Clinical trial NCT03302416
Conditions: Healthy
Sponsor: University of Pittsburgh
Start date: 2016-06-01; Completion date: 2019-06-01
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To determine if \[C-11\]NOP-1A receptor binding (VT) can be altered by an intravenous hydrocortisone (cortisol) challenge through CRF-NOP interactions

Detailed description:
Examines changes in \[C-11\]NOP-1A pharmacokinetics caused by an intravenous hydrocortisone challenge (1 mg/kg)

Arms: arm 1: Baseline condition and Post-hydrocortisone (1 mg/Kg, intravenous) condition
Interventions: intervention 1: Hydrocortisone intervention 2: [C-11]NOP-1A
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
COVER PAGE 
 
NCT number: 03302416 
 
Official Title: In Vivo Imaging of Corticotropin-releasing Factor - 
Nociceptin Receptor Interactions 
 
  
 
 
 
Document date: 11/13/2018 


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Section: Triage
     [reviewer notes¬] 
Provide a short title for this study 
Provide a short title for this study (200 characters or less):
CRF – nociceptin receptor interactions
CRF – nociceptin receptor interactions 
T1.0
T1.0
Select the type of application:
Select the type of application:
New Research Study  
 
T2.0
T2.0
Is the proposed research study limited to the inclusion of deceased individuals?
Is the proposed research study limited to the inclusion of deceased individuals? 
* No
T2.1
T2.1
Are any research activities being conducted at the VA Pittsburgh Healthcare
Are any research activities being conducted at the VA Pittsburgh Healthcare
System or with VA funds?
System or with VA funds? 
* No
 
  
     [reviewer notes¬] 
T3.0
T3.0
What is the anticipated risk to the research participants?
What is the anticipated risk to the research participants?
Greater Than Minimal Risk
 
  


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Section: Cover Sheet
     [reviewer notes¬] 
CS1.0
CS1.0
What is the reason for this submission?
What is the reason for this submission?
New Research Protocol Submission
CS1.1
CS1.1
Has this research study been approved previously by the University of Pittsburgh
Has this research study been approved previously by the University of Pittsburgh
IRB?
IRB?
* 
*  No
CS1.1.1
CS1.1.1
Has this research study (or a substantially similar research study) been previously
Has this research study (or a substantially similar research study) been previously
disapproved by the University of Pittsburgh IRB or, to your knowledge, by any other
disapproved by the University of Pittsburgh IRB or, to your knowledge, by any other
IRB?
IRB?
* 
*  No
  
     [reviewer notes¬] 
CS2.0
CS2.0
Title of Research Study:
Title of Research Study:
In vivo imaging of corticotropin-releasing factor – nociceptin receptor interactions
In vivo imaging of corticotropin-releasing factor – nociceptin receptor interactions
CS2.0.1
CS2.0.1
   
Requested approval letter wording:
Requested approval letter wording:
CS2.1
CS2.1
Research Protocol Abstract:
Research Protocol Abstract:
Basic investigations postulate that an imbalance between neurotransmitters regulating the
stress and anti-stress systems underlie negative reinforcement and relapse in addiction.
Nociceptin, which binds to the nociceptin/orphanin FQ peptide (NOP) receptor, is one such
neuropeptide transmitter that exerts its anti-stress effects by counteracting the functional
effects of corticotropin-releasing factor (CRF), the primary stress-mediating neuropeptide
transmitter in the brain. Basic investigations suggest that CRF and nociceptin facilitate and
inhibit anxiety-like behaviors, respectively. Convergent with this is data from animal models of
alcoholism that support increased CRF and decreased nociceptin levels in the extended
amygdala as the reason for anxiety-like behaviors that underlie relapse in addiction. This
postulation is further supported by the ability of CRF1 receptor antagonists and NOP receptor
agonists to blunt the reinforcing and motivational effects of alcohol on a range of addictive
behaviors. Thus, it is of considerable interest to develop a methodology to examine CRF-NOP
interactions in human addicts. Here, we will evaluate healthy humans with [C-11]NOP-1A and
PET to determine if hydrocortisone-induced increases in amygdala CRF leads to altered NOP
receptor binding. This experiment will for the ﬁrst time document an in vivo interaction between
CRF and NOP, and set the stage for evaluating if this interaction is abnormal in addiction in
future investigations.
 
 


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CS2.2
CS2.2
Select the category that best describes your research:
Select the category that best describes your research:
Biomedical research
     [reviewer notes¬] 
CS3.0
CS3.0
Name of the Principal Investigator:
Name of the Principal Investigator:
Rajesh Narendran
Note: Adjunct faculty of the University, including lecturers and instructors, are not permitted
to serve as a PI or Faculty Mentor but may serve as co-investigators. Refer to Chapter 4 on
the HRPO website for more information.
CS3.1
CS3.1
Afﬁliation of Principal Investigator:
Afﬁliation of Principal Investigator:
UPitt faculty member 
 
If you chose any of the Pitt options
Pitt options, please indicate the speciﬁc campus:
Main Campus - Pittsburgh
 If you chose the UPitt faculty member option, provide the PI’s University Faculty Title:
Associate Professor  
CS3.2
CS3.2
Address of Principal Investigator:
Address of Principal Investigator:
UPMC Presbyterian, B938
200 Lothrop Street
Pittsburgh, PA 15213 
CS3.3
CS3.3
Recorded Primary Afﬁliation of the Principal Investigator:
Recorded Primary Afﬁliation of the Principal Investigator:
U of Pgh | School of Medicine | Psychiatry 
CS3.4
CS3.4
Identify the School, Department, Division or Center which is responsible for
Identify the School, Department, Division or Center which is responsible for
oversight of this research study:
oversight of this research study:
U of Pgh | School of Medicine | Radiology 
 
 
CS3.5
CS3.5
Telephone Number of Principal Investigator:
Telephone Number of Principal Investigator:
412-647-5176 
CS3.6
CS3.6
Recorded Current E-mail Address of Principal Investigator to which all notiﬁcations
Recorded Current E-mail Address of Principal Investigator to which all notiﬁcations


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will be sent:
will be sent:
narendranr@upmc.edu
CS3.7
CS3.7
Fax Number:
Fax Number:
412-647-0700
CS3.8
CS3.8
Does this study include any personnel from Carnegie Mellon University, and/or use
Does this study include any personnel from Carnegie Mellon University, and/or use
any CMU resources or facilities (e.g., Scientiﬁc Imaging and Brain Research Center
any CMU resources or facilities (e.g., Scientiﬁc Imaging and Brain Research Center
(SIBR)?
(SIBR)?
* 
*  No
CS3.9
CS3.9
Is this your ﬁrst submission, as PI, to the Pitt IRB?
Is this your ﬁrst submission, as PI, to the Pitt IRB?  
* 
*  No
  
     [reviewer notes¬] 
CS4.0
CS4.0
List of Co-Investigators:
List of Co-Investigators: 
Last
First
Organization
Mason Neale U of Pgh | School of Medicine | Radiology
Mountz James U of Pgh | School of Medicine | Radiology
 
  
  
     [reviewer notes¬] 
CS5.0
CS5.0
Name of Primary Research Coordinator:
Name of Primary Research Coordinator:
Savannah Tollefson
 
 
 
CS5.1
CS5.1
Address of Primary Research Coordinator:
Address of Primary Research Coordinator:
UPMC Presbyterian
PUH-B 938
200 Lothrop Street
Pittsburgh, PA 15213
CS5.2
CS5.2
Telephone Number of Primary Research Coordinator:
Telephone Number of Primary Research Coordinator:
412-586-9888
412-586-9888


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CS6.0
CS6.0
Name of Secondary Research Coordinator:
Name of Secondary Research Coordinator:
Rehima Jordan
CS6.1
CS6.1
Address of Secondary Research Coordinator:
Address of Secondary Research Coordinator: 
 
UPMC Presbyterian
PUH-B 938
200 Lothrop Street
Pittsburgh, PA 15213
CS6.2
CS6.2
Telephone Number of Secondary 
Telephone Number of Secondary Research Coordinator:
Research Coordinator:
 
412-246-5829
CS6.3
CS6.3
Key Personnel/Support Staff (Only list those individuals who require access to
Key Personnel/Support Staff (Only list those individuals who require access to
OSIRIS): 
OSIRIS): 
Last
First
Organization
Antonetti
Kathie
U of Pgh | School of Medicine | Radiology
Flanigan
Margaret U of Pgh | School of Medicine | Radiology
Gertler
Josh
U of Pgh | School of Medicine | Radiology
Himes
Michael
UPMC | Hospital Divisions | Presbyterian/Shadyside | Radiology
Ruszkiewicz James
U of Pgh | School of Medicine | Radiology
Stoughton
Clara
U of Pgh | School of Medicine | Radiology
Tollefson
Savannah U of Pgh
     [reviewer notes¬] 
CS7.0
CS7.0
Will this research study use any Clinical and Translational Research Center (CTRC)
Will this research study use any Clinical and Translational Research Center (CTRC)
resources?
resources?
No
  
     [reviewer notes¬] 
CS8.0
CS8.0
Select the entity responsible for scientiﬁc review.
Select the entity responsible for scientiﬁc review.
 
External Scientiﬁc Review Completed
External Scientiﬁc Review Completed – The scientiﬁc merit of this research protocol
scientiﬁc merit of this research protocol
has been conﬁrmed
has been conﬁrmed by an external scientiﬁc review committee as a condition of funding. 
 
  
     [reviewer notes¬] 
CS9.0
CS9.0
Does this research study involve the administration of an investigational drug or
Does this research study involve the administration of an investigational drug or
an FDA-approved drug that will be used for research purposes?
an FDA-approved drug that will be used for research purposes?
* Yes  


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CS9.1
CS9.1
Do you plan to utilize the Investigational Drug Service (IDS) to dispense the
Do you plan to utilize the Investigational Drug Service (IDS) to dispense the
drug?
drug? 
* Yes
 
CS10.0
CS10.0
Is this research study being conducted under a University of Pittsburgh-based,
Is this research study being conducted under a University of Pittsburgh-based,
sponsor-investigator IND or IDE application?
sponsor-investigator IND or IDE application?
 
* 
*  No 
If YES, you are required to submit the IND or IDE application and all subsequent FDA
correspondence through the Ofﬁce for Investigator-Sponsored IND and IDE Support (O3IS). 
Refer to applicable University policies posted on the O3IS website  (www.O3IS.pitt.edu).
  
     [reviewer notes¬] 
CS11.0
CS11.0
Use the 'Add' button to upload one or more of the following:
Use the 'Add' button to upload one or more of the following:
the sponsor protocol (including investigator initiated studies) and/or
the sponsor protocol (including investigator initiated studies) and/or
other brochures
other brochures
the multi-center protocol and consent form template, 
the multi-center protocol and consent form template, if applicable
if applicable
Name Modiﬁed Date
Is this research study supported in whole or in part by industry?  This includes
Is this research study supported in whole or in part by industry?  This includes
the provision of products (drugs or devices).  
the provision of products (drugs or devices).  
 
* 
*  No
Is this a multi-centered study?
Is this a multi-centered study?
* 
*  No
 
 
     [reviewer notes¬] 
CS12.0
CS12.0
Does your research protocol involve the evaluation or use of procedures that emit
Does your research protocol involve the evaluation or use of procedures that emit
ionizing radiation?
ionizing radiation?
* 
*  Yes 
HUSC GUIDANCE 
HUSC GUIDANCE 
REQUIREMENTS FOR THE REVIEW OF HUMAN SUBJECT RESEARCH PROTOCOLS BY
REQUIREMENTS FOR THE REVIEW OF HUMAN SUBJECT RESEARCH PROTOCOLS BY
THE 
THE 
HUMAN USE SUBCOMMITTEE (HUSC), RADIATION SAFETY COMMITTEE
HUMAN USE SUBCOMMITTEE (HUSC), RADIATION SAFETY COMMITTEE


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(effective 7/1/2018)
For Research Protocols Involving the Use or Evaluation of Diagnostic or Therapeutic
Diagnostic or Therapeutic
Procedures
Procedures that Emit Ionizing Radiation: 
• Formal HUSC review/approval is required if the:
1. research protocol involves the use or the evaluation (i.e., for safety and/or
effectiveness) of a radioactive agent or a device that is not currently FDA-approved for
commercial marketing; including radioactive drugs or devices that are the subject of a
FDA-accepted IND or IDE application or approved for clinical investigations under the
FDA’s Radioactive Drug Research Committee (RDRC) process. 1
2. research protocol addresses (i.e, in the objectives or speciﬁc aims) the evaluation (i.e.,
for safety and/or effectiveness) or involves the use of a FDA-approved
radiopharmaceutical or device-associated procedure for an “experimental” indication or
using “experimental” procedures (i.e., an indication or procedures that are not consistent
with standard clinical practice or the current FDA-approved product labeling). 1
Note: HUSC review/approval is not required for research protocols that involve
the use of diagnostic procedures being performed, in a manner and frequency
that are consistent with standard clinical practice, for subject screening or to
evaluate the outcome of a treatment regimen. This would include diagnostic
procedures for off-label uses that are routinely performed in clinical practice. 1,2,3
Note: HUSC review/approval is not required for research protocols that involve
the use of therapeutic procedures being performed in a manner and frequency
that is consistent with standard clinical practice. 1,2,3
3. research protocol involves the enrollment of individuals (e.g., healthy volunteers) who
will not be undergoing the procedure in association with the diagnosis or treatment of a
disease or condition. 1
For Humanitarian Use Devices: 
• Formal HUSC review/approval is required for all Humanitarian Use Devices that emit ionizing
radiation.
For any questions related to these requirements or their application, contact the Chair of the
HUSC (412-647-0736) or the University’s Radiation Safety Ofﬁcer (412-624-2728).
1 All research protocols wherein the parameters (e.g., dose, dosing frequency) for performing
the procedure(s) that emit ionizing radiation are deﬁned in the protocol must include an
Authorized User (i.e., a physician or dentist who has expertise and who is credentialed in the
respective medical specialty) as a listed co-investigator; i.e., so as to ensure adequate
notiﬁcation and respective compliance with the protocol. 
2 The risks of radiation exposure associated with the diagnostic or therapeutic procedure must
continue to be addressed in the protocol and consent form using the standard, HUSC-accepted
wording. (For diagnostic procedures refer to the University Human Research Protection Ofﬁce
website – www.hrpo.pitt.edu: A-Z Guidance/Radiation Guidance. For therapeutic procedures,
address the speciﬁc risks currently known to be associated with the respective procedure.
3 The University of Pittsburgh IRB, at its discretion, may request formal HUSC review of the
research protocol.
CS12.1
CS12.1
After reviewing the HUSC guidance above, does your research protocol require
After reviewing the HUSC guidance above, does your research protocol require
HUSC review?
HUSC review? (Note: University of Pittsburgh’s Radiation Safety Committee oversight is
 


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limited UPMC Presbyterian-Shadyside, Magee Women’s Hospital of UPMC, Children’s Hospital of
Pittsburgh-UPMC, and Hillman Cancer Center.  If other sites, you will be required to obtain
approval from your radiation safety ofﬁcer.  Please contact askirb@pitt.edu for more
information.)
Yes 
Upload Radiation Forms:
Name
Modiﬁed Date
Narendran NOP Corticotropin
3/16/2016 3:08 PM
Updated dosimetry Table
3/30/2016 8:29 PM
CS13.0
CS13.0
Does this research study involve the deliberate transfer of recombinant or
Does this research study involve the deliberate transfer of recombinant or
synthetic nucleic acid molecules into human subjects?
synthetic nucleic acid molecules into human subjects?
 
* 
*  No
Upload Appendix M of NIH Guidelines:
Name
Modiﬁed Date
 
CS14.0
CS14.0
Are you using UPMC facilities and/or UPMC patients during the conduct of your
Are you using UPMC facilities and/or UPMC patients during the conduct of your
research study?
research study?
 
* 
*  Yes 
If Yes, upload completed Research Fiscal Review Form:
Name
Modiﬁed Date
FRIAR PRO16030242.docx
3/18/2016 3:25 PM
  
     [reviewer notes¬] 
CS15.0
CS15.0
Indicate the sites where research activities will be performed
Indicate the sites where research activities will be performed
and/or private information will be obtained.
and/or private information will be obtained.
Choose all sites that apply and/or use Other
Other to include sites not listed:
Sites:
University of Pittsburgh
UPMC
 
University of Pittsburgh
University of Pittsburgh
Campus:
Main Campus - Pittsburgh
List university owned off-campus research sites if applicable:


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UPMC
UPMC 
Sites:
UPMC Presbyterian
UPMC Western Psychiatric Institute & Clinic
 
 
 
If you selected School
School, International
International or Other
Other, list the sites:
 
*For research being conducted at non Pitt or UPMC sites, upload a
For research being conducted at non Pitt or UPMC sites, upload a
site permission letter granting the researcher permission to
site permission letter granting the researcher permission to
conduct their research at each external site:
conduct their research at each external site:
Name Modiﬁed Date
 
CS15.1
CS15.1
Have you, 
Have you, Rajesh Narendran
Rajesh Narendran , veriﬁed that all members of the
, veriﬁed that all members of the
research team have the appropriate expertise, credentials, and if
research team have the appropriate expertise, credentials, and if
applicable, hospital privileges to perform those research
applicable, hospital privileges to perform those research
procedures that are their responsibility as outlined in the IRB
procedures that are their responsibility as outlined in the IRB
protocol?
protocol?
* 
*  Yes
 
CS15.2
CS15.2
Describe the availability of resources and the adequacy of the
Describe the availability of resources and the adequacy of the
facilities to conduct this study:
facilities to conduct this study:
* 
*  UPMC Presbyterian MRI Center: for MR scans.
UPMC Presbyterian PET Center: for PET scans, protected servers for data
security, storage and distribution of data and biologic samples. 
PET Ofﬁce Space: for screening patients and controls.
UPMC Prebyterian University Hospital ED: for medical emergency
management that may arise in subjects during conduct of research.
 
  
     [reviewer notes¬] 
CS16.0
CS16.0
Special Research Subject Populations: 
Special Research Subject Populations: 
Categories
None
     [reviewer notes¬] 


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CS17.0
CS17.0
Does your research involve the experimental use of any type of human stem cell?
Does your research involve the experimental use of any type of human stem cell?
* 
*  No
 
     [reviewer notes¬] 
 
NIH Deﬁnition of a Clinical Trial
NIH Deﬁnition of a Clinical Trial
A research study
A research study11 in which one or more human subjects
 in which one or more human subjects22 are prospectively
 are prospectively
assigned
assigned3 to one or more interventions
 to one or more interventions44 (which may include placebo or other
 (which may include placebo or other
control) to evaluate the effects of those interventions on health related
control) to evaluate the effects of those interventions on health related
biomedical or behavioral outcomes.
biomedical or behavioral outcomes.5
1 See Common Rule deﬁnition of research at 45 CFR 46.102(d) .
2 See Common Rule deﬁnition of human subject at 45 CFR 46.102(f) .
3 The term “prospectively assigned” refers to a pre-deﬁned process (e.g., randomization)
speciﬁed in an approved protocol that stipulates the assignment of research subjects
(individually or in clusters) to one or more arms (e.g., intervention, placebo, or other
control) of a clinical trial.
4 An intervention is deﬁned as a manipulation of the subject or subject’s environment for
the purpose of modifying one or more health-related biomedical or behavioral processes
and/or endpoints.  Examples include:  drugs/small molecules/compounds; biologics;
devices; procedures (e.g., surgical techniques); delivery systems (e.g., telemedicine,
face-to-face interviews); strategies to change health-related behavior (e.g., diet,
cognitive therapy, exercise, development of new habits); treatment strategies;
prevention strategies; and, diagnostic strategies.
5 Health-related biomedical or behavioral outcome is deﬁned as the pre-speciﬁed goal(s)
or condition(s) that reﬂect the effect of one or more interventions on human subjects’
biomedical or behavioral status or quality of life.  Examples include:  positive or negative
changes to physiological or biological parameters (e.g., improvement of lung capacity,
gene expression); positive or negative changes to psychological or neurodevelopmental
parameters (e.g., mood management intervention for smokers; reading comprehension
and /or information retention); positive or negative changes to disease processes;
positive or negative changes to health-related behaviors; and, positive or negative
changes to quality of life.
CS18.0
CS18.0
* 
* Based on the above information, does this study meet the NIH deﬁnition of a
Based on the above information, does this study meet the NIH deﬁnition of a
clinical trial?
clinical trial?
  
Yes
Yes 
No 
 
 
If Yes, click Save and then Click Here For Study Team's CITI Training Records .  Please ensure all
personnel's training is up to date


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Section: Section 1 - Objective, Aims, Background and Signiﬁcance
     [reviewer notes¬] 
1.1
1.1
Objective: What is the overall purpose of this research study?
Objective: What is the overall purpose of this research study?  (Limit response to 1-
2 sentences.)
To develop an imaging methodology to examine corticotropin-releasing factor (CRF)-nociceptin
receptor (NOP) interactions in humans. 
 
