Clinical trial NCT02805972
Conditions: Obesity
Keywords: Obesity Binge eating
Sponsor: University of California, San Francisco
Start date: 2017-05-20; Completion date: 2018-07-25
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to understand how the opioid system is involved in eating behavior.

Detailed description:
Obesity is associated with greater risk for cardiovascular disease (CVD), stroke, diabetes, and mortality, and is a heterogeneous condition with various causes and thus a diversity of intervention targets. Compulsive overeating afflicts 30% of people seeking obesity treatment and increases risk for CVD factors. This trial involves two participant visits to test whether opioid blockade (Day 1 or 2, depending on randomization), compared to placebo (Day 1 or 2, depending on randomization), will elicit common symptoms of opioid withdrawal, including nausea. Participants will receive each condition on separate days.

Arms: arm 1: 4 mg / 0.1 ml Naloxone at visit 1, followed by 0.1 ml saline (Placebo) at visit 2 (with a washout period in between the two visits) arm 2: 0.1 ml saline (Placebo) at visit 1, followed by 4 mg / 0.1 ml Naloxone at visit 2 (with a washout period in between the two visits)
Interventions: intervention 1: Naloxone intervention 2: Placebo
Intervention descriptions: intervention 1: 4 mg / 0.1 ml intervention 2: 0.1 ml

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: Biology and Experience of Eating 
NCT Number: NCT02805972 
Document Date: January 16th, 2017 
Document Type: Protocol 


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Clinical Research Protocol 
OPIATE WITHDRAWAL RESPONSES TO INTRANASAL NALOXONE AS AN 
INDEX OF ALTERED ENDOGENOUS OPIOID ACTIVITY AMONG 
INDIVIDUALS WITH OBESITY: A FEASIBILITY AND EFFICACY STUDY 
 
Protocol Number: 
HECHTMASON1 
Version Date: 
15 January 2016 
Investigational Product: 
Naloxone Hydrochloride, administered intranasally 
(Intranasal Naloxone) 
IND Number: 
Pending 
Development Phase: 
Feasibility 
Sponsor: 
Frederick M. Hecht, MD 
UCSF Osher Center for Integrative Medicine 
Department of Medicine 
Professor, School of Medicine 
1545 Divisadero Street, Suite 301 
San Francisco, CA 94115 
Funding Organization: 
National Heart Blood and Lung Institute (NHLBI) 
Principal Investigator: 
Name: Ashley E. Mason, PhD 
Telephone: (847) 452 1408 
E-mail: ashley.mason@ucsf.edu 
Medical Monitor: 
Name: Frederick M. Hecht, MD 
Telephone: (415) 476 4082 (x431) 
E-mail: rick.hecht@ucsf.edu 
Coordinating Center: 
NA 
 
Approvals: 
 
 
 
Frederick M. Hecht, MD 
Professor, School of Medicine 
Date 
 
 
 
 
Ashley E. Mason, PhD 
Postdoctoral Researcher, School of Medicine 
Date 


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This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time. The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure. Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information. 
 
Principal Investigator 
Ashley E. Mason PhD 
Postdoctoral Researcher 
University of California 
San Francisco, CA 
 
 
Co-Investigators 
Frederick M. Hecht, MD 
Professor of Medicine 
University of California 
San Francisco, CA 
Elissa S. Epel, PhD 
Professor of Psychiatry 
University of California 
San Francisco, CA 
Michaela Kiernan, PhD 
Senior Research Scientist 
Stanford University 
Palo Alto, CA 


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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing Frederick M. Hecht, MD with complete and timely information, as outlined in 
the protocol. It is understood that all information pertaining to the study will be held 
strictly confidential and that this confidentiality requirement applies to all study staff at 
this site. Furthermore, on behalf of the study staff and myself, I agree to maintain the 
procedures required to carry out the study in accordance with accepted GCP principles 
and to abide by the terms of this protocol. 
 
Protocol Number: HECHTMASON1 
 
Protocol Title: OPIATE WITHDRAWAL RESPONSES TO INTRANASAL 
NALOXONE AS AN INDEX OF ALTERED ENDOGENOUS OPIOID ACTIVITY 
AMONG INDIVIDUALS WITH OBESITY: A FEASIBILITY AND EFFICACY 
STUDY 
 
Protocol Date: 15 January 2016 
 
 
 
 
Investigator Signature 
Date 
Ashley E. Mason, PhD 
UCSF Osher Center for Integrative Medicine 
Department of Medicine 
University of California, San Francisco 
1545 Divisadero Street, Suite 301 
San Francisco, CA 94115 
 
 
 
 
Sponsor / Co-Investigator Signature 
Date 
Frederick M. Hecht, MD 
UCSF Osher Center for Integrative Medicine 
Department of Medicine 
Professor, School of Medicine 
1545 Divisadero Street, Suite 301 
  San Francisco, CA 94115 
 


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TABLE OF CONTENTS 
1 
BACKGROUND ................................................................................................... 12 
1.1 
Overview of Non-Clinical Studies .......................................................................... 13 
1.2 
Overview of Clinical Studies .................................................................................. 13 
2 
STUDY RATIONALE .......................................................................................... 14 
2.1 
Risk / Benefit Assessment ....................................................................................... 15 
3 
STUDY OBJECTIVES ......................................................................................... 15 
3.1 
Primary Objective ................................................................................................... 15 
3.2 
Secondary Objectives .............................................................................................. 16 
4 
STUDY DESIGN ................................................................................................... 16 
4.1 
Study Overview ....................................................................................................... 16 
4.2 
Total Study Duration: .............................................................................................. 16 
5 
CRITERIA FOR EVALUATION ....................................................................... 16 
5.1 
Primary Efficacy Endpoint ..................................................................................... 16 
5.2 
Secondary Efficacy Endpoints ................................................................................ 16 
5.3 
Safety Evaluations .................................................................................................. 16 
6 
SUBJECT SELECTION ...................................................................................... 17 
6.1 
Study Population ..................................................................................................... 17 
6.2 
Inclusion Criteria .................................................................................................... 17 
6.3 
Exclusion Criteria ................................................................................................... 17 
7 
CONCURRENT MEDICATIONS ...................................................................... 17 
7.1 
Allowed Medications and Treatments .................................................................... 17 
7.2 
Prohibited Medications and Treatments .................................................................. 18 
8 
STUDY TEST AND CONTROL PRODUCTS .................................................. 18 
8.1 
Method of Assigning Subjects to Treatment Groups .............................................. 18 
8.2 
Blinding ................................................................................................................... 18 
8.3 
Formulation of Test and Control Products .............................................................. 18 
8.3.1 
Formulation of Test Product ............................................................................... 19 
8.3.2 
Formulation of Control Product .......................................................................... 19 
8.3.3 
Packaging and Labeling ...................................................................................... 19 
8.4.1 
Dosage/Dosage Regimen .................................................................................... 21 
8.4.2 
Dispensing ........................................................................................................... 21 
8.4.3 
Preparation of Study Syringes ............................................................................. 22 
8.4.4 
Storage ................................................................................................................ 22 
8.5 
Test and Control Product Accountability ................................................................ 23 
8.6 
Measures of Treatment Compliance ....................................................................... 23 
9 
STUDY PROCEDURES AND GUIDELINES .................................................. 23 
9.1 
Clinical Assessments .............................................................................................. 23 
9.1.1 
Concomitant Medications ................................................................................... 23 
9.1.2 
Demographics ..................................................................................................... 23 
9.1.3 
Medical History ................................................................................................... 23 
9.1.4 
Physical Examination .......................................................................................... 23 
9.1.5 
Vital Signs ........................................................................................................... 24 


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9.1.6 
Adverse Events ................................................................................................... 24 
9.2 
Clinical Laboratory Measurements ......................................................................... 24 
9.2.1 
Pregnancy Test .................................................................................................... 24 
9.2.2 
Urinalysis ............................................................................................................ 24 
9.2.3 
Salivary Cortisol Measurements ......................................................................... 24 
10 
EVALUATIONS BY VISIT ................................................................................. 24 
11 
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION .......... 26 
11.1 
Adverse Events ....................................................................................................... 26 
11.2 
Serious Adverse Experiences (SAE) ....................................................................... 27 
11.2.1 
Serious Adverse Experience Reporting .............................................................. 28 
11.3 
Medical Monitoring ................................................................................................ 28 
12 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS ..................... 28 
12.1 
Withdrawal of Subjects from the Study .................................................................. 29 
12.2 
Replacement of Subjects ......................................................................................... 29 
13 
PROTOCOL VIOLATIONS ............................................................................... 29 
14 
DATA SAFETY MONITORING ........................................................................ 29 
15 
STATISTICAL METHODS AND CONSIDERATIONS ................................. 29 
15.1 
Data Sets Analyzed ................................................................................................. 29 
15.2 
Demographic and Baseline Characteristics ............................................................. 29 
15.3 
Analysis of Primary Endpoint ................................................................................. 30 
15.4 
Analysis of Secondary Endpoints ........................................................................... 30 
15.5 
Sample Size and Randomization ............................................................................. 30 
16 
DATA COLLECTION, RETENTION, AND MONITORING ........................ 31 
16.1 
Data Collection Instruments ................................................................................... 31 
16.2 
Data Management Procedures ................................................................................. 31 
16.3 
Data Quality Control and Reporting ....................................................................... 32 
16.4 
Archival of Data ...................................................................................................... 32 
16.5 
Availability and Retention of Investigational Records ........................................... 32 
16.6 
Monitoring .............................................................................................................. 33 
16.7 
Subject Confidentiality ........................................................................................... 33 
17 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS .... 33 
17.1 
Protocol Amendments ............................................................................................. 33 
17.2 
Institutional Review Boards and Independent Ethics Committees ......................... 33 
17.3 
Informed Consent Form .......................................................................................... 34 
17.4 
Publications ............................................................................................................. 34 
17.5 
Investigator Responsibilities ................................................................................... 36 
18 
APPENDIX A: NALOXONE HYDROCHLORIDE PACKAGE INSERT .... 40 
19 
APPENDIX B: SYRINGE ASSEMBLY ............................................................. 44 
20 
APPENDIX C: STUDY TRAINING LOG ......................................................... 45 
21 
APPENDIX D: TEST AND CONTROL PRODUCT ACCOUNTABILITY 
LOG 46 


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22 
APPENDIX E: SCHEDULE OF EVENTS BY STUDY VISIT ........................ 47 
23 
APPENDIX F: SUBJECT TRACKING LOG ................................................... 48 
24 
APPENDIX G: SPECIMEN ACCOUNTABILITY LOG ................................. 49 
25 
APPENXIX H: TASTE TEST ACCOUNTABILITY ....................................... 50 
26 
APPENDIX I: ADVERSE EVENT ACCOUNTABILITY LOG ..................... 51 
27 
APPENDIX J: PROTOCOL VIOLATION / INCIDENT REPORTING 
FORM ................................................................................................................................ 52 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BMI 
Body Mass Index 
CITI 
Collaborative Institutional Training Initiative 
CFR 
Code of Federal Regulations 
CHR 
Committee on Human Research (UCSF IRB) 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IM 
Intramuscular 
IN 
Intranasal 
IT 
Information Technology 
IUD 
Intrauterine Device 
IV 
Intravenous 
MAD 
Mucosal Atomization Device 
OS 
Operating System 
PI 
Principal Investigator 
SAE 
Serious adverse experience 
SID 
Subject Identification Number 
SC 
Subcutaneous 
SQL 
Structured Query Language 
SSL 
Secure socket layer 
UCSF 
University of California – San Francisco 
VPN 
Virtual private network 


