication for this study, acetaminophen, may cause liver damage 
and rarely death due to overdosing and/or mixing with alcohol. Early symptoms of liver damage 
include, but are not limited to, nausea, vomiting, sweating, and general malaise (not feeling well). 
Subjects should not take more than four 500 mg tablets during a 24-hour period. If you drink 3 or 
more alcoholic beverages per day you should tell the study doctor. Regular use of acetaminophen 
may increase the risk of chronic kidney failure, but only in those individuals with pre-existing 
kidney disease. Acetaminophen has no significant side effects on the kidney if your kidney function 
is normal and the dosing instructions are followed. Prior to receiving study treatment, your blood 
will be tested to see if your kidneys and liver are functioning well.
4) Placebo:
There is the risk that you will not get the study drug or your normal medication, and you may see no 
improvement in your condition or your symptoms may get worse.
This is not a complete list of side effects and others may occur. Tell your doctor about any unusual 
or bothersome side effects. If you have an allergic reaction to the study drugs seek emergency help 
and contact the study doctor as soon as possible. Signs of an allergic reaction include hives; 
difficulty breathing; swelling of your face, lips, tongue, or throat. 
5) Omeprazole
Omeprazole is a proton pump inhibitor that is prescribed to prevent any gastrointestinal upset due to 
intake of naproxen.   
The side effects for omeprazole (given with a capsule of naproxen) include common and less 
serious symptoms such as headache, diarrhea, nausea, stomach pain, vomiting, and gas.  Less 
common but serious side effects include: rash, face swelling, throat tightness, and difficulty 
breathing. 
A number of drugs should not be taken while receiving omeprazole; these include atazanavir, 
nelfinavir,and saquinavir.  Omeprazole may interfere with ketoconazole, iron salts, erlotinib, 
ampicillin esters, digoxin, and mycophenolate mofetil, clopidogrel, and cilostazol so please tell the 
study staff if you are taking any of these medications.  In addition, drugs such as diazepam, 
warfarin, phenytoin, cyclosporine, disulfiram, benzodiazepines can be prolonged in their 
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elimination when taking in conjunction with omeprazole. Please make sure the study staff knows if 
you are taking any of these medications during the study so you can be monitored appropriately. In 
case such interactions would result in any clinically meaningful increase in risk you will be 
excluded for safety reasons.
Blood Draw
The risks of taking blood include pain, a bruise at the point where the blood is taken, redness and 
swelling of the vein and infection, and a rare risk of fainting.
Self-Report Questionnaires
Some of the questions asked may be upsetting or you may feel uncomfortable answering them. If 
you do not wish to answer a question, you may skip it and go to the next question. 
Functional Magnetic Resonance Imaging
For the fMRI test, you will lie in a small closed area inside a large magnetic tube for up to 60 
minutes at a time. Some people are scared or anxious in small places (otherwise known as 
claustrophobic). Because the test requires that participants lie as still as possible with only minimal 
movements, back pain may worsen during the test.  During the test, study staff will continuously 
ask you about your level of pain and will discontinue the scan at any time requested. You will be 
asked about any concerns you may have prior to testing. If you cannot tolerate being in the MRI 
scanner, you will not be able to participate in the study. 
The MRI pictures from this study will not be in a form readable by either you or your doctor; 
therefore, a copy of the MRI pictures and/or the results of your individual study will neither be 
available to you nor your doctor. While the MRI pictures in this study are not formally reviewed by 
a radiologist, if in the course of processing the images we notice any abnormality that would be 
possibly important to your health, we will tell you and a doctor you name.
Will being in this study help me in any way? We cannot promise any benefits to you or others 
from your taking part in this research. However, possible benefits include decreased low back pain 
and the potential to avoid being in a chronic pain state. It is also possible that you will receive no 
benefit from taking part in this study.
Taking part in this study may help scientists to better understand how chemical interactions in the 
brain determine the type of pain, chronic or acute, in an individual following an injury. It will also 
help scientists to determine if early treatment with Carbidopa/Levodopa and Naproxen may benefit 
patients with sub-acute low back pain. This study may also help inform future research studies 
involving individuals with sub-acute low back pain.
What other procedures or courses of treatment might be available to me?   
You do not have to take part in this research study.  Instead of being in this study, you can consult a 
physician about your lower back pain and obtain other FDA-approved methods of treatment. 