 
1.2
1.2
Speciﬁc Aims: List the goals of the proposed study (e.g., describe the relevant
Speciﬁc Aims: List the goals of the proposed study (e.g., describe the relevant
hypotheses or the speciﬁc problems or issues that will be addressed by the
hypotheses or the speciﬁc problems or issues that will be addressed by the
study).
study).
Aim 1: To determine if [C-11]NOP-1A receptor binding (VT) can be altered by an intravenous
hydrocortisone (cortisol) challenge through CRF-NOP interactions. 
In rodents, an injection of CRF into the lateral cerebroventricle results in increased NOP receptor
expression (Rodi et al., 2008). We will test the existence of such an interaction in 20 healthy
human subjects by measuring [C-11]NOP-1A VT under control conditions and following the
administration of intravenous cortisol (hydrocortisone, 1 mg/kg). Note: Intravenous CRH is not
used as a challenge, because it is not transported from the blood to the brain (Martins et al.,
1996). Intravenous hydrocortisone (1mg/kg) will be used as the challenge, because in vivo
microdialysis studies in sheep have demonstrated that it can cross the blood-brain barrier and
increase CRF levels in the amygdala by ~ 200% (Cook, 2002; Schwartz et al., 1972).
Hydrocortisone increases amygdala CRF levels via its action on type 2 glucocorticoid receptors
(Cook, 2002). 
The hypothesis is that hydrocortisone-induced increases in amygdala CRF will result in higher [C-
11]NOP-1A VT. This would suggest that transmission at NOP receptors is increased to
counteract hydrocortisone’s activation of CRF and the brain stress system. If successful, future
studies will be proposed with this hydrocortisone- [C-11]NOP-1A PET imaging paradigm to
examine CRF-NOP interactions in addictive disorders. 
 
1.3
1.3
Background: Brieﬂy describe previous ﬁndings or observations that provide the
Background: Brieﬂy describe previous ﬁndings or observations that provide the
background leading to this proposal.
background leading to this proposal. 
A1. Nociceptin: a functional CRF antagonist
The endogenous neuropeptide, nociceptin, and its target NOP receptor are structurally similar
to dynorphin A and its target kappa opioid receptors (Meunier et al., 1995; Reinscheid et al.,
1995). However, nociceptin has no afﬁnity for the classical mu, kappa and delta opioid
receptors, and endogenous opioids, such as endorphins, enkephalins, dynorphin, etc., do not
bind to the NOP receptor. Nociceptin and neuropeptide Y are postulated to be components of
an anti-stress system in the brain that counteracts stress and anxiety, which is typically
mediated by CRF, norepinephrine, orexin, vasopressin and dynorphin (Koob, 2008). Consistent
with this notion, nociceptin has been shown to block stress-induced analgesia, anorexia, and
anxious behaviors in rodents (Ciccocioppo et al., 2002; Jenck et al., 1997; Mogil et al., 1996).
Also, nociceptin knockout mice show increased anxiety-like behaviors and are unable to adapt
to repeated stress, compared to wild-type mice (Koster et al., 1999). 
Nociceptin also has no appreciable afﬁnity for CRF receptors. However, nociceptin has been
shown to oppose the functions of extra-hypothalamic CRF and, thus, exert an anti-stress effect
(Ciccocioppo et al., 2004a). Studies have convincingly demonstrated that the administration of
nociceptin in the extended amygdala inhibits CRF -induced anorexia and anxiety-like symptoms
in rodents (Ciccocioppo et al., 2002; Ciccocioppo et al., 2004a; Ciccocioppo et al., 2003;
Ciccocioppo et al., 2001; Rodi et al., 2008). Furthermore, studies that have evaluated restraint-
 


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stress in rodents show an ~ 70% increase in NOP receptor protein expression in the extended
amygdala to counteract increases in CRF (Ciccocioppo et al., 2014a). This increase in NOP
receptor expression is detectable in animals ~ 6 hours following exposure to restraint stress.
However, this increase in NOP receptors is not detectable 20 minutes following restraint stress
(personal communication with Dr. Ciccocioppo), and is not accompanied by changes in the
endogenous nociceptin (Ciccocioppo et al., 2014a). This suggests that the restraint-stress
induced increase in amygdala NOP receptors is not due to endogenous competition between the
ligand and the receptor site, but rather indicative of new receptor synthesis or recycling of
internalized receptors to the cell membrane. Increased NOP receptor expression is likely an
adaptive response to stress. Consistent with this nociceptin has been shown to block CRF-
induced increases in GABAA mediated inhibitory postsynaptic potential (IPSP) more strongly in
restraint stress animals with increased NOP receptors compared to control animals (Ciccocioppo
et al., 2014a). In a more direct documentation of CRF-NOP interactions, an injection of CRF into
the lateral cerebroventricle led to a 2-fold increase in NOP receptor expression in the bed
nucleus of the stria terminalis (BNST) after six hours (Rodi et al., 2008). Again, consistent with
the notion that increased NOP receptor expression is an adaptive response to increased
CRF/stress, an injection of nociceptin into the BNST (or lateral cerebroventricle) blocked CRF-
induced anxiety-like behaviors (Rodi et al., 2008). Based on these data, it is tempting to
speculate that abnormal CRF-NOP interactions underlie the anxiety-like symptoms in several
psychiatric and addictive disorders. For example, it is possible that the inability to effectively
upregulate NOP receptors to counteract increased CRF in stress-related conditions might be
predictive of risk and relapse in alcoholism. It may also be predictive of risk for anxiety disorders
such as post-traumatic stress disorder –another disorder in which both the CRF and NOP
receptors have been implicated (Zhang et al., 2012). Finally, there are other non-CRF mediated
mechanisms that contribute to the anti-stress effects of nociceptin as well. They include its
ability to modulate the release of multiple neurotransmitters including dopamine, serotonin,
acetylcholine, glutamate and GABA via stimulation of NOP receptors that are located pre-
synaptically on the axon terminals of these neurons (Schlicker and Morari, 2000). These non-
CRF mechanisms will not be the focus of this application.
A2. CRF-NOP interactions: relevance in addiction
The three phases of addiction are intoxication, withdrawal and craving. In contrast to dopamine
release that drives positive reinforcement in the intoxication phase, an imbalance between the
brain stress (CRF, orexin, vasopressin and dynorphin) and anti-stress systems (neuropeptide Y
and nociceptin) has been postulated to drive negative reinforcement in the withdrawal and
craving phases (Koob, 2008). Studies by Koob and colleagues have demonstrated that
neurotransmitters in the brain stress and anti-stress systems work in series or in parallel in the
extended amygdala to impact emotional states and contribute to relapse. Within the extended
amygdala, stress-mediators such as CRF increase GABAA inhibitory post-synaptic potentials
(IPSCs), whereas anti-stress mediators such as nociceptin decrease GABAA IPSCs (Roberto and
Siggins, 2006). Because most neurons in the extended amygdala are GABA-ergic inhibitory
interneurons or projection neurons, the GABA-ergic tone in this region regulates the ﬂow of
information through the intra-amygdala circuits. This in turn inﬂuences both local and output
neurons to downstream regions that mediate a behavioral response. To summarize, stimulation
of CRF receptors: increases GABA transmission in the extended amygdala; promotes anxiety-like
behaviors; and increases alcohol consumption (Roberto et al., 2010). In contrast, stimulation of
NOP receptors: blocks CRF-induced increases in GABA transmission in the extended amygdala;
diminishes anxiety; and prevents conditioned reinstatement in animals that self-administer
alcohol (Ciccocioppo et al., 2014a; Ciccocioppo et al., 2004b; Cruz et al., 2012; Rodi et al.,
2008). These basic studies have led investigators to postulate a therapeutic role for increasing
transmission at NOP receptors to counteract an overactive CRF system and, by extension, block
negative reinforcement and stress-induced relapse in alcoholism (Witkin et al., 2014).
Furthermore, intracerebroventricular administration of nociceptin has also been shown to


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attenuate positive reinforcement by reducing mesolimbic DA release following a drug reward
(cocaine and morphine). Microdialysis studies have demonstrated decreased cocaine- and
morphine- induced DA release in the nucleus accumbens following intra- ventral tegmental area
(VTA) and intra-nucleus accumbens nociceptin administration (Di Giannuario and Pieretti, 2000;
Di Giannuario et al., 1999; Lutfy et al., 2001; Murphy et al., 1996; Vazquez-DeRose et al.,
2013). It is likely that nociceptin directly modulates midbrain DA neurons to impact DA release
because 50-90% of tyrosine hydroxylase positive cells (TH +) in the VTA (and substantia nigra)
express NOP receptors (Maidment et al., 2002; Norton et al., 2002). Alternatively, an effect for
pre-synaptic NOP receptors on DA terminals cannot be ruled out because administration of
nociceptin into the nucleus accumbens reduces DA release as well (Vazquez-DeRose et al.,
2013). The mechanisms by which nociceptin can both block negative reinforcement via CRF
antagonism and attenuate positive reinforcement via reduction in mesolimbic DA transmission in
rodent addiction models make it an attractive therapeutic target to pursue in human addicts.
Increased transmission at NOP receptors not only blocks the rewarding properties of alcohol in
the conditioned place preference behavioral paradigm (Ciccocioppo et al., 1999; Kuzmin et al.,
2009), but also reduces alcohol consumption (Ciccocioppo et al., 1999). It is also effective in
preventing the somatic and affective signs of alcohol withdrawal in alcohol-dependent rodents
during both acute and protracted withdrawal (Economidou et al., 2011). Highly relevant to the
clinic is its ability to block cue- and stress-induced alcohol reinstatement following prolonged
abstinence in rodent models of alcoholism (Ciccocioppo et al., 2004b; Martin-Fardon et al.,
2000). Most of the aforementioned studies were conducted in rodents that prefer and
consume large amounts of alcohol. These alcoholic animals demonstrate increased NOP receptor
expression (mRNA) and receptor density (Bmax) in the extended amygdala, ventral tegmental
area (VTA), and cortex compared to controls (Economidou et al., 2008). Thus, it is tempting to
speculate that an increase in NOP receptors in alcohol-preferring rodents is a compensatory
adaptation to increased CRF and related stress in alcoholism. This is supported by studies that
show increasing NOP receptor mediated transmission by an injection of nociceptin into the CeA
will suppress alcohol self-administration (Economidou et al., 2008; Gustafsson et al., 2005).
The only human study to date that has evaluated NOP receptors in postmortem brains found a
1.4-fold reduction in NOP receptor mRNA in the CeA in alcoholics compared to controls (Kuzmin
et al., 2009). No such differences were evidenced in the hippocampus and prefrontal cortex.
These human data are in sharp contrast to the upregulation of NOP receptors reported in
alcohol preferring rodents. The exact reasons for the discrepancy between rodent and human
results with respect to NOP receptor gene expression are unclear. One possibility is that
decreased NOP receptor expression may indicate a failure to adequately compensate for
increased CRF transmission in human alcoholics with more severe and chronic disease relative to
that in the alcohol-preferring rodents. This would indicate a more effective compensatory
upregulation of NOP receptors in response to increased CRF transmission in alcohol-preferring
rodents. Finally, the importance of abnormalities in nociceptin and NOP receptors is further
highlighted by data from genetic studies that support a link between alcoholism and
polymorphisms in the genes encoding for them (Huang et al., 2008; Xuei et al., 2008). A major
gap in the existing addiction literature is that no in vivo methodology exists to examine CRF-
NOP interactions. Thus, the development of a methodology to examine CRF-NOP interactions in
vivo in the living human brain will have a major impact in understanding addictive disorders in
which stress is linked to relapse. 
A3. Imaging of NOP receptors with [C-11]NOP-1A and PET 
In a major advancement, the imaging group at NIMH recently radiolabeled and successfully
validated a NOP receptor antagonist radiotracer [C-11] (S)-3-(2'-ﬂuoro-6',7'-
dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran]-1-yl)-2-(2-ﬂuorobenzyl)-N-methylpropanamide
(NOP-1A) for use in humans (Pike et al., 2011). [C-11]NOP-1A binds with relatively high afﬁnity
to NOP receptors (KD, 0.15 nM). [C-11]NOP-1A total uptake in various brain regions (VT) is
consistent with the known distribution of NOP receptors in human and primate brain (relatively


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high density in amygdala, striatum and cerebral cortex; and moderate density in cerebellum and
midbrain) (Berthele et al., 2003; Bridge et al., 2003; Kimura et al., 2011; Lohith et al., 2012).
Blocking studies in primates with the speciﬁc NOP receptor antagonist SB-612111 (KD 0.33
nM, 1mg/kg intravenously) indicate that 50-70% of [C-11]NOP-1A VT in brain regions
represents speciﬁc binding to NOP receptors (Kimura et al., 2011). [C-11]NOP-1A
demonstrates desirable pharmacokinetics in humans: brain uptake peaks relatively quickly (~ 10
min) and washes out rapidly; brain data is modeled well by a 2-tissue compartment kinetic
analysis; VT values in brain regions range from 7 to 15; VT remains stable following 70 min of
data acquisition; and the test-retest variability for VT is an acceptable ≤ 15% in all brain regions
(Lohith et al., 2014; Lohith et al., 2012).
[C-11]NOP-1A has been administered to approximately 50 subjects at the University of
Pittsburgh PET facility by the PI in his prior research studies. Subject populations that it has
been administered to include healthy subjects, alcoholics, cocaine addicts and PTSD subjects.
To date no adverse reactions have been reported with its use. 
A4. Summary: A wealth of pre-clinical literature implicates the stress and anti-stress
neuropeptides CRF and nociceptin in negative reinforcement and relapse in alcoholism. If the
proposed experiments were successful in showing increased NOP receptor binding in response
to greater amygdala CRF levels induced by a hydrocortisone challenge, this would support the
use of this imaging paradigm to examine in vivo interactions between CRF and NOP in humans.
Such results would have far reaching implications in efforts to characterize the brain stress and
anti-stress systems in addiction (Koob, 2008)., and other psychiatric disorders (e.g., post-
traumatic stress disorder, major depression, etc.,). Characterizing CRF-NOP interactions in
humans with drug and alcohol use disorders is an important step in informing the ﬁeld of the
therapeutic potential for CRF antagonist and NOP agonist medications to treat addiction. For
example, if we show that there is a smaller compensatory increase in NOP receptors in response
to CRF release in alcoholics compared to controls, this would support the clinical development
of novel NOP agonist compounds (MT-7716 and Ro 64-6198) that have shown promise in
rodent models of alcoholism (Ciccocioppo et al., 2014b; de Guglielmo et al., 2014; Kallupi et al.,
2014; Kuzmin et al., 2007). 
 
1.4
1.4
Signiﬁcance: Why is it important that this research be conducted? What gaps in
Signiﬁcance: Why is it important that this research be conducted? What gaps in
existing information or knowledge is this research intended to ﬁll?
existing information or knowledge is this research intended to ﬁll? 
A major gap in the existing addiction literature is that no in vivo methodology exists to examine
the interactions between corticotropin-releasing factor and nociceptin receptors in humans. The
availability of an imaging paradigm to examine these interactions would have far reaching
implications in characterizing the role of stress and anti-stress neuropeptides in addiction and
other psychiatric disorders.
  


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Section: Section 2 - Research Design and Methods
     [reviewer notes¬] 
2.1
2.1
Does this research study involve the 
Does this research study involve the use
use or evaluation of a drug, biological, or
 or evaluation of a drug, biological, or
nutritional (e.g., herbal or dietary) supplement?
nutritional (e.g., herbal or dietary) supplement?
* 
*  Yes
2.1.1
2.1.1
Does this research study involve an evaluation of the safety and/or effectiveness
Does this research study involve an evaluation of the safety and/or effectiveness
of one or more marketed nutritional (e.g., herbal or dietary) supplements for the
of one or more marketed nutritional (e.g., herbal or dietary) supplements for the
diagnosis, prevention, mitigation or treatment of a speciﬁc disease  or condition or
diagnosis, prevention, mitigation or treatment of a speciﬁc disease  or condition or
symptoms characteristic of a specﬁc disease or condition?
symptoms characteristic of a specﬁc disease or condition?
* No
  
     [reviewer notes¬] 
2.1.2
2.1.2
Does this research study involve the use or evaluation of one or more drugs or
Does this research study involve the use or evaluation of one or more drugs or
biologicals 
biologicals not
not currently approved by the FDA for general marketing?
 currently approved by the FDA for general marketing?
* 
*  Yes
2.1.2.1
2.1.2.1
List 
List each
each of the unapproved drugs or biologicals being used or evaluated in this
 of the unapproved drugs or biologicals being used or evaluated in this
research study. 
research study. 
Specify for 
Specify for each listed
each listed drug or biological the corresponding IND number, HUSC
 drug or biological the corresponding IND number, HUSC
(RDRC) number (for applicable radioactive drugs):
(RDRC) number (for applicable radioactive drugs):
 
Drug/biologic
IND #
HUSC #
View [C-11]NOP-1A
 
HUSC 0725
 
  
     [reviewer notes¬] 
2.1.3
2.1.3
Does this research involve the 
Does this research involve the use 
use or an evaluation of the effectiveness and/or
or an evaluation of the effectiveness and/or
safety of one or more drugs or biologicals currently approved by the FDA for
safety of one or more drugs or biologicals currently approved by the FDA for
general marketing? 
general marketing? 
* 
*  Yes 
 
 
 
2.1.3.1
2.1.3.1
Are the FDA-approved drugs or biologicals being evaluated in this research study
Are the FDA-approved drugs or biologicals being evaluated in this research study
for a new clinical indication, different population, or route of administration
for a new clinical indication, different population, or route of administration
and/or dosage level that is not currently speciﬁed in the FDA-approved product
and/or dosage level that is not currently speciﬁed in the FDA-approved product


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labeling?
labeling?
Drugs are often used Off-Label
Off-Label during routine practice.  Before answering this question,
review the FDA product labeling (http://labels.fda.gov) for the approved "Indications and
Usage."  If being used off-label, answer Yes
Yes to this question.  You are required to provide
information and/or upload the package insert for each drug that is administered for research
purposes.
* Yes 
If you respond YES
YES, an IND number or the FDA written concurrence of IND exemption may be
required.
2.1.3.1.1
2.1.3.1.1
By using the "Add" button available below, list and specify the following for 
By using the "Add" button available below, list and specify the following for each
each
of the FDA-approved drugs or biologicals being evaluated under this research
of the FDA-approved drugs or biologicals being evaluated under this research
study. 
study. 
Whether data from this research will be reported to the FDA in support of a new
indication for the use of this drug product or to support any other signiﬁcant change in
the labeling (i.e., new indication).  If Yes
Yes, provide the corresponding IND number. 
Whether data from this research will be used to support a signiﬁcant change in the
advertising for this drug product (i.e., new advertisement).  If Yes
Yes, provide the
corresponding IND number.
Whether the proposed 'off-label' evaulation of the approved drug is felt to signiﬁcantly
increase the risks (or decrease the acceptability of risk) compared to the current
approved uses of this drug or biological. If Yes
Yes, provide the corresponding IND number. 
If No
No, provide a justiﬁcation for why the risk is not increased or the acceptablity of risk
is not decreased (i.e., risk justiﬁcation).
 
