A Pilot Study to Evaluate the Effects of Castration on the Pharmacokinetics of Zolpidem After Single Dose Administration in Men With Prostate Cancer Undergoing Androgen Deprivation Therapy Compared to Normal Healthy Females
Phase: PHASE1
Conditions: Prostatic Neoplasms
Sponsor: National Cancer Institute (NCI)



Abbreviated Title: Castration on Zolpidem PK
Version Date: 02/08/2022
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PRÉCIS
Background:

Zolpidem is currently approved for the treatment of patients with insomnia.

Women reported experiencing an increased incidence of adverse effects than men, 
resulting in a reduction of the recommended dose of zolpidem for women.

Zolpidem metabolism is affected by both age and gender; the recommended dose for the 
elderly and female populations is 5mg daily.

Subsequent studies have shown that women experience greater exposure to zolpidem 
than men, potentially due to androgen-driven differences in enzyme expression. 

A preclinical study showed that castrated male rats exhibited zolpidem pharmacokinetics 
similar to that of female rats, providing further evidence to suggest that zolpidem 
pharmacokinetics are androgen-driven. 
Objectives:

To evaluate the effect of castration on the pharmacokinetics of a single 5-mg dose of 
zolpidem in participants with prostate cancer undergoing androgen deprivation therapy 
(pre- vs. post-castration therapy) compared to normal healthy females.
Eligibility:

Participants with prostate cancer (rising PSA and testosterone levels ≥ 100 ng/dL)

Females in good health condition or without significant diseases

After androgen deprivation therapy, castrate testosterone levels <50 ng/dL 

ECOG 0-1 
Design:

Comparative, single-dose pharmacokinetic study.

Men with prostate cancer  (pre-castration) and normal healthy females will receive 
treatment with a single dose of 5 mg tablet of zolpidem followed by 8-hour 
pharmacokinetic evaluation of zolpidem and its metabolites.

Men will then undergo androgen deprivation therapy and when castrate testosterone 
levels <50 ng/dL (post-castration), they will receive another 5 mg single dose of 
zolpidem followed by 8-hour pharmacokinetic evaluation of zolpidem and its 
metabolites.

Normal healthy females will receive treatment with a single dose of 5 mg tablet of 
zolpidem followed by 8-hour pharmacokinetic evaluation of zolpidem and its 
metabolites.

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TABLE OF CONTENTS 
PRÉCIS...........................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................3
STATEMENT OF COMPLIANCE ................................................................................................5
1.
INTRODUCTION ...................................................................................................................5
1.1
Study Objectives ...............................................................................................................5
1.2
Background and Rationale................................................................................................5
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .........................................................9
2.1
Eligibility Criteria .............................................................................................................9
2.2
Screening Evaluation ......................................................................................................12
2.3
Participant Registration and Status Update Procedures..................................................13
2.4
Baseline Evaluation.........................................................................................................13
3
STUDY IMPLEMENTATION .............................................................................................14
3.1
Study Design...................................................................................................................14
3.2
Drug Administration .......................................................................................................14
3.3
Study Calendar................................................................................................................16
3.4
Cost and Compensation ..................................................................................................18
3.5
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................18
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................19
4.1
General Guidelines..........................................................................................................19
4.2
CNS Depressants.............................................................................................................19
4.3
Drugs affecting Cytochrome P450..................................................................................20
5
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES ..........20
5.1
Biospecimen Collection ..................................................................................................20
5.2
Sample Processing ..........................................................................................................21
5.3
Sample Storage, Tracking and Disposition.....................................................................21
6
DATA COLLECTION AND EVALUATION .....................................................................22
6.1
Data Collection ...............................................................................................................22
6.2
Data Sharing Plans..........................................................................................................23
6.3
Toxicity Criteria..............................................................................................................23
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...24
7.1
Definitions.......................................................................................................................24
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................24

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7.3
NCI Clinical Director Reporting.....................................................................................24
7.4
NIH Required Data and Safety Monitoring Plan............................................................24
8
STATISTICAL CONSIDERATIONS ..................................................................................25
8.1
Statistical hypotheses ......................................................................................................25
8.2
Sample size determination ..............................................................................................25
8.3
Populations for analysis ..................................................................................................25
8.4
Statistical analyses ..........................................................................................................25
9
HUMAN SUBJECTS PROTECTIONS................................................................................27
9.1
Rationale For Subject Selection......................................................................................27
9.2
Participation of Children.................................................................................................27
9.3
Participation of Subjects Unable to Give Consent..........................................................27
9.4
Evaluation of Benefits and Risks/Discomforts ...............................................................27
9.5
Risks/Benefits Analysis ..................................................................................................28
9.6
NIH Healthy Volunteers .................................................................................................28
9.7
Consent Process and Documentation..............................................................................28
10
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................30
10.1
Study Discontinuation and Closure.............................................................................30
10.2
Quality Assurance and Quality Control ......................................................................30
10.3
Conflict of Interest Policy ...........................................................................................30
10.4
Confidentiality and Privacy.........................................................................................31
11
PHARMACEUTICAL INFORMATION .............................................................................31
11.1
ZOLPIDEM.................................................................................................................31
12
REFERENCES ......................................................................................................................35
13
APPENDIX A - Performance Status Criteria........................................................................37

Abbreviated Title: Castration on Zolpidem PK
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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1. INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective

To evaluate the effect of castration on the pharmacokinetics of a single 5-mg dose of 
zolpidem by comparing the overall exposure of participants with prostate cancer before 
and after undergoing androgen deprivation therapy (pre- vs. post-castration therapy) and 
to the exposure of normal healthy females.
1.2
BACKGROUND AND RATIONALE 
1.2.1
Zolpidem Background 
Zolpidem is a nonbenzodiazepine imidazopyridine drug which functions as an agonist of the 
GABAA receptor to induce sleep. It displays high specificity for the benzodiazepine-1 receptor 
subtype over others. Receptor binding of zolpidem increases GABA activity and that of inhibitory 
synapses. It has a short clearance time making it beneficial for patients with difficulty falling asleep 
[1]. Insomnia is a common problem for many and recently zolpidem has been widely prescribed. 
However, some patients maintain the effects of the drug for long durations, mainly drowsiness 
upon waking the following morning. This can impair one’s ability to perform necessary tasks or 
operate motor vehicles effectively [2]. With women and the elderly reporting higher incidences of 
insomnia, research has moved towards investigating the pharmacokinetic properties of zolpidem 
in differing populations [3, 4].
1.2.2
Sex Differences in Zopidem Pharmacokinetics 
Women have reported a higher incidence of persisting adverse effects from zolpidem than men. 
Subsequent studies analyzed the pharmacokinetics properties of zolpidem in males and females. 