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PROTOCOL SYNOPSIS 
 
TITLE 
OPIATE WITHDRAWAL RESPONSES TO INTRANASAL 
NALOXONE AS AN INDEX OF ALTERED ENDOGENOUS 
OPIOID ACTIVITY AMONG WOMEN WITH OBESITY: A 
FEASIBILITY AND EFFICACY STUDY 
SPONSOR 
Frederick M. Hecht, MD 
FUNDING 
ORGANIZATION 
National Heart Blood and Lung Institute (NHLBI) 
NUMBER OF SITES 
1 
RATIONALE 
Understanding what drives compulsive overeating among individuals 
with obesity will lead to the development of more effective 
treatments. A large body of literature implicates the endogenous 
opioid system in eating behavior. Researchers have published the use 
of exogenous opioidergic blockade as a method to assess endogenous 
opioid activity in obesity1,2. Data suggest that women are more 
sensitive to exogenous opioidergic blockade. Our work shows that 
withdrawal responses, as indexed by nausea following opioidergic 
antagonism using oral naltrexone, are associated with non- 
homeostatic eating in obese women1,2. To (1) reduce the amount of 
time needed to investigate associations between eating behavior, 
obesity, and the endogenous opioid system, thereby reducing subject 
burden, and (2) take the initial steps toward the development of a cost- 
and time-effective method to assess endogenous opioid activity in 
women, we plan to evaluate the use of naloxone hydrochloride 
administered intranasally (intranasal naloxone). 
STUDY DESIGN 
This is a single-center, double-blind, placebo-controlled, randomized, 
crossover trial design. 
PRIMARY 
OBJECTIVE 
1. To determine if 2 mg/2 mL intranasal naloxone elicits the 
withdrawal symptom of nausea (present versus absent) in obese 
women. 
SECONDARY 
OBJECTIVES 
1. To determine if 2 mg/2 mL intranasal naloxone elicits other 
withdrawal symptoms, as measured by subjective opiate 
withdrawal scales3 in obese women 
2. To determine the rate of the cortisol response following 2 mg/2 
mL intranasal naloxone in obese women 
NUMBER OF 
SUBJECTS 
24 women 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
1. 
Subject must be able to complete written informed consent 
procedures and be able to comply with the requirements of the 
study. 
2. 
Women aged 18 years or older 
3. 
Obese, as defined by BMI greater than or equal to 30 


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4. 
Self-reported binge eating as defined in DSM-5, in the last 4 
weeks 
5. 
If sexually active with men and pre-menopausal, must agree to 
use birth control (e.g., barrier methods, oral contraceptive) 
6. 
Must have negative pregnancy test at visit 1 
Exclusion Criteria: 
1. Presence of a condition or abnormality that in the opinion of the 
Investigator would compromise the safety of the subject or the 
quality of the data 
2. Pregnant or breastfeeding 
3. Known hypersensitivity to naloxone hydrochloride or to any 
ingredients in naloxone hydrochloride 
4. Allergies to any ingredients in naloxone hydrochloride 
5. History of or current alcoholism 
6. History of or current drug dependence 
7. Bulimia Nervosa as defined in DSM 5 
8. Current or past use of opiate-containing medications in the last 30 
days 
9. Plan to use opiate-containing medications during the study days 
10. Use of opiate medications or drugs, which are contraindicated 
with naloxone hydrochloride 
11. Medical conditions that are contraindicated with intranasal 
procedures: Nasal septal abnormalities, nasal trauma, epistaxis, 
excessive nasal mucus, and intranasal damage caused by the use 
of substances (e.g., cocaine) 
12. Severe hypotension (<90/60 mmHg) 
13. Recent or current use of vasoconstrictor or vasodilator 
medications 
14. Current or history of diabetes 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
2 mg/2 mL Naloxone Hydrochloride (Intranasal Naloxone) 
1 mg/1 mL administered per nostril using a nasal mucosal atomization 
device (MAD) (manufactured by Teleflex, Inc., Research Triangle 
Park, NC, USA). 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
2 mL 0.9% sodium chloride (Intranasal Placebo) 
1 mL administered per nostril using a nasal mucosal atomization 
device (MAD) (manufactured by Teleflex, Inc., Research Triangle 
Park, NC, USA). 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be in the study for up to 3 weeks. There will be a period 
of at least 24 hours between visits 1 and 2. 
Web-based eligibility: Screening for self-report eligibility criteria, 
approx. 15 minutes 
Phone Screen: Phone call to review eligibility and schedule visit 1, 
planning for visit 1, approx. 15 minutes 
Visit 1: In-person baseline assessment (screening for pregnancy and 


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drug use), approx. & Administration day 1 (approximately 1.5-2 
hours) 
Visit 2: Administration day 2 (approximately 1.5-2 hours) 
Recruitment and participation are expected to take 6 months 
CONCOMITANT 
MEDICATIONS 
Allowed: 
1. Medications are permitted with use of naloxone hydrochloride 
unless listed below under “prohibited” 
Prohibited: 
1. Current use of opiate-containing medications 
2. Current use of vasoconstrictor medication 
3. Initiation of new medications that are contraindicated with 
naloxone hydrochloride use during the study period 
4. Current use of insulin 
EFFICACY 
EVALUATIONS 
1. Self-reported nausea at 0 minutes (pre-administration), and 10 and 
30 minutes following administration of test product or control 
product 
2. Self-reported symptoms of withdrawal as measured by the 
subjective opiate withdrawal scale (SOWS3) at 0 minutes (pre- 
administration), and 10 and 30 minutes following administration 
of test product or control product 
3. Salivary cortisol values at 0 minutes (pre-administration) and 20 
and 50 minutes following administration of test product or control 
product 
PRIMARY ENDPOINT 
1. Presence or absence of the self-reported withdrawal symptom of 
nausea following administration of the test versus control product. 
SECONDARY 
ENDPOINTS 
1. Scores on self-report Subjective Opiate Withdrawal Scale 
(SOWS)3 following administration of the test versus control 
product. 
2. Rate of the cortisol response, as measured by salivary cortisol, 
following administration of the test versus control product. 
OTHER 
EVALUATIONS 
N/A 
SAFETY 
EVALUATIONS 
Incidence of unexpected adverse events. Subjects will be monitored 
for unexpected adverse events and serious adverse events following 
administration of the test product and control product. 
PLANNED INTERIM 
ANALYSES 
Due to the current study design and safety profile of this test product, 
no interim analyses are planned. 
STATISTICS 
Primary Analysis Plan 
McNemar’s tests will be performed to evaluate whether there is a 
statistically significant difference in nausea response (dichotomously 
scored as present or absent) across test product (intranasal naloxone) 
and control product (intranasal placebo) conditions. 


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Rationale for Number 
of Subjects 
We do not expect any nausea responses to the control product, just as 
we typically do not expect side effects from placebos. Under the null 
hypothesis of no difference between conditions, we would also expect 
no nausea responses under the alternative hypothesis. In terms of 
probability, “no responses” implies a probability of 0: In other words, 
an impossible event. A single nausea response to the test product 
would decisively refute the null. But nausea responses, under either 
condition, are not literally impossible. We have therefore powered 
against the expected value of 0 by using the beta distribution with r = 
0 as a Bayesian prior, in place of the usual point value. The beta with 
r = 0 is a U-shaped distribution concentrating most of the density on 
the extreme values. Specifically, for values of p from .01 to .99, in .01 
increments, we calculated the ordinate of the beta distribution with 
trial values of N; calculated the one-tailed rejection region (outcomes 
of fewer than 0 nausea responses were not considered) for that value 
of p and N; calculated the power for that N and an alternative value of 
p (e.g., .4); then used the corresponding ordinate for each value of p as 
a weight, and calculated the average across the range from .01 to .99 
as our estimate of power. Since nausea responses are not literally 
impossible, we also explored power with null proportions up to .3, 
with the alternatives in the below table. For these nonzero values, a 
standard binomial power analysis would have sufficed, but for 
consistency we have used the corresponding Bayesian priors. The beta 
prior with r = N/10, for example, will concentrate probability on 
values near .1, whereas that with r = 0 will concentrate it around 
0. The latter, approximating the impossible event, of course yields 
high power, whereas power declines as the binomial becomes more 
symmetrical. For the values of potential interest to us, an N of 24 will 
suffice for 80%+ power. (Following from the above rationale, the 
entries in the table below do not correspond to standard power 
calculations for the McNemar test. The test for 0% vs. 40%, for 
example, is a test of whether the percentages for the two populations 
are both 20%; the power of this test is just 1 of 99 values averaged, 
with weights from the beta distribution, for the results in the table 
below). 
% Endorsing Nausea 
Number 
Needed (N) 
Power to detect 
difference 
Control 
Product 
Test 
Product 
0% 
20% 
20 
.811 
0% 
30% 
12 
.823 
0% 
40% 
9 
.844 
10% 
40% 
16 
.817 
20% 
50% 
21 
.805 
30% 
60% 
24 
.805 
Reference: Uebersax, J.S. Bayesian unconditional power analysis 
(2007). 