Approved
Drug/Biologic
New
Indication
New
Advertisement Risk Concern
Risk
Justiﬁcation/No
IND
IND
#
Hydrocortisone IV is approved
by the FDA for a variety of
medical indications: IV
Hydrocortisone (solut-cortef)
is FDA approved to be
administered to (1) Allergic
states: Control of severe or
incapacitating allergic
conditions intractable to
adequate trials of
conventional treatment in
asthma, atopic dermatitis,
contact dermatitis, drug
hypersensitivity reactions,
perennial or seasonal allergic
rhinitis, serum sickness,
transfusion reactions. (2)
Dermatologic diseases:
Bullous dermatitis


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View Intravenous
hydrocortisone no
no
herpetiformis, exfoliative
erythroderma, mycosis
fungoides, pemphigus, severe
erythema multiforme
(Stevens-Johnson syndrome).
(3) Endocrine disorders:
Primary or secondary
adrenocortical insufﬁciency
(hydrocortisone or cortisone
is the drug of choice;
synthetic analogs may be
used in conjunction with
mineralocorticoids where
applicable; in infancy,
mineralocorticoid
supplementation is of
particular importance),
congenital adrenal
hyperplasia, hypercalcemia
associated with cancer,
nonsuppurative thyroiditis.
(4) Gastrointestinal diseases:
To tide the patient over a
critical period of the disease
in regional enteritis (systemic
therapy) and ulcerative
colitis. (5) Hematologic
disorders: Acquired
(autoimmune) hemolytic
anemia, congenital (erythroid)
hypoplastic anemia (Diamond-
Blackfan anemia), idiopathic
thrombocytopenic purpura in
adults (intravenous
administration only;
intramuscular administration
is contraindicated), pure red
cell aplasia, selected cases of
secondary thrombocytopenia.
(6) Miscellaneous: Trichinosis
with neurologic or myocardial
involvement, tuberculous
meningitis with subarachnoid
block or impending block
when used concurrently with
appropriate antituberculous
chemotherapy. (7) Neoplastic
diseases: For the palliative
management of leukemias
and lymphomas. (8) Nervous
System: Acute exacerbations
of multiple sclerosis; cerebral
edema associated with
IV
hydrocortisone
has been
administered to
healthy humans
in a off-label
manner at
doses ≤ 200
mg with no
serious side
effects in
several
previous
research
studies (Jung
et al., 2014;
Symonds et al.,
2012; Wachtel
et al., 2001;
Wachtel and de
Wit, 2001).
Thus, in
administering
hydrocortisone
1 mg/kg IV to
 


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primary or metastatic brain
tumor, or craniotomy. (9)
Ophthalmic diseases:
Sympathetic ophthalmia,
uveitis and ocular
inﬂammatory conditions
unresponsive to topical
corticosteroids. (10) Renal
diseases: To induce diuresis
or remission of proteinuria in
idiopathic nephrotic syndrome
or that due to lupus
erythematosus. (11)
Respiratory diseases:
Berylliosis, fulminating or
disseminated pulmonary
tuberculosis when used
concurrently with appropriate
antituberculous
chemotherapy, idiopathic
eosinophilic pneumonias,
symptomatic sarcoidosis.
(12) Rheumatic disorders: As
adjunctive therapy for short-
term administration (to tide
the patient over an acute
episode or exacerbation) in
acute gouty arthritis; acute
rheumatic carditis; ankylosing
spondylitis; psoriatic arthritis;
rheumatoid arthritis, including
juvenile rheumatoid arthritis
(selected cases may require
low-dose maintenance
therapy). For the treatment
of dermatomyositis, temporal
arteritis, polymyositis, and
systemic lupus
erythematosus. In this study,
we propose to administer
hydrocortisone at a dose of
1mg/kg, IV, (i.e., < 100 mg
because our subjects typically
weight 70-100 Kgs) to
healthy controls to evaluate
interactions between CRF and
nociceptin receptors. This is
far below the FDA approved
maximum IV dose of 500 mg.
Thus, it should not
signiﬁcantly increase (or
decrease the acceptability of
risk) compared to currently
healthy
controls the
risk is not
increased or
acceptability of
risk is not
decreased


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approved uses.
Upload information on FDA approved indications/doses and FDA exemption letter
Upload information on FDA approved indications/doses and FDA exemption letter
if applicable
if applicable:
Name
Modiﬁed Date
Solu-Cortef package
insert.pdf
3/30/2016 3:56
PM
 
  
     [reviewer notes¬] 
2.2
2.2
Will this research 
Will this research use
use or evaluate the safety and/or effectiveness of one or
 or evaluate the safety and/or effectiveness of one or
more devices?
more devices?
 
* 
*  No 
 
  
     [reviewer notes¬] 
2.3
2.3
Summarize the general classiﬁcation (e.g., descriptive, experimental) and
Summarize the general classiﬁcation (e.g., descriptive, experimental) and
methodological design (e.g., observational, cross-sectional, longitudinal,
methodological design (e.g., observational, cross-sectional, longitudinal,
randomized, open-label single-blind, double-blind, placebo-controlled, active
randomized, open-label single-blind, double-blind, placebo-controlled, active
treatment controlled, parallel arm, cross-over arm) of the proposed research
treatment controlled, parallel arm, cross-over arm) of the proposed research
study, as applicable.
study, as applicable.
experimental, open-label
2.3.1
2.3.1
Does this research study involve a placebo-controlled arm?
Does this research study involve a placebo-controlled arm?
* 
*  No
     [reviewer notes¬] 
2.4
2.4
Will any research subjects be withdrawn from known effective therapy for the
Will any research subjects be withdrawn from known effective therapy for the
purpose of participating in this research study?
purpose of participating in this research study?
* 
*  No 
 
  
     [reviewer notes¬] 
2.5
2.5
Will screening procedures (i.e., procedures to determine research subject
Will screening procedures (i.e., procedures to determine research subject
eligibility) be performed speciﬁcally for the purpose of this research study?
eligibility) be performed speciﬁcally for the purpose of this research study?
* 
*  Yes


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2.5.1
2.5.1
List the
List the screening
screening procedures that will be performed for the purpose of this
procedures that will be performed for the purpose of this
research study.  Do NOT include the inclusion/exclusion criteria in this section as
research study.  Do NOT include the inclusion/exclusion criteria in this section as
they will be addressed in section 3; questions 3.13 and 3.14.
they will be addressed in section 3; questions 3.13 and 3.14.
Pre-study visit screening procedures (~6 hours)
Once the written consent has been obtained, all potential participants will undergo a clinical
evaluation, which takes approximately 6 hours to complete and may be done on separate days.
The testing consist of the following:
(1) PET facility screening form to ensure subjects can undergo PET and MRI scans.
(2) Psychiatric evaluation: Structured Clinical Interview for DSM-5 (SCID 5 – research version) will
be used to determine psychiatric diagnoses; As subjects are healthy controls they will only
receive the SCID 5 screening modules (this is the non-patient version). If there is a clinical
suspicion based on these screening modules that the subject may have alcohol use disorder or
cannabis use disorder, or psychosis or major depression, etc., the corresponding modules may
be done to exclude these disorders in healthy controls. The need to do these corresponding
modules will be performed at the PI's discretion based on his review of the screening module;
Time needed: 2 hours
(3) Medical evaluation: We will do a routine physical examination (15 to 20 minutes) and a
medical evaluation with laboratory tests, e.g., EKG, VS, hemoglobin, hematocrit, total leukocyte
with differential, plasma electrolytes, BUN/Cr, liver and thyroid function (TSH level), urinalysis
and toxicology, and serum pregnancy for female subjects of child bearing potential (i.e., females
who have not undergone a surgical sterilization procedure or who are not at least one year post-
menopausal). 
Medical test results will be reviewed prior to study entry. The laboratory tests will not be
repeated if they have been performed within the past six months. [Note that the serum
pregnancy test, and urine toxicology prior to PET scans will not fall into this category]. In
addition, other study measures such as MRIs and cognitive tasks will not be repeated if they
have been performed under another IRB approved Psychiatric Molecular Imaging Program (PMIP)
protocol within the past 6 months. 
(4) Stress and anxiety rating scales:
(a) Perceived stress scale (PSS) (Cohen et al., 1983): A 14-item scale that measures the degree
to which situations in an individual’s life are appraised as stressful.
(b) Hamilton Anxiety Rating Scale (HAM A) (Hamilton, 1959): A 14-item scale that measures
anxiety-like symptoms.
(c) Center for Epidemiological Studies in Depression (CES-D): A 20 item scale that measures
depression.
The records of the subjects who fail screening after signing consent are not destroyed, but
maintained as any subject who continues the research study with the reason for exclusion
mentioned in it. 
All clinical assessments, including the SCID will be administered by research coordinators and co-
investigators as delegated by the PI. The PI will supervise the research coordinators till they are
deemed competent to do it on their own; He will also assist them as questions arise in the
future. 
Screening procedures may be done after initiation or completion of the experimental procedures


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depending on MRI and PET schedules because this is a study that involves healthy controls. For
example, rating scales such as HAM-A, PSS, CES-D, etc., that do not determine a subject's
inclusions/exclusion may be done on the day, or even after scans. It may also involve doing a
MRI before labs, if the subject has no contraindications on the PET/MRI screening. However, a
PET will not be done before completion of the SCID and labs because they are necessary to rule
out low hemoglobin, current psych and drug use disorders etc.)
  
     [reviewer notes¬] 
 
2.6
2.6
Provide a detailed description of all research activities (e.g., all drugs or devices;
Provide a detailed description of all research activities (e.g., all drugs or devices;
psychosocial interventions or measures) that will be performed for the purpose of
psychosocial interventions or measures) that will be performed for the purpose of
this research study. 
this research study. 
This description of activities should be complete and of sufﬁcient detail to permit
an assessment of associated risks.  
At a minimum the description should include:
all research activities
all research activities
personnel (by role) performing the procedures
personnel (by role) performing the procedures
location of procedures
location of procedures
duration of procedures
duration of procedures
timeline of study procedures
timeline of study procedures
All study assessments, and evaluations will be done for research purposes (including any clinical
research) with nothing that falls into the category of 'clinical care'. In this research, subjects will
be studied as detailed below.
DRUG/DEVICE INFORMATION
I). [C-11]NOP-1A
[C-11]NOP-1A is not approved by the FDA for routine clinical use. However, its use in this
research study is considered to be generally safe and effective as determined by the University
of Pittsburgh Radioactive Drug Research Committee (RDRC) in accordance with FDA regulations.
[C-11]NOP-1A will be prepared according to the information and protocols described in the
respective Drug Master File approved by the University of Pittsburgh Radioactive Drug Research
Committee. The amount of radioactivity injected for [C-11]NOP-1A will be 12 mCi/scan based
on previously published reports (Lohith et al., 2012). A radioactive dose of approximately 12
mCi will provide adequate signal to noise ratio to quantify NOP receptors (Lohith et al., 2012).
[C-11]NOP-1A has been previously administered to humans and documented to have “no
pharmacological effects” at the mass dose levels that will be administered (Note: the mass
limits for this study will be the same as in RDRC approved Drug Master File for [C-11]NOP-1A).
II). Intravenous Hydrocortisone, (Solu-Cortef ®) 
Intravenous hydrocortisone is Food and Drug Administration (FDA) approved for steroid-
responsive disorders (e.g., inﬂammation, status asthmaticus, acute adrenal insufﬁciency, etc.)
when oral therapy is not feasible. The hydrocortisone dose and route of administration that we
 


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propose in this research protocol is consistent with the use recommended in its package insert
information (Solu-Cortef®, package insert, http://www.pdr.net/drug-summary/solu-cortef?
druglabelid=1880#3). The proposed dose of hydrocortisone (1mg/kg, IV, i.e., ≤ 100 mg) that
will be used in this imaging study is far below the FDA approved maximum IV dose of 500 mg.
In previously published research studies, IV hydrocortisone has been administered to healthy
humans at doses ≤ 200 mg with no serious side effects (Jung et al., 2014; Symonds et al.,
2012; Wachtel et al., 2001; Wachtel and de Wit, 2001). Intravenous hydrocortisone 1 mg/Kg
will be formulated as listed in the FDA package and dispensed in a ﬁnal volume of 50mL normal
saline by the Investigative Drug Service (IDS). 
STUDY DAYS (EXPERIMENTAL PROCEDURES)
No more than 6 months will be allowed to elapse between the pre-study visit and study visit.
The study will take place over approximately 3 experimental days.
The subject will receive a venous line for infusion of the radiopharmaceutical and an arterial line
for blood sampling.
The entire PET/CT scanning session will require about 8 hours to complete while the study day
could last as long as 10 hours (if the MR and PET are done in the same day). 
In the unlikely event that the experimental PET/CT procedures cannot be completed in a single
day (due to a non-functional MRI scanner, PET camera or cyclotron or any other unavoidable
reason), the subject may be given the option to return within 30 days to complete the study.
On this “completion” day, participant preparation again consists of intravenous and arterial
catheterization. The scanning protocol will continue from the point that the protocol was
aborted on the initial day. No subject will receive more than 2-3 low-dose CT scans, two [C-
11]NOP-1A PET scans and one hydrocortisone challenge, regardless of whether the study is
completed in one or two days. That is, the total radiation exposure over the two-PET scanning
days will not be signiﬁcantly greater than if the entire procedure had been completed in one
day, however the participant would receive an additional intravenous, arterial catheterization,
low-dose CT scan and additional urine drug and pregnancy screens. 
All tests for this research study will be performed at either the MR Research Center (MRRC) on
the 8th ﬂoor of UPMC Presbyterian University Hospital (PUH) or the PET Facility on the 9th ﬂoor
of UPMC PUH (directly above the MRRC).
The goal of the study is to determine if [C-11]NOP-1A receptor binding (VT) can be altered by
an intravenous hydrocortisone (cortisol) challenge through CRF-NOP interactions. Twenty
heathy control subjects will be studied twice with [C-11]NOP-1A before and after an
intravenous hydrocortisone challenge (1 mg/Kg).
SPECIFIC METHODS AND DESIGN
I). MRI Protocol
Structural MRI: All female participants will undergo a urine pregnancy test prior to MRI. Subjects
will undergo an MRI procedure for anatomical localization of regions-of-interest (ROI).
Participants with a questionable history of metallic fragments will not be included in the study.
A single MRI study will be performed prior to the ﬁrst PET study. The MRI examinations will be
conducted on the 8th ﬂoor in the UPMC MRRC, which is located directly below the PET Facility,
using a 3T scanner. A volumetric MPRAGE sequence will provide the anatomical framework for
ROI analysis. This sequence is optimized to maximize the contrast among gray matter, white
matter, and cerebral spinal ﬂuid and provides high-resolution delineation of cortical and


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subcortical structures. Imaging time for this pulse sequence is less than 8 minutes, with total
time for the MRI scan estimated at 30 minutes. MRI data will be transferred to the PET Facility
over the electronic network and co-registered with the PET data on a SUN Workstation using
software routinely used for this purpose (Woods et al., 1992). The registered MRI will be used
as an individualized anatomic map for the selection of ROIs used in the analysis of the PET data.
The MRI might be obtained on the same day as a PET scan when possible to reduce
transportation costs and inconvenience. Finally, the MRI will not be repeated if they have been
performed under another IRB approved Psychiatric Molecular Imaging Program (PMIP) protocol
within the past 6 months. 
II). PET Protocol
PET scans will be acquired at the 9th ﬂoor PET Facility at UPMC PUH using a Siemens PET/CT
(3D acquisition mode) scanner. Each participant will receive both a baseline [C-11]NOP-1A PET
scan and post-hydrocortisone [C-11]NOP-1A PET scan following hydrocortisone administration
in order to examine CRF-NOP receptor interactions.
Subject Preparation:
A). Baseline review of medical and medication history (to document no change from screening).
B). A urine pregnancy test is done on females of child bearing potential (i.e., females who have
not undergone a surgical sterilization procedure or who are not at least one year post-
menopausal) to conﬁrm that pregnancy has not occurred between the time of the screening
and the PET. In addition, a statement of use of a method of contraception for all subjects in the
past 15 days (abstinence, barrier methods, oral contraceptive medications, etc.) is obtained.
C). A urine drug screen and alcohol breath analyzer to ensure the subject did not abuse any
illicit drugs or alcohol prior to the PET scan (this test will occur prior to the placement of the
venous and arterial catheters). Subjects will be informed that this test will occur. 
D). The preparation of the subject will include the placement of a venous line and an arterial
line. An anesthesiologist will place the arterial line. The purpose of these lines is as follows:
Arterial line (all subjects):
1. Blood sampling for [C-11]NOP-1A arterial concentration.
2. The arterial line will be placed after completion of the Allen test and inﬁltration of the skin
with 1 to 2% lidocaine.
If the arterial line cannot be obtained for any reason, the PET study will NOT proceed as an
arterial input function is necessary for the derivation of the primary outcome measure, total
distribution volume (VT). Note: As the radiotracer [C-11]NOP-1A does not have a reference
region (i.e., region devoid of NOP-1A speciﬁc binding), it is necessary to have the arterial input
for appropriate quantitation of NOP-1A binding (Kimura et al., 2011).
Venous line (all subjects):
1. [C-11]NOP-1A (single bolus).
E). Blood pressure, heart rate and temperature will be documented prior to the PET scan. 
F). Before the PET and CT scan procedures are initiated, a wrist band (Empatica, E4) will be
placed on the subject’s wrist that does not have the arterial line. This wrist band which looks
similar to ‘apple watch’ will continuously monitor and record the subjects’ heart rate, inter-beat
interval, and electrodermal activity. Subjects will wear this wrist band till the completion of both
their PET/CT scans. 


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G). A low-dose CT scan to correct the PET scan measurements for attenuation will be
performed in a few minutes.
H). Following this CT scan, 12 mCi of [C-11]NOP-1A will be injected intravenously. Dynamic PET
data will be collected for 70 min. 
I). At the end of this scan, the subject will be a provided a brief (~5 to 10 min) break to relax
out of the scanner.
J). Subjects will then be administered 1 mg/kg of intravenous hydrocortisone as a bolus over
90 seconds. Following this, subjects will be monitored by the investigative team for subjective
and objective adverse events (see monitoring listed below).
K). A second low-dose CT scan and [C-11]NOP-1A scan will be acquired a minimum of 3.5-hours
post hydrocortisone, identical to the methods outlined previously. The timing of the second [C-
11]NOP-1A administration and subsequent PET scanning (i.e., ~ 3.5 to 4.5 hours) is based on
previous basic science studies that have documented CRF-NOP interactions (Ciccocioppo et al.,
2014a; Rodi et al., 2008). The proposed timing will also ensure that the maximum increase in
amygdala cortisol and CRF (Tmax ~ 25 to 30 min) following intravenous hydrocortisone
(1mg/kg) has occurred prior to the PET scan (Cook, 2002). 
Blood Sampling during [C-11]NOP-1A PET scans: Periodic arterial blood sampling will be
performed during the PET studies for the quantitative data analyses (i.e. measurement of the
radiotracer and its metabolites in the blood). These blood draws will not exceed 130 ml (about
9 tablespoonfuls) of blood in total. For each PET scans, hand-drawn arterial blood samples (0.5
ml) will be collected throughout the scan with no more than 20 collected during the ﬁrst 2 min
and no more than 15 collected at intervals of increasing duration minutes (no more than 35
total samples). Also, larger blood samples (3-5 ml) will be obtained at no more than 8 times
during each PET scan for the determination of radiolabeled metabolites and protein binding. This
would amount to no more than 43 arterial samples and a blood volume loss of no more than 60
ml (4-5 tablespoonfuls)/scan (60 * 2 scans = 120 mL). In addition to this two 3-5 mL blood
samples will be drawn for measuring cortisol plasma levels for each post-hydrocortisone scan (2
* 5* 1 scan =10 mL). The timing of these cortisol blood samples will be t=0 and 1h post-
hydrocortisone 
L). Following this scan, all subjects will receive:
1. Physical Exam.
2. Mental Status Exam.
3. EKG.
4. Vital Signs measurement.
M). The subject will be evaluated by a physician to ensure they meet the following discharge
criteria:
1. a blood pressure of > 90/60 and < 150/90.
2. a heart rate > 50 or < 110.
3. no reported subjective or objective side effects from the hydrocortisone at discharge.
4. a normal EKG (or not clinically signiﬁcant, or no change from baseline EKG as determined by a
physician)
5. a normal physical exam.
6. a normal mental status exam.
N). Healthy control who meet the above listed criteria following the PET scans will be


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discharged home. 
SUBJECT MONITORING:
A). Subject monitoring prior to the PET Scan
1. A physician will review screening labs, EKG and medical evaluation (see attached) prior to
scan day.
2. Baseline review of systems and medication history (to document no change from screening).
3. Vital signs.
4. Urine toxicology screen.
5. A statement of use of a method of contraception for all subjects in the past 15 days
(abstinence, barrier methods, oral contraceptive medications, etc.).
6. All female subjects of child bearing potential will undergo urine pregnancy testing to rule out
pregnancy on the day of the PET scans prior to any of the PET scanning procedures.
B). Subject monitoring during PET scans
1. An experienced technician will be in both visual and verbal contact with the participant at all
times during the study. If the participant voices any difﬁculty or desires to be removed from
the scanner, or if the technician sees any indication that the participant is experiencing
discomfort, the participant will be immediately removed from the scanner and verbally
reassured.
C). Subject monitoring on hydrocortisone 
1. The hydrocortisone will be administered by a physician investigator familiar with the protocol.
The physician investigator will also be available in the PET facility to monitor the subject on
hydrocortisone.
2. Blood pressure and heart rate will be recorded once prior to hydrocortisone and following
hydrocortisone every ten minutes for the ﬁrst 60 minutes, then every 15 minutes thereafter
(up to at least 120 min).
3. Subjects will be assessed once at baseline (time 0), once at 60 minutes post-hydrocortisone
(t=60 min), and once before the second [C-11]NOP scan with visual analog scales such as the
PSS, HAM-A and CES D (scales attached in 2.8) to evaluate their subjective feelings while on
hydrocortisone. 
2.6.1
2.6.1
Will blood samples be obtained as part of this research study?
Will blood samples be obtained as part of this research study?
* 
*  Yes 
*If submitting a protocol for expedited review, it should be clear that the planned blood draws
are within the parameters described here: http://www.hhs.gov/ohrp/policy/expedited98.html 
(see Expedited Research Category #2)
If Yes
Yes, address the frequency, volume per withdrawal, the total volume per visit, and the
qualiﬁcations of the individual performing the procedure:
Blood Sampling During Screening (total 35mL):
During screening, approximately 30-35 ml of blood will be drawn for routine medical tests. This
will be done only once.
Blood Sampling During PET Imaging (total 130 mL):
Periodic arterial blood sampling will be performed during the PET studies for the quantitative
data analyses (i.e. measurement of the radiotracer and its metabolites in the blood). These
blood draws will not exceed 130 ml (about 9 tablespoonfuls) of blood in total. For each PET


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scan, hand-drawn arterial blood samples (0.5 ml) will be collected throughout the scan with no
more than 20 collected during the ﬁrst 2 min and no more than 15 collected at intervals of
increasing duration minutes (no more than 35 total samples). Also, larger blood samples (3-5
ml) will be obtained at no more than 8 times during each PET scan for the determination of
radiolabeled metabolites and protein binding. This would amount to no more than 43 arterial
samples and a blood volume loss of no more than 60 ml (4-5 tablespoonfuls)/scan (60 * 2
scans = 120 mL). In addition to this, two 3 to 5 mL blood samples will be drawn for measuring
cortisol plasma levels for each post-hydrocortisone scan (2 * 5* 1 scan =10 mL). The timing of
these cortisol blood samples will be t=0 and t=60 min post-hydrocortisone challenge.
Thus, the cumulative amount of blood drawn for the screening and PET studies will be 165 mL
(35 + 130 mL).
 