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In one study of healthy non-elderly individuals, females consistently experienced 40-50% higher 
AUC values (280 ng*h/mL vs 187 ng*h/mL) and a higher CMAX (77 ng/mL vs 53 ng/mL) as seen 
in Figure 1[5]. This suggested slower clearance than males across several dosage levels. Such 
results led the FDA to decrease the recommended dose for female by half in 2013. The current 
FDA recommended dose is 5 mg for women and elderly or debilitated patients and either 5 or 10 
mg for men. Despite acknowledgement of the sex-specific difference in zolpidem 
pharmacokinetics, the underlying mechanism has not been fully understood. 
Sex-specific differences were thought to be attributed to differences in zolpidem metabolism. After 
administration zolpidem is initially metabolized by several cytochrome P450 enzymes. These 
enzymes hydrolyze the drug into one of three metabolites, contingent on the site of action. The 
most influential enzyme is CYP3A4, which is responsible for about 60% of CYP-mediated 
zolpidem metabolism. These metabolites are then converted to aldehydes by alcohol 
dehydrogenases (ADHs). The aldehyde is then converted to a carboxylic acid by aldehyde 
dehydrogenases (ALDHs). The two main zolpidem derived carboxylic acids are zolpidem phenyl 
4-carboxylic acid (ZPCA) and zolpidem 6-carboxylic acid (ZCA) which constitute about 72-86% 
and 10% of the original dose, respectively [6]. Previously mentioned sex-specific differences could 
not be ascribed to CYP3A4, as females have greater CYP3A4 activity than men [7]. However, 
males express more ADH and ALDH in the gastrointestinal tract than females [8-12]. 
A comparison of elderly and young men revealed drastic changes in pharmacokinetics. Compared 
to young men, elderly men recorded vastly decreased oral clearance (276 mL/min vs 820 mL/min) 
as well as higher CMAX (93 ng/mL vs 40 ng/mL), AUC (400 ng*h/mL vs 110 ng*h/mL), and a 
longer half-life (2.7 h vs 1.5 h). The same analysis in women also revealed an increased AUC (398 
ng*h/mL vs 249 ng*h/mL) and decreased clearance (209 mL/min vs 376 mL/min) with age but to 
a far lesser degree. Further analysis showed that elderly men posted values closer to that of women 
than younger men. This might be explained by free serum testosterone concentrations, which were 
found to be lower in elderly than younger men (10.5 pg/mL vs 19.0 pg/mL). When compared to 
Figure 1. Mean (SE) plasma zolpidem in male and female subjects after ZST doses of 3.5 
mg. Mean (SE) total area under the plasma zolpidem concentration curve (AUC) in male 
and female subjects after the three doses of ZST (1.0 mg, 1.75 mg, and 3.5 mg). Statisti 
Statistical comparisons of male and female groups using Student’s t‐test: *P = .05; **P < 
.05. SE, standard error; ZST, zolpidem sublingual tablet.

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1.2.3
Rationale  
Previous studies have revealed sex differences affecting zolpidem pharmacokinetic properties. 
Females were found to experience greater exposure to the drug resulting in an increased incidence 
of adverse effects. One study attributed these differences to a discrepancy in zolpidem clearance 
between sexes [5]. This led to a revision to dosing protocols where females and elderly receive 
half the dose of males. However, a subsequent preclinical study suggested that these differences 
may be androgen-driven and be caused by a difference in absorption [14]. This clinical study will 
provide a unique opportunity to observe the effects of castration on zolpidem pharmacokinetics in 
humans. The findings could lend more evidence that sex differences in zolpidem pharmacokinetics 
are driven by androgens that affect first-pass metabolism and absorption more than clearance.
Subjects of Asian descent often have a lack of alcohol dehydrogenase isoenzyme activity in the 
stomach tissue [15, 16], express atypical ADH2*2 that rapidly converts alcohols into aldehydes 
[17], and harbor the E487K polymorphism in ALDH2 that inactivates the conversion of aldehydes 
into carboxylates [18]. Thus, these individuals often have altered alcohol disposition as compared 
to other world populations. Since we observed that ADH and ALDH affect zolpidem disposition 
in animals as a function of plasma androgen, Asians will be excluded from this study.
Figure 3. Zolpidem plasma (A) Cmax and (B) AUClast by sex and castration status. Data 
are represented by bar graphs depicting the mean ± the standard error of the mean (SEM), 
and p-values were determined by Bailer’s Z-test.

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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria – for male cohort
2.1.1.1
Participants must have histologically or cytologically confirmed prostate cancer. Note: 
If histologic documentation is unavailable, a clinical course consistent with prostate 
cancer is acceptable. 
2.1.1.2
Participants must be eligible for and must be planning to undergo androgen deprivation 
therapy
2.1.1.3
Testosterone levels ≥ 100 ng/dL
2.1.1.4
Participants must have progressive prostate cancer as indicated by either PSA 
progression (PSA progression is defined as two consecutively rising PSAs above the 
nadir post-definitive therapy and an absolute value greater than 1.0 ng/mL separated by 
at least 2 weeks) or radiographic progression based on RECIST v1.1 or Prostate Cancer 
Working Group 3 (PCWG3).
2.1.1.5
ECOG performance status 0 to 1 (see APPENDIX A)
2.1.1.6
Participants must have normal organ and marrow function as defined below:

Hemoglobin
≥ 9 g/dL

leukocytes
≥ 3,000/mcL

absolute neutrophil count
≥ 1,500/mcL

platelets
≥ 150,000/mcL

total bilirubin
within normal institutional limits

AST(SGOT)/ALT(SGPT)
≤ institutional upper limit of normal

creatinine
within normal institutional limits
OR

creatinine clearance
≥ 60 mL/min/1.73 m2 for participants with 
creatinine levels above institutional normal
(calculated via Cockcroft-Gault equation)
2.1.1.7
Participants must not have other concurrent malignancies (within the past 2 years with 
the exception of non-melanoma skin cancer and Rai Stage 0 chronic lymphocytic 
leukemia), in situ carcinoma of any site, or life threatening illnesses, including untreated 