Physical therapy may be of additional benefit. Your physician can tell you about what medication 
might be available to you.
Will it cost me anything to participate in this research study?
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There will be no costs to you for being in this study.  You will be provided with all study drugs and 
all procedures will be done free of charge for this study.
What should I do if I am injured as a result of being in this study? 
If you become ill or get an injury or illness as a result of study medications or procedures you 
should seek medical treatment through your doctor or treatment center of choice. You should 
promptly tell the study doctor about any illness or injury. Payment for this treatment will be your 
responsibility. 
The hospital [university, researchers] will not pay for medical care required because of a bad 
outcome resulting from your participation in this research study. This does not keep you from 
seeking to be paid back for care required because of a bad outcome.
Who can I talk to?
If you have questions, concerns, or complaints, or think the research has hurt you, you can contact 
the research team. The Study Coordinator can be reached at 312-503-2886 Monday through Friday, 
9a.m. to 5 p.m. Dr. Apkar V. Apkarian is the person in charge of this research study and can be 
reached at 312-503-0404 Monday through Friday, 9 a.m. to 5 p.m. For questions arising during the 
evenings or weekends, you may call 312-649-2964 and ask for Dr. Schnitzer to be paged.
This research has been reviewed and approved by an Institutional Review Board (“IRB”). You may 
talk to them at (312) 503-9338 or irb@northwestern.edu if:
o
Your questions, concerns, or complaints are not being answered by the research team.
o
You cannot reach the research team.
o
You want to talk to someone besides the research team.
o
You have questions about your rights as a research participant.
o
You want to get information or provide input about this research.
What happens if I do not want to be in this research? 
You can leave the research at any time and it will not be held against you.
If you choose to be in this study, you have the right to be treated with respect, including respect for 
your decision whether or not you wish to continue or stop being in the study.  You are free to 
choose to stop being in the study at any time.  
Choosing not to be in this study or to stop being in this study will not result in any penalty to you or 
loss of benefit to which you are entitled.  Specifically, your choice to not be in this study will not 
negatively affect your right to any present or future medical treatment.  
Any new findings developed during the course of this research that may affect your willingness to 
continue in this study will be shared with you. 
What happens to the information collected for the research?  
Efforts will be made to limit the use and disclosure of your personal information, including research study 
and medical records, to people who have a need to review this information. We cannot promise complete 
secrecy. Organizations that may inspect and copy your information include the IRB and other 
representatives of this institution. The sponsor, monitors, auditors, the IRB, the US Food and Drug 
Administration will be granted direct access to your medical records to conduct and oversee the research. 
By signing this document, you are authorizing this access. We may publish the results of this research. 
However, we will keep your name and other identifying information confidential. 
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A description of this clinical trial will be available on http://www.ClinicalTrials.gov (ClinicalTrials.gov 
Identifier: NCT01951105) as required by U.S. Law. This Web site will not include information that can 
identify you. At most, the Web site will include a summary of the results. You can search this Web site at 
any time. 
What else do I need to know?
o
If you need medical care because of taking part in this research study, contact the investigator and 
medical care will be made available. Generally, this care will be billed to you, your insurance, or 
other third party. Northwestern University has no program to pay for medical care for research-
related injury.
o
If you complete all visits, you will get up to $410 for taking part in this research study.  If you 
withdraw from the study, you will be paid for the portions that you completed.  
Compensation will be paid to you according to the following schedule:
Visit
Amount
Payment Type
Screening  Visit 1
$25, up to $20 for transportation and validation for free parking
Cash
Baseline Imaging 
Visit 2
$50, up to $20 for transportation and validation for free parking
Cash
Treatment Visits 3 – 7
$25, up to $20 for transportation and validation for free parking, 
per visit
Check, Cash
Visit 8
Final Imaging:$50, up to $20 for transportation and validation 
for free parking
No Final Imaging: $25, up to $20 for transportation and 
validation for free parking
Check, Cash
o
Study payments will be given to you in cash at the time of your study visit. For Visit 2 and 
Visit 8 you will be mailed a $50 check to your home in addition to the $20 you receive for 
travel expenses. If you choose to drive and are given a parking validation for free parking $5 
will be subtracted from the $20 cash for transportation. The Accounting Services at 
Northwestern University will be given your name, address, and Social Security Number in 
order to issue payment for your participation. Study payments are considered taxable income 
and reportable to the IRS. A Form 1099 will be sent to you if your total payments for 
research participation are $600 or more in a calendar year.
o
You will also receive financial compensation when you rate your back pain. You will be 
asked to rate your pain 3 times a day. In doing so you may earn 75 cents/day (25 
cents/response, 3 times per day maximum) and $147 over the course of the entire study. At 
the end of the study, you will receive the total amount of money earned from this application 
in check form.  Study payments are considered taxable income and reportable to the IRS. A 
Form 1099 will be sent to you if your total payments for research participation are $600 or 
more in a calendar year.