 
Study Flow Chart:
Study Flow Chart:
Name
Modiﬁed Date
Flow chart.xlsx
3/30/2016 9:39 PM
     [reviewer notes¬] 
2.7
2.7
Will 
Will follow-up procedures
follow-up procedures be performed speciﬁcally for research purposes?  Follow-
 be performed speciﬁcally for research purposes?  Follow-
up procedures may include phone calls, interviews, biomedical tests or other
up procedures may include phone calls, interviews, biomedical tests or other
monitoring procedures.
monitoring procedures.
* 
*  Yes
Detailed procedures listed in the textbox below:
A follow-up telephone call will be made approximately 1 to 7 days after the last scan to the
healthy control subjects to enquire about any adverse events he or she may have encountered
related to the scans.
  
     [reviewer notes¬] 
2.8
2.8
Does this research study involve the use of any questionnaires, interview or
Does this research study involve the use of any questionnaires, interview or
survey instruments?
survey instruments?
* 
*  Yes
 
 
Upload a copy of all materials except for the SCID or KSADS which are on ﬁle at
Upload a copy of all materials except for the SCID or KSADS which are on ﬁle at
the IRB.  The use of all instruments must be addressed in question 2.6 and/or
the IRB.  The use of all instruments must be addressed in question 2.6 and/or
question 2.7 (except for an exempt submission where they should be addressed
question 2.7 (except for an exempt submission where they should be addressed
on the appropriate uploaded exempt form).
on the appropriate uploaded exempt form).


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Name
Modiﬁed Date
PSS
3/11/2016 2:21 PM
CES-D.pdf
3/11/2016 2:20 PM
HAM-A
3/11/2016 2:21 PM
Previously the name and publisher for commercially available materials were listed
Previously the name and publisher for commercially available materials were listed
in the textbox below but effective 9/1/2015, all materials (except for the SCID
in the textbox below but effective 9/1/2015, all materials (except for the SCID
and KSADS) must be uploaded using the Add button above.
and KSADS) must be uploaded using the Add button above.
     [reviewer notes¬] 
2.9
2.9
If subjects are also patients, w
If subjects are also patients, will any clinical procedures that are being used for
ill any clinical procedures that are being used for
their conventional medical care also be used for research purposes?
their conventional medical care also be used for research purposes?
* 
*  no
 
If Yes,
Yes, describe the clinical procedures (and, if applicable, their frequency) that will be used for
research purposes: 
2.10
2.10
The blood sample question was moved to 2.6.1.
     [reviewer notes¬] 
2.11
2.11
What is the total duration of the subject's participation in this research study
What is the total duration of the subject's participation in this research study
across all visits, including follow-up surveillance?
across all visits, including follow-up surveillance?
* 
*  < 6 months
     [reviewer notes¬] 
 
2.12
2.12
Does this research study involve any type of planned deception? 
Does this research study involve any type of planned deception? 
If Yes, you are required to request an alteration of the informed consent process (question 4.7)
* 
*  No
  
     [reviewer notes¬] 
 
2.13
2.13
Does this research study involve the use of 
Does this research study involve the use of UPMC/Pitt protected health
UPMC/Pitt protected health
information
information that will be de-identiﬁed by an IRB approved "honest broker" system?
 that will be de-identiﬁed by an IRB approved "honest broker" system?
 
* 
*  No
  
     [reviewer notes¬] 


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2.14
2.14
Will protected health information from a UPMC/Pitt HIPAA covered entity be
Will protected health information from a UPMC/Pitt HIPAA covered entity be
accessed
accessed for research purposes or will
 for research purposes or will research data be placed in
research data be placed in the UPMC/Pitt
 the UPMC/Pitt
medical record?
medical record?
* 
*  Yes
 
If you answer Yes
Yes, you are required to submit this study to the Research Informatics Ofﬁce,
Health Record Research Request (R3). Per UPMC Policy HS-RS0005, all research projects that
access or involve UPMC electronic protected health information (e-PHI) must be submitted to
R3, with the exception of clinical trials that are contracted through the UPMC Ofﬁce of
Sponsored Programs and Research Support (OSPARS).  
Complete the R3 intake form available at http://rio.pitt.edu/services. An R3 representative will
conduct a review. You will be notiﬁed once your R3 review is complete or if anything further is
needed. 
Describe the medical record information that will be collected from the UPMC/Pitt
Describe the medical record information that will be collected from the UPMC/Pitt
HIPAA covered entity and/or the research-derived information that will be placed
HIPAA covered entity and/or the research-derived information that will be placed
in the medical records.
in the medical records.
This research study may involve the recording of current and/or future identiﬁable medical
information from the hospital and/or other outpatient records. The information that will be
recorded will be limited to information concerning diagnosis, age, level of education, past
medical and psychiatric history, previous MRI, CT scans, and results of any blood tests. This
information will be used for the purpose of identifying whether subjects meet the conditions for
participation in this study.
This research study may result in identiﬁable information that will be placed into medical
records held at the UPMC. The nature of the identiﬁable information resulting from participation
in this research study that will be recorded in the medical record includes the results of the MRI
or laboratory tests done while participating in the study, that may at a rare instance need to be
read for a medical reason (such as abnormal MR or tests).
2.14.1
2.14.1
Will protected health information from a 
Will protected health information from a non-UPMC/Pitt HIPAA covered entity
non-UPMC/Pitt HIPAA covered entity be
 be
obtained for research purposes or will research data be placed in the 
obtained for research purposes or will research data be placed in the non-
non-
UPMC/Pitt medical record
UPMC/Pitt medical record?  
?  
* 
*  Yes
If Yes, describe how the HIPAA requirements will be met:
If Yes, describe how the HIPAA requirements will be met:
In some rare instances, it may be necessary to obtain medical records from a non-UPMC/Pitt
hospital stay or PCP's ofﬁce to ensure the subject meets the inclusion/exclusion criteria for the
study. If this is necessary and the case, the research team will have the subject sign a formal
HIPAA medical release of information to obtain these records that will then be placed in the
research chart with a copy of the signed release of information.


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I, 
I, Rajesh   Narendran , certify that any member of my research team accessing,
, certify that any member of my research team accessing,
reviewing and/or recording information from medical records have completed the
reviewing and/or recording information from medical records have completed the
CITI Privacy & Information Security course or, if completed within the past year,
CITI Privacy & Information Security course or, if completed within the past year,
the Internet-Based Studies in Education and Research (ISER) HIPAA for
the Internet-Based Studies in Education and Research (ISER) HIPAA for
Researchers (Formerly RPF Module 6). The HIPAA certiﬁcates must be available for
Researchers (Formerly RPF Module 6). The HIPAA certiﬁcates must be available for
review if audited but do not need to be uploaded into this OSIRIS application.
review if audited but do not need to be uploaded into this OSIRIS application.
* Yes
2.14.2
2.14.2
Are you requesting a waiver of the requirement to obtain written HIPAA
Are you requesting a waiver of the requirement to obtain written HIPAA
authorization for the collection of the PHI?
authorization for the collection of the PHI?
* No
  
     [reviewer notes¬] 
2.15
2.15
Does this research study involve the long-term storage (banking) of biological
Does this research study involve the long-term storage (banking) of biological
specimens? 
specimens? 
 
* 
*  Yes
2.15.1
2.15.1
Broadly describe the intended future use of the banked biological specimens:
Broadly describe the intended future use of the banked biological specimens:
All blood samples collected during the scan will be stored in a locked freezer at the PET Facility.
These samples that will be identiﬁed only by a code number will be stored till completion and
analysis of all your study results (less than 2 years). Subject identity on these records and any
blood samples collected will be indicated by a code rather than by a name. These de-identiﬁed
blood samples may be sent to outside laboratories that perform specialized analysis (such as
cortisol assays).
2.15.2
2.15.2
Indicate the planned length of storage of the banked biological specimens:
Indicate the planned length of storage of the banked biological specimens:
* < 2 years
2.15.3
2.15.3
Will biological specimens be stored 
Will biological specimens be stored without
without identiﬁers or linkage codes?
 identiﬁers or linkage codes?
    
* No
  
     [reviewer notes¬] 
2.15.4
2.15.4
Will subjects (including family members, if applicable) be informed of their
Will subjects (including family members, if applicable) be informed of their
personal results from analyses performed on their biological specimens?
personal results from analyses performed on their biological specimens?
 


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* 
*  No
     [reviewer notes¬] 
2.15.4.1
2.15.4.1
Justify why the personal results will
Justify why the personal results will
not
not be disclosed to the research
 be disclosed to the research
subjects at this time. Under
subjects at this time. Under
what conditions, if
what conditions, if
any, might personal results be
any, might personal results be
disclosed to research subjects in
disclosed to research subjects in
the future?
the future?
This is an imaging study in healthy
controls to evaluate the feasibility of an
imaging paradigm, i.e., can hydrocortisone
displace [C-11]NOP-1A binding. There is
no such clinical relevance in disclosing the
results of these imaging data to the
subjects. We do not foresee any condition
in which these data will be clinically
relevant and warrant disclosure to the
subjects.
Note: If the personal results of analyses
performed on the banked specimen will not be
disclosed to research subjects, the informed
consent document corresponding to this
research study should address why this
information is not being provided.  If the
personal results of such analyses may be
disclosed to research subjects in the future, the
conditions for such disclosure should also be
addressed in the informed consent form.
     [reviewer notes¬] 
2.15.4.7
2.15.4.7
Describe the procedures that will be employed to protect the conﬁdentiality of
Describe the procedures that will be employed to protect the conﬁdentiality of
subjects' private information associated with use of biological specimens:
subjects' private information associated with use of biological specimens:
All biological specimens collected (example, blood samples for cortisol levels, etc.) will be de-
identiﬁed. Thus, the subjects’ information or identifying information will not be compromised. 
 
 
2.15.4.8
2.15.4.8
Will the banked biological specimens or data derived from them be provided
Will the banked biological specimens or data derived from them be provided
with subject identiﬁers
with subject identiﬁers to any secondary investigators or external entities?
to any secondary investigators or external entities?
* 
*  No
2.15.4.9
2.15.4.9
Will  research subjects be remunerated in the event of the future commercial
Will  research subjects be remunerated in the event of the future commercial
development of inventions or products based on the research use of
development of inventions or products based on the research use of
their biological specimens?
their biological specimens?
* 
*  No
     [reviewer notes¬] 
2.16
2.16
Will research participants be asked to provide information about their family
Will research participants be asked to provide information about their family
members or acquaintances?
members or acquaintances?
* 
*  Yes
2.16.1
2.16.1
Describe what information about the third party will be obtained from the
Describe what information about the third party will be obtained from the
participant:
participant:
Family Medical and Psychiatric History
Screened subjects will be asked to provide data on family history for medical, psychiatric illness


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and drug use disorders. The only information documented is the relationship to the participant
and that no names, date of birth or other identiﬁers will be documented.
2.16.2
2.16.2
If the information about the third party is of a 
If the information about the third party is of a private nature
private nature, can the 
, can the identity
identity of
 of
the third party be readily ascertained or associated with this information?
the third party be readily ascertained or associated with this information?
*
No
 
Describe the private
private information
information that will be collected and recorded about the third party: 
We simply intend to ask information from subjects---medical illness, mental illness and drug and
alcohol use in ﬁrst- and second-degree relatives---to determine items which would be
exclusionary for the subject's participation in this study, or related to imaging outcome
measures derived in the subject. This information will be no different than the family history
obtained during a routine physical and psychiatric exam.
  
     [reviewer notes¬] 
2.17
2.17
What are the main outcome variables that will be evaluated in this study?
What are the main outcome variables that will be evaluated in this study?
The main outcome measure will be the change in [C-11]NOP-1A VT elicited by hydrocortisone-
stimulated CRF (∆ VT). ∆ VT will be calculated as the difference between VT measured in the
post-hydrocortisone condition and VT measured in the baseline condition on that day (VT
BASE), and expressed as a percentage of VT BASE. 
 
2.18
2.18
Describe the statistical approaches that will be used to analyze the study data.
Describe the statistical approaches that will be used to analyze the study data.
* 
*  Addressed below:
To determine if [C-11]NOP-1A receptor binding (VT) is increased following the administration of
hydrocortisone. This would suggest that there is a compensatory upregulation of NOP receptors
to enhance transmission at this site in response to CRF release. Such an interpretation would be
consistent with nociceptin, a component of the brain’s anti-stress system counteracting CRF, a
component of the brain’s stress system. The change in [C-11]NOP-1A VT elicited by
hydrocortisone-stimulated CRF (∆ VT) will be calculated as the difference between VT measured
in the post-hydrocortisone condition and VT measured in the baseline condition on that day (VT
BASE), and expressed as a percentage of VT BASE. Scan parameters between baseline and post-
hydrocortisone conditions will be performed with paired t-tests. The effect of hydrocortisone on
[C-11]NOP-1A VT will be evaluated in the individual ROIs with two tailed paired t-tests. A false
discovery rate (FDR) correction with = 0.05 will be applied to correct for multiple comparisons in
the ROIs (Benjamini and Hochberg, 1995). Exploratory analyses will be performed using a LMM
to evaluate the effects of gender on change in [C-11]NOP-1A VT (∆ VT) elicited by
hydrocortisone-stimulated CRF. The effect of hydrocortisone on [C-11]NOP-1A VT in high (e.g.,
amygdala) and low binding regions (e.g., midbrain, cerebellum) will be contrasted as well.
Hydrocortisone-induced changes in clinical variables such as PSS, HAM-A, Heart rate variability,
and skin conductance (from E4 wrist band) will also be correlated with the ∆ [C-11]NOP-1A VT.
     [reviewer notes¬] 
2.19
2.19
 


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Will this research be conducted in (a) a foreign country and/or (b) at a site (e.g.,
Will this research be conducted in (a) a foreign country and/or (b) at a site (e.g.,
Navajo Nation) where the cultural background of the subject population differs
Navajo Nation) where the cultural background of the subject population differs
substantially from that of Pittsburgh and its surrounding communities?
substantially from that of Pittsburgh and its surrounding communities?
* 
*  No
Note that copies of training records, licenses, certiﬁcates should be maintained in the study
regulatory binder and are subject to audit by the Research Conduct and Compliance Ofﬁce
(RCCO).
In addition, individuals planning to conduct human subject research outside the United States
must complete an optional module on the CITI training website: International Studies.  Click
here to access the instruction sheet for accessing optional CITI modules.
 
  
     [reviewer notes¬] 
2.21
2.21
Will this research study be conducted within a nursing home located in
Will this research study be conducted within a nursing home located in
Pennsylvania?
Pennsylvania?
* 
*  No 
 
  


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Section: Section 3 - Human Subjects
     [reviewer notes¬] 
Section 3 - Human Subjects
Section 3 - Human Subjects
3.1
3.1
What is the age range of the subject population?
What is the age range of the subject population?
18-40 
 
3.2
3.2
What is their gender?
What is their gender?
* 
*  Both males and females 
 Provide a justiﬁcation if single gender selected:
3.3
3.3
Will any racial or ethnic subgroups be explicitly excluded from participation?
Will any racial or ethnic subgroups be explicitly excluded from participation?
* 
*  No  
If Yes
Yes, identify subgroups and provide a justiﬁcation: 
 
3.4
3.4
For studies conducted in the U.S., do you expect that all subjects will be able to
For studies conducted in the U.S., do you expect that all subjects will be able to
comprehend English?
comprehend English?
* 
*  Yes 
  
     [reviewer notes¬] 
3.5
3.5
Participation of Children
Participation of Children: Will children less than 18 years of age be studied?
: Will children less than 18 years of age be studied?
* 
*  No
 
If No
No, provide a justiﬁcation for excluding children: 
Children < 18 years cannot be exposed to radiation the purpose of this study.
  
     [reviewer notes¬] 
3.6
3.6
Does this research study involve prisoners, or is it anticipated that the research
Does this research study involve prisoners, or is it anticipated that the research
study may involve prisoners?
study may involve prisoners?
* 
*  No
 
  
     [reviewer notes¬] 
3.7
3.7
Will pregnant women be knowingly and purposely included in this research study?
Will pregnant women be knowingly and purposely included in this research study?


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* 
*  No
  
     [reviewer notes¬] 
3.8
3.8
Does this research study involve neonates of uncertain viability or nonviable
Does this research study involve neonates of uncertain viability or nonviable
neonates?
neonates?
* 
*  No
 
  
     [reviewer notes¬] 
3.9
3.9
Fetal Tissues:
Fetal Tissues: Does this research involve the use of fetal tissues or organs?
 Does this research involve the use of fetal tissues or organs?
* 
*  No
  
     [reviewer notes¬] 
--->
3.10
3.10
What is the total number of subjects to be studied at this site, including subjects
What is the total number of subjects to be studied at this site, including subjects
to be screened for eligibility?
to be screened for eligibility?
Note: The number below is calculated by summing the data entered in question 3.11. Any
additions or changes to the values entered in 3.11 will be reﬂected in 3.10.
* 
*  60
 
3.11
3.11
Identify each of the disease or condition speciﬁc subgroups (include healthy
Identify each of the disease or condition speciﬁc subgroups (include healthy
volunteers, if applicable) that will be studied.  
volunteers, if applicable) that will be studied.  
Click on the "Add" button and specify for 
Click on the "Add" button and specify for each
each subgroup:
 subgroup:
1) how many subjects will undergo research related procedures at this site; and
1) how many subjects will undergo research related procedures at this site; and
2) if applicable, how many subjects will be required to undergo screening
2) if applicable, how many subjects will be required to undergo screening
procedures (e.g., blood work, EKG, x-rays, etc.) to establish eligibility.
procedures (e.g., blood work, EKG, x-rays, etc.) to establish eligibility.  Do Not
Do Not
include subjects who will undergo 
include subjects who will undergo preliminary telephone screening
preliminary telephone screening.
* 
* 
 
Subgroup
Number to undergo research
procedures
Number to undergo screening
procedures
View Healthy
controls
20
60
 
 


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3.12
3.12
Provide a statistical justiﬁcation for the total number of subjects to be enrolled
Provide a statistical justiﬁcation for the total number of subjects to be enrolled
into this research study at the multicenter sites or this site.
into this research study at the multicenter sites or this site.
* 
*  Described below: 
 
No previous [C-11]NOP-1A PET studies have evaluated the effect of hydrocortisone challenge
on its binding. To that extent, the studies that are being proposed in this protocol will allow for
the computation of effect size and planning for an adequately powered future investigation. In
the absence of these data, we used published data from basic investigations to make
assumptions for an effect size and power calculations.
In the study by Rodi et al., infusion of 1µg CRF in rodents was associated with a 100% increase
in NOP mRNA (Rodi et al., 2008). Based on prior microdialysis studies, we postulate a 2.2-fold
increase in amygdala CRF following the 1 mg/kg IV hydrocortisone challenge (Cook, 2002). This
is physiologically meaningful because it is in line with increases in amygdala CRF (~1 to 4-fold
increase) that have been reported in animal models of addiction (Merlo Pich et al., 1995;
Richter et al., 1995; Richter and Weiss, 1999; Richter et al., 2000). However, the exact
magnitude that this will translate to increased NOP receptor binding as measured by [C-
11]NOP-1A is unknown. Assuming a relatively modest 10% increase in binding to NOP receptors
(VT) in response to CRF released by the hydrocortisone challenge, and a 10 - 14% within-
subject test-retest variability for [C-11]NOP-1A VT (Lohith et al., 2014), the study is powered
at 0.96 to 0.76 to detect an effect at the p < 0.05 level using a two tailed paired t test with a
sample size of n = 16. It is possible that some subjects may not tolerate the hydrocortisone
infusion to complete the PET scans. Thus, we request permission to study an additional 4
subjects, for a total n=20. Note: If we observe an effect on [C-11]NOP-1A VT as reported in
Rodi et al. (100% increase in NOP mRNA), the study will be powered at 1.0.
 