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infection (must be at least 1 week off intravenous antibiotic therapy before beginning 
zolpidem).
2.1.1.8
Ability of subject to understand and the willingness to sign a written informed consent 
document.
2.1.1.9
Ability to swallow study medication.
2.1.1.10 Willingness to travel to NIH for follow-up visits.
2.1.1.11 Men age > 18 years of age. Children are excluded because prostate cancer is not 
common in pediatric populations.
2.1.2
Inclusion Criteria - for normal healthy female cohort
2.1.2.1
Females age > 18 years of age
2.1.2.2
Good health conditions or without significant diseases, according to best medical 
judgement.
2.1.2.3
If breastfeeding, must be willing to discard breastmilk for 24 hours following zolpidem. 
2.1.2.4
Ability of subject to understand and the willingness to sign a written informed consent
2.1.2.5
Ability to swallow study medication.
2.1.3
Exclusion Criteria - for male cohort 
2.1.3.1
Participants who are receiving any other investigational agents (in the past 28 days) or 
herbal medications (within 1 day).
2.1.3.2
Participants who have received systemic chemotherapy for prostate cancer will not be 
eligible.
2.1.3.3
Known hypersensitivity to Zolpidem or chemically related compounds; history of 
serious adverse reactions or hypersensitivity to any drug.
2.1.3.4
Clinically significant cardiac disease, e.g. New York Heart Association (NYHA) classes 
III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled hypertension, 
myocardial infarction in the previous 6 months as confirmed by an electrocardiogram 
(ECG).
2.1.3.5
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection,symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.
2.1.3.6
HIV-positive participants on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with zolpidem. Appropriate studies 
will be  undertaken in participants receiving combination antiretroviral therapy when 
indicated.
2.1.3.7
Participants with known active treatment for Hepatitis B and C infections.
2.1.3.8
Participants who are taking medications that may alter the metabolism of zolpidem. 
This includes strong CYP3A4 inhibitors or inducers or CYP3A4 substrates with a 

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narrow therapeutic index. For a current table of Substrates, Inhibitors and Inducers 
please access the following website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Drug
InteractionsLabeling/ucm093664.htm
2.1.3.9
History or presence of hepatic or gastrointestinal diseases, or other condition that 
interferes with drug absorption, distribution, excretion or metabolism.
2.1.3.10 Participants currently taking other sedative hypnotic medications
2.1.3.11 Participants with a known history of psychiatric issues
2.1.3.12 Participants at risk for fall or who have had recent fractures
2.1.3.13 Participants of Asian descent 
2.1.4
Exclusion Criteria - for normal healthy female cohort
2.1.4.1
Chronic therapy with any drugs, except contraceptives
2.1.4.2
History of hepatic, kidney, lungs, gastrointestinal, epileptic, hematologic or psychiatric 
disease; hypotension or hypertension, of any etiology, that requires pharmacological 
treatment; history of myocardial infarction, angina and/or heart failure.
2.1.4.3
Use of regular medications within 2 weeks prior study enrollment or use of any 
medications within one week prior to study enrollment, except contraceptives or cases 
which, based on drug's or metabolite's half-life, complete elimination can be assumed.
2.1.4.4
Hospitalization for any reason up to 8 weeks before enrollment.
2.1.4.5
Any condition, according to investigator's best judgement, that prevents the subject to 
participate in the trial
2.1.4.6
Pregnancy, labor or miscarriage within 12 weeks before admission predicted date.
2.1.4.7
Known hypersensitivity to zolpidem or chemically related compounds; history of 
serious adverse reactions or hypersensitivity to any drug.
2.1.4.8
Females of Asian descent
2.1.4.9
History of taking estrogen derivatives, androgens, or similar hormonal replacement or 
supplementation products. Past and current use of hormonal contraceptives is allowed.  
2.1.5
Recruitment Strategies
This study will be listed on available websites (www.clinicaltrials.gov, 
https://ccr.cancer.gov/clinical-trials/patients ) and participants will be recruited from the current 
participant population at NIH. This study will be posted on NIH websites and on NIH social 
media forums. Recruitement flyers may be used to advertise this study in future.  
Healthy women volunteers may be self-referred or recruited through the healthy volunteer office 
and may include NIH employees. Recruitment, enrollment and compensation of NIH employee 
subjects will be consistent with NIH policy 2300-630-3, Leave Policy for NIH Employees 
Participating in Medical Research Studies (see Section 9.6).

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2.2
SCREENING EVALUATION
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects. 

Review of existing medical records to include H&P, laboratory studies, etc.  

Review of existing  MRI, x-ray, or CT images.

Review of existing photographs or videos.

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes.
A waiver of consent for these activities has been requested in Section 9.7.1.
2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the consent for this 
study for screening. Assessments performed at outside facilities or on another NIH protocol 
within the timeframes below may also be used to determine eligibility once a participant has 
signed the consent.
2.2.2.1
For men

Pathological confirmation: Participants must have histopathological documentation of 
prostate cancer prior to enrollment. Note: If no pathologic documentation is available, a 
clinical course consistent with prostate cancer is acceptable.

Within 8 weeks of study entry: 
o
CT scan reports (only required if confirmation of radiographic progression is 
necessary; both scans performed on another protocol at NIH and scans outside 
NIH are acceptable)
o
ECG 
o
Laboratory tests: CBC with differential, Creatinine, ALT, AST, total bilirubin, 
PT/PTT, serum PSA, testosterone level, 
o
Focused history, physical examination with documentation of weight and ECOG 
performance status.
2.2.2.2
For women

Pregnancy test (serum or urine) within 3 days before study entry. 

Within 8 weeks of study entry: 
o
ECG 
o
Laboratory tests: CBC with differential, Creatinine, ALT, AST, total bilirubin, 
PT/PTT, 
o
Focused history, physical examination with documentation of weight.

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2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here. 
2.3.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE).
2.3.2
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Prostate cancer cohort
Participants with prostate cancer undergoing androgen 
deprivation therapy (pre- vs. post-castration therapy) 
2
Healthy females cohort
Normal healthy females 
Arms
Number
Name
Description
1
Zolpidem pre and post 
castration
5 mg oral dose of zolpidem prior to undergoing ADT 
followed by 5 mg oral dose of zolpidem after ADT and 
testosterone reaches castrate levels
2
One time zolpidem
Single 5 mg oral dose of zolpidem
Arm Assignment
Participants in Cohort 1 will be directly assigned to Arm 1.
Participants in Cohort 2 will be directly assigned to Arm 2.
2.4
BASELINE EVALUATION
Tests performed during screening do not need to be repeated if performed within 17 days prior to 
the first administration of zolpidem.
2.4.1
For men, and women

History and physical examination.