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1 
BACKGROUND 
Opioid antagonists, such as intravenously and intranasally delivered naloxone (brand 
name: Narcan), are used clinically throughout the US to acutely reverse opiate drug 
overdose4–6. A nasal naloxone spray device was recently approved for opioid overdose: 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473505.htm. 
Intranasal naloxone administration has been effectively completed by lay people who 
complete brief training generally led by non-medical trained professionals7. Depot 
naloxone injections, as well as an oral formulation (naltrexone) are used throughout the 
US as ongoing treatments to promote sobriety among individuals with substance use 
disorders8. Opioid antagonism can induce withdrawal symptoms that are well documented 
in the literature, such as nausea, sweating, and jitteriness. Associations between the 
endogenous opioid system and neural factors underlying eating behavior are well- 
documented9–12. 
The Diagnostic and Statistical Manual (DSM) of Mental Disorders – 5th edition outlines 
criteria for substance dependence, and several self-report measures have been constructed 
to diagnose substance use disorders. In the past 10 years, researchers have proposed and 
begun to investigate food addiction by considering food as other researchers have 
considered other substances (i.e., illicit drugs, alcohol13,14). Food addiction has been 
proposed as a phenotype in obesity15,16, and more than 30% of treatment-seeking 
individuals with obesity endorse compulsive overeating17,18, defined as the consumption 
of large amounts of food whilst feeling out of control over one’s eating. 
The endogenous opioidergic system, specifically, µ-opioid activity, plays a critical role in 
the neural experience of reward that follows from eating highly palatable food9,19, 
especially foods high in sugars10,20,21. Eating these foods acutely stimulates the release of 
endogenous opioids, which, in turn, promotes further eating. Chronic overeating of these 
highly palatable and possibly addictive foods21–23 can alter µ-opioid activity in ways that 
increase susceptibility to, and intensify experiences of, food cravings24–27. In short-term 
experimental studies, rats chronically consuming a highly palatable diet that are then 
either removed from this diet or administered an µ-opioid antagonist display opioid- 
withdrawal behavior10. Animal studies also show that administration of a µ-opioid 
antagonist decreases short-term ingestion of highly palatable, sweet food, even using 
doses of a µ-opioid antagonist that do not impact intake of standard chow21,28. One phase 
II placebo-controlled 24-week study (N = 138) of intranasal naloxone for binge eating 
disorder has been reported in abstract form at the American Psychiatric Association’s 
166th annual meeting, but has not been published29. It involved intranasal naloxone (2 mg) 
(or intranasal placebo) before binge eating up to 2 times daily (up to 4 mg intranasal 
naloxone total daily). Eighty-one percent of subjects completed the trial, and there were 
no serious adverse events. Results indicated that naloxone, relative to placebo, resulted in 
less time spent binge eating and greater weight loss from weeks 12 to 24. This trial was 
registered at clinicaltrials.gov (NCT01567670). 
We have published data showing that overweight and obese women who report nausea (a 
common opioid withdrawal symptom30) following ingestion of a standard 50 mg dose of 
the µ-opioid antagonist naltrexone31 also report greater emotional, reward-driven, and/or 
binge eating1,2,32. Thus, antagonizing the endogenous opioid system is a promising method 


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by which to test for altered µ-opioid activity related to problematic overeating that does 
not require expensive imaging procedures. The method that my colleagues and I at UCSF 
have used involves oral naltrexone31, which requires several hours of data collection due 
to a slower mechanism of action. Utilizing intravenous administration, while rapid, would 
pose additional subject burden and discomfort, as it involves injection by needle. Using 
intranasally administered naloxone, which is now used clinically throughout the US and is 
has been fast-tracked for FDA approval for drug overdose, would dramatically reduce 
subject burden (reduces study period from 4 hours to less than 1 hour), and would obviate 
the use of needles. 
 
1.1 
Overview of Non-Clinical Studies 
Naloxone Hydrochloride Injection Package Insert: See Appendix A. 
 
From Package Insert: Carcinogenesis, Mutagenesis, and Impairment of Fertility 
Studies in animals to assess the carcinogenic potential of naloxone hydrochloride have not 
been conducted. Naloxone hydrochloride was weakly positive in the Ames mutagenicity 
and in the in vitro human lymphocyte chromosome aberration test but was negative in the 
in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone 
marrow chromosome aberration study. Reproduction studies conducted in mice and rats at 
doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/ day 
(when based on surface area or mg/m2), demonstrated no embryotoxic or teratogenic 
effects due to naloxone hydrochloride. 
 
From Package Insert: Use in Pregnancy 
Teratogenic Effects: Pregnancy Category C: Teratology studies conducted in mice and 
rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 
mg/day (when based on surface area or mg/m2), demonstrated no embryotoxic or 
teratogenic effects due to naloxone hydrochloride. There are, however, no adequate and 
well-controlled studies in pregnant women. Because animal reproduction studies are not 
always predictive of human response, naloxone hydrochloride should be used during 
pregnancy only if clearly needed. 
 
1.2 
Overview of Clinical Studies 
From Package Insert: Pharmacokinetics: Distribution, Metabolism, and Elimination 
Following parenteral administration, naloxone is distributed in the body and readily 
crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma 
albumin is the major binding constituent, but significant binding of naloxone also occurs 
to plasma constituents other than albumin. It is not known whether naloxone is excreted 
into human milk. Naloxone hydrochloride is metabolized in the liver, primarily by 
glucuronide conjugation with naloxone-3-glucoronide as the major metabolite. In one 
study the serum half-life in adults ranged from 30 to 81 minutes (mean 64 ± 12 minutes). 
In a neonatal study the mean plasma half-life was observed to be 3.1 ± 0.5 hours. After an 
oral or intravenous dose, about 25-40% of the drug is excreted as metabolites in urine 
within 6 hours, about 50% in 24 hours, and 60-70% in 72 hours. 


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From Package Inserts: Clinical Pharmacology 
Naloxone hydrochloride prevents or reverses the effects of opioids including respiratory 
depression, sedation, and hypotension. It can also reverse the psychotomimetic and 
dysphoric effects of agonist-antagonists such as pentazocine. Naloxone hydrochloride is 
an essentially pure opioid antagonist, i.e., it does not possess the “agonistic” or morphine- 
like properties characteristic of other opioid antagonists. When administered in usual 
doses and in the absence of opioids or agonistic effects of other opioid antagonists, it 
exhibits essentially no pharmacologic activity. Naloxone hydrochloride has not been 
shown to produce tolerance or cause physical or psychological dependence. In the 
presence of physical dependence on opioids, naloxone hydrochloride will produce 
withdrawal symptoms. However, in the presence of opioid dependence, opiate withdrawal 
symptoms may appear within minutes of naloxone hydrochloride administration and 
subside in about 2 hours. The severity and duration of the withdrawal syndrome are 
related to the dose of naloxone hydrochloride and to the degree and type of opioid 
dependence. 
 
From Published Research: Route of Administration 
Recent research indicates that intranasal administration (IN) is similar in effectiveness to 
IM delivery in reversing opioid (heroin) overdose33. IN administration is considered an 
effective option in the treatment of overdose when IV administration is impossible or 
undesirable5. Animal data indicate that the peak plasma levels following intranasal 
delivery occurs within 3 minutes of administration34. 
 
Figure 1. Structure of naloxone hydrochloride. 
 
2 
STUDY RATIONALE 
More than 30% of individuals who are overweight or obese and seeking treatment for 
weight loss endorse problems with binge-like, compulsive overeating17,18. A large body of 
research has documented overlaps between the endogenous opioid system and eating 
behavior9–12, and in the past decade, food addiction has been proposed as a phenotype in 
obesity15,16. Data show that women are more sensitive to exogenous opioidergic blockade, 
as defined by experiencing nausea and other withdrawal-like effects more often than 
men35,36. 
 
We have published data showing that overweight and obese women who report nausea (a 
common opioid withdrawal symptom30) following ingestion of a standard 50 mg dose of 
the µ-opioid antagonist naltrexone31 also report greater emotional, reward-driven, and/or 


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binge eating1,2,32. Our studies have found that women who endorsed nausea responses 
following naltrexone ingestion had larger reductions in self-reported overeating and 
greater weight loss when assigned to a weight loss intervention with mindful eating 
training rather than when assigned to a standard weight loss intervention. Both studies1,2, 
however, used oral administration (naltrexone), which required three hours of observation 
to capture data from the time period involving peak response31. Thus, antagonizing the 
endogenous opioid system is a promising method by which to test for altered µ-opioid 
activity related to problematic overeating. 
 
Intranasal naloxone has been shown to achieve peak plasma levels in 3 minutes in 
rodents34. Although IV administration would reduce the amount of time needed, this 
would add a needle stick and therefore increase subject burden. Hence, to (1) reduce the 
amount of time needed to investigate associations between eating behavior, obesity, and 
the endogenous opioid system, thereby reducing subject burden, and (2) take the initial 
steps toward the development of a cost- and time-effective method to assess endogenous 
opioid activity in women, we plan to evaluate the use of naloxone hydrochloride 
administered intranasally (intranasal naloxone). This study will provide important 
preliminary data for future studies investigating treatment matching for weight loss 
interventions. The development of an intranasal naloxone protocol may contribute to the 
identification of individuals who may benefit from the incorporation of intervention 
components traditionally used in substance misuse treatment (e.g., opioid misuse) into 
their weight-loss intervention program. 
 
2.1 
Risk / Benefit Assessment 
The most significant potential benefit of this study is to contribute to the development of 
an inexpensive, non-invasive method for assessing endogenous opioidergic activity in 
obesity. This study will generate key preliminary data for investigating this method, which 
may prove useful in identifying individuals with obesity who engage in binge-like, 
compulsive overeating (“opioid-mediated eating”) that requires treatment modalities 
traditionally used to treat substance dependence disorders. 
Intranasal Naloxone-related risks 
Intranasal naloxone is known to reverse (and is used for the purpose of reversing) opioid 
overdose and can reverse the analgesic effects of an opioid analgesic being taken 
chronically (e.g., for pain)4–6,37. Intranasal naloxone has minimal dug interaction 
potential5. Intranasal naloxone is not used as a continuous medication and is used in acute 
situations involving overdose, meaning that individuals receiving intranasal naloxone are 
not tested for the use of other medications prior to receiving it. See Appendix A for 
package insert. 
 
3 
STUDY OBJECTIVES 
 
3.1 
Primary Objective 
1. To determine if 2 mg/2 mL intranasal naloxone (1 mg/1 mL per nostril) elicits the 
withdrawal symptom of nausea (present versus absent) in obese women (compared 
to intranasal placebo). 


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3.2 
Secondary Objectives 
1. To determine if 2 mg/2 mL intranasal naloxone (1 mg/1 mL per nostril) elicits other 
withdrawal symptoms, as measured by subjective opiate withdrawal scales3 in 
obese women (compared to intranasal placebo). 
2. To determine the rate of the salivary cortisol response following intranasal 
naloxone administration in obese women (compared to intranasal placebo). 
 
4 
STUDY DESIGN 
4.1 
Study Overview 
This is a single center, double-blind, placebo-controlled, randomized, crossover trial that 
will include 24 subjects. Subjects will be in the study for up to 3 weeks. Total time 
involved will be approximately 5-6 hours. There will be a period of at least 24 hours 
between study Visits 1 and 2. 
 
4.2 
Total Study Duration: 
Total duration of subject participation will be up to 3 weeks, with one session of web- 
based screening, one session involving a telephone screening call to confirm eligibility 
and introduce the subject to the study and two lab sessions involving administration of test 
and control products (first lab session includes urine screen). Total duration of the study, 
including recruitment and subject study completion, is expected to be 6 months. 
 
5 
CRITERIA FOR EVALUATION 
 
5.1 
Primary Efficacy Endpoint 
Presence or absence of the self-reported withdrawal symptom of nausea following 
administration of test product (intranasal naloxone) versus following administration of the 
control product (intranasal placebo). We will assess for presence of nausea (before and) 
following administration of each the test and the control products. 
 
5.2 
Secondary Efficacy Endpoints 
1. Scores on self-report Subjective Opiate Withdrawal Scale (SOWS)3 following 
administration of the test versus control products. A complete score that captures the 
full range of withdrawal responses my reveal a withdrawal syndrome that occurs, in 
addition to, or in the absence of, nausea. 
2. Rate of the cortisol response following administration of the test versus control 
products as measured by salivary cortisol. Cortisol increases following opioidergic 
blockade may index the degree to which an individual’s opioid system controls the 
hypothalamic-pituitary-adrenal (HPA) axis, which is responsible for physiologic stress 
responses. 
 