     [reviewer notes¬] 
3.13
3.13
Inclusion Criteria: List the speciﬁc criteria for 
Inclusion Criteria: List the speciﬁc criteria for inclusion
inclusion of potential subjects.
 of potential subjects.
1) Males or females between 18 and 40 years old, of all ethnic and racial origins. 
 
3.14
3.14
Exclusion Criteria: List the speciﬁc criteria for 
Exclusion Criteria: List the speciﬁc criteria for exclusion
exclusion of potential subjects from
 of potential subjects from
participation.
participation.
(1) Current DSM-5 psychiatric disorders including tobacco, alcohol and substance use disorders;
and no past history of treatment of DSM5 disorders (SCID screening modules). 
(2) History of binge drinking as deﬁned in NIAAA criteria in the past month
(http://www.niaaa.nih.gov/alcohol-health/). NIAAA deﬁnes "binge drinking" as a pattern of
drinking that brings blood alcohol concentration (BAC) levels to 0.08 g/dL. This typically occurs
after 4 drinks for women and 5 drinks for men—in about 2 hours; 
(3) Recreational abuse of opiates, sedative-hypnotics, cocaine, amphetamines, MDMA, and PCP,
as well as cannabis use (urine drug screen on PET day, and screening day);
(4) Currently on any prescription medical or psychotropic medication; 
(5) Current or past severe medical, endocrine, cardiovascular, immunological or neurological
illnesses as assessed by a complete medical history, physical and lab work; 
(6) Currently pregnant or breast-feeding;
(7) History of radioactivity exposure via prior nuclear medicine studies or occupational exposure
in past twelve months; 


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(8) Metallic objects in the body that are contraindicated for MRI; 
(9) First-degree relative with psychosis or mood or anxiety disorders (due to risk for
hydrocortisone to trigger such symptoms). 
3.15
3.15
Will HIV serostatus be evaluated speciﬁcally for the purpose of participation in
Will HIV serostatus be evaluated speciﬁcally for the purpose of participation in
this research study?
this research study?
* 
*  No 
If Yes
Yes, provide a justiﬁcation:
 


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Section: Section 4 - Recruitment and Informed Consent Procedures
     [reviewer notes¬] 
4.1
4.1
Select all recruitment methods to be used to identify potential subjects:
Other Strategies: Described below
 
 
 
 
 
4.2
4.2
Provide a detailed description of your recruitment methods, including identifying
Provide a detailed description of your recruitment methods, including identifying
and initiating contact with participants:
and initiating contact with participants:  
Individuals who participate in this study will be recruited via IRB: PRO07080146 (Title: Healthy
subjects participating in the screening procedures for positron emission tomography (PET)
imaging studies; PI: Dr. Narendran). Interested healthy subjects who contact us for other PMIP
research protocols may also be offered this study. These subjects will be consented directly
into this study, and undergo screening procedures listed in 2.5. 
PRO07080146 is a healthy control screening protocol that establishes minimal eligibility from a
medical and psychiatric standpoint. It screens prospective individuals for psychiatric, addictive
disorders and medical problems prior to enrolling them into PET research protocols. 
Detailed screening and recruitment methods are in PRO7080146: 
Brieﬂy, PRO07080146 contains advertisements, to recruit subjects in age range 18-55 years
old. However, only subjects who ﬁt the age range for this particular study, 18-40 years old, will
be enrolled. Subjects, who are typically enrolled in PRO7080146, are interested in a PET
research study and have given us permission to contact them about PET studies. We typically
invite them to schedule them via phone--subjects are notiﬁed that we have a study they may
be appropriate for, and if they are willing to come in to consent for this study with the PI (Note:
There is no speciﬁc script involved or letters sent out because subjects are only provided with
details of the study they are eligible for in person by the PI). If agreeable, they are consented in
an in-person interview.
  
Note: Questions jump from 4.2 to 4.6 as questions 4.3-4.5 have been removed and the information is now
captured in 4.1
     [reviewer notes¬] 
4.6
4.6
Are you requesting a 
Are you requesting a waiver to document
waiver to document informed consent for any or all
 informed consent for any or all
participants, for any or all procedures? (e.g., a verbal or computerized consent
participants, for any or all procedures? (e.g., a verbal or computerized consent


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script will be used, but the subjects will not be required to sign a written informed
script will be used, but the subjects will not be required to sign a written informed
consent document.
consent document.  This is not a waiver to obtain consent
This is not a waiver to obtain consent.
* 
*  No
  
     [reviewer notes¬] 
4.7
4.7
Are you requesting a waiver to obtain informed consent or an alteration of the
Are you requesting a waiver to obtain informed consent or an alteration of the
informed consent process for any of the following? 
informed consent process for any of the following? 
 
* Yes
 
4.7.1
4.7.1
If Yes, select the reason(s) for your request:
If Yes, select the reason(s) for your request:
Review of identiﬁable medical records and/or specimens
General Requirements: The Federal Policy [45 CFR 46.116 (d)]
[45 CFR 46.116 (d)] speciﬁes in order for a
waiver of consent to be approved, the request must meet four criteria. For each request, you
will be asked to provide a justiﬁcation addressing how each of these criterion is met.
 
 
Review of identiﬁable medical records:
Review of identiﬁable medical records:  [Note: A waiver of HIPAA Authorization must be
requested (2.14.2)]  Include the
Include the approximate number of medical records and/or
approximate number of medical records and/or
specimens that will be accessed and enter -1 in 
specimens that will be accessed and enter -1 in question 3.11 for the number of
question 3.11 for the number of
subjects to be enrolled.
subjects to be enrolled.
The research involves no more
than minimal risk to the subjects;
[45 CFR 46.116 (d)(1)]
[45 CFR 46.116 (d)(1)]
Evaluating the potential subjects' medical records to see if
they meet any exclusions, for example a prior MRI scans, or
Orbital X-ray scan to rule out metal in their eye.
The waiver or alteration will not
adversely affect the rights and
welfare of the subjects;
[45 CFR 46.116 (d)(2)]
[45 CFR 46.116 (d)(2)]
Because all subjects are healthy controls, the review of their
medical records for minimum eligibility will not be
exclusionary.
The research could not
practicably be carried out
without the waiver or alteration;
[45 CFR 46.116 (d)(3)]
[45 CFR 46.116 (d)(3)]
If subjects cannot conﬁrm certain inclusion/exclusions, for
example prior radiation exposure in a research study, or lack
of metal in eyes in a welder, they will not be able to
participate in the study.
Yes, if there are concerns, subjects will be provided with


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Whenever appropriate, the
subjects will be provided with
additional pertinent information
after participation.
[45 CFR 46.116 (d)(4)]
[45 CFR 46.116 (d)(4)]
additional pertinent information after participation.
 
 
 
 
4.7.2
4.7.2
Under what circumstances (if any) will you obtain consent from some of these
Under what circumstances (if any) will you obtain consent from some of these
subjects?
subjects?
If a subject's information cannot be conﬁrmed by a simple medical record review, we will seek
formal consent (for example, need to talk to their primary care physician about whether they
have been exposed to metal/radiation).
  
     [reviewer notes¬] 
4.8
4.8
Are you requesting an exception to the requirement to obtain informed consent
Are you requesting an exception to the requirement to obtain informed consent
for research involving the evaluation of an 'emergency' procedure?
for research involving the evaluation of an 'emergency' procedure?
Note
Note: This exception allows research on life-threatening conditions for which available
treatments are unproven or unsatisfactory and where it is not possible to obtain informed
consent.
* 
*  No
 
     [reviewer notes¬] 
 
4.9
4.9
Upload all consent documents for watermarking:
Upload all consent documents for watermarking:
Draft Consent Forms for editing:
Name
Modiﬁed Date
Consent.docx 9.26.2017 9/26/2017 9:19 AM
 
     


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Approved Consent Form(s):
Name
Modiﬁed Date
Consent.docx 9.26.2017 11/16/2018 2:43 PM
     [reviewer notes¬] 
4.10
4.10
Will all potential 
Will all potential adult
adult subjects be capable of providing direct consent for study
 subjects be capable of providing direct consent for study
participation?
participation? 
* 
* 
Yes 
 
  
     [reviewer notes¬] 
4.11
4.11
At what point will you obtain the informed consent of potential research subjects
At what point will you obtain the informed consent of potential research subjects
or their authorized representative?
or their authorized representative?
Prior to performing any of the screening procedures 
 
4.11.2
4.11.2
Taking into account the nature of the study and subject population, indicate how
Taking into account the nature of the study and subject population, indicate how
the research team will ensure that subjects have sufﬁcient time to decide whether
the research team will ensure that subjects have sufﬁcient time to decide whether
to participate in this study.  In addition, describe the steps that will be taken to
to participate in this study.  In addition, describe the steps that will be taken to
minimize the possibility of coercion or undue inﬂuence.
minimize the possibility of coercion or undue inﬂuence.
Subjects will always be assessed by a physician investigator. If the subject is in active treatment
with one of the investigators, that particular investigator/co-investigator will not consent the
subject. Subjects are typically provided as much time as necessary before they decide to sign
the informed consent. They are also informed that they are free to withdraw at any time in the
study if they do not feel comfortable undergoing any of the study procedures.
  
     [reviewer notes¬] 
4.12
4.12
Describe the 
Describe the process
process that you will employ to ensure the subjects are fully
 that you will employ to ensure the subjects are fully
informed about this research study. 
informed about this research study. 
* 
*  Addressed below: 
This description must include the following elements:
This description must include the following elements:
who from the research team will be involved in the consent process (both the discussion
and documentation);
person who will provide consent or permission; 
information communicated; and
 


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any waiting period between informing the prospective participant about the study and
obtaining consent
In addition, address the following if applicable based on your subject population:
process for child assent and parental permission
continued participation if a child subject turns 18 during participation
process for obtaining proxy consent and assent for decisionally impaired subjects
continued participation if subject regains capacity to consent
Informed consent shall be obtained (prior to initiating research procedures) by the PI, by a
physician co-investigator. The physician co-investigators will be educated in the research
procedures related to imaging studies, and trained and supervised by Dr. Narendran prior to
conducting the informed consent process by themselves (Study PI). 
All risks and beneﬁts of the study will be discussed and reviewed with the subject. The subject
will be given as much time as needed to review the consent form, ask questions, and discuss
the study procedures with the study physician. The investigator will gauge the subject's
understanding of the study procedures through direct questioning of the potential subject
about said procedures. The investigator, co-investigator will then obtain written informed
consent. 
4.13
4.13
Are you requesting an exception to either IRB policy related to the informed
Are you requesting an exception to either IRB policy related to the informed
consent process?
consent process?
For studies involving a drug, device or surgical procedures, a licensed physician who is
a listed investigator is required to obtain the written informed consent unless an
exception to this policy has been approved by the IRB 
For all other studies, a listed investigator is required to obtain consent (Note: In order to
request an exception to this policy, the study must be minimal risk)
* 
*  No
If Yes
Yes, provide a justiﬁcation and describe the qualiﬁcations of the individual who will obtain
consent:
 
 
4.14
4.14
Will you inform research subjects about the outcome of this research study
Will you inform research subjects about the outcome of this research study
following its completion?
following its completion?
* 
*  No 
 
If Yes
Yes, describe the process to inform subjects of the results:


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Section: Section 5 - Potential Risks and Beneﬁts
     [reviewer notes¬] 
5.1
5.1
Describe potential risks (physical, psychological, social, legal, economic or
Describe potential risks (physical, psychological, social, legal, economic or
other) associated with screening procedures, research interventions/interactions,
other) associated with screening procedures, research interventions/interactions,
and follow-up/monitoring procedures performed speciﬁcally for this study: 
and follow-up/monitoring procedures performed speciﬁcally for this study: 
* 
* 
View
Research Activity:
Research Activity:
Arterial Catheterization  
Common Risks:
Common Risks:
Complications resulting from such short-term arterial catheterizations
infrequently include bleeding, occlusion, or clotting. Incidence of
complication increases with the duration of catheterization and are rare
when catheters remained in place less than 4 days. Sixteen
investigators followed 106 subjects who had arterial lines placed in the
context of a PET study (Jons et al 1997). Abnormalities were reported
in 8 of 106 (7.5%) cases, all of which were benign and did not require
further medical attention. They included redness over the puncture site
with pain (n = 1), hematoma (n=2), swelling over the puncture site (n =
2), slow radial and ulnar capillary reﬁll (n = 2, one also had associated
cold temperature in the territories of these arteries, however both were
within normal limits), index ﬁnger contraction (n = 1; causal relationship
unclear). Of these eight cases, three (37.5%) were inpatients
diagnosed with anorexia nervosa, a condition that may represent a risk
factor. All abnormalities were benign, did not affect motor function, and
did not require medical intervention. 
Infrequent Risks:
Infrequent Risks:
We make every effort to minimize participant risk by ensuring that all
arterial catheterizations will be performed by qualiﬁed
anesthesiologists. There is an even more rare risk of cutting off
circulation to the hand with arterial catheters, which could result in the
need for surgical repair or, in rare instances, could result in the loss of
use of part or all of the hand. These complications are rare and usually
occur in medically ill patients who have catheters in their wrists for
several days. In the proposed study, arterial catheters will remain in
place no more than 8 hours.  
Other Risks:
Other Risks:
No Value Entered 
View
Research Activity:
Research Activity:
Blood Sampling  
Common Risks:
Common Risks:
Slight bruising, bleeding, soreness, dizziness, and fainting when drawing
blood.  
Infrequent Risks:
Infrequent Risks:
Infection. 
Other Risks:
Other Risks:
Thrombosis. 
View
Research Activity:
Research Activity:
Interview and Questionnaires (SCID, Rating Scales) 
Common Risks:
Common Risks:
The only infrequent risk (expected to occur in 1-10 out of 100) from
these questions is that sometimes people can feel uncomfortable about
discussing their personal issues.  
Infrequent Risks:
Infrequent Risks:
No Value Entered 
 


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Other Risks:
Other Risks:
No Value Entered 
View
Research Activity:
Research Activity:
Risk of [C-11]NOP-1A Exposure  
Common Risks:
Common Risks:
Adverse reactions to the [C-11]NOP-1A doses used in this study have
not been reported. 
Infrequent Risks:
Infrequent Risks:
However, the possibility exists for a rare allergic reaction, which may
include rash, shortness of breath, and itching to [C-11]NOP-1A to
which the participant will be exposed. A physician or RN will therefore
be available at all times during the study and an emergency cart will be
in close proximity. Other physical risks involve possible (10-25 out of
100 people) muscle aches from lying still for 3 hours or more. If
adverse effects would occur that require medical intervention, this is
furnished by UPMC.  
Other Risks:
Other Risks:
No Value Entered 
View
Research Activity:
Research Activity:
Risk of Breach of Conﬁdentiality  
Common Risks:
Common Risks:
No Value Entered 
Infrequent Risks:
Infrequent Risks:
Breach of conﬁdentiality could impact future insurability, employability,
etc. 
Other Risks:
Other Risks:
Since this is a single-site, open study with a relatively small number of
subjects, the data and safety monitoring plan will be implemented using
close monitoring of individual subjects by a single individual (the PI).
The PI or co-investigators are in daily contact with the research staff
who test the participants, score and enter the data and will monitor
their procedures to ensure that conﬁdentiality is maintained. We will do
everything in our power to protect conﬁdentiality. Information gathered
as part of the study including all research records in locked ﬁles, and
the identity of all specimens and medical information by a research
record number, rather than by the subject’s name or social security
number.  
View
Research Activity:
Research Activity:
Risk of Hydrocortisone 
Common Risks:
Common Risks:
Headache, nausea, vomiting, dizziness, insomnia, restlessness,
depression, anxiety, unusual moods, increased sweating, increased hair
growth, reddened face, thinned skin, easy bruising, tiny purple spots,
and irregular menstrual periods. Typically, these side effects are not
bothersome and are reversible with time. 
Infrequent Risks:
Infrequent Risks:
Other rare, but serious adverse events reported in "medially ill
individuals" include anaphylaxis, bradycardia, cardiac arrest, dermatitis,
decreased carbohydrate and glucose tolerance, ﬂuid retention,
abdominal distention, bowel/bladder dysfunction, negative nitrogen
balance, aseptic necrosis of femoral and humeral heads, convulsions,
emotional instability, exophthalmoses, glaucoma. 
Other Risks:
Other Risks:
It is also possible that hydrocortisone may interfere with the intended
effects of vaccination or can increase their risk when exposed to fungal
or viral infections. 
Research Activity:
Research Activity:
Risk of Lidocaine  


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View
Common Risks:
Common Risks:
The use of Lidocaine may result in mild reactions, including a metallic
taste, ringing in the ear. 
Infrequent Risks:
Infrequent Risks:
Allergic reaction, which may include shortness of breath, itching,
rashes, etc. 
Other Risks:
Other Risks:
No Value Entered 
View
Research Activity:
Research Activity:
Risk of Lorazepam 
Common Risks:
Common Risks:
Sedation. 
Infrequent Risks:
Infrequent Risks:
Dizziness, weakness, unsteady gait. 
Other Risks:
Other Risks:
Serious allergic reaction, which may include rash, itching, swelling,
severe dizziness, trouble breathing. 
View
Research Activity:
Research Activity:
Risk of MRI 
Common Risks:
Common Risks:
There is a substantial risk (more than 25 out of 100 people) to persons
who have metallic objects inside their bodies, as the magnet in the MR
scanner can cause these to move. Consequently, participants with
pacemakers or metallic objects located in the eye, ear, brain or blood
vessel walls will be excluded.  
Infrequent Risks:
Infrequent Risks:
There is an infrequent risk (1-10 out of 100 people) of heart rhythm
disturbances in patients who have previous heart rhythm abnormalities.
These subjects will be excluded as well. Women who are pregnant
should not undergo MRI because of the possible harmful effects to the
fetus. These subjects will be excluded. People with claustrophobia may
ﬁnd this procedure uncomfortable. Participants who developed
claustrophobic anxiety during scanning found that this fear dissipated
within 15 min while remaining in the scanner, or as necessary, after
exiting the scanner. Should the participant develop claustrophobic
feelings during the study, or for any reason cannot endure remaining in
the scanner, the study will be stopped and the participant will be
removed from the scanner. 
Other Risks:
Other Risks:
No Value Entered 
View
Research Activity:
Research Activity:
Risk of Radiation Exposure  
Common Risks:
Common Risks:
No Value Entered 
Infrequent Risks:
Infrequent Risks:
No Value Entered 
Other Risks:
Other Risks:
Participation in this research study will involve exposure to radiation
associated with the low-dose CT scans and the administration of [C-
11]NOP-1A. If participants undergo 2 low-dose CT scans and two
injections (12 mCi/injection) of [C-11]NOP-1A, the total radiation
exposure will be equivalent to a uniform whole body dose of 0.42 rem
(less than 10 % or approximately 1/10th of the annual whole body
radiation exposure of 5 rems permissible to radiation workers by federal
guidelines). Each additional low-dose CT scan, if required, will result in a
uniform whole body radiation dose of about 0.016 rem. This radiation
dose is not expected to produce any harmful effects, although there is
no known minimum level of radiation exposure considered to be totally
free of the risk of causing genetic defects or cancer. The risk
associated with the amount of radiation exposure participants receive


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in this study is considered low and comparable to every day risks. No
PET studies will be performed on pregnant or potentially pregnant
women, as conﬁrmed by pregnancy testing performed at screening and
prior to each PET scanning session. In order to limit the amount of
radiation exposure received by research subjects, all individuals
currently exposed to radiation in the workplace are excluded, as well as
individuals who have participated in radioactive drug studies during the
previous year wherein the total cumulative annual radiation dose (i.e.,
from participation in the previous radioactive drug study [studies] and
this study) would exceed the radiation dose limits speciﬁed in the FDA
regulations (i.e., 21 CFR 361.1) that govern the research use of [C-
11]NOP-1A in this study. 
View
Research Activity:
Research Activity:
Venous Catheterization  
Common Risks:
Common Risks:
No Value Entered 
Infrequent Risks:
Infrequent Risks:
Insertion of a catheter for intravenous injection of the PET
radiopharmaceutical is rarely associated with the chance of infection
(less than 1 out of 100 people), but more commonly associated with
slight pain, bruising, bleeding or soreness at the puncture site (10-25
out of 100 people).  
Other Risks:
Other Risks:
No Value Entered 
 
5.1.1
5.1.1
Describe the steps that will be taken to prevent or to minimize the severity of
Describe the steps that will be taken to prevent or to minimize the severity of
the potential risks:
the potential risks:
 