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
Laboratory and urine studies: CBC with differential, PT/PTT, and Acute care panel 
(Serum sodium, Potassium test, Serum chloride, CO2, Creatinine, Glucose test, BUN); 
Mineral panel (Albumin, Calcium, Magnesium, Phosphorous – serum); Hepatic Panel 
(Alkaline phosphatase, ALT, AST, direct and total bilirubin); Gamma-GT, LDH, total 
cholesterol, total protein, Serum PSA (only for men), uric acid, urinalysis; 
androstenedione level, dihydrotestosterone level, estradiol level 

ECG 

Vital signs including weight 

Height (if not previously recorded at any time)
2.4.2
For women, additionally following test will be done:

Pregnancy Test (serum or urine) must be repeated within 3 days of receiving zolpidem.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is single-dose, comparative trial evaluating the effect of castration on the pharmacokinetics 
of a single 5-mg dose of zolpidem in participants with prostate cancer (cohort 1, arm 1) 
undergoing androgen deprivation therapy (pre- vs. post-castration therapy) compared to normal 
healthy females (cohort 2, arm 2). In men with prostate cancer, males (pre-castration, n=10) will 
receive oral zolpidem in the form of a 5 mg tablet. Blood samples will be collected for 
pharmacokinetic analysis at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, and 8-hours post-dose. This 
cohort of men will then undergo androgen deprivation therapy until castrate testosterone levels 
reach <50 ng/dL. When castrate testosterone levels reach <50 ng/dL (post-castration), they will 
receive another 5 mg single dose of zolpidem followed by 8-hr PK evaluation (as described 
above for pre-castrate men) of zolpidem and its metabolites.
Normal healthy females (n=10) will receive a single dose of 5 mg tablet of zolpidem followed by 
8-hr PK evaluation of zolpidem and its metabolites. Blood samples will be collected for PK 
analysis at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, and 8-hours post-dose.
3.2
DRUG ADMINISTRATION
The rate and extent of absorption of zolpidem is influenced by dosage coincident with food. For 
orally administered immediate-release and controlled‐ release zolpidem, coadministration with a 
standard high‐fat meal slows the rate of absorption and reduces the extent of absorption. These 
findings are described in the product label, but are not published in the literature. The effect of 
zolpidem may be slowed by ingestion with or immediately after a meal. In a food effect study on 
the rate and extent of absorption of zolpidem from a standard 3.5 mg dose of the buffered zolpidem 
sublingual tablet, zolpidem plasma levels were lower in the fed state compared to the fasting state 
from 20 minutes to 3 hour post‐dose. Beyond 4 hour post‐dose, zolpidem levels in the fed state 
exceeded the fasting levels, but net total AUC was not significantly different between the 
conditions [19]. Therefore, we recommend that participants should fast (no caloric intake) for at 
least 4 hours prior to being administered the dose of the study medication.

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Subjects are admitted to the Clinical Center on Day 1 in the evening (for the first 8-hours of PK 
sampling) and will take a single 5 mg dose of an oral zolpidem tablet. Participants will be advised 
to have an early dinner (~18:00) and must have fasted for at least 4 hours prior to taking the study 
medication. The clinical research personnel or designee will administer the study medication at 
approximately 23:00 hours with ambient temperature water to a total volume of about 240 mL. 
Subjects are required to swallow the study medication whole and not chew the medication prior to 
swallowing. The subjects are required to refrain from drinking beverages other than water during 
the first 4 hours after dosing. Water is allowed except 1 hour pre and post dose. 
Subjects may be discharged the following day when the blood draws have completed.  One day 
following discharge, a study coordinator will contact the subject via phone to query for any adverse 
events. 
This will be repeated for the men who receive a second dose of zolpidem when their castrate 
testosterone levels reach <50 ng/dL (post-castration).  Baseline tests as described in Section  2.4.1 
will be obtained when the subject is admitted to the hospital for the second dose of zolpidem. 

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3.3
STUDY CALENDAR
3.3.1
Cohort 1 (Prostate Cancer)
1.
Baseline and day 1 assessments already performed at screening do not need to be repeated 
if peformed within 17 days prior to the first administration of zolpidem.
2.
CBC with differential, creatinine, ALT, AST, total bilirubin, PT/PTT, serum PSA, serum 
testoterone
3.
CBC with differential, PT/PTT, and Acute care panel (Serum sodium, Potassium test, 
Serum chloride, CO2, Creatinine, Glucose test, BUN); Mineral panel (Albumin, Calcium, 
Magnesium, Phosphorous – serum); Hepatic Panel (Alkaline phosphatase, ALT, AST, 
direct and total bilirubin); Gamma-GT, LDH, total cholesterol, total protein, serum PSA, 
uric acid, urinalysis; androstenedione level, dihydrotestosterone level, estradiol level 
4.
If not previously recorded at any time.
Period 1
Period 2
Procedure
Screening
Baseline1
Day 1
Day 3
Day 1
Day 3
Confirmation of 
diagnosis
X
History and PE
X
X
X
X
Vital signs (including 
weight)
X
X
X
X
Height4
X
Performance Score
X
X
Labs 
X2
X3
X3
X3
ECG
X
X
PKs
X
X
Adverse Events
X
X
X
X
Concomitant 
Medications
X
X
Follow up phone call
X
X

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3.3.2
Cohort 2 (Healthy Females)
1.
Except for pregnancy test, baseline and day 1 assessments already performed at screening 
do not need to be repeated if peformed within 17 days prior to zolpidem administration. 
Pregnancy test must be repeated within 3 days prior to receiving zolpidem.
2.
Please refer to Section 2.2 for details.
3.
Please refer to Section 2.4 for details. 
4.
If not previously recorded at any time
Period 1
Procedure
Screening
Baseline1
Day 11
Day 3
History and PE
X
X
X
Vital sign (including 
weight)
X
X
X
Height4
X
Performance Score
X
Urine or serum hCG
X
X
Labs
X2
X3
X3
Androstendione, 
dihydrotestosterone 
and estradiol levels
X
ECG
X
X
PK
X
Adverse Events
X
X
Concomitant 
Medications
X
Follow up phone call
X

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3.4
COST AND COMPENSATION
3.4.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they 
are not covered by insurance company. Medicines that are not part of the study treatment will not 
be provided or paid for by the NIH Clinical Center.    
3.4.2
Compensation
All study participants will be compensated for each blood sample collected for PK analysis as 
follows:

$20 for the 1st pre-dose PK sample

$20 for the 2nd (0.25 hours) PK sample

$20 for the 3rd (0.5 hours) PK sample

$20 for the 4th (1 hour) PK sample 

$20 for the 5th (1.5 hours) PK sample

$20 for the 6th (2 hours) PK sample

$20 for the 7th (3 hours) PK sample

$20 for the 8th (4 hours) PK sample

$20 for the 9th (8 hours post dose) PK sample
All remuneration will be directed to be paid to the participant via check through standard 
compensation procedures. These funds are intended to compensate for time away from work that 
is required to participate in this study. As we intend to recruit from the local metropolitan region, 
we will not provide remuneration for meals, lodging or transportation. If a participant withdraws 
from study, no future compensation will be made, but prior compensation will not be revoked.
All subjects will not receive direct benefit from their study participation in this protocol.
All subjects will only be compensated if samples are collected solely for research purposes.
3.4.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation. Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate. The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.   
If subjects return to clinic solely for any clinical/non-research reasons, subjects will not be 
reimbursed.
3.5
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety phone 
call one day following discharge.
3.5.1
Criteria for removal from protocol therapy