5.3 
Safety Evaluations 
Incidence of unexpected adverse events. 


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6 
SUBJECT SELECTION 
 
6.1 
Study Population 
Subjects with a diagnosis of obesity using BMI criteria who meet the inclusion and 
exclusion criteria will be eligible for participation in this study. 
 
6.2 
Inclusion Criteria 
1. Subject must be able to complete written informed consent procedures and be able to 
comply with the requirements of the study 
2. Women aged 18 years or older 
3. Obese as defined by BMI greater than or equal to 30 
4. Self-reported binge eating as defined in DSM-5, in the last 4 weeks 
5. If sexually active with men and pre-menopausal, must agree to use an acceptable 
form of birth control (e.g., barrier methods, oral contraceptive) 
6. Must have negative pregnancy test at visit 1 
 
6.3 
Exclusion Criteria 
1. 
Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the subject or the quality of the data 
2. 
Pregnant or breastfeeding 
3. 
Known hypersensitivity to naloxone hydrochloride (intranasal naloxone) or to any 
ingredients in naloxone hydrochloride 
4. 
Allergies to any ingredients in naloxone hydrochloride 
5. 
History of or current alcoholism 
6. 
History of or current drug dependence 
7. 
Bulimia Nervosa as defined in DSM 5 
8. 
Current or use of opiate-containing medications in the last 30 days 
9. 
Plans to use opiate-containing medications during the study days 
10. Use of opiate medications or drugs, which are contraindicated with naloxone 
hydrochloride 
11. Medical conditions that are contraindicated with intranasal administrations: Nasal 
septal abnormalities, nasal trauma, epistaxis, excessive nasal mucus, and intranasal 
damage caused by the use of substances (e.g., cocaine) 
12. Severe hypotension (<90/60 mmHg) 
13. Recent or current use of vasoconstrictor or vasodilator medications 
14. Current or history of diabetes 
 
7 
CONCURRENT MEDICATIONS 
 
7.1 
Allowed Medications and Treatments 
Medications are allowed except for treatments noted in the exclusion criteria described 
above and as noted in the prohibited medications section below. 
1. Medications permitted with use of naloxone hydrochloride are allowed. 


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7.2 
Prohibited Medications and Treatments 
The following medications are prohibited during the study and administration will be 
considered a protocol violation. 
1. Subjects may not use opiate-containing medications during the study period. This is 
because they are contraindicated with naloxone hydrochloride use. 
2. Subjects may not use vasoconstrictor medications during the study period. This is 
because they are contraindicated with naloxone hydrochloride use. 
3. Subjects may not initiate new medications that are contraindicated with naloxone 
hydrochloride use during the study period. 
4. Subjects may not be using insulin. 
 
8 
STUDY TEST AND CONTROL PRODUCTS 
 
8.1 
Method of Assigning Subjects to Treatment Groups 
Twenty-four eligible subjects will be randomly assigned to receive the test product 
(intranasal naloxone) or control product (intranasal placebo) first (on visit 1 versus on visit 
2) in a 1:1 ratio using a SAS-based computer-generated randomization table computed by 
Scott Fields, PharmD, of the UCSF Research Pharmacy Staff. 
8.2 
Blinding 
Due to the objectives of the study, the identity of the test product and control product will 
be unknown to investigators, study staff, and subjects, excepting two study staff, who will 
prepare study syringes (see 8.4.3 Preparation of Study Syringes). The following study 
procedures will be in place to ensure double-blind administration of the test product and 
control product: 
Access to the randomization table will be strictly controlled and available only to the 
UCSF Research Pharmacy staff who create it and the two unblinded study staff who will 
prepare study syringes at each subject visit. 
The study blind will be broken on completion of the clinical study and after the study 
database has been locked. 
During the study, the blind may be broken only in emergencies when knowledge of the 
subject’s condition (control or text product) is necessary for further subject management. 
When possible, the Investigator will discuss the emergency with the Medical Monitor, 
Frederick M. Hecht, MD, prior to unblinding. 
 
8.3 
Formulation of Test and Control Products 
Though nasal administration of naloxone was recently FDA approved and is available in a 
pre-loaded device from Adapt Pharmaceuticals as shown in Figure 2a, below 
(http://www.narcannasalspray.com/), the proposed study will use a Mucosal Atomization 
Device (MAD) with a standard syringe attached, as shown in Figure 2b, below 
(http://intranasal.net/OpiateOverdose/default.htm). This is because the proposed study 
requires a blinded control condition (intranasal placebo). To date, published literature has 
used the method depicted in Figure 2b with a 2 mg dose of naloxone to test the 


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effectiveness of intranasal administration against intramuscular administration in 
reversing opioid overdose and found this dose to be clinically effective5. 
Figure 2a (left): Adapt Pharmaceuticals NARCAN Naloxone Nasal Spray 4 mg/0.1 mL 
Figure 2b (right): Mucosal Atomization Device (MAD), manufactured by Teleflex, Inc. 
(Research Triangle Park, NC) affixed to 2 mg/2 mL naloxone syringe 
 
 
8.3.1 Formulation of Test Product 
Naloxone hydrochloride is a clear solution that requires no reconstitution (see Table 2 for 
formulation) and is manufactured by International Medication Systems, a subsidiary of 
Amphastar Pharmaceuticals (http://www.amphastar.com/our-products.html). The 
intranasal mucosal atomization device (MAD) is manufactured by Teleflex 
(http://www.lmana.com/pwpcontrol.php?pwpID=6359). Intranasal naloxone was 
developed for acute reversal of opioid overdose when intravenous and intramuscular 
methods are not available or desirable4. 
Table 2: Formulation and Measured pH of Naloxone Hydrochloride 
 
Naloxone Hydrochloride (Per 1 mL) 
Active Ingredient, mg Naloxone Hydrochloride, 1 mg 
Other ingredient, mg 
Sodium Chloride, 8.35 mg 
Other ingredient 
Hydrochloric acid (to adjust pH) 
pH 
Range: 3.0 to 4.0 
8.3.2 Formulation of Control Product 
The 10 mL, single-use vials of 0.9% sodium chloride is manufactured by Hospira 
(http://www.hospira.com/en/products_and_services/drugs/SODIUM_CHLORIDE_INJEC 
TION_09). 
 
8.3.3 Packaging and Labeling 
Packaging: The control product (intranasal placebo; 0.9% sodium chloride) will be 
received from Hospira in 10 mL, single-use vials. The test product (intranasal naloxone; 
naloxone hydrochloride) will be received from International Medication Systems in 2 mL, 
single-use syringes. 


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For full pictorial description of syringe assembly, see Appendix B or 
http://www.lmana.com/files/lma_623_mad_nasal_procedure_guide.pdf?PHPSESSID=5ac 
33303fd1793f2edb171ce0958f3dd 
Labeling: Vials containing the control product (intranasal placebo) are manufactured with 
clear labeling as such. Syringes containing the test product (intranasal naloxone) are 
manufactured with clear labeling as such. See Figure 3. 
 
Figure 3. Packaging for test product (left) and control product (r ight). 
8.4 Supply of Test and Control Products at the Site 
The PI (or designee) will collect (in person) the box with the label depicted in Figure 4 
that contains thirty 10 mL vials of the control product and thirty 2 mg/2 mL syringes of 
the test product and transport it to the UCSF Osher Center for Integrative Medicine at the 
UCSF Mount Zion Campus, 1545 Divisadero Street, 3rd Floor, Suite 301, San Francisco, 
California, 94115. The test and control products will be collected by the PI (or designee) 
only after site activation. 


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UCSF Research Pharmacy 
505 Parnassus Avenue, Room M39C 
San Francisco, CA, 94143 
(415) 353 1798 
Study protocol: HECHTMASON1 
Date dispensed:   
 
Institutional Review Board (IRB) Approval #:   
 
Frederick M. Hecht MD 
Ashley E. Mason, PhD 
30 vials 10 mL 0.9% sodium chloride solution (saline), Lot #   
 
30 syringes 2 mg/2 mL naloxone hydrochloride (naloxone), Lot #   
 
“Caution: Limited by Federal (or United States) law to Investigational Use.” 
Figure 4: Label that UCSF Research Pharmacy Staff will place on the box containing 
syringes of the test product and vials of the control product. 
 
8.4.1 Dosage/Dosage Regimen 
All subjects receive the control product and test product at different study visits (visits 1 
and 2, which occur on different days). There will be a period of at least 24 hours between 
visits 1 and 2, as the period of time between each administration day does not impact 
analyses assessing primary or secondary outcomes. Subjects will be administered the test 
product (intranasal naloxone), 1 mg/1 mL per nostril, on one of their two visit days. 
Subjects will be administered the control product (intranasal placebo), 1 mL per nostril, on 
one of their two visit days. 
8.4.2 Dispensing 
Scott Fields, PharmD, of the UCSF Research Pharmacy, will order the test and control 
products from their manufacturers listed in 8.3.1 Formulation of the Test Product and 
8.3.2 Formulation of the Control Product. Unblinded study staff will prepare the syringes 
and affix them to the mucosal atomization device (MAD; see section 8.4.3 Preparation of 
Study Syringes). Ashley E. Mason, PhD, will administer the prepared test and control 
products to subjects. Ashley E. Mason, PhD and Frederick Hecht, MD (Medical Monitor) 
have carefully reviewed the documents prepared by the Massachusetts Department of 
Public Health (http://www.mass.gov/eohhs/docs/dph/substance-abuse/core-competencies- 
for-naloxone-pilot-participants.pdf), which include intranasal naloxone administration 
instructions in the context of training potential overdose responders to recognize and 
respond to an opioid overdose. They have also reviewed a step-by-step video that 
demonstrates assembly of the MAD (https://www.youtube.com/watch?v=Uq6AxrEY3Vk) 
that was developed and produced to train individuals seeking core competencies in 
intranasal naloxone administration. Dr. Hecht will supervise Dr. Mason in trial runs of 
completing intranasal administration using the MAD prior to subject enrollment. Dr. 


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Mason will document all training related to this study in a Study Training Log, and Dr. 
Hecht will review and initial each entry (Appendix C). 
 