1. Risk of Arterial Catheterization
The arterial catheterization risks will be minimized, prior to the procedure, as each participant
will undergo an Allen’s test to ensure competency of collateral arterial circulation. Lidocaine
may be used to reduce the pain during arterial catheterization and there is a rare (less than 1
out of 100 people) risk of allergic reaction, which could rarely (less than 1 out of 100 people)
be life-threatening, to the Lidocaine. Further, we will make every effort to minimize participant
risk by ensuring that all arterial catheterizations will be performed by qualiﬁed anesthesiologists.
Indeed, this is our routine practice in the UPMC PUH PET Facility and we have an excellent safety
record. Speciﬁcally, we have performed over 1000 arterial catheterizations for PET research
studies from 1996 through September 2002 with no serious complications, such as ischemia,
irreversible injury, infection or other serious problems. Experienced medical personnel will
perform all catheter placements and a fully equipped medical cart is located in the PET Facility.
2. Risk of Blood Sampling/Loss
Adverse effects of blood sampling will be minimized by exclusion of subjects with low
hemoglobin levels during screening.
3. Risk of Interview and Questionnaires 
Only trained clinical research coordinators will perform these rating scales. These coordinators
are supervised by PMIP program manager, Ms. Jennifer Paris, who is a certiﬁed LPC (licensed
psychology counselor). Participants experiencing anxiety or tearfulness during the psychological
assessments will be reassured that they are just there to do their best and it does not matter
how well they score. They will be encouraged to continue, but allowed to stop if they feel too
 


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distressed. 
4. Risk of Adverse Reaction from [C-11]NOP-1A
Adverse reactions to the [C-11]NOP-1A dosage used in this study have not been reported.
However, the possibility exists for a rare (1 out of 100 people) reaction to any of the drugs or
procedures to which the participant will be exposed. A physician will be available during the
study and an emergency cart will be in close proximity. 
5. Risk of Breach of Conﬁdentiality
We will do everything in our power to protect conﬁdentiality. Information gathered as part of
the study including all research records in locked ﬁles, all specimens and medical information are
identiﬁed by a research record number, rather than by the subject’s name or social security
number.
6. Risk of Lidocaine
Subjects will be asked if they are allergic to Lidocaine or Novocain, commonly used in dental
procedures, in order to minimize the risk of a serious allergic reaction.
7. Risk of MRI
The MR scan risks will be minimized by thorough participant screening. The PI, research team
and MRI technicians will ask the participant a list of questions about previous activities that
could potentially put them at risk for having metal in their body. If there is a possibility of metal
being present in the participant’s body, the participant will be excluded from the study
protocol.
8. Risk of Radiation Exposure
In order to limit the amount of radiation exposure received by research subjects, all individuals
currently exposed to radiation in the workplace are excluded, as well as individuals who have
participated in radioactive drug studies during the previous year wherein the total cumulative
annual radiation dose (i.e., from participation in the previous radioactive drug study [studies]
and this study) would exceed the radiation dose limits speciﬁed in the FDA regulations (i.e., 21
CFR 361.1) that govern the research use of [C-11]NOP-1A in this study.
9. Venous Catheterization
Risks of venous catheterization will be minimized by utilizing trained personal to insert the
catheter.
10. Risk of Hydrocortisone
The proposed dose of hydrocortisone (1mg/kg, IV, i.e., ≤ 100 mg) in this study is far below the
FDA approved maximum IV dose of 500 mg. This will reduce the risk of these serious adverse
effects. Furthermore, IV hydrocortisone has been administered to healthy humans at doses ≤
200 mg with no serious side effects in several previous research studies (Jung et al., 2014;
Symonds et al., 2012; Wachtel et al., 2001; Wachtel and de Wit, 2001). 
Speciﬁc measures and precautions to prevent medical and psychiatric effects:
Subjects will be screened for absence of signiﬁcant past and current medical conditions with a
complete medical history, physical examination, routine blood tests (that will include CBC with
differential counts, electrolytes, liver, thyroid, adrenal, kidney function tests, and creatine
kinase) urine toxicology and EKG. They will be excluded if they have any history of
cardiovascular disease, arrhythmias, or an abnormal EKG. In addition, subjects with a prior or
current history of immune-compromise, HPA-axis dysfunction, Cushing’s syndrome, obesity,
hyperglycemia, hyperlipidemia, cataracts, glaucoma, and osteoporosis will be excluded. Finally,
subjects with a family history for mood, anxiety and psychotic disorder will be excluded as well.


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The study will be cancelled if the subject has a blood pressure < 90/60 or > 150/90.
During and after the hydrocortisone administration, subjects will be under constant monitoring
for serious adverse events (including anaphylaxis, bradycardia, etc.). Administration of
hydrocortisone will take place in the presence of a physician. A twelve lead EKG, a code cart,
and deﬁbrillator are available in the room in case of complications. If there is a drop in blood
pressure, IV ﬂuids will be used to control the blood pressure response. In case of chest pain,
chest tightness or other symptoms suggestive of cardiac ischemia, the experiment will be
canceled and a twelve lead EKG will be immediately obtained to rule out angina (ST segment
elevation or depression as compared to the baseline EKG) or arrhythmia. If serious medical signs
and symptoms persist > 10 minutes, the subjects will be taken to the UPMC Presbyterian ER for
further medical treatment. If psychiatric signs and symptoms persist > 10 minutes (example,
depression, anxiety, etc.), the subjects will be managed by the PI (starting with re-assurance,
and if need oral lorazepam 1-2 may be administered). If these symptoms persist and are a
cause for a concern then a referral will be made to a higher level of care, example WPIC
psychiatric emergency room. All subjects who receive hydrocortisone will be monitored for a
minimum of 6 hours in the PET facility, following hydrocortisone administration. Subjects will be
evaluated by a physician and discharged home only if they meet the following criteria: (a) a
blood pressure of > 90/60 and < 150/90 (b) a heart rate > 50 or < 110 (c) no reported
subjective or objective side effects from the hydrocortisone at discharge (d) a normal EKG (or
not clinically signiﬁcant, or no change from baseline as determined by a physician) (e) a normal
physical exam (f) and a normal mental status exam.
5.2
5.2
What steps will be taken in the event that a clinically signiﬁcant, unexpected
What steps will be taken in the event that a clinically signiﬁcant, unexpected
disease or condition is identiﬁed during the conduct of the study?
disease or condition is identiﬁed during the conduct of the study?
* 
*  Addressed below:
 Addressed below:
If a clinically signiﬁcant, unexpected disease or condition occurs during the conduct of the study
that is directly related to study intervention, it will be evaluated and managed by one the
physician investigators. If this event is an emergency, the subject will be taken to the UPMC
Presbyterian ER and medical care will be initiated as needed.
5.3
5.3
All the risk questions (screening, intervention/interaction, follow-up) have been merged into
one question (5.1).
     [reviewer notes¬] 
5.4
5.4
Do any of the research procedures pose a physical or clinically signiﬁcant
Do any of the research procedures pose a physical or clinically signiﬁcant
psychological risk to women who are or may be pregnant or to a fetus?
psychological risk to women who are or may be pregnant or to a fetus?
* Yes
5.4.1
5.4.1
List the research procedures that pose a risk to pregnant women or fetuses:
List the research procedures that pose a risk to pregnant women or fetuses:
Exposure to radiation can lead to abnormal fetal development.
5.4.2
5.4.2
Describe the steps that will be taken to rule out pregnancy prior to exposing
Describe the steps that will be taken to rule out pregnancy prior to exposing
women of child-bearing potential to the research procedures that pose a risk to
women of child-bearing potential to the research procedures that pose a risk to
pregnant women or fetuses:
pregnant women or fetuses:
A urine pregnancy test will be performed on all women of child-bearing potential on the day of,


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and prior to, the PET scanning procedures.
5.4.3
5.4.3
Describe the measures to prevent pregnancy, and their required duration of use,
Describe the measures to prevent pregnancy, and their required duration of use,
that will be discussed with women of child-bearing potential during and following
that will be discussed with women of child-bearing potential during and following
exposure to research procedures:
exposure to research procedures:
1. Subjects will receive a blood pregnancy test at screening.
2. A urine pregnancy test will be performed on all women of child-bearing potential on the day
of, and prior to, the PET scanning procedures.
3. In addition, all female subjects will be educated and instructed to use contraception two-
weeks prior to undergoing any of the radiation related procedures. A conﬁrmation of their use of
protection is documented in the case report form.
  
     [reviewer notes¬] 
5.5
5.5
Do any of the research procedures pose a potential risk of causing genetic
Do any of the research procedures pose a potential risk of causing genetic
mutations that could lead to birth defects?
mutations that could lead to birth defects?
* 
*  Possibly or Deﬁnitely
5.5.1
5.5.1
List the research procedures that pose a potential risk of genetic mutations/birth
List the research procedures that pose a potential risk of genetic mutations/birth
defects:
defects:
Exposure to radiation can lead to abnormal fetal development.
5.5.2
5.5.2
Describe the measures to prevent pregnancy, and their required duration of
Describe the measures to prevent pregnancy, and their required duration of
use, in female subjects and female partners of male subjects during and following
use, in female subjects and female partners of male subjects during and following
exposure to research procedures: 
exposure to research procedures: 
1. Subjects will receive a blood pregnancy test at screening.
2. A urine pregnancy test will be performed on all women of child-bearing potential on the day
of, and prior to, the PET scanning procedures.
3. In addition, all female subjects will be educated and instructed to use contraception two-
weeks prior to undergoing any of the radiation related procedures. A conﬁrmation of their use
of protection is documented in the case report form.
 
  
     [reviewer notes¬] 
5.6
5.6
Are there any alternative procedures or courses of treatment which may be of
Are there any alternative procedures or courses of treatment which may be of
beneﬁt to the subject if they choose not to participate in this study?
beneﬁt to the subject if they choose not to participate in this study?
* 
*  Not applicable
If Yes
Yes, describe in detail:
 
 


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     [reviewer notes¬] 
5.7
5.7
Describe the speciﬁc endpoints (e.g., adverse reactions/events, failure to
Describe the speciﬁc endpoints (e.g., adverse reactions/events, failure to
demonstrate effectiveness, disease progression) or other circumstances
demonstrate effectiveness, disease progression) or other circumstances
(e.g., subject's failure to follow study procedures) that will result in discontinuing
(e.g., subject's failure to follow study procedures) that will result in discontinuing
a subject’s participation?
a subject’s participation?
* 
*  Describe below:
Subjects will be withdrawn from the study at their request or by the determination of the study
physician. Reasons could include experiencing claustrophobia during the MRI or PET scan, or
experiencing adverse effects from hydrocortisone, or [C-11]NOP-1A, failure of adherence to
research protocol. 
 
     [reviewer notes¬] 
5.8
5.8
Will any individuals 
Will any individuals other
other than the investigators/research staff involved in the
 than the investigators/research staff involved in the
conduct of this research study and authorized representatives of the University
conduct of this research study and authorized representatives of the University
Research Conduct and Compliance Ofﬁce (RCCO) be permitted access to research
Research Conduct and Compliance Ofﬁce (RCCO) be permitted access to research
data/documents (including medical record information) associated with the
data/documents (including medical record information) associated with the
conduct of this research study?
conduct of this research study?
* 
*  Yes
  
5.8.1
5.8.1
Identify the 'external' persons or entity who may have access to research
Identify the 'external' persons or entity who may have access to research
data/documents and the purpose of this access:
data/documents and the purpose of this access:
Other research investigators interested in this topic may be provided access to the de-
identiﬁed data for data pooling and replication of these data.
5.8.2
5.8.2
Will these 'external' persons or entity have access to identiﬁable research
Will these 'external' persons or entity have access to identiﬁable research
data/documents?
data/documents?
*
No; the research data/documents will be coded and subject identiﬁers removed prior to access
by the external persons
If Yes
 Yes, describe how they will protect the conﬁdentiality of the research data:
5.9
5.9
Has or will a Federal Certiﬁcate of Conﬁdentiality be obtained for this research
Has or will a Federal Certiﬁcate of Conﬁdentiality be obtained for this research
study?
study?
* 
*  No
 
5.10
5.10
Question has been moved to 5.17
Question has been moved to 5.17


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5.11
5.11
Question has been moved to 5.16
Question has been moved to 5.16
  
     [reviewer notes¬] 
5.12
5.12
Does participation in this research study offer the potential for 
Does participation in this research study offer the potential for direct beneﬁt
direct beneﬁt to
 to
the research subjects?
the research subjects?
No - Describe the general beneﬁts to society (e.g., increased knowledge; improved safety;
better health; technological advancement) that may result from the conduct of this research
study. 
 
Describe the beneﬁt:
The general beneﬁts to society from this particular research protocol include gaining a better
understanding of the effect of nociceptin-corticotrophin interactions. It is possible that future
studies using this paradigm may detect that this interaction is abnormal in addictive and
psychiatric disorders, and lead to better treatments. 
 
5.13
5.13
Describe the data and safety monitoring plan associated with this study. If the
Describe the data and safety monitoring plan associated with this study. If the
research study involves multiple sites, the plan must address both a local and
research study involves multiple sites, the plan must address both a local and
central review process.
central review process.
The study results will be monitored on a bi-monthly basis to ensure appropriate data collection
and study procedures justify the continuation of the study. The PI will ensure that the IRB, and
when applicable (i.e., if felt to be related to administration of a radioactive drug) the RDRC, is
immediately notiﬁed of any adverse event. Dr. Narendran is routinely notiﬁed of any medical
concerns during the conduct of the study. The PET methodology, including the arterial blood
draw procedure, is reviewed at least monthly to ensure that risk is minimized and participant
comfort maximized. Expected and unexpected serious (including fatal) adverse reactions and
major unresolved disputes between the research investigator(s) and the research participant or
between research investigator(s) will be expeditiously reported to the IRB and, when applicable
(i.e., if felt to be related to administration of a radioactive drug) the RDRC as per Chapter 3,
Section 3.3 of the IRB reference manual. At the time of renewal, the IRB will be provided with a
summary indicating the frequency of the monitoring, cumulative adverse event data,
information regarding participant safety or ethics changes, conﬁdentiality issues, beneﬁt-to-risk
changes and recommendations on continuing, changing or terminating the study. None of the
investigators have a conﬂict of interest with the radiotracer ([C-11]NOP-1A) or hydrocortisone
being used in this study.
 
 
     [reviewer notes¬] 
Section 5 - Potential Risks and Beneﬁts of Study Participation
Section 5 - Potential Risks and Beneﬁts of Study Participation
5.14
5.14
What precautions will be used to ensure subject privacy is respected? 
What precautions will be used to ensure subject privacy is respected? (e.g. the
research intervention will be conducted in a private room; the collection of sensitive information
about subjects is limited to the amount necessary to achieve the aims of the research, so that
no unneeded sensitive information is being collected, drapes or other barriers will be used for
subjects who are required to disrobe)
 
 


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1) All research intervention will be conducted in a private room.
2) The collection of sensitive information about subjects is limited to the amount necessary to
achieve the aims of the research, so that no unneeded sensitive information is being collected.
3) Drapes or other barriers will be used for subjects who are required to disrobe for procedures,
such as EKG, etc.
5.15
5.15
What precautions will be used to maintain the conﬁdentiality of identiﬁable
What precautions will be used to maintain the conﬁdentiality of identiﬁable
information? 
information? (e.g., paper-based records will be kept in a secure location and only be
accessible to personnel involved in the study, computer-based ﬁles will only be made available
to personnel involved in the study through the use of access privileges and passwords, prior to
access to any study-related information, personnel will be required to sign statements agreeing
to protect the security and conﬁdentiality of identiﬁable information, whenever feasible,
identiﬁers will be removed from study-related information, precautions are in place to ensure
the data is secure by using passwords and encryption, because the research involves web-
based surveys, audio and/or video recordings of subjects will be transcribed and then destroyed
to eliminate audible identiﬁcation of subjects)
 
1) To minimize these risks, a study code number will be assigned and no subject will be
identiﬁed by name. This will ensure subject conﬁdentiality. The study code will be used to
identify all data. The code containing the subject’s name and number will be kept secure by the
Study Investigator in a password protected electronic database behind UPMC ﬁrewall at PET
Facility. All the investigator's research personnel will be allowed access to information on a need
to know basis only.
2) All data collected will be kept in locked ﬁle cabinets in a locked and secured area.
3) All imaging data stored in electronic archives such as computers are de-identiﬁed, password
protected and/or stored on the PET/MR imaging facility servers that are behind a UPMC Fire
wall. Images that are acquired do not typically have any identifying data of the subjects
entered. They are de-identiﬁed by the technician and assigned a code--the link between this
code and imaging data ﬁles are maintained in a protected PET facility database.
 
 
 
 
 
5.16
5.16
If the subject withdraws from the study, describe what, if anything, will happen to
If the subject withdraws from the study, describe what, if anything, will happen to
the subject’s research data or biological specimens.
the subject’s research data or biological specimens.
If the subject withdraws from the study their clinical and imaging data will be de-identiﬁed.
These de-identiﬁed data that was collected up until the time they withdrew consent may
continued to be cited in analysis and/or publications with reasons for withdrawal of consent .
Biological specimens such as blood samples that are stored for future analysis will be destroyed
after the subject withdraws consent because there is no use for them unless the subject
completes the entire imaging protocol.  
5.17
5.17
Following the required data retention period, describe the procedures
Following the required data retention period, describe the procedures utilized to
utilized to
protect subject conﬁdentiality. 
protect subject conﬁdentiality. (e.g., destruction of research records; removal of
identiﬁers; destruction of linkage code information; secured long-term retention)
All research records will be kept in locked, secured facilities for at least 7 years or until the
investigators have completed analyzing and publishing the data, whichever occurs later. After
that time, data will be secured for long-term retention (this will include PET and MRI images that
will be archived in the PET Facility servers).


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Section: Section 6 - Costs and Payments
     [reviewer notes¬] 
 
6.1
6.1
Will research subjects or their insurance providers be charged for any of the
Will research subjects or their insurance providers be charged for any of the
procedures (e.g., screening procedures, research procedures, follow-up
procedures (e.g., screening procedures, research procedures, follow-up
procedures) performed for the purpose of this research study?
procedures) performed for the purpose of this research study?
* 
*  
No 
  
     [reviewer notes¬] 
6.2
6.2
Will subjects be compensated in any way for their participation in this research
Will subjects be compensated in any way for their participation in this research
study?
study?
* 
*  Yes
6.2.1
6.2.1
Describe the amount of payment or other remuneration offered for
Describe the amount of payment or other remuneration offered for
complete participation in this research study.
complete participation in this research study.
Healthy Control Participants (HC) will be paid up to $1100 for their participation in this
protocol.
6.2.2
6.2.2
Describe the amount and term of payment or other remuneration that will be
Describe the amount and term of payment or other remuneration that will be
provided for partial completion of this research study.
provided for partial completion of this research study.
Healthy Control Participants (payment breakdown for the total of $1100)
1) One hundred dollars ($100.00) will be paid for completing all listed screening procedures
(SCID, psychiatric rating scales, physical exam, blood work);
2) Fifty dollars ($50.00) will be paid for completion of the structural MRI scan;
3) One hundred dollars ($100.00) for the arterial line;
4) Two hundred and ﬁfty dollars ($250.00) for completion of each [C-11]NOP-1A PET scan
($250.00 x2 =$500);
5) One hundred and ﬁfty ($150.00) for completion of the hydrocortisone challenge;
6) Two hundred dollars ($200.00) bonus for completion of all the above listed procedures.
In addition, any parking fees or transportation costs related to participation in this study will be
reimbursed.
 
  


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Section: Section 7 - Qualiﬁcations and Source(s) of Support
     [reviewer notes¬] 
7.1
7.1
Summarize the qualiﬁcations and expertise of the principal investigator and listed
Summarize the qualiﬁcations and expertise of the principal investigator and listed
co-investigators to perform the procedures outlined in this research
co-investigators to perform the procedures outlined in this research
study.               
study.               
Rajesh Narendran, M.D. is an Associate Professor in Radiology and Psychiatry. Dr. Narendran
completed a schizophrenia research fellowship at Columbia University, NY, NY prior to coming to
the University of Pittsburgh. He has extensive experience in PET imaging of brain receptors in
humans. He is currently a research psychiatrist at the University of Pittsburgh PET Facility. Dr.
Narendran is also a fully licensed PA physician and a board-certiﬁed psychiatrist who treats
drug/alcohol addicted and psychiatric patients at the UPMC WPIC re:solve crisis center. He has
15+ years of experience in clinical psychiatry and continues to be active in clinical practice.
Since 2001, he has published numerous clinical research studies in cocaine use disorder and
alcoholism in leading clinical psychiatric journals, such as American Journal of Psychiatry and
Biological Psychiatry.
N. Scott Mason, Ph.D. is an Associate Professor of Radiology. Dr. Mason has research interests
in the development and application of radiosynthetic methods in the development of PET
radioligands for the various receptor systems. Recent efforts have included the development of
radioligands for use in PET oncology applications, as well as the application of PET in the area of
developmental biology. He will be responsible for the production and quality control of [C-
11]NOP-1A.
James M. Mountz, M.D., Ph.D. is a Professor of Radiology, Division of Nuclear Medicine, and
Director of NeuroNuclear Medicine. He has been involved in imaging and stroke rehabilitation for
over 20 years.
 