Screen failure

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
Completion of protocol therapy/interventions

Participant requests to be withdrawn from active therapy/interventions

Unacceptable Toxicity (defined as any adverse event attributable to zolpidem that is 
Grade 3 or higher as per CTCAE v4.0)

Investigator discretion

Permanent loss of capacity to give consent
3.5.2
Off-Study Criteria

Completed study follow-up period 

Participant requests to be withdrawn from study

Permanent loss of capacity to give consent 

Death
4
CONCOMITANT MEDICATIONS/MEASURES
Participants may be on concomitant drugs to prevent bone loss, including calcium, vitamin D, 
bisphosphonates and denosumab.
Other supportive care with blood components, antibiotics, analgesics, general medical therapy, 
etc., will be delivered as required.
4.1
GENERAL GUIDELINES
All medications (other than study drug) and significant non-drug therapies (including physical 
therapy and blood transfusions) taken within 28 days before starting study treatment through the 
final follow up phone call should be reported on the CRF.
While participants are on protocol treatment, all medications required for the health of the 
participant are allowed with the following exceptions:

Concurrent chemotherapy 

Concurrent radiation therapy 

Concurrent immunotherapy 

Concurrent anti-cancer radionuclides 

Concurrent systemic corticosteroid use (daily or every other day for continued use > 14 
days)

Concomitant use of secondary hormonal treatments

Concomitant use of herbal supplements

Concomitant use of medications mentioned in Sections 2.1.3.8 and 2.1.4.3.
4.2
CNS DEPRESSANTS 

Co-administration of zolpidem with other CNS depressants increases the risk of CNS 
depression. Concomitant use of zolpidem with these drugs may increase drowsiness and 
psychomotor impairment, including impaired driving ability. Zolpidem tartrate was 

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evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. 

Imipramine in combination with zolpidem produced no pharmacokinetic interaction other 
than a 20% decrease in peak levels of imipramine, but there was an additive effect of 
decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced 
no pharmacokinetic interaction, but there was an additive effect of decreased alertness 
and psychomotor performance.

An additive adverse effect on psychomotor performance between alcohol and oral 
zolpidem was demonstrated.

Concomitant administration of zolpidem and sertraline increases exposure to zolpidem 
and should be avoided.

After multiple doses of zolpidem tartrate and fluoxetine an increase in the zolpidem half-
life (17%) was observed and should be avoided. There was no evidence of an additive 
effect in psychomotor performance.
4.3
DRUGS AFFECTING CYTOCHROME P450  

Some compounds known to induce or inhibit CYP3A may affect exposure to zolpidem. 
The effect of drugs that induce or inhibit other P450 enzymes on the exposure to 
zolpidem is not known.

Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the 
pharmacodynamic effects of zolpidem. Use of CYP3A4 inducers in combination with 
zolpidem may decrease the efficacy of zolpidem. Co-administration of zolpidem with 
strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, 
rifampin, rifapentine) may decrease the plasma exposure of zolpidem and are not allow 
while on study. Selection of a concomitant medication with no or minimal CYP3A4 
induction potential is recommended. 

Ketoconazole, a potent CYP3A4 inhibitor, increased the exposure to zolpidem and is not 
allowed while on study. 

Concomitant use of zolpidem with narrow therapeutic index drugs that are metabolized 
by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus and tacrolimus), should be avoided, as zolpidem may 
decrease their exposure. 

Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) 
and St. John’s Wort may also reduce the plasma exposure of zolpidem and should be 
avoided if possible. 

Grapefruit, Seville oranges, and starfruit affect P450 and PgP activity. Concomitant use 
should be avoided. 
5
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
5.1
BIOSPECIMEN COLLECTION
Male participants will be administered a 5 mg dose of zolpidem before and after castration. Post-
castration dose will be given when castrate testosterone levels reach <50 ng/dL followed by 8-hr 
PK evaluation. Normal healthy females will be administered a single dose of 5 mg tablet of 
zolpidem followed by 8-hr PK evaluation of zolpidem and its metabolites. 

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Pharmacokinetic blood samples will be collected with sodium heparin as the anticoagulant. 
Venous blood samples for plasma will be collected at the following times: pre-dose and 0.25, 
0.5, 1, 1.5, 2, 3, 4, and 8-hours post-dose. The Clinical Pharmacology Program will 
quantitatively measure zolpidem, zolpidem phenyl 4-carboxylic acid, and zolpidem 6-carboxylic 
acid using a validated uHPLC-MS/MS assay with a lower limit of quantitation of 0.5 ng/mL. 
Immediately place specimens on wet ice and refrigerate. The date and exact time of each blood 
draw should be recorded on the sample tube and the PK sheet.
5.2
SAMPLE PROCESSING
All samples will be sent to and stored in 
 Lab 
 
. Place all samples on ice (4ºC).
Please e-mail 
 at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 
For immediate help, call 
 (main blood processing core number) or, if no answer, 
 (main clinical pharmacology lab number).
For questions regarding sample processing, contact 
 
Noncompartmental pharmacokinetic (PK) parameters will be calculated using Phoenix 
WinNonlin v6.3 (Certara, Cary, NC), including AUC0-24hr, AUCINF, apparent oral clearance 
(dose/AUCINF), terminal elimination rate (kel), half-life (ln2/kel), apparent oral volume of 
distribution.  The maximum plasma concentration (CMAX) and time to CMAX (TMAX) will be 
recorded as observed values. PK parameters will be used to identify differences based on sex, 
androgen levels, age, etc. 
5.3
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a 
. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. 
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required. 
Any transfer of materials to other NIH or non-NIH investigators will occur following NIH 
Intramural Research Program guidelines. If the subject withdraws consent the participants’ data 
will be excluded from future distributions, but data that have already been distributed for 
approved research use will not be able to be retrieved.
Upon arrival in the 
 blood samples will be centrifuged 
and the plasma transferred into cryovials for storage at -80° C until the time of analysis. 
All PK samples will be barcoded, with data entered and stored in the Labmatrix utilized by the 
CPP. This is a secure program, with access to Labmatrix limited to defined CPP personnel, who 
are issued individual user accounts. Installation of Labmatrix is limited to computers specified by 
. These computers all have a password restricted login screen. The program creates a 
unique barcode ID for every sample and sample box, which cannot be traced back to participants 
with Labmatrix access. The data recorded for each sample includes the patient ID, name, trial 
name/protocol number, time drawn, cycle time point, dose, material type, as well as box and 
freezer locations. Participant demographics associated with the clinical center participant number 

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
Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the 
participant’s outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in Section 7.2.1. 
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:

Coded, linked data in an NIH-funded or approved public repository.  