8.4.3 Preparation of Study Syringes 
Study syringes will be prepared by two unblinded study staff who have completed all 
UCSF training required to conduct research with human subjects as detailed by the UCSF 
Institutional Review Board (IRB; http://www.research.ucsf.edu/chr/Train/chrTrain.asp). 
UCSF requires completion of the Collaborative Institutional Training Initiative (CITI) 
Course in the Protection of Human Research Subjects (https://www.citiprogram.org/) and 
HIPAA Training (http://www.research.ucsf.edu/chr/HIPAA/chrHIPAAtrng.asp). 
Documentation of successful completion of this training (and any additional training 
stipulated by the UCSF IRB) will be reviewed by Dr. Mason and this documentation will 
be stored with study documents as described in 8.4.4 Storage. 
The unblinded study staff will review the Massachusetts Department of Public Health 
materials (document and video linked in section 8.4.2 Dispensing). These study staff will 
also complete a UCSF Learning Module on aseptic techniques (portal to training: 
https://learningcenter.ucsfmedicalcenter.org/) entitled, Sterile Technique: Key Concepts 
and Practices.” Frederick M. Hecht, MD, the Medical Monitor and Sponsor of this 
proposal, who is a practicing physician with privileges at UCSF, will (1) verify their 
completion of this course, and (2) provide them with hands-on training in aseptic 
techniques and syringe preparation. 
Prior to each study visit, the unblinded study staff will consult the randomization table that 
was generated by the UCSF Research Pharmacy Staff to determine which of the following 
two procedures to follow: 
1. For the control product (intranasal placebo), the unblinded study staff will draw 2 
mL of the 0.9% sodium chloride from the original 10 mL vial into a standard 3 mL 
syringe, and then affix this to a nasal mucosal atomization device (MAD; see 
Figure 2b). 
2. For the test product (intranasal placebo), the unblinded study staff will draw 2 mL 
of the naloxone hydrochloride from the original 2 mL syringe into a standard 3 mL 
syringe, and then affix this to a MAD (see Figure 2b). 
The study staff will then log which product she has prepared in the (paper) Test and 
Control Product Accountability Log (Appendix D) and then will provide Dr. Mason with 
the prepared MAD. 
 
8.4.4 
Storage 
The test and control products (as well as all other study materials) will be stored at the 
study site for visits 1 and 2 (UCSF Osher Center for Integrative Medicine at the UCSF 
Mount Zion Campus, 1545 Divisadero Street, 3rd Floor, San Francisco, California, 94115) 
in Suite 301. Suite 301 requires a numeric passcode for entry and houses a room that 
requires badge entry (and tracks all entries), wherein materials will be stored. This room 
maintains a controlled temperature range of 15 to 30ºC (59 to 86ºF). All materials will be 
stored in one of three study-specific locked cabinets (includes 1 locked file cabinet), 
which will maintain cool and dry environments. In the event that the temperature of the 


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room (in Suite 301 of the aforementioned address) in which the test and control products 
are stored or at the UCSF Research Pharmacy exceeds or falls below this range, this will 
be reported to the Sponsor. 
 
8.5 Test and Control Product Accountability 
An accurate and current accounting of the dispensing of the test and control products will 
be maintained on an ongoing basis by the unblinded study staff. Specifically, the number 
of doses of the test and control products dispensed will be recorded on the Test and 
Control Product Accountability Log (see Appendix D), which will be stored in the locked 
cabinets described in 8.4.4 Storage. 
 
8.6 Measures of Treatment Compliance 
N/A 
 
9 
STUDY PROCEDURES AND GUIDELINES 
A ‘Schedule of Events by Study Visit’ representing the required testing procedures to be 
performed for the duration of the study is diagrammed in Appendix E. All subject visits 
will be documented in the Subject Tracking Log (Appendix F). See 16 Data Collection, 
Retention, and Monitoring, for details. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject. 
Subjects will be compensated for their time and travel expenditures, up to $200 total. 
Subjects will be paid up to $50 for completion of each study visit, and up to an additional 
$50 upon completion of all study visits. 
 
9.1 
Clinical Assessments 
All clinical assessment information will be collected on study-specific forms. 
 
9.1.1 Concomitant Medications 
All concomitant medication and concurrent therapies will be documented during the 
Phone Screen, and re-confirmed at lab visits. 
 
9.1.2 Demographics 
Demographic information (date of birth, gender, race) will be recorded during the Phone 
Screen and confirmed at visit 1. 
 
9.1.3 Medical History 
Relevant medical history, including history of or current disease and other pertinent 
medical history will be recorded at the Phone Screen. 
 
9.1.4 Physical Examination 
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9.1.5 Vital Signs 
Blood pressure will be measured at visit 1. 
 
9.1.6 Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates), severity, outcome, treatment and relation to study drug 
will be recorded on case report forms (CRFs). 
 
9.2 
Clinical Laboratory Measurements 
 
9.2.1 
Pregnancy Test 
A urine pregnancy test will be obtained from all subjects at visit 1. 
 
9.2.2 
Urinalysis 
Urine will be obtained for pregnancy testing and testing for opioid drug/medication use at 
visit 1. 
 
9.2.3 
Salivary Cortisol Measurements 
Saliva collected for determination of cortisol levels will be collected at both visits 1 and 2. 
Specimens will be collected prior to receiving the control or test product, as well as 20 and 
50 minutes after receiving the control or test product, using the passive drool technique, 
which involves subjects drooling into a collection tube. All specimen collections will be 
documented on the Specimen Accountability Log (Appendix G). The passive drool 
technique protocol is located on page 6 of the following manual: 
https://www.salimetrics.com/assets/documents/Saliva_Collection_Handbook.pdf 
Materials for this procedure are detailed here: 
https://www.salimetrics.com/collection-systems 
These tubes will be labeled with the subject ID number, visit number, and date, and stored 
in the study freezer. Once all samples are collected, all samples will be shipped on dry ice 
for batch processing at the Hellhammer Laboratory. The Sponsor and PI have an existing 
collaborative relationship with this laboratory and maintain ongoing e-correspondence. 
 
Hellhammer Laboratory shipping address: 
Biochemisches Labor, Unversitaet Trier 
FB 1, Biol. und Klin. Psychologie 
Frau Fritzen/Frau Reinert/Frau Scholtes 
Karl-Marxstr. 94-96 
54290 Trier 
Germany 
10 EVALUATIONS BY VISIT 
Table 1. Study events, description, and length of time involved 
Event 
Description 
Length 
Web-based 
eligibility 
Screening for self-report eligibility (inclusion and 
exclusion) criteria 
<15 minutes 


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screening 
Phone Screen 
Confirm eligibility criteria 
Schedule baseline assessment 
Review food buffet menu options 
<15 minutes 
Visit 1 
Screening for specimen-based exclusion criteria 
Self-report measures of eating behavior 
Computerized cognitive tasks 
Test or control product administration day 1 
1.5 to 2 hours 
Visit 2 
Test or control product administration day 2 
1.5 to 2 hours 
 
Web-based eligibility screening: 
• 
Subjects who meet all inclusion criteria and who have none of the exclusion criteria on 
the UCSF-hosted web-based eligibility screening website (wherein they provide their 
phone number) will be called by study staff to complete the Phone Screen. 
 
Phone Screen: 
• 
Verify Eligibility: Review inclusion and exclusion criteria with subject to ensure 
eligibility, including relevant medications, demographics, and medical history. 
• 
Review Protocol: Review study protocol to ensure subject’s willingness to partake in 
each component of the study, including the time commitment and locations of visits 1 
and 2, as well as self-report measures, a urine screen for pregnancy and opiate 
drug/medication use, eating pre-selected foods from a “buffet” of preferred foods at 
two study visits, receiving the intranasal naloxone and intranasal placebo, and 
providing saliva samples. 
• 
Schedule Visits 1 and 2: Schedule subject’s visits 1 and 2. There will be a period of at 
least 24 hours between visits 1 and 2, and, as the period of time between each 
administration day does not impact analyses assessing primary or secondary outcomes, 
the amount of time between administrations will vary according to the subject’s 
schedules so as to reduce subject burden. 
 
Visits 1 and 2: Control Product and Test Product Administration Visits: 
• 
Location: Subjects will present to the UCSF Mount Zion Campus, 1545 Divisadero 
Street, 3rd Floor, Suite 301, San Francisco, California, 94115. 
• 
Clinical Assessments Conducted by Study Staff: 
• 
Objective Weight and Height Measures: Staff will collect the subject’s height 
and weight. 
• 
Blood pressure: Staff will collect blood pressure. 
• 
Pregnancy and Opiate Drug/Medication Screen: Staff will collect a urine 
sample to test for pregnancy and use of opioid drugs/medications. 
• 
Randomization: Dr. Mason will report the subject’s ID number and eligibility status to 
the unblinded study staff, who will consult the randomization table generated by the 
UCSF Research Pharmacy staff (which will dictate the ordering in which the subject 
will receive the test and control products at each visit). 
• 
Taste Test Procedure: At visits 1 and 2, subjects will eat for 10 minutes from a food 
buffet that includes foods that they selected during visit 1 (different foods will be 
provided at each visits 1 and 2 so as not to repeat foods). All foods will be served in 


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large bowls and in large quantities, factors that are known to non-consciously increase 
intake40. Bowls of food will be weighed before and after the “taste test” period and 
this information will be documented (Appendix H). As commonly done in studies 
involving hedonic eating, subjects will indicate (on paper forms) how much they liked 
each food on paper questionnaires after tasting each food, as done in prior studies 
examining the role of opioid involvement in liking of foods41,42. 
• 
Administration of Test Product (Intranasal Naloxone) or Control Product (Intranasal 
Placebo): Subjects will receive each the test product (intranasal naloxone) (2 mg/ 2 
mL, 1 mg/1 mL per nostril) and control product (intranasal placebo, 1 mL per nostril) 
via a nasal mucosal atomization device (MAD; See 8.4.3 Syringe Assembly) in a 
randomized order (per the randomization table generated by the UCSF Research 
Pharmacy and accessible only to unblinded study staff) on visits 1 and 2, immediately 
following the food buffet procedure. 
• 
Self-Report Measures: Subjects will self-report their level of nausea (present versus 
absent) in the context of completing the SOWS3 prior to receiving either the test or 
control product, as well as 10 and 30 minutes after receiving the test or control 
product. 
• 
Saliva Samples (Salivary Cortisol): Subjects will provide saliva samples prior to 
receiving the test and control products, as well as 20 and 50 minutes after receiving 
the test or control products. 
 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment. An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product. An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the Adverse Event Accountability 
Log (Appendix I) and in the subject’s CRF. Adverse events will be described by duration 
(start and stop dates and times), severity, outcome, treatment and relation to study drug, or 
if unrelated, the cause. 
AE Severity 
The guidelines shown in Table below should be used to grade severity. It should be 
pointed out that the term “severe” is a measure of intensity and that a severe AE is not 
necessarily serious. 


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Table 3. AE Severity Grading 
 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study agent should be assessed using the following the 
guidelines in Table . 
Table 4. AE Relationship to Study Drug 
 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
1. death 
2. a life-threatening adverse experience 
3. inpatient hospitalization or prolongation of existing hospitalization 
4. a persistent or significant disability/incapacity 
5. a congenital anomaly/birth defect 
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed. 


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11.2.1 Serious Adverse Experience Reporting 
All SAEs that occur (whether or not related to study drug) will be documented per UCSF 
CHR (IRB) Guidelines 
(http://www.research.ucsf.edu/chr/guide/Violation_Incident_Guidelines.asp). The 
collection period for all SAEs will begin after informed consent is obtained and end after 
procedures for the final study visit (visit 2) have been completed. 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC. 
 