HIPAA Authorization
We are committed to respect your privacy and to keep your personal information confidential.  
When choosing to take part in this study, you are giving us the permission to use your personal 
health information that includes health information in your medical records and information that can 
identify you. For example, personal health information may include your name, address, phone 
number or social security number. Health information that we may collect and use for this research 
includes: 
•
Results of physical examinations
•
Medical history including back pain history and family history of back pain
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•
Lab tests, or certain health information indicating or relating to a particular condition as well 
as diaries and questionnaires
•
Records about study medication or drugs
•
Records about MRI scans
•
Substance abuse information: current recreational drug use or history of alcohol or drug 
abuse
Once we have your health information listed above, we may share some of this information with the 
following people. Please note that any research information shared with people outside of 
Northwestern University and its clinical partners (or affiliates) will not contain your name, address, 
telephone or social security number or any other direct personal identifier unless disclosure of the 
direct identifier is required by law [except that such information may be viewed by the Study 
sponsor and its partners or contractors at the Principal Investigator’s office]. 
•
Authorized members of the Northwestern University workforce, who may need to see your 
information, such as administrative staff members from the Office for Research, Office for 
Research Integrity and members of the Institutional Review Board (a committee which is 
responsible for the ethical oversight of the study), 
•
Clinical affiliates, including but not limited to the Northwestern Medical Faculty Foundation 
(NMFF), Northwestern Memorial Hospital (NMH), and Northwestern Memorial Physicians Group 
(NMPG).  Your participation in this clinical trial will be tracked in an electronic database and may 
be seen by investigators running other trials that you are enrolled in and by your healthcare 
providers.  
•
Other University research centers and University contractors who are also working on the study,
•
Study monitors and auditors who make sure that the study is being done properly, 
•
Government agencies and public health authorities, such as the Food and Drug Administration 
(FDA) and the Department of Health and Human Services (DHHS).
Those persons who get your health information may not be required by Federal privacy laws (such as the 
Privacy Rule) to protect it.  Some of those persons may be able to share your information with others 
without your separate permission.
The results of this study may also be used for teaching, publications, or presentation at scientific meetings. 
However, your name and personal information will not be used.
Although you may revoke consent to participation in this research at any time and in any format, you must 
revoke authorization for use or disclosure of your health information in writing. To revoke your 
authorization, write to:
Dr. Apkar Vania Apkarian, PhD
Department of Physiology
300 E. Superior Street, Room 7-705
Chicago, Illinois 60611
tel. (312) 503-0404
You do not have to authorize the use or disclosure of your health information; however, you will not be 
allowed to take part in this research study. If you do not authorize the use or disclosure of your health 
information, it will not affect your treatment by health care providers, or the payment or enrollment in any 
health plans, or affect your eligibility for benefits.
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Optional Elements:
The following research activities are optional, meaning that you do not have to agree to them in 
order to participate in the research study. Please indicate your willingness to participate in these 
optional activities by placing your initials next to each activity.
________   The researcher may contact me in the future to see whether I am interested in participating in 
other research studies such as saliva collection.
Consent Summary: 
I have read this consent form and the research study has been explained to me. I have been given time to ask 
questions, and have been told whom to contact if I have more questions.  I agree to be in the research study 
described above. A copy of the consent form will be provided to me after I sign it.  
A copy of this signed consent document, information about this study and the results of any test or procedure 
done may be included in my medical record and may be seen by my insurance company.
Your signature documents your permission to take part in this research.
Signature of participant
Date
Printed name of participant
Signature of person obtaining consent
Date
Printed name of person obtaining consent
 Time of consent: _______________
IRB #: STU00081444-MOD0033 Approved by NU IRB for use on or after 4/27/2017 through 6/5/2017.