Coded, linked data in BTRIS 
How and where will the data be shared? 
Data will be shared through:

An NIH-funded or approved public repository.  Insert name or names: ClinicalTrials.gov.

BTRIS

Publication and/or public presentations.
When will the data be shared? 

Before publication.

At the time of publication or shortly thereafter.
6.3
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
participant while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 

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7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found here.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. 
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director. A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to 
 
 at 
 within one business day of learning of the death
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis (at least weekly) when participants are 
being actively treated on the trial to discuss each participant. Decisions about dose level 
enrollment and dose escalation if applicable will be made based on the toxicity data from prior 
participant. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
Section 7.2.1 will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each participant to 
ensure safety and data accuracy. The principal investigator will personally conduct or supervise 
the investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 

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8
STATISTICAL CONSIDERATIONS  
8.1
STATISTICAL HYPOTHESES
Primary efficacy endpoints: 
In male participants, AUC after completing androgen deprivation therapy compared to AUC 
prior to receiving androgen deprivation therapy.
Secondary Efficacy endpoints:
AUC in females compared to males after receiving androgen deprivation therapy, to establish the 
approximate equivalence of the two groups with respect to this endpoint.
8.2
SAMPLE SIZE DETERMINATION
Ten males will receive Zolpedim and have an AUC determined based on the initial 
administration of the agent. Then following androgen deprivation therapy, they will receive a 
second administration of the agent and have the AUC determined. With 10 evaluable 
participants, there would be 80% power to detect the difference in the two measurements with an 
effect size of 1.0 (1.0 SD of the difference between the two AUC values for each male subject) 
using a paired t-test with a 0.05 two-sided significance level.
Ten female normal volunteers will receive Zolpedim and have an AUC determined based on this 
single administration of the agent. The AUC for females will be compared to the AUC in males 
after receiving androgen deprivation therapy, to establish the approximate equivalence of the two 
groups with respect to this endpoint. Assuming AUC values on the order of 200 ug*h/mL, it is 
considered that if AUC for post-ADT males is not less than 30-40 ug*h/mL below that of females, 
that this would be bioequivalent. When there are 10 females and 10 post-ADT males, a two group 
0.10 one-sided t-test will have 81% power to reject the null hypothesis that the AUCs from males 
and females are not equivalent (the difference in means, mmale – mfemale, is 40 or farther from zero, 
assuming that the female values would be higher) in favor of the alternative hypothesis that the 
means of the two groups are equivalent, if the expected difference in means is 10 ug*h/mL and the 
common standard deviation is 30 ug*h/mL. 
Evaluable subject is defined as the one who completes all parts of the study. Subjects who drop 
out of the study will be replaced. To account for possible dropouts and screen failures, the 
accrual ceiling for each arm will be set at 15 for a total accrual ceiling of 30 participants. 
8.3
POPULATIONS FOR ANALYSIS
Modified intention to treat. Only participants who receive full dose administrations of the agents 
(two doses for males; one dose for females) will be included.
8.4
STATISTICAL ANALYSES
8.4.1
General Approach 
AUC values will be obtained for pre-ADT males, post-ADT males, and healthy female 
volunteers. The AUC values will be compared between the time points for males to see if the 
AUC increases significantly, and the AUC values will be compared between those of post-ADT 
males and healthy females to see if they are at least approximately equivalent.

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8.4.2
Analysis of the Primary Efficacy Endpoints
The AUCs in pre-ADT males will be subtracted from the paired values in males once they are 
post-ADT and tested for a difference using a paired t-test with a two-sided 0.05 significance 
level, or a Wilcoxon signed rank test if the paired differences are not normally distributed.  The 
mean or median of the differences and a 95% confidence interval on the difference will be 
reported.
8.4.3
Analysis of the Secondary Endpoints 
The AUC values will be compared between those of post-ADT males and healthy females to see 
if they are at least approximately equivalent. A one-sided 90% confidence interval on the 
difference between the mean of the values of post-ADT males and healthy females will be 
constructed and interpreted in order to assess whether the two groups have approximately 
equivalent AUC values.
8.4.4
Safety Analyses
None will be performed. 
8.4.5
Baseline Descriptive Statistics 
None will be provided.
8.4.6
Planned Interim Analyses
None will be performed. 
8.4.7
Subgroup Analyses
Descriptive evaluations of parameters in the groups based on gender will be undertaken and 
reported on the basis of gender.
8.4.8
Tabulation of Individual Participant Data
No individual participant data will be tabulated.
8.4.9
Exploratory Analyses
Estimation of the pharmacokinetic parameters obtained and estimates of sample statistics such as 
means, standard deviations, medians, interquartile ranges, etc. may be determined. PK 
parameters may be compared between the males and females using Wilcoxon rank sum tests. 
Other tests to evaluate the trends or differences in values obtained may be undertaken for 
exploratory purposes.  

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9
HUMAN SUBJECTS PROTECTIONS 
9.1
RATIONALE FOR SUBJECT SELECTION
9.1.1
Selection Based on Ethnicity, and Race
Subjects from all racial/ethnic groups, except Asians (see Section 1.2.3 for exclusion rationale), 
are eligible for this study if they meet the eligibility criteria. Efforts will be made to extend 
accrual to a representative population, but in this preliminary study, a balance must be struck 
between participant safety considerations and limitations on the number of individuals exposed 
to potentially toxic and/or ineffective treatments on one hand and the need to explore ethnic 
aspects of clinical research on the other hand. If differences in outcome that correlate with ethnic 
identity are noted, accrual may be expanded or a follow-up study may be written to investigate 
those differences more fully. Women are eligible for this protocol as participants in the healthy 
female cohort.
9.2
PARTICIPATION OF CHILDREN
Because no dosing or adverse event data are currently available on the use zolpidem in 
participants <18 years of age and because prostate cancer is uncommon in pediatric populations, 
children are excluded from this study, but may be eligible for future pediatric trials.
9.3
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol. Adults who become 
incapacitated or cognitively impaired during the course of the study will be removed from the 
study as the study involves no direct benefit.  
9.4
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
9.4.1
Alternative Approaches or Treatments
Participants will be consented verbally and in writing regarding the risks and benefits of this 
trial, the treatment requirements, and alternative approaches to entering on this trial.
9.4.2
Procedure for Protecting Against or Minimizing any Potential Risks
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity. This study may involve risks to participants, which are currently unforeseeable. All 
participants will have blood tests, examinations and scans as described in the protocol evaluation 
(Section 3.3 Study Calendar). Participants will also be required to have a local physician to 
provide long-term care and to monitor for complications. If participants suffer any physical 
injury as a result of the participation in this study, immediate medical treatment is available at 
the Clinical Center, National Cancer Institute, Bethesda, Maryland. Any injury will be evaluated 
and treated in keeping with the benefits or care to which participants are entitled under 
applicable regulations.
9.4.3
Provisions for Monitoring Data Collection to Ensure Safety of Subjects
As information is gathered from this trial, clinical results will be shared with participants as they 
become available. Laboratory and clinical data will be frequently gathered and any new 