11.3 
Medical Monitoring 
Frederick M. Hecht, MD, is the Medical Monitor for this study and should be contacted 
directly at these numbers to report medical concerns or questions regarding safety. 
Phone: (415) 476-4082 extension #431 
Pager: (415) 443-1599 
Frederick M. Hecht, MD will be the primary person responsible for study adverse event 
monitoring and will report adverse events and unanticipated problems to the UCSF IRB. 
All subjects will be monitored for possible adverse events and unanticipated problems 
throughout the study period. 
 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue. 
The following is a list of possible reasons for study treatment discontinuation: 
• 
Subject withdrawal of consent (or assent) 
• 
Subject is not compliant with study procedures 
• 
Adverse event that in the opinion of the investigator would be in the best interest 
of the subject to discontinue his or her participation 
• 
Protocol violation requiring discontinuation of study protocol 
• 
Lost to follow-up 
• 
Sponsor request for early termination of study 
• 
Positive pregnancy test at visit 1 or self-reported pregnancy at visits 2 or 3 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals. The reason for the subject’s withdrawal from the study will be specified in 
the Subject Tracking Log (Appendix F) and the subject’s CRF. 


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12.1 Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue. This will be 
documented in the Subject Tracking Log (Appendix F) and the subject’s CRF. 
 
12.2 Replacement of Subjects 
Subjects who withdraw from the study will be replaced. 
 
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, research assistant(s), investigator, or 
Sponsor fails to adhere to significant protocol requirements affecting the inclusion, 
exclusion, subject safety and primary endpoint criteria. Protocol violations for this study 
include, but are not limited to, the following: 
• 
Failure to meet inclusion/exclusion criteria 
• 
Use of a prohibited concomitant medication or drug 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Sponsor will determine if a protocol violation will result in 
withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be completed on the online UCSF CHR (IRB) 
portal (this form is reproduced in Appendix J). As requested by the UCSF CHR (IRB), the 
Sponsor and Principal Investigator will consult with the UCSF Privacy Office 
(http://hipaa.ucsf.edu/) when completing this form. This form will be electronically signed 
by the Principal Investigator. A printed copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files. 
 
14 DATA SAFETY MONITORING 
N/A 
 
15 STATISTICAL METHODS AND CONSIDERATIONS 
 
15.1 Data Sets Analyzed 
All eligible subjects who are randomized into the study and complete, at a minimum, visit 
2, will be included in analyses. Michael Acree, PhD, a statistician at the UCSF Osher 
Center for Integrative Medicine, will perform the data analysis for this study. 
 
15.2 Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized: race, age, height 
and weight. 


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15.3 Analysis of Primary Endpoint 
McNemar’s tests will be performed to evaluate whether there is a statistically significant 
difference in nausea response (dichotomously scored as present or absent) across the test 
product (intranasal naloxone) and control product (intranasal placebo) conditions. 
 
15.4 Analysis of Secondary Endpoints 
 
Linear mixed effects regression modeling will be performed to assess differences across 
conditions in rate of cortisol change over the course of all assessments (baseline and 20 
and 50 minutes post-administration). 
 
15.5 
Sample Size and Randomization 
We do not expect any nausea responses to the control product. Under the null hypothesis 
of no difference between conditions, we would also expect no nausea responses under the 
alternative. In terms of probability, “no responses” implies a probability of 0: In other 
words, an impossible event. A single nausea response to intranasal naloxone would 
decisively refute the null. But nausea responses, under either condition, are not literally 
impossible. We have therefore powered against the expected value of 0 by using the beta 
distribution with r = 0 as a Bayesian prior, in place of the usual point value. The beta with 
r = 0 is a U-shaped distribution concentrating most of the density on the extreme values. 
Specifically, for values of p from .01 to .99, in .01 increments, we calculated the ordinate 
of the beta distribution with trial values of N; calculated the one-tailed rejection region 
(outcomes of fewer than 0 nausea responses were not considered) for that value of p and 
N; calculated the power for that N and an alternative value of p (e.g., .4); then used the 
corresponding ordinate for each value of p as a weight, and calculated the average across 
the range from .01 to .99 as our estimate of power. Since nausea responses are not literally 
impossible, we also explored power with null proportions up to .3, with the alternatives in 
the below table. For these nonzero values, a standard binomial power analysis would have 
sufficed, but for consistency we have used the corresponding Bayesian priors. The beta 
prior with r = N/10, for example, will concentrate probability on values near .1, whereas 
that with r = 0 will concentrate it around 0. The latter, approximating the impossible 
event, of course yields high power, whereas power declines as the binomial becomes more 
symmetrical. For the values of potential interest to us, an N of 24 will suffice for 80%+ 
power. (Following from the above rationale, the entries in the table below do not 
correspond to standard power calculations for the McNemar test. The test for 0% vs. 40%, 
for example, is a test of whether the percentages for the two populations are both 20%; the 
power of this test is just 1 of 99 values averaged, with weights from the beta distribution, 
for the results in the table below). 
% Endorsing Nausea 
Number 
Needed (N) 
Power to detect 
difference 
Control 
Product 
Test 
Product 
0% 
20% 
20 
.811 
0% 
30% 
12 
.823 
0% 
40% 
9 
.844 
10% 
40% 
16 
.817 


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20% 
50% 
21 
.805 
30% 
60% 
24 
.805 
Reference: Uebersax, J.S. Bayesian unconditional power analysis (2007). 
 
16 DATA COLLECTION, RETENTION, AND MONITORING 
 
16.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject. 
Study personnel will enter data from source documents corresponding to a subject’s visit 
into the protocol-specific paper Case Report Form (CRF) when the information 
corresponding to that visit is available. Subjects will not be identified by name in the 
study database or on any study documents to be collected by the Sponsor (or designee), 
but will be identified by a four-digit subject identification number (SID). All paper 
documents will be kept in study-specific locked cabinets described in 8.4.4 Storage. 
If a correction is made on a CRF, the study staff member will line through the incorrect 
data, write in the correct data, and initial and date the change. 
The PI is responsible for all information collected on subjects enrolled in this study. All 
data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the PI. A copy of the CRF will remain at the PI’s site at the 
completion of the study. 
 
16.2 Data Management Procedures 
The data will be entered into an electronic database that will be managed by Michael 
Coccia, MA, who will serve as a study Database Manager. His office is located at 3333 
California Street, 4th Floor, Center for Health and Community, San Francisco, CA. 
Michael Coccia, MA, works as a Database Manager and statistician for Dr. Epel’s and 
others’ ongoing trials. The Database Manager will be responsible for data processing, in 
accordance with procedural documentation. Database lock will occur once quality 
assurance procedures have been completed. 
 
The UCSF Departments of Medicine and Psychiatry comply with federal, state, 
University, and campus electronic information security requirements through a 
combination of physical, technical, procedural, and management controls. At the 
procedural level, all researchers working with human subjects undergo security awareness 
training for HIPAA and the handling of sensitive data. All employees of the University of 
California, San Francisco are required to obtain Security Awareness Training and 
implement appropriate security measures. 
 
The Osher Center for Integrative Medicine has a password-protected computer network 
that is connected into the greater UCSF system and network file servers, with high-speed 
Internet access. A HIPAA-compliant server is dedicated to research data storage. Access 
to this server is restricted to persons on the UCSF network, and requires network log-on 
authentication for access. Access to digital research data is further restricted to particular 
study staff and investigators working on projects, and access to research files is logged so 


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that there is a record of which individuals have accessed files. Daily back-up is performed 
on network servers. Extensive information technology (IT) support is provided for all 
computer operations through the UCSF IT Service. 
 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
 
16.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. 
Query reports (Data Clarification Requests) pertaining to data omissions and 
discrepancies will be forwarded to the Investigators and study monitors for resolution. 
The study database will be updated in accordance with the resolved queries. All changes 
to the study database will be documented. 
 
16.4 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained. The Database Manager backs up databases in conjunction with any updates or 
changes to the database. 
Study data will be stored on a HIPAA-compliant encrypted server managed by UCSF IT 
services that is privately maintained and hardware firewalled. Website communications 
are encrypted using a Secure Socket Layer (SSL) certificate and server access is restricted 
to research personnel working on campus or through the university Virtual Private 
Network (VPN). Access to study data will be restricted to approved study staff. File 
access is logged and audited by UCSF IT. UCSF IT performs daily backup of network 
servers. Laptop computers used for data collection or analysis are configured with full- 
disk encryption and antivirus software. UCSF IT is reachable 24/7 by telephone for any 
technological issues, including servers or critical data center equipment issues. 
 
16.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to authorized representatives of the 
Sponsor, IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon request. A file for 
each subject must be maintained that includes the signed Informed Consent, HIPAA 
Authorization and Assent Form and copies of all source documentation related to that 
subject. The Investigator must ensure the reliability and availability of source documents 
from which the information on the CRF was derived. 
All study documents (subject files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years following marketing of 
the investigational product or for two years after centers have been notified that the IND 
has been discontinued. There may be other circumstances for which the Sponsor is 
required to maintain study records and, therefore, the Sponsor should be contacted prior to 
removing study records for any reason. 


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16.6 Monitoring 
Monitoring will be conducted by the Sponsor according to the U.S. CFR Title 21 Parts 50, 
56, and 312 and ICH Guidelines for GCP (E6). 
 
16.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a Subject Identification Number (SID) 
will identify all study subjects on CRFs and other documentation submitted to the 
Sponsor. Additional subject confidentiality issues (if applicable) are covered in the 
Clinical Study Agreement. 
 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by SID only. All study records will be kept in a locked file 
cabinet and code sheets linking a subject’s name to a SID will be stored separately in 
another locked file cabinet. Clinical information will not be released without written 
permission of the subject, except as necessary for monitoring by the FDA. The 
Investigator must also comply with all applicable privacy regulations (e.g., Health 
Insurance Portability and Accountability Act of 1996, EU Data Protection Directive 
95/46/EC). 
 
17.1 Protocol Amendments 
The study investigators will write any amendment to the protocol. Protocol amendments 
cannot be implemented without prior written IRB/IEC approval except as necessary to 
eliminate immediate safety hazards to subjects. A protocol amendment intended to 
eliminate an apparent immediate hazard to subjects may be implemented immediately, 
provided the IRBs are notified within five working days. 
 
17.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC prior to 
study initiation. Serious adverse experiences regardless of causality will be reported to the 
IRB/IEC in accordance with the standard operating procedures and policies of the 
IRB/IEC, and the Investigator will keep the IRB/IEC informed as to the progress of the 
study. The Investigator will obtain assurance of IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
subject recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB/IEC. The IRB/IEC’s written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated. The IRB/IECs unconditional approval statement will be 
transmitted by the Investigator to the Sponsor prior to the shipment of study supplies to 


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the site. This approval must refer to the study by exact protocol title and number and 
should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the subjects or when the change(s) involves only logistical or administrative aspects of the 
study. Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained. 
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the subjects or the conduct of the 
study; an annual update and/or request for re-approval; and when the study has been 
completed. 
 
17.3 Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor for approval prior to submission to the 
IRB/IEC. The consent form generated by the Investigator must be acceptable to the 
Sponsor and be approved by the IRB/IEC. The written consent document will embody the 
elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. The Investigator will place 
IRB/IEC-approved copy of the Informed Consent Form in the locked study file cabinet. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial. Information should be given in both oral and written 
form and subjects must be given ample opportunity to inquire about details of the study. 
If appropriate and required by the local IRB/IEC, assent from the subject will also be 
obtained. A copy of the signed consent form (and assent) will be given to the subject and 
the original will be maintained with the subject’s records. 
 