     [reviewer notes¬] 
7.2
7.2
Indicate all sources of support for this research study.
Indicate all sources of support for this research study.
* 
* 
Selections
Federal: Upload a copy of the entire grant application (including the cover sheet)
(including the cover sheet) if our site
is the awardee institution; for federal contracts, upload a copy of the research plan
 
If Federal
Federal support, provide the sponsor information:
 
Federal
sponsor
Grant Title
Grant
number
Awardee
institution
Federal grant
application
View NIH/NIDA
In vivo imaging of corticotropin
releasing factor-nociceptin receptor
interactions
DA042633 Univ of
Pittsburgh
R21
DA042633.pdf(0.01)
 
For projects not supported by a federal grant, upload the research plan that was submitted for
funding:


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Name Modiﬁed Date
If Industry
Industry support, provide the sponsor information and level of support:
If Foundation
Foundation support, provide the sponsor information:
If Other
Other support, provide the support information and level of support:
     [reviewer notes¬] 
 
7.3
7.3
Is this study funded in part or whole by a PHS Agency?
Is this study funded in part or whole by a PHS Agency?
 * 
*  Yes 
 
Does any investigator* involved in this study (select all that apply):
Does any investigator* involved in this study (select all that apply):
 
Name
A. 
A. Have a ﬁnancial interest (aggregated value of equity and remuneration** during the
past or next twelve months) in a publicly-traded entity
publicly-traded entity that either sponsors*** this
research or owns the technology being evaluated or developed that exceeds $5,000 but
$5,000 but
not $10,000
not $10,000?
B. 
B. Have a ﬁnancial interest (aggregated value of equity and remuneration during the past
or next twelve months) in a publicly-traded entity
publicly-traded entity that either sponsors this research or
owns the technology being evaluated or developed that exceeds $10,000
$10,000?
C. 
C. Receive remuneration (during the past or next twelve months) from a non-publicly
non-publicly
traded entity
traded entity that either sponsors this research or owns the technology being evaluated
or developed that exceeds $5,000 but not $10,000
$5,000 but not $10,000?
D. 
D. Receive remuneration (during the past or next twelve months) from a non-publicly
non-publicly
traded entity
traded entity that either sponsors this research or owns the technology being evaluated
or developed that exceeds $10,000
$10,000?
E. 
E. Have equity in a non-publicly traded entity
non-publicly traded entity that either sponsors this research or
owns the technology being evaluated or developed?
F. 
F. Receive reimbursement or sponsorship of travel expenses (for one trip or a series of
trips during the past or next twelve months) by an outside entity that either sponsors this
research or owns the technology being evaluated or developed that exceeds $5,000
$5,000?
G. 
G. Have rights as either the author or inventor of intellectual property
intellectual property being evaluated
or developed in this research that is the subject of an issued patent or has been optioned
or licensed to an entity?
H. 
H. Have an ofﬁcer or management position**** with a Licensed Start-up Company
Licensed Start-up Company
overseen by the COI Committee that either sponsors this research or owns the technology
being evaluated or developed?
I. 
I. Receive compensation of any amount when the value of the compensation would be
affected by the outcome of this research, such as compensation that is explicitly greater


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for a favorable outcome than for an unfavorable outcome or compensation in the form of
an equity interest in the entity that either sponsors this research or owns the technology
being evaluated or developed?
None
None of the above options apply and there are no other ﬁnancial conﬂicts of
 of the above options apply and there are no other ﬁnancial conﬂicts of
interest in the conduct of this research.
interest in the conduct of this research.
*Investigator
*Investigator means the PI, co-investigators, and any other member of the study team,
regardless of title, who participates in the design, conduct, or reporting of this research, as well
as his/her spouse, registered domestic partner, dependents, or other members of his/her
household. The PI is responsible for ensuring that s/he and all other relevant
The PI is responsible for ensuring that s/he and all other relevant
members of the study team review the above questions describing Signiﬁcant
members of the study team review the above questions describing Signiﬁcant
Financial Interests. 
Financial Interests. 
**
**such as salary, consulting fees, honoraria, or paid authorship
***
***through the provision of funds, drugs, devices, or other support for this research
****
****Such as serving on the Board of Directors or Board of Managers or a position that carries a
ﬁduciary responsibility to the company (e.g., CEO, CFO, CTO, or CMO).
  


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Section: Supporting Documentation
     [reviewer notes¬] 
 
Supporting Documentation Section
Supporting Documentation Section
References and Other Attachments
References and Other Attachments
 
Additional documents:
Name
Modiﬁed Date
Version
Data security
form
7/26/2016
4:28 PM
0.01
R21
DA042633.pdf
3/11/2016
3:38 PM
0.01
References.pdf 3/11/2016
3:40 PM
0.01
 
Please use the Add button to the left to upload additional
documents if needed.
     [reviewer notes¬] 
ClinicalTrials.gov is a registry and results database of publicly and privately supported
ClinicalTrials.gov is a registry and results database of publicly and privately supported
clinical studies of human participants conducted around the world
clinical studies of human participants conducted around the world.
"Applicable clinical trials" are required by 
by federal law
federal law to be registered in ClinicalTrials.gov.
Applicable Clinical Trials (ACTs) are studies that meet the following criteria:
The study is an interventional study AND 
The study intervention is a drug, biologic, medical device, radiation or genetic AND
The Study is not Phase 0 or 1 AND
The study has at least one site in the United States or is conducted under an investigational new
drug application or investigational device exemption
NIH Policy
NIH Policy
Effective January 18, 2017, revised NIH Policy requires that all clinical trials funded in whole or in part by
the NIH be registered and results information posted on ClinicalTrials.gov. 
As deﬁned by the NIH, a clinical trial is:
A research study in which one or more human subjects are prospectively assigned to one or more
interventions (which may include placebo or other control) to evaluate the effects of those
interventions on health related biomedical or behavioral outcomes.
The NIH Policy extends beyond the Food and Drug Administration Amendment Act (FDAAA 801)
requirements in that it requires registration and results reporting of:
clinical trials of behavioral, surgical and other types of health and medical interventions


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phase 1 studies of drugs and biological products
small feasibility studies of device products 
Failure to submit all required registration and results information requested on ClinicalTrials.gov can
jeopardize University grant funding, the future funding of the grantee and subject the University of
Pittsburgh to future monetary penalties.
In addition, to promote transparency of the clinical trials process, the International Committee of Medical
Journal Editors (ICMJE) has established a policy requiring the entry of clinical trials in a public registry,
such as ClinicalTrials.gov, prior to subject enrollment as a condition of consideration for publication of
the trial results.
* 
* Based on the above information, will this study be registered in ClinicalTrials.gov?
Based on the above information, will this study be registered in ClinicalTrials.gov?
Yes 
 
Who will serve as the Responsible Party?
Who will serve as the Responsible Party? UPMC/Pitt Investigator or IND/IDE Pitt Sponsor 
Why are you registering your study?
Why are you registering your study? (Check all that apply)
It is strongly encouraged by the NIH
If you are not yet registered and need to establish an account for the PI or other research staff that
may need to access the record, please send an email to the  University of Pittsburgh PRS administrator
at ctgov@pitt.edu with the following information for each individual:
Full name
Telephone number
Pitt or UPMC email address
If you have any questions or concerns, please email us at ctgov@pitt.edu. 
To ﬁnd out additional information about how to register your study go to:
https://www.clinicaltrials.gov/ct2/manage-recs/how-register  
 
  

ICF_001.pdf: 
COVER PAGE 
 
NCT number: 03302416 
 
Official Title: In Vivo Imaging of Corticotropin-releasing Factor - 
Nociceptin Receptor Interactions 
 
  
 
 
 
Document date: 11/13/2018 


                                                                                                    Page 1 of 16                                            
 
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
 
 
 
CONSENT TO ACT AS A PARTICIPANT IN A RESEARCH STUDY 
  
Title of Study:  In vivo imaging of corticotropin-releasing factor-nociceptin 
receptor interactions  
 
PRINCIPAL INVESTIGATOR: 
Rajesh Narendran, M.D.  
Associate Professor of Radiology and Psychiatry 
B-938 PUH, PET Facility 
200 Lothrop Street 
Pittsburgh, PA 15213 
(412) 647-0736   
 
CO-INVESTIGATORS 
James M. Mountz, Ph.D. 
Professor of Radiology 
B-938 PUH, PET Facility 
200 Lothrop Street 
Pittsburgh, PA 15213 
(412) 647-0736 
N. Scott Mason, Ph.D. 
Associate Professor of Radiology 
B-938 PUH, PET Facility 
200 Lothrop Street 
Pittsburgh, PA 15213 
(412) 647-0736 
 
 
 
 
 
Funding Source: National Institute on Drug Abuse (NIDA) 


                                                                                                    Page 2 of 16                                            
 
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
Why is this research being done? 
This study is being done to examine an interaction between two proteins in the brain-- 
corticotropin-releasing hormone (CRH) and nociceptin. CRH and nociceptin are used by the 
brain to pass messages between brain cells. Both these proteins seem to play an important role in 
regulating pain, stress, and reward function. Studies have reported abnormalities in both these 
proteins in animal models of addiction. Thus, we are interested in developing a methodology to 
study this interaction in humans. 
     
Positron emission tomography (PET) is a nuclear medicine medical imaging technique that 
produces 3-dimensional images of the body.  PET scanning will be used to examine nociceptin 
receptor levels in your brain after the injection of the radiotracer [11C]NOP-1A. The PET scan 
works by measuring a very small amount of this radioactive substance in your brain.  PET scans 
need to be corrected for the partial blockage of signal caused by body tissues.  The PET signal 
correction can be measured by a low radiation dose computed tomography (CT) scan.  A CT 
scan is a method to take pictures of your brain using X-rays. You will undergo two CT scans and 
two [11C]NOP-1A PET scans in this study. In addition, following the first [11C]NOP-1A  
PET/CT scan, you will be given an intravenous injection of  hydrocortisone before undergoing 
the second [11C]NOP-1A PET/CT scan. Hydrocortisone increases the amount of CRH in the 
brain. It is used in this study so that we can examine the effect of CRH on nociceptin receptors. 
By comparing the two [11C]NOP-1A PET/CT scans (before and after hydrocortisone) done in the 
same day, we can understand more about how CRH and nociceptin interact in the brain. This 
interaction is likely critical to one's ability to manage stress and experience anxiety symptoms.  
 
Who is being asked to take part in this research study? 
You are being asked to participate in this study because you are a healthy individual. Participants 
in this study may be males or females, 18 – 40 years of age. Females cannot be pregnant or 
breast feeding an infant. This study is being performed on a total of 20 healthy individuals at this 
medical center. 
 
What procedures will be performed for research purposes? 
All study procedures, assessments, and clinical research evaluations are done for research 
purposes.  If you decide to take part in this study, you will undergo the following research 
procedures that are not part of your standard medical care: 
 
Screening Procedures:  
Procedures to determine if you are eligible to take part in a research study are called “screening 
procedures”. This will require you to come to the PET Facility (UPMC Presbyterian Hospital, B-
wing 9th floor) for approximately 6 hours.  For this research study, the screening procedures 
include: 
 
1. You will receive a comprehensive psychiatric and physical evaluation before entering the 
study. The psychiatric evaluation will include several standard questions, computerized 


                                                                                                    Page 3 of 16                                            
 
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
tasks, and open-ended questions about your mental health. The physical evaluation will 
include a physical exam, heart tracing (electrocardiogram), urinalysis, and blood tests 
(approximately 35 ml or 2.5 tablespoons). The blood test will make sure your body 
chemistry is normal and if you are pregnant (women only). The urine analysis will check 
if there are drugs of abuse in your system. You may also be asked questions pertaining to 
the medical and psychiatric history of your family members without specific identifying 
information. The physical exam will be done by one of our doctors. 
 
2. If you are a woman who could possibly be pregnant, you will need to have a pregnancy 
test prior to participation on the study day. A blood sample will be taken for this 
pregnancy test at screening and a urine sample on the PET scan day. Pregnant women, or 
women who are currently breast-feeding an infant, will not be allowed to take part in this 
study. 
 
3. The screening evaluations (6 hours) will need to be completed prior to the actual PET 
scanning studies. The investigators will spread this 6-hour screening evaluation over 
multiple days, if necessary, to accommodate your schedule. 
 
Experimental Procedures: 
Once you qualify to take part in this research study, you will be required to come in to UPMC 
Presbyterian University Hospital (PUH) a minimum of 2 times to complete the imaging related 
experimental procedures: Once for MRI, which will take 2 hours, and once for PET/CT scans, 
which will take 8 hours. If you prefer, an effort will be made by the research team to complete 
the MRI and PET/CT scans in a single day. However, completing both the MRI and PET/CT 
scans in a single day will increase the duration of this visit to 10 hours. You will undergo the 
following imaging-related experimental procedures: As alcohol, drugs, and some medications 
(over the counter or prescription) may alter your brain chemistry and interact with 
hydrocortisone, you will be required not to use any of them 48 hours prior to the PET study. If 
you do use alcohol, drugs, or medications, please notify the research investigators. You will be 
required to pass a urine drug test on the day of the PET scan. 
 
MRI scan day 
The MRI scan will be done at the UPMC PUH MR Research Facility. A structural magnetic 
resonance imaging (or MRI) system will be used to take pictures of your brain before the PET 
scanning is done. MRI is a diagnostic test that produces pictures that look very much like x-ray 
pictures. A MRI machine, or scanner, uses a large magnet with no radioactive substances. The 
MRI scanner is a large tunnel-like machine. You will receive a urine pregnancy test to confirm 
that you are not pregnant for women who could possibly be pregnant. You will lie on a table that 
will move you into the tunnel for about 30 minutes. You will be required to lie still during the 
scan. The scanner makes loud, banging sounds during the study, but you will still be able to talk 
to and hear responses from the technician who is performing the test.  MRI is routinely used in 
medical practices.   


                                                                                                    Page 4 of 16                                            
 
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
 
Because of the powerful magnet, you will be instructed to remove all jewelry and any other 
objects that might contain metal before entering the scan room. You will also be asked, by a 
nurse in the MR center, a list of questions about earlier activity that may put you at risk for 
having metal in your body.  If there is a possibility of metal being present in your body, you will 
not be able to participate in this study. The MRI scan will require your lying on a narrow table 
that slides into a small tunnel. Because you must lie with your head and neck inside the tunnel, it 
is possible that you might become anxious and frightened in the enclosed space. Some people 
might have had such reactions of anxiety and fear in similar situations that involved enclosed 
spaces in the past.  Should you become anxious or frightened during the study, or for any reason 
feel that you cannot remain in the scanner, the study will be stopped and you will be removed 
from the scanner.  
 
PET/CT and hydrocortisone scan day 
You will undergo the PET studies with [11C]NOP-1A before and after the administration of 
hydrocortisone on this day. These procedures will be done at the UPMC PUH PET Research 
Facility.   
 
PET scanning of the brain works by measuring a small amount of radioactive chemical 
(radiotracer) in different parts of the brain. You will be given the radiotracer before each PET 
scan. The amount of radiotracer is measured in “mCi” amounts (as a drink is measured in 
ounces). You will be given 12 mCi or less of the radiotracer for each scan. The radiotracer 
[11C]NOP-1A used in this study is not currently approved by the FDA (Food and Drug 
Administration); however, its use in this research study is considered to be generally safe and 
effective and is approved by the University of Pittsburgh Radioactive Drug Research Committee 
in accordance with FDA regulations (21 CFR 361.1). You will receive two [11C]NOP-1A 
PET/CT scans as part of this research study, once before and once after you are injected with 
hydrocortisone. 
 
Hydrocortisone is measured in "milligrams, mg". The amount of hydrocortisone you receive will 
be adjusted according to your body weight (measured in kilograms, Kg). You will be injected 
with 1 mg/kg body weight of hydrocortisone via an intravenous (IV) line. Although IV 
hydrocortisone is currently approved by the FDA for the treatment of severe allergic reactions, 
severe asthma, adrenal gland insufficiency, certain infections, etc., it is not approved for the use 
proposed in this research study. You will receive one IV injection of hydrocortisone 1 mg/kg as 
part of this research study. 
 
You will undergo the following procedures on this day:  
 
• On arrival for the PET scanning procedures, you will receive a urine pregnancy test to 
confirm that you are not pregnant (for women who could possibly be pregnant); and a 
urine drug test and alcohol breath-analyzer to ensure you have not used any street drugs 


                                                                                                    Page 5 of 16                                            
 
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
or alcohol prior to the scan. Your blood pressure and heart rate will be checked to ensure 
that you are safe to receive hydrocortisone before you undergo any scan procedures.  
 
• You will not be able to smoke during the study. However, you can drink water or non-
caffeinated beverages. Light snacks will be provided during the study. 
 
• Trained medical personnel will use a needle to place a small plastic tube in a vein in your 
arm.  (called an “IV”). This small plastic tube will be used to inject the radiotracers and 
hydrocortisone during the study.  
 
• Following this, an anesthesiologist will place another plastic tube in the artery in your 
wrist (called an “arterial line”) so that the blood can be drawn during the study.  Before 
inserting the plastic tube, the doctor will first use an anesthetic (lidocaine) to numb your 
wrist area.  
 
• A Empatica E4 wrist band that resembles a watch will be placed on your wrist that does 
not have the arterial line. The purpose of this E4 wrist band is to monitor various 
measures of stress that affect your body (for example, heart rate and rhythm variations, 
skin electrical variations, etc.) during scan procedures.  
 
• You will be asked to lie on your back and remain very still on a PET scanner table during 
the scan.  
 
• After you are positioned on the scanning table as comfortably as possible, a low-dose CT 
scan will be performed in a few minutes. 
 
• [11C]NOP-1A will then be injected into your body through the tube in your vein. 
 
• [11C]NOP-1A PET scan #1 (baseline condition) will begin at the time of radiotracer 
injection and last approximately 70 minutes. 
 
• After this scan, you will be allowed to take a short break to get out of the scanner 
(approximately 5-10 min). 
 
• You will be connected to an automated blood pressure machine that will monitor your 
blood pressure and heart rate.  
 
• You will then be injected with hydrocortisone 1 mg/kg through the IV line. After the 
administration of hydrocortisone, your blood pressure and heart rate will be recorded 
every ten minutes for the first 60 minutes and then every 15 minutes (for 2 hours). In 
addition, you will be asked several questions about how you are feeling while on 


                                                                                                    Page 6 of 16                                            
 
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
hydrocortisone. 
 
• You will be asked to lie back in the PET scanner and we will perform another low-dose 
CT scan identical to the first CT scan (approximately 3.5 hours after hydrocortisone). 
 
• This will be followed by [11C]NOP-1A PET scan #2 (post-hydrocortisone condition), 
which will be identical to the first PET scan (approximately 70 minutes) and occur 
approximately 3.5 hours after you were administered the hydrocortisone. 
 
• Blood samples will be drawn for the entire time (20 samples during the first 2 minutes 
and another 15 samples during the next 70 minutes) that you are in the PET scanner for 
each PET scan. No more than 130 mL (about 9 tablespoons) of blood will be taken from 
your body.  The samples will be used to determine the amount and fate of the radiotracer 
in blood over time (how much sticks to protein, how much broken down by the body). 
These samples will also be used to measure stress hormones such as cortisol that are 
present in your blood.  
 
• Following the completion of the hydrocortisone and scan procedures, you will receive a 
physical exam and a mental status exam. These exams, as well as your blood pressure, 
heart rate and heart tracing (electrocardiogram), will need to be within an acceptable safe 
range prior to your discharge home. 
 
• You will be asked to avoid activities that require strain on your wrist for 36 hours. This is 
to prevent bleeding from the area where the tube in your artery was placed. 
 
• You will be asked to avoid the use of alcohol or drugs for 36 hours, because it may 
interact with the hydrocortisone. 
 
Follow-up Procedures:  
A follow-up telephone call will be made to you by the research team approximately 2-7 days after 
the last scan to inquire about any adverse events you may have encountered related to the scans or 
the hydrocortisone.  
 
What are the possible risks, side effects, and discomforts of this research study? 
As with any experimental procedure, there may be adverse events or side effects that are 
currently unknown and certain of these unknown risks could be serious or life threatening. 
Possible risks of this research study may be due to the hydrocortisone, the arterial catheter,  the 
radiation exposure from the PET and CT scan, the [11C]NOP-1A, the venous catheter and blood 
sampling, study questions and breach of confidentiality.   
 