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significant finding(s) found during the course of the research, which may affect a participant’s 
willingness to participate further, will be explained. Confidentiality of information concerning 
participants will be maintained, including in all publications and presentations results from this 
study. Names of participants and/or material identifying participants will not be released without 
permission, except as such release is required by law. Records at the National Cancer Institute 
are maintained according to current legal requirements, and are made available for review, as 
required by the Food and Drug Administration or other authorized users, only under the 
guidelines established by the Federal Privacy Act.
9.5
RISKS/BENEFITS ANALYSIS
The risks of blood draw are relatively small. In addition, the drug (5 mg of zolpidem) being used 
in this study has been approved by the FDA for the short-term treatment of insomnia 
characterized by difficulties with sleep initiation.
9.6
NIH HEALTHY VOLUNTEERS
NIH staff and family members of study team members may be enrolled in this study as this 
population meets the study entry criteria.  Neither participation nor refusal to participate as a 
subject in the research will have an effect, either beneficial or adverse, on the participant’s 
employment or position at NIH. Staff will be expected to comply with policy 2300-630-3, Leave 
Policy for NIH Employees Participating in Medical Research Studies.
Every effort will be made to protect participant information, but such information may be 
available in medical records and may be available to authorized users outside of the study team 
in both an identifiable an unidentifiable manner.
The NIH FAQs for NIH Staff Who are Considering Participation in NIH Research found in 
policy 404 – Research Involving NIH Staff will be made available. Please see Section 9.7.2 for 
consent of NIH Staff.
9.7
CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant for review prior to consenting. A designated study investigator will carefully explain 
the procedures and tests involved in this study, and the associated risks, discomforts and benefits. 
In order to minimize potential coercion, as much time as is needed to review the document will 
be given, including an opportunity to discuss it with friends, family members and/or other 
advisors, and to ask questions of any designated study investigator. A signed informed consent 
document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s).  Whether in person or remote, the privacy 
of the subject will be maintained. Consenting investigators (and participant/consent designee, 
when in person) will be located in a private area (e.g., clinic consult room). When consent is 
conducted remotely, the participant/consent designee will be informed of the private nature of 
the discussion and will be encouraged to relocate to a more private setting if needed.  

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Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document.  When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures:

Adobe platform (which is not 21 CFR Part 11 compliant); or,  

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) found here.
9.7.1
Request for Waiver of Consent for Screening Activities
Prior to the subject signing the consent for this study pre-screening activities listed in Section 
2.2.1 may be performed. 
We request a waiver of consent for these activities as they involve only minimal risk to the 
subjects. A waiver will not adversely affect the rights and welfare of the subjects given that the 
activities are only intended to determine suitability for screening for participation in research 
protocols. These activities could not practicably be carried out without the wavier as central 
recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for 
multiple studies and obtaining consent for each one is beyond their resources. The subjects will 
be provided with additional pertinent information after participation as they will be informed 
whether or not they are eligible to sign a consent for additional screening.
9.7.2
Consent for NIH Staff
Consent for NIH staff will be obtained as detailed in Section 9.6 with following additional 
protections:
Consent from staff members will be obtained by an individual independent of the staff member’s 
team whenever possible. In addition, if the participant is in a subordinate relationship with an 
investigator on the research team or is part of the work unit where the research is taking place, 
the consent procedure will be independently monitored by the CC Department of Bioethics 
Consultation Service in order to minimize the risk of undue pressure on the staff member.

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10 REGULATORY AND OPERATIONAL CONSIDERATIONS 
10.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, and regulatory authorities.  If the study is prematurely terminated 
or suspended, the Principal Investigator (PI) will promptly inform study participants and the 
Institutional Review Board (IRB) and will provide the reason(s) for the termination or 
suspension. Study participants will be contacted, as applicable, and be informed of changes to 
study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants;

Insufficient compliance to protocol requirements;

Data that are not sufficiently complete and/or evaluable; and/or, 

Determination that the primary endpoint has been met.
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the IRB.
10.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing and inspection by local and regulatory 
authorities.
10.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial.  The study leadership in conjunction with the National Cancer Institute has 

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established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest.
10.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators 
and their staff. This confidentiality is extended to cover testing of biological samples and genetic 
tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. 
All research activities will be conducted in as private a setting as possible.
The study monitor, representatives of the Institutional Review Board (IRB), and/or regulatory 
agencies may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records 
for the participants in this study. The clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB or Institutional policies and 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by the clinical site and by NCI CCR research staff will be secured and password protected. 
At the end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
11 PHARMACEUTICAL INFORMATION
11.1 ZOLPIDEM
11.1.1 Source 
Zolpidem will be obtained from commercial sources and dispensed by the Clinical Center 
pharmacy.