17.4 Publications 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions. The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). 


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17.5 
Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and make changes only after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to 
include amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312. 


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33. Kerr, D., Kelly, A.-M., Dietze, P., Jolley, D. & Barger, B. Randomized controlled trial 
comparing the effectiveness and safety of intranasal and intramuscular naloxone for 
the treatment of suspected heroin overdose. Addiction 104, 2067–2074 (2009). 
34. Hussain, A., Kimura, R., Chong-Heng, H. & Kashihara, T. Nasal absorption of 
naloxone and buprenorphine in rats. Int. J. Pharm. 21, 233–237 (1984). 
35. Roche, D. & King, A. C. Sex differences in acute hormonal and subjective response to 
naltrexone: The impact of menstrual cycle phase. Psychoneuroendocrinology 52, 59– 
71 (2015). 


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36. Roche, D., Childs, E., Epstein, A. M. & King, A. C. Acute HPA axis response to 
naltrexone differs in female vs. male smokers. Psychoneuroendocrinology 35, 596– 
606 (2010). 
37. Kelly, A.-M. et al. Randomised trial of intranasal versus intramuscular naloxone in 
prehospital treatment for suspected opioid overdose. Med J Aust 182, 24–7 (2005). 
38. Epel, E. et al. The Reward-Based Eating Drive Scale: A self-report index of reward- 
based eating. PloS One 9, e101350 (2014). 
39. Nijs, I. M. T., Franken, I. H. A. & Muris, P. The modified Trait and State Food- 
Cravings Questionnaires: Development and validation of a general index of food 
craving. Appetite 49, 38–46 (2007). 
40. Wansink, B. Environmental factors that increase the food intake and consumption 
volume of unknowing consumers. Annu Rev Nutr 24, 455–479 (2004). 
41. Yeomans, M. R. & Gray, R. W. Effects of naltrexone on food intake and changes in 
subjective appetite during eating: evidence for opioid involvement in the appetizer 
effect. Physiol. Behav. 62, 15–21 (1997). 
42. Yeomans, M. R. & Gray, R. W. Selective effects of naltrexone on food pleasantness 
and intake. Physiol. Behav. 60, 439–446 (1996). 


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18 APPENDIX A: NALOXONE HYDROCHLORIDE PACKAGE INSERT 
 


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19 APPENDIX B: SYRINGE ASSEMBLY 


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20 APPENDIX C: STUDY TRAINING LOG 
Protocol Institutional Review Board #:   
 
Protocol Title: Opiate withdrawal responses to intranasal naloxone as an index of altered 
endogenous opioid activity among individuals with obesity: A feasibility and efficacy study 
Principal Investigator: Ashley E. Mason PhD 
Sponsor: Frederick M. Hecht, MD 
 
 
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21 APPENDIX D: TEST AND CONTROL PRODUCT ACCOUNTABILITY LOG 
 
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22 APPENDIX E: SCHEDULE OF EVENTS BY STUDY VISIT 
Protocol Institutional Review Board #:   
 
Protocol Title: Opiate withdrawal responses to intranasal naloxone as an index of altered 
endogenous opioid activity among individuals with obesity: A feasibility and efficacy study 
Principal Investigator: Ashley E. Mason PhD 
Sponsor: Frederick M. Hecht, MD 
 
VISIT 1 
VISIT 2a 
Informed Consent 
X 
Medical History 
X 
Height 
X 
Weight 
X 
Demographics 
X 
Pregnancy Test (Urine) 
X 
Drug Screen (Urine) 
X 
Measures of Eating Behavior (Self-Report) 
X 
Randomization 
X 
Food Buffet Menu Selection 
X 
Vital Signs (Pulse Rate, Temperature, Blood Pressure 
X 
Taste Test Procedure 
X 
X 
Administration of Control Product or Test Product 
X 
X 
Self-report Measures of Nausea (SOWS) 
X 
X 
Saliva 
X 
X 
Adverse Experiences 
X 
X 
Concomitant Medication Review 
X 
X 
a 
At least 24 hours after Visit 1 


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23 APPENDIX F: SUBJECT TRACKING LOG 
Protocol Institutional Review Board #:   
 
Protocol Title: Opiate withdrawal responses to intranasal naloxone as an index of altered 
endogenous opioid activity among individuals with obesity: A feasibility and efficacy study 
Principal Investigator: Ashley E. Mason PhD 
Sponsor: Frederick M. Hecht, MD 
 
Subject 
Study ID 
# 
Projected 
or Actual 
24 PHONE 
SCREE 
N 
25 DATE 
Visit #1 
Date 
26 VISIT 
#2 
27 DATE 
28 DATE AND 
REASON IF 
EARLY 
TERMINATIO 
N 
(please initial) 
Projected: 
Actual: 
Projected: 
Actual: 
Projected: 
Actual: 
Projected: 
Actual: 
Projected: 
Actual: 
Projected: 
Actual: 
Projected: 
Actual: 
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29 APPENDIX G: SPECIMEN ACCOUNTABILITY LOG 
Protocol Institutional Review Board #:   
 
Protocol Title: Opiate withdrawal responses to intranasal naloxone as an index of altered 
endogenous opioid activity among individuals with obesity: A feasibility and efficacy study 
Principal Investigator: Ashley E. Mason PhD 
Sponsor: Frederick M. Hecht, MD 
 
Subject 
ID # 
Visit 
Number 
Saliva 
Specimen # 
Date and 
Time of 
Collection 
Storage 
Location 
Initials of 
Person 
Collecting 
Sample 
Date and 
Time of 
Shipping/ 
Release 
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30 APPENXIX H: TASTE TEST ACCOUNTABILITY 
Protocol Institutional Review Board #:   
 
Protocol Title: Opiate withdrawal responses to intranasal naloxone as an index of altered 
endogenous opioid activity among individuals with obesity: A feasibility and efficacy study 
Principal Investigator: Ashley E. Mason PhD 
Sponsor: Frederick M. Hecht, MD 
 
Subject 
ID# 
Visit # Date 
Food 
Item 
Name 
Bowl # 
(Label on 
bottom of 
bowl) 
Empty 
Bowl 
Weight 
Filled 
Bowl 
Weight 
(Pre- 
eating) 
Filled 
Bowl 
Weight 
(Post- 
eating) 
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31 APPENDIX I: ADVERSE EVENT ACCOUNTABILITY LOG 
Protocol Institutional Review Board #:   
 
Protocol Title: Opiate withdrawal responses to intranasal naloxone as an index of altered 
endogenous opioid activity among individuals with obesity: A feasibility and efficacy study 
Principal Investigator: Ashley E. Mason PhD 
Sponsor: Frederick M. Hecht, MD 
 
Subject 
ID # 
Start 
Date 
of 
Event 
*Date 
Event 
Resolved 
Descripti 
on of 
Event 
Severit 
y of 
Event 
Nature 
of 
Event 
Relationship 
of Event 
Action with 
study drug 
1- No Action 
2- Interrupted 
3- Discontinued 
Is this an 
unanticipated 
problem 
involving 
risks to 
subjects or 
others? 
**Date 
Report 
Sent to 
IRB 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
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of   
 
* All events should be resolved or noted as unresolved at the time of subject’s discontinuation in the study 
(i.e. study complete or subject withdrawal) 
** Report all adverse events in accordance with UCSF CHR (IRB) Guidelines 
(http://www.research.ucsf.edu/chr/Guide/Adverse_Events_Guidelines.asp - 2) 


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32 APPENDIX J: PROTOCOL VIOLATION / INCIDENT REPORTING FORM 
Protocol Institutional Review Board #:   
 
Protocol Title: Opiate withdrawal responses to intranasal naloxone as an index of altered 
endogenous opioid activity among individuals with obesity: A feasibility and efficacy study 
Principal Investigator: Ashley E. Mason PhD 
Sponsor: Frederick M. Hecht, MD 
 
Date of First Awareness of Violation or Incident: 
 
 
Participant ID (or number of affected participants if more than one): 
 
 
Report to the CHR within 10 working days of awareness: 
  Change in protocol necessary to immediately protect research participants or others 
 
Report to the CHR within 10 working days of awareness: 
Major Protocol Violation 
  Incorrect research treatment or intervention given 
  Enrollment of participant ineligible per CHR protocol 
  Procedure/lab required by protocol not done 
  Procedure/lab done outside the required window 
Major Research-Related Incident 
  Problem with the informed consent or recruitment process 
  Significant concern or complaint received 
  Lapse in study approval 
  Loss of adequate resources 
  Unauthorized disclosure of private information (e.g., stolen or lost research 
data, privacy incident) 
  Other type of Major Protocol violation or Incident 
If Other, explain: 
What happened and how did it happen: 
 
What are the consequences or possible consequences of the event: 
What you have done in response to the event: 
What you have done to prevent recurrence of this type of event: 
Explain whether the event has been resolved: 
 
Is a modification needed 
  Yes 
  No 


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If YES, specify what will be modified: 
  Protocol 
  Consent form(s) 
  Other 
Specify Other: 
 
If YES, explain when the modification will be submitted. If NO explain why a 
modification is not needed: 
 
Actions Taken: Check all that apply 
  Participant has been withdrawn from further study participation 
  Study treatment for all subjects has been stopped (temporarily) 
  Study treatment for all subjects has been stopped (permanently) 
  Approved study data analysis plan modified 
  Sponsor has been notified 
  Other 
If Other, please explain: 
 
Did this event involve a definite or possible subject injury: 
  Yes 
  No 
This report involves a SF VA Medical Center patient, tissue, or data: 
  Yes 
  No 
 
Late Submissions: If this report is being submitted late [after 10 working days from first 
awareness, per the above], please explain 1) why this report is late, and 2) how late 
submissions will be avoided in the future: 


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Breach of Confidentiality Questions (section applies only if section 1.0 indicates a breach 
of confidentiality. 
The Breach of Confidentiality involves: 
  Social security number(s) 
  Electronic PHI 
  Non-Electronic PHI 
  Notification of the UCSF HIPAA Office 
Do you plan to inform subjects of the breach: 
  Yes 
  No 
If YES, describe your plan for informing subjects of the breach. If NO, explain why not. 
 
The PI and Sponsor will consult the UCSF Privacy Office at 415 353-2750 or affiliate 
Privacy Office when devising this plan. 