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Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
Risk of hydrocortisone: Hydrocortisone is similar to a natural hormone produced by your 
adrenal glands. It is a corticosteroid drug used to relieve inflammation (swelling, heat, redness 
and pain).  
 
Common side effects of hydrocortisone include headache, nausea, vomiting, dizziness, insomnia, 
restlessness, depression, anxiety, unusual moods, increased sweating, increased hair growth, 
reddened face, acne, thinned skin, easy bruising, tiny purple spots, and irregular (or absent) 
menstrual periods. Typically, these symptoms tend to be mild and go away with time.  
 
Hydrocortisone can also cause skin rash, swollen feet, ankles, legs, vision problems, eye pain, 
muscle pain and weakness, black tarry stools, unusual bleeding and severe depression.  These 
symptoms could be indicative of severe allergic reaction (anaphylaxis), heart problems 
(abnormal heart rhythm, heart attacks, heart failure, etc.,), serious skin problems, precipitation of 
diabetes, kidney and liver problems (fluid retention, abdominal distension, bowel/bladder 
problems etc.,), seizure disorder, fractures of hip and shoulder bones, seizure disorder, 
psychiatric problems and eye problems (glaucoma, exophthalmos).  
 
Hydrocortisone can also dampen your immune system. Thus, it is necessary for you not to 
undergo vaccination and avoid exposure to medical procedures that may increase your risk 
fungal or viral infections immediately before and after the hydrocortisone infusion.  
 
A study physician will be available at all times to help you during and after you are injected with 
hydrocortisone.  If you experience minor complications following the hydrocortisone injection, 
the study physician will manage your symptoms. This may involve administering intravenous 
fluids to manage your blood pressure, administering lorazepam for anxiety, etc.  If you develop 
or experience any of the serious or extremely serious side effects to the hydrocortisone, you will 
be taken to the UPMC Presbyterian ER for medical treatment.   
 
Hydrocortisone has been shown to interact with several prescription and non-prescription 
medications. Therefore, it is important that you inform the study investigators of any medications 
you take before and immediately after the study.  
 
Lorazepam is an anti-anxiety medication. This may be used as a rescue-medication in this study 
if you experience increased anxiety symptoms following the hydrocortisone challenge. The most 
commonly noted adverse events associated with lorazepam are sedation , dizziness, weakness, 
and unsteadiness. Rarely, a serious allergic reaction may occur which would include: rash, 
itching, swelling, severe dizziness, trouble breathing. 
 
Risk of arterial catheters: There is a very rare risk of complication from the arterial line, 
including slight pain, swelling, bruising at the puncture site, dizziness, fainting, bleeding, 
infection, or blood clot.  The formation of such blood clots as a solid swelling (hematoma) in the 
nearby skin, soft tissue or muscle in your wrist could sometimes lead to pain. In most cases, 


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     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
these hematomas resolve by themselves and are manageable with over the counter pain meds and 
warm compresses. However, in rare cases, they may need to be surgically removed to alleviate 
this pain.  There is also a very rare risk of cutting off circulation to your hand, which could result 
in the need for surgical repair or, in rare instances, could result in the loss of use of part or all of 
the hand. These complications are rare and usually occur in medically ill patients who have the 
arterial line in their wrists for several days.  In contrast, the arterial line will remain in your arm 
for several hours for this study. You should also be aware that repeated placements of IVs or 
arterial lines can increase the risk of discomfort or complications. 
 
Lidocaine, an FDA-approved local anesthetic (numbing medicine), will be used to decrease the 
discomfort of having the arterial line placed. The use of Lidocaine may result in mild reactions 
including a metallic taste, ringing in the ear, and rarely allergic reactions.  If you know you are 
allergic to Lidocaine or Novocain, commonly used in dental procedures, please tell the 
investigator. The symptoms of an allergic reaction would include excessive pain, redness or 
swelling near the site of injection, a body rash after injection, or wheezing and difficulty 
breathing after injection.   
 
No more than 165 ml (about 12 tablespoons) of blood will be drawn during the entire study. This 
total amount of blood drawn is less than a typical blood donation and unlikely to cause any 
serious health risks. 
 
Placement of arterial lines for PET research at the University of Pittsburgh has been performed 
over 1000 times without serious complications such as ischemia (decrease in blood supply) or 
permanent injury. Only experienced medical personnel place these arterial lines to minimize 
these risks. 
 
Risks of Radiation Exposure: The study procedures will result in exposure to radiation from 
the CT component of the PET/CT scans and from the two injections (12 mCi/injection) of the 
[C-11]NOP-1A. The total amount of radiation exposure that you will receive from the PET scan 
procedures is equivalent to a uniform whole body dose of 0.42 rem (a unit of radiation exposure). 
This dose is less than 10 % or 1/10th of the annual whole body radiation exposure (5 rems) 
permitted for radiation workers by federal regulations. Each additional CT scan, if required, will 
result in a uniform whole body radiation dose of 0.016 rem. There is no known minimum level 
of radiation exposure that is recognized as being totally free of the risk of causing genetic defects 
(cellular abnormalities) or cancer.   
 
Studies involving radiation are discouraged during pregnancy because of potential risk to the 
fetus. Hence, it is important that you not become pregnant within a few days prior to your 
participation in the PET scanning procedures (which would not be detected by a pregnancy test) 
or during your participation in the PET scanning procedures (if performed over multiple days).  
Avoiding sexual activity is the only certain method to prevent pregnancy. However, if you 
choose to be sexually active, you should use an appropriate “double barrier” method of birth 


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     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
control (such as female use of a diaphragm, intrauterine device (IUD), or contraceptive sponge, 
in addition to male use of a condom) or the female should be using prescribed “birth control” 
pills, injections, or implants at least two weeks prior to the PET/CT scans. At screening and the 
day of the PET scan, women must have a pregnancy test showing negative results. Women who 
are currently nursing will not be permitted to participate in this study.   
 
The risk associated with the amount of radiation exposure you will receive during this research 
study is considered low and comparable to everyday risks.  Because the investigators assume that 
this study represents the only research exposure to radiation that you will be exposed to, it is 
important that you inform the investigators if you have participated in other research studies 
during the past year or if your job results routinely in exposure to radiation.  
 
Risk of [11C]NOP-1A: There is a rare risk you may experience an allergic reaction such as rash, 
shortness of breath and itching from the radiotracer injection of [11C]NOP-1A. 
 
Risks of venous catheter and venous blood sampling: There is a rare risk associated with the 
chance of infection and a more common risk of slight bruising, bleeding, soreness, dizziness and 
fainting associated with taking blood from a vein. 
 
Risks of MRI: If you are known to have metal inside your body, e.g., aneurysm clips or 
pacemakers, you will be excluded from the study because the magnet in the MR scanner can 
cause these to move. Participants with dental fillings can be studied without risks. Infrequently, 
heart rhythm disturbances can arise in those who have previous heart rhythm abnormalities. 
Infrequently people become claustrophobic (highly fearful of the small space) while in the 
machine.  If you experience such sensation, the staff will stop the procedure immediately and 
you will be quickly removed from the scanner. During the MRI, you will be in voice contact 
with the staff at all times.  
 
Risks of the Study Questions: We will be asking you many questions concerning your feelings, 
emotions, and behaviors at different stages of the study (i.e., screening day and PET/CT scan 
day). Assessments are done so that we can monitor your physical and emotional states during the 
study.  The only infrequent risk to you from these questions is that sometimes people can feel 
uncomfortable about discussing their personal issues. On the other hand, most people find this 
process to be a very positive experience.  However, if for any reason you do not want to share 
your feelings and emotions on certain issues during the study, let the interviewers know and they 
will stop asking further questions.   
 
Risks of Breach of Confidentiality: Breaches in confidentiality could impact future insurability, 
employability if there is a medical or psychiatric illness that you may have that may be exposed 
inadvertently during the screening process.  To minimize these risks, a study code number will 
be assigned to you so you will not be identified by your name. This will ensure your 


                                                                                                    Page 10 of 16                                            
 
           
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     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
confidentiality. The study code will be used to identify your data.  All data collected will be kept 
in locked file cabinets in a locked and secured area. 
 
What are possible benefits from taking part in this research study? 
You will not receive any direct benefit from your participation in this research study. It is 
possible the imaging methods developed in this study will be used to study brain chemistry in 
psychiatric and neurological illnesses in the future.  
 
If I agree to take part in this research study, will I be told of any new risks that may be found 
during the course of the study? 
You will be promptly notified if any new information develops during the conduct of this 
research study, which may cause you to change your mind about continuing to participate. 
 
Will my insurance provider or I be charged for the costs of any procedures performed as part 
of this research study? 
None of the services and/or procedures (MRI, PET Scan, blood tests, hydrocortisone or 
examinations) you receive during this research study will be billed to you or your health 
insurance. If you get a bill or believe your health insurance has been billed for something that is 
part of the study, notify a member of the research team or UPMC Patient Billing Services. 
 
Will I be paid if I take part in this research study? 
You may receive up to $1100 for taking part in this study.  If you have completed all of the 
written assessments, the interview with the physician, the physical exam, laboratory screening 
with blood work, EKG and then ruled as not eligible for continued participation in the study or 
you decide to discontinue your participation in the study, you will be paid $100 for your time. 
You will receive $50 for completion of the structural MRI. You will receive $100 for completion 
of the arterial line. You will receive $150 for completion of the hydrocortisone. You will receive 
$250 for the completion of each PET scan in this study. You will receive a $200 bonus for 
completion of all the above listed procedures. In addition, you will be reimbursed for any 
parking fees related to your participation in this study.  
 
Payment received as compensation for participation in research is considered taxable income for 
a research subject.  If payments are more than $600 in any one calendar year, the University of 
Pittsburgh is required to report this information to the Internal Revenue Service (IRS).  Research 
subject payments exceeding $600 during any calendar year will result in a 1099 (Miscellaneous 
Income) form being issued to the research subject and a copy will be sent to the IRS. 
 
If the researchers have access to some of your data (for example, a MRI scan) from the recent 
participation in a research study with them, and decide it does not need to be repeated again, you 
will not be compensated for these procedures that are not performed (as per payment schedule 
listed above).      
 


                                                                                                    Page 11 of 16                                            
 
           
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     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
 
Who will pay if I am injured as a result of taking part in this research study? 
University of Pittsburgh researchers and their associates who provide services at the University 
of Pittsburgh Medical Center (UPMC) recognize the importance of your voluntary participation 
in their research studies.  These individuals and their staffs will make reasonable efforts to 
minimize, control, and treat any injuries that may arise as a result of this research. If you believe 
that you are injured as a result of the research procedures being performed, please immediately 
contact the Principal Investigator or a co-investigator listed on the first page of this form. 
 
Emergency medical treatment for injuries solely and directly related to your participation in this 
research study will be provided to you by the hospitals of the UPMC. It is possible that the 
UPMC may bill your insurance provider for the costs of this emergency treatment, but none of 
these costs will be charged directly to you.  If your research-related injury requires medical care 
beyond this emergency treatment, you will be responsible for the costs of this follow-up care 
unless otherwise specifically stated below.  There is no plan for monetary compensation.  You do 
not, however, waive any legal rights by signing this form. 
 
Who will know about my participation in this research study? 
Any information about you obtained from or for this research study will be kept as confidential 
(private) as possible. All paper records that could identify your involvement in this research 
study will be stored in a locked file cabinet. All electronic records that could identify your 
involvement will be stored in password-protected files. All blood samples collected during the 
scan will be stored in a locked freezer at the PET Facility. These samples that will be identified 
only by a code number will be stored till completion and analysis of all your study results (less 
than 2 years).  Your identity on these records and any blood samples collected will be indicated 
by a case number rather than by your name. Your de-identified blood samples may be sent to 
outside laboratories that perform specialized analysis (such as cortisol assays). Although it is 
highly unlikely, there is still the possibility that information on your identity could be linked 
back to your research information.  For this reason, additional protections will be taken with the 
information linking the case numbers with your identity.  For example, information linking case 
numbers to your identity will be kept separate from the research records in locked or password-
protected files. Access to your research records will be limited to the researchers listed on the 
first page of this form and authorized representatives of the University of Pittsburgh. It is also 
possible that data from this study may be shared with other investigators who are interested in 
addiction and imaging. You will not be identified by name in any publication of the research 
results. 
 
Data Sharing and Re-contacting:  
Your identifiable data (which include your clinical assessments, MRI, etc) and medical record 
information (which include your medical and psychiatric diagnosis, lab work, etc.,) will be 
shared with other imaging studies that you have consented to participate within Dr. Narendran's 


                                                                                                    Page 12 of 16                                            
 
           
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     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
research group. The sharing of such data may allow for the researchers to not have to repeat 
some of these experimental procedures on you again.   
The de-identified data (without any information that could identify you) gathered in this study 
may be combined with other similar de-identified data gathered in separate studies performed 
here at UPMC or at other research centers in a secure, password-protected database managed by 
the investigators of this study. This combined, de-identified data and (without any information 
that could identify you) may form the basis of scientific publications and may be shared in the 
future with researchers within or outside of UPMC who are interested in studying neuroimaging 
in relation to neuropsychiatric disorders.  
 
 
Will this research study involve the use or disclosure of my identifiable medical information? 
This research study will involve the recording of past, current and/or future identifiable medical 
information from your hospital and/or other outpatient records. The information that will be 
recorded will be limited to information concerning your medical history as it relates to 
inclusion/exclusion, previous MRI or CT scans, and results of any blood tests. This information 
will be used for the purpose of identifying whether you meet the conditions for participation in 
this study. 
 
This research study may result in identifiable information that will be placed into your medical 
records held at the UPMC. The nature of the identifiable information resulting from your 
participation in this research study that will be recorded in your medical record includes the 
results of pregnancy tests (for women of childbearing potential) and tests done on blood samples 
taken during the screening visit. 
 
Who will have access to identifiable information related to my participation in this research 
study? 
In addition to the investigators and funding agency listed on the first page of this authorization 
(consent) form and their research staff, the following individuals will or may have access to 
identifiable information (which may include your identifiable medical information) related to 
your participation in this research study:  
 
• The staff of the University of Pittsburgh Medical Center PET facility and MUH-CTRC 
will have access to your identifiable research information (which may include your 
identifiable medical information) for the purpose of performing the PET studies and 
monitoring done as part of this protocol. 
 
• Authorized representatives of the University of Pittsburgh Research Conduct and 
Compliance Office may review your identifiable research information (which may 
include your identifiable medical information) for the purpose of monitoring the 
appropriate conduct of this research study. 
 


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     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
• In unusual cases, the investigators may be required to release identifiable information 
(which may include your identifiable medical information) related to your participation in 
this research study in response to an order from a court of law. If the investigators learn 
that you or someone with whom you are involved is in serious danger of potential harm, 
they will need to inform, as required by Pennsylvania law, the appropriate agencies. 
 
• Authorized representatives of the U.S. Food and Drug Administration may review and/or 
obtain identifiable information (which may include your identifiable medical 
information) related to your participation in this research study because of this agency’s 
oversight of the research use of radiotracers and hydrocortisone. While the U.S. Food and 
Drug Administration understands the importance of maintaining the confidentiality of 
your identifiable research and medical information, the University of Pittsburgh and 
UPMC cannot guarantee the confidentiality of this information after it has been obtained 
by the U.S. Food and Drug Administration. 
 
• Authorized representatives of the UPMC hospitals or other affiliated health care 
providers may have access to identifiable information (which may include your 
identifiable medical information) related to your participation in this research study for 
the purpose of (1) fulfilling orders, made by the investigators, for hospital and health care 
services (e.g., laboratory tests, diagnostic procedures) associated with research study 
participation; (2) addressing correct payment for tests and procedures ordered by the 
investigators; and/or (3) for internal hospital operations (i.e. quality assurance). 
 
• Authorized representatives of the Sponsor of this research which is the National Institute 
of Health may review and/or obtain identifiable information (which may include your 
identifiable medical information) related to your participation in this research study 
because of this Sponsor’s obligation to fund and regulate this research  
 
For how long will the investigators be permitted to use and disclose identifiable information 
related to my participation in this research study? 
The investigators may indefinitely continue to use and disclose, for the purposes described 
above, identifiable information (which may include your identifiable medical information) 
related to your participation in this research study. It is University policy that all research records 
be maintained for a period of at least 7 years following final reporting or publication of a project. 
After that time, de-identified data, which include PET and MRI images will be secured for long 
term retention in the PET imaging facility electronic archives.   
 
May I have access to my medical information that results from my participation in this 
research study? 
 In accordance with the UPMC Notices of Privacy Practices document that you have been 
provided, you are permitted access to information (including information resulting from your 
participation in this research study) contained within your medical records (such as screening lab 


                                                                                                    Page 14 of 16                                            
 
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
results) filed with your health care provider unless otherwise specifically stated below. You will 
not have access to information generated by this research (such as MRI and PET scans), which is 
not part of your medical record. 
 
Is my participation in this research study voluntary?  
Your participation in this research study, to include the use and disclosure of your identifiable 
information for the purposes described above, is completely voluntary. (Note, however, that if 
you do not provide your consent for the use and disclosure of your identifiable information for 
the purposes described above, you will not be allowed, in general, to participate in the research 
study.) Whether or not you provide your consent for participation in this research study will have 
no effect on your current or future relationship with the University of Pittsburgh. Whether or not 
you provide your consent for participation in this research study will have no effect on your 
current or future medical care at a UPMC hospital or affiliated health care provider or your 
current or future relationship with a health care insurance provider. 
 
May I withdraw, at a future date, my consent for participation in this research study?   
You may withdraw, at any time, your consent for participation in this research study, to include 
the use and disclosure of your identifiable information for the purposes described above. (Note, 
however, that if you withdraw your consent for the use and disclosure of your identifiable 
information for the purposes described above, you will also be withdrawn, in general, from 
further participation in this research study.) Any identifiable research or medical information 
recorded for, or resulting from, your participation in this research study prior to the date that you 
formally withdrew your consent may continue to be used and disclosed by the investigators for 
the purposes described above. Biological samples such as blood samples will be destroyed after 
you withdraw consent because they cannot be used by the investigators unless you complete the 
PET/CT scans. 
 
To formally withdraw your consent for participation in this research study, you should provide a 
written and dated notice of this decision to the principal investigator of this research study at the 
address listed on the first page of this form. 
 
Your decision to withdraw your consent for participation in this research study will have no 
effect on your current or future relationship with the University of Pittsburgh. Your decision to 
withdraw your consent for participation in this research study will have no effect on your current 
or future medical care at a UPMC hospital or affiliated health care provider or your current or 
future relationship with a health care insurance provider. 
 
If I agree to participate in this research study, can I be removed from the study without my 
consent?  
It is possible that you may be removed from the research study by the investigators if, for 
example, you are a female and your pregnancy test proves to be positive, if you are unable to 


                                                                                                    Page 15 of 16                                            
 
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
remain abstinent from drugs and alcohol, if you are claustrophobic or can not undergo the MRI 
scan for any reason, or if your psychological tests indicate you are not appropriate for this study.   
 
Any identifiable research or medical information recorded for, or resulting from, your 
participation in this research study prior to the date that you were withdrawn from participation 
may continue to be used and disclosed by the investigators for the purposes described. 
 
 
***************************************************************************** 
 
 


                                                                                                    Page 16 of 16                                            
 
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 11/13/2018 
Renewal Date:  11/12/2019 
 
IRB #:   PRO16030242 
 
 
 
 
VOLUNTARY CONSENT:  
The above information has been explained to me and all of my current questions have been 
answered. I understand that I am encouraged to ask questions, voice concerns or complaints 
about any aspect of this research study during the course of this study, and that such future 
questions, concerns or complaints will be answered by a qualified individual or by the 
investigator(s) listed on the first page of this consent document at the telephone number(s) given. 
I understand that I may always request that my questions, concerns or complaints be addressed 
by a listed investigator.  I understand that I may contact the Human Subject Protection Advocate 
of the IRB Office, University of Pittsburgh, (1-866-212-2668) to discuss problems, concerns, and 
questions; obtain information; offer input; or discuss situations in the event that the research 
team is unavailable. By signing this form, I agree to participate in this research study and provide 
my authorization to share my medical records with the research team.  A copy of this consent 
form will be given to me. 
 
_____________________________  
____________________________ 
Participant’s Printed Name 
 
 
Participant’s Signature 
 
___________ 
Date 
 
CERTIFICATION OF INFORMED CONSENT: 
I certify that I have explained the nature and purpose of this research study to the above-named 
individual and I have discussed the potential benefits and possible risks of the study 
participation.  Any questions the individual has about this study have been answered, and we will 
always be available to address future questions, concerns or complaints as they arise. I further 
certify that no research component of this protocol was begun until after this consent form was 
signed. 
 
____________________________________ 
 
_____________________ 
Printed Name of Person Obtaining Consent  
 
Role in Research Study 
 
____________________________________ 
 
____________ 
Signature of Person Obtaining Consent 
 
 
Date