ICF_001.pdf: 
Official Title: Biology and Experience of Eating 
NCT Number: NCT02805972 
Document Date: June 27th, 2017 
Document Type: Informed Consent Form 


IRB NUMBER: 16-19392 
1 
 
 
IRB APPROVAL DATE: 06/27/2017 
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO IRB EXPIRATION DATE: 06/26/2018 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
Study Title: Biology and Experiences of Eating (BEE) 
This is a clinical trial, a type of research study. This study is about brain responses to snack and 
dessert foods among people who report that they sometimes overeat. It is being run by Ashley 
Mason, PhD and Frederick Hecht, MD, of the Osher Center for Integrative Medicine, and Elissa 
Epel, PhD, of the UCSF Department of Psychiatry. One of the study staff or researchers will explain 
this study to you. 
Clinical trials include only people who choose to take part. Please take your time to make your 
decision about participating. You may discuss your decision with your family and friends and with 
your health care team. If you have any questions, you can contact the study team using the 
information at the end of this form and you will receive a response from a team member or from the 
study doctor (Dr. Hecht). 
You are being asked to take part in this study because you are female, meet criteria for obesity, and 
said that you binge eat. 
Why is this study being done? 
The purpose of this study is to understand the chemical and brain responses that lead to rewarding 
feelings after eating tasty food. In the future, this may help researchers understand how to develop 
treatments to help people stop binge eating. 
Who pays for this study? 
The National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH), 
pays for the conduct of this study. 
What drug is used in this study? 
Naloxone hydrochloride (Narcan) will be sprayed into your nose on one occasion during this study. 
Naloxone hydrochloride is approved by the US Food and Drug Administration (the FDA) as a 
treatment for the effects of overdosing on heroin or other opiate drugs. In this study it will be used to 
help understand the effects of eating on the brain for people who are not taking opiates. This is 
considered an investigational use. 
How many people will take part in this study? 
About 40 people will take part in this study. 
What will happen if I take part in this research study? 
Study Overview: 
In this study you will talk to a staff member on the phone, complete some questionnaires 
online, and purchase some of your favorite foods (which we will reimburse you for) before you 
attend each of two lab visits at the UCSF Osher Center. At these lab visits, you’ll do some 


IRB NUMBER: 16-19392 
2 
 
 
IRB APPROVAL DATE: 06/27/2017 
computerized games, eat some snacks and rate them, and use a nasal spIrRaByE.XPMIRoATre
IONdDeAtTaEi:ls06/26/2018 
about each part of the study are below. 
Phone screening 
Time: 5-15 minutes 
A study staff member will confirm some of your information, ask a few eligibility questions, and make 
sure that all your questions are answered. If you are eligible to continue the staff member will 
schedule your lab visits and email you the online questionnaires. 
Online questionnaires 
Time: 10 minutes each 
You will fill out questionnaires the nights before each of your visits with us that you will receive by 
email. These questions ask about your eating behavior and demographic information. You can fill out 
the online questionnaires anytime before your scheduled lab visits. 
Pre-Visit Food Shopping 
Time: 60 minutes or less 
You will purchase foods (up to $25 total) from nearby locations in the hour prior to your lab visit. You 
will save receipts from these purchases and study staff will reimburse you in cash for these 
purchases before you leave each lab visit. 
Lab visits 
Time: Visit One - 3 hours / Visit Two - 2.5 hours 
Location: UCSF Osher Center for Integrative Medicine, 1545 Divisadero St., 3rd Floor 
The lab visits will be in the afternoon, and must be at least 1 day apart. We will work with you to 
schedule a convenient day. At these visits you will: 
 
• Provide a urine sample to ensure that you are not pregnant or using drugs or medications that 
may cause a reaction with the study medication (visit 1 only) 
• Do some computerized games to measure things like attention and reaction speed 
• Do a “taste test” with food of your choice 
• Take a nasal spray 
• Provide saliva samples 
• Report on how you’re feeling physically and mentally 
At one of the visits, the nasal spray will contain the FDA-approved dose of 4mg naloxone, the 
medication being studied. At the other visit it will contain placebo, an inactive substance (salt water). 
A computer random number generator will determine whether you get the placebo at the first visit and 
the naloxone at the second visit, or vice versa. Neither you or the study staff will know which nasal 
spray you are getting at each lab visit. 


IRB NUMBER: 16-19392 
3 
 
 
How long will I be in the study? 
IRB APPROVAL DATE: 06/27/2017 
IRB EXPIRATION DATE: 06/26/2018 
 
The two lab visits will be scheduled times that are convenient for you. They must be at least 1 
calendar day apart. The researchers estimate that most participants will complete the study within 3 
weeks of agreeing to participate, but this may vary depending on your schedule. The total time you 
spend on all study activities will probably be less than 7 hours (which includes 2 hours of food 
shopping: One hour before each visit). 
Can I stop being in the study? 
Yes. You can decide to stop at any time. Please tell the study staff or one of the study researchers if 
you would like to stop. 
There are no risks caused by stopping the study. However, if you decide to stop shortly after taking 
the nasal spray you may wish to wait in the lab for 30 minutes to see if you experience any side 
effects. 
One of the study researchers may stop you from taking part in this study at any time if he or she 
believes it is in your best interest, if you do not follow the study rules, if he/she believes that you are 
not an appropriate participant for the study, or if the study is stopped. 
What side effects or risks can I expect from being in the study? 
Medication side effects 
You may have side effects after taking the nasal spray. Everyone taking part in the study will be 
watched carefully for any side effects. For healthy people who are not taking opiate drugs, all of the 
known side effects of naloxone are mild and go away within about an hour. 
You should talk to the study staff about any side effects you experience while taking part in the study. 
The staff member may contact the study doctor, or you can ask to speak to the study doctor if you 
wish. 
Side effects related to naloxone nasal spray can include: 
• 
Increased blood pressure 
• 
Musculoskeletal pain (pain in bones, muscles, or joints) 
• 
Headache 
• 
Nausea 
• 
Nasal dryness 
• 
Nasal edema (swelling) 
• 
Nasal congestion 
• 
Nasal inflammation 
Reproductive risks: Pregnant women are excluded from this study as it is not known whether 
naloxone has any risks for developing fetuses. If you think you might be pregnant, please tell the 
researchers. 


IRB NUMBER: 16-19392 
4 
 
 
IRB APPROVAL DATE: 06/27/2017 
Unknown Risks: Naloxone may have side effects that no one knows about yet.IRTBhEeXPrIReAsTeIOaNrcDhAeTEr:s06w/2i6ll/2018 
let you know if they learn anything that might make you change your mind about participating in the 
study. 
For more information about risks and side effects, please contact the study doctor, Dr. Hecht, at 
Rick.Hecht@ucsf.edu or (415) 476 4082, extension 431. 
Privacy risks 
Your information could be disclosed in a security breach. This might lead to embarrassment or to 
others learning about your health, medication use, or pregnancy status. The study uses industry- 
standard encryption and multiple layers of data security to minimize this possibility, and security 
breaches are extremely rare. 
Are there benefits to taking part in the study? 
There will be no direct benefit to you from participating in this study. However, this study will help 
doctors and scientists learn more about the biological and psychological experiences of eating tasty 
foods. In the future, this information might help create treatments for people who binge eat or have 
food cravings. 
What other choices do I have if I do not take part in this study? 
You are free to choose not to participate in this study. If you decide not to take part in this study, there 
will be no penalty to you. You will not lose any of your regular benefits, and you can still get care the 
way you usually do. 
 
How will information about me be kept confidential? 
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total privacy. 
Research records will be kept as confidentially as possible. All specimens and data collected will be 
coded (your name will not be stored in the same file as your study data). The study will protect your 
data from unauthorized access using physical and electronic security protocols. All information that is 
sent over the internet will use industry-standard encryption and authentication methods. 
No information will be shared with your doctor or insurance provider, or anyone else not directly 
involved with the study. If information from this study is published or presented at scientific meetings, 
your name and other personal information will not be used. 
Your personal information may be given out if required by law. Additionally, organizations that may 
look at and/or copy your medical records for research, quality assurance, and data analysis include: 
• The University of California 
• The National Heart, Lung, and Blood Institute 
• Government agencies, e.g., the Food and Drug Administration (FDA), involved in keeping 
research safe for people. 


IRB NUMBER: 16-19392 
5 
 
 
What are the costs of taking part in this study? 
You will not be charged for any of the study activities. 
Will I be paid for taking part in this study? 
IRB APPROVAL DATE: 06/27/2017 
IRB EXPIRATION DATE: 06/26/2018 
In return for your time and effort, you will be paid in amazon.com giftcards at each study visit for each 
part of your participation in this study: 
• $10 in Amazon.com giftcards for completing the online questionnaires ($5 each at visit 1 and 
visit 2) 
• 
$75 in Amazon.com giftcards for completing the first lab visit (visit 1) 
• 
$125 in Amazon.com giftcards for completing the second lab visit (visit 2) 
You will be reimbursed in cash at each visit for the cost of the foods you bought before each study 
visit, up to $25 per visit; you will be required to provide receipts so that we can reimburse you. 
You will be reimbursed for $4.50 for round trip MUNI transportation or will be provided with parking 
stickers for the UCSF Mt. Zion Garage for each visit. 
What happens if I am injured because I took part in this study? 
It is important that you tell the Principal Investigator, Dr. Mason, or the study doctor, Dr. Hecht, if you 
feel that you have been injured because of taking part in this study. You can reach Dr. Mason at (415) 
514 6820 or ashley.mason@ucsf.edu. You can reach Dr. Hecht at (415) 476 4082, extension 431. 
Treatment and Compensation for Injury: If you are injured as a result of being in this study, 
the University of California will provide necessary medical treatment. The costs of the 
treatment may be billed to you or your insurer just like any other medical costs, or covered by 
the University of California, depending on a number of factors. The University does not 
normally provide any other form of compensation for injury. For further information about this, 
you may call the office of the Committee on Human Research at (415) 476 1814. 
What are my rights if I take part in this study? 
Taking part in this study is your choice. You may choose either to take part or not to take part in the 
study. If you decide to take part in this study, you may leave the study at any time. No matter what 
decision you make, there will be no penalty to you and you will not lose any of your regular benefits. 
Leaving the study will not affect your medical care. You can still get your medical care from our 
institution. 
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment 
by signing this form. 


IRB NUMBER: 16-19392 
6 
 
 
Who can answer my questions about the study? 
IRB APPROVAL DATE: 06/27/2017 
IRB EXPIRATION DATE: 06/26/2018 
 
You can contact the study team with any questions, concerns, or complaints you have about this 
study. You will receive a prompt response from a staff member, the lead researcher, or the study 
doctor, as appropriate. 
 
• Email: BeeStudy@UCSF.edu 
• Phone: (415) 476 7634 
If you wish to contact the principal investigator directly, you can reach Dr. Mason at (415) 514 6820 or 
ashley.mason@ucsf.edu. 
If you wish to contact the study doctor directly, you can reach Dr. Hecht at Rick.Hecht@ucsf.edu or 
(415) 476 4082 extension 431. 
If you wish to ask questions about the study or your rights as a research participant to someone other 
than the researchers or if you wish to voice any problems or concerns you may have about the study, 
please call the Office of the Committee on Human Research at (415) 476 1814. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include 
a summary of the results. You can search this Web site at any time. 
************************************************************ 
 
CONSENT 
You have been given copies of this consent form and the Experimental Subject's Bill of Rights to 
keep. 
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to participate or to 
withdraw at any point in this study without penalty or loss of benefits to which you are otherwise 
entitled. 
If you wish to participate in this study, you should sign below. 
 
 
 
Date 
Participant's Signature for Consent 
 
 
Print name of Participant 
 
 
Date 
Person Obtaining Consent 
 
 
Print name of Person Obtaining Consent