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11.1.2 Toxicity 
11.1.2.1  CNS Depressant Effects and Next-Day Impairment
Zolpidem, like other sedative-hypnotic drugs, has central nervous system (CNS) depressant 
effects. Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic 
antidepressants, alcohol) increases the risk of CNS depression. Dosage adjustments of zolpidem 
and of other concomitant CNS depressants may be necessary when zolpidem is administered 
with such agents because of the potentially additive effects. The use of zolpidem with other 
sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is 
not recommended.
The risk of next-day psychomotor impairment, including impaired driving, is increased if 
zolpidem is taken with less than a full night of sleep remaining (7 to 8 hours); if a higher than the 
recommended dose is taken; if co-administered with other CNS depressants or alcohol; or if co-
administered with other drugs that increase the blood levels of zolpidem. Participants should be 
warned against driving and other activities requiring complete mental alertness if zolpidem is 
taken in these circumstances.
Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may 
be a possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, 
sleepiness, blurred/double vision, reduced alertness and impaired driving the morning after 
therapy. In order to minimize this risk a full night of sleep (7-8 hours) is recommended.
11.1.2.2 Severe Anaphylactic and Anaphylactoid Reactions
Cases of angioedema involving the tongue, glottis or larynx have been reported in patients after 
taking the first or subsequent doses of sedative-hypnotics, including zolpidem. Some patients 
have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that 
suggest anaphylaxis. Some patients have required medical therapy in the emergency department. 
If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal. 
Participants who develop angioedema after treatment with zolpidem should not be rechallenged 
with the drug.
11.1.2.3 Abnormal Thinking and Behavioral Changes
Abnormal thinking and behavior changes have been reported in patients treated with 
sedative/hypnotics, including zolpidem. Some of these changes included decreased inhibition 
(e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation 
and depersonalization. Visual and auditory hallucinations have been reported.
In controlled trials of zolpidem 10 mg taken at bedtime < 1% of adults with insomnia reported 
hallucinations. In a clinical trial, 7% of pediatric patients treated with zolpidem 0.25 mg/kg taken 
at bedtime reported hallucinations versus 0% treated with placebo.
Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of 
a sedative-hypnotic, with amnesia for the event) have been reported in sedative-hypnotic-naive 
as well as in sedative-hypnotic-experienced persons. Although behaviors such as “sleep-driving” 
have occurred with zolpidem alone at therapeutic doses, the co-administration of zolpidem with 
alcohol and other CNS depressants increases the risk of such behaviors, as does the use of 
zolpidem at doses exceeding the maximum recommended dose. Due to the risk to the participant 

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and the community, discontinuation of zolpidem should be strongly considered for participants 
who report a “sleep-driving” episode.
Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) 
have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with 
“sleep-driving”, patients usually do not remember these events. Amnesia, anxiety and other 
neuro-psychiatric symptoms may also occur.
It can rarely be determined with certainty whether a particular instance of the abnormal 
behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying 
psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or 
symptom of concern requires careful and immediate evaluation.
11.1.2.4 Withdrawal Effects
There have been reports of withdrawal signs and symptoms following the rapid dose decrease or 
abrupt discontinuation of zolpidem. Monitor participants for tolerance, abuse, and dependence
11.1.2.5 Other Adverse Effects 
Approximately 4% of 1,701 patients who received zolpidem at all doses (1.25 to 90 mg) in U.S. 
premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions 
most commonly associated with discontinuation from U.S. trials were daytime drowsiness 
(0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).
Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar 
foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly 
associated with discontinuation from these trials were daytime drowsiness (1.1%), 
dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).
Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients 
were given zolpidem revealed that four of the seven discontinuations during double-blind 
treatment with zolpidem (n=95) were associated with impaired concentration, continuing or 
aggravated depression, and manic reaction; one patient treated with placebo (n =97) was 
discontinued after an attempted suicide.
11.1.3 Formulation and Preparation 
Zolpidem tartrate is a gamma-aminobutyric acid (GABA) A agonist of the imidazopyridine class 
and is available in 5 mg and 10 mg strength tablets for oral administration. Chemically, zolpidem 
is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1). 
Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, 
alcohol, and propylene glycol. It has a molecular weight of 764.88.Each zolpidem tablet includes 
the following inactive ingredients: hydroxypropyl methylcellulose, lactose, magnesium stearate, 
micro-crystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide. 
The 5 mg tablet also contains FD&C Red No. 40, iron oxide colorant, and polysorbate 80.
Zolpidem is available in 5 mg strength (generic) tablets for oral administration. Tablets are not 
scored.

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11.1.4 Stability and Storage 
Store zolpidem tablets at controlled room temperature 20°–25°C (68°–77°F) in a dry place and 
keep the container tightly closed. 
The company providing the drug will also provide the expiration date for each lot allocated to 
this study.
11.1.5 Administration Procedures
The effect of zolpidem may be slowed by ingestion with or immediately after a meal. Therefore, 
zolpidem will be administered under fasting conditions (no caloric intake for at least 4 hours 
before dosing). Participants will swallow tablets whole. 

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12 REFERENCES
1.
Pichard, L., et al., Oxidative metabolism of zolpidem by human liver cytochrome P450S. 
Drug Metab Dispos, 1995. 23(11): p. 1253-62.
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3.
Zhang, B. and Y.K. Wing, Sex differences in insomnia: a meta-analysis. Sleep, 2006. 
29(1): p. 85-93.
4.
Kamel, N.S. and J.K. Gammack, Insomnia in the elderly: cause, approach, and 
treatment. Am J Med, 2006. 119(6): p. 463-9.
5.
Greenblatt, D.J., et al., Gender differences in pharmacokinetics and pharmacodynamics 
of zolpidem following sublingual administration. J Clin Pharmacol, 2014. 54(3): p. 282-
90.
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Von Moltke, L.L., et al., Zolpidem metabolism in vitro: responsible cytochromes, 
chemical inhibitors, and in vivo correlations. Br J Clin Pharmacol, 1999. 48(1): p. 89-97.
7.
Wolbold, R., et al., Sex is a major determinant of CYP3A4 expression in human liver. 
Hepatology, 2003. 38(4): p. 978-88.
8.
Estonius, M., et al., Distribution of alcohol and sorbitol dehydrogenases. Assessment of 
mRNA species in mammalian tissues. Eur J Biochem, 1993. 215(2): p. 497-503.
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Aasmoe, L. and J. Aarbakke, Sex-dependent induction of alcohol dehydrogenase activity 
in rats. Biochem Pharmacol, 1999. 57(9): p. 1067-72.
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Westerlund, M., et al., High and complementary expression patterns of alcohol and 
aldehyde dehydrogenases in the gastrointestinal tract: implications for Parkinson's 
disease. FEBS J, 2007. 274(5): p. 1212-23.
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Quertemont, E., Genetic polymorphism in ethanol metabolism: acetaldehyde contribution 
to alcohol abuse and alcoholism. Mol Psychiatry, 2004. 9(6): p. 570-81.
12.
Koppaka, V., et al., Aldehyde dehydrogenase inhibitors: a comprehensive review of the 
pharmacology, mechanism of action, substrate specificity, and clinical application. 
Pharmacol Rev, 2012. 64(3): p. 520-39.
13.
Olubodun, J.O., et al., Pharmacokinetic properties of zolpidem in elderly and young 
adults: possible modulation by testosterone in men. Br J Clin Pharmacol, 2003. 56(3): p. 
297-304.
14.
Peer, C.J., et al., Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related 
Differences in Clearance of Zolpidem in Rats. Front Pharmacol, 2016. 7: p. 260.
15.
Baraona, E., et al., Lack of alcohol dehydrogenase isoenzyme activities in the stomach of 
Japanese subjects. Life Sci, 1991. 49(25): p. 1929-34.
16.
Dohmen, K., et al., Ethnic differences in gastric sigma-alcohol dehydrogenase activity 
and ethanol first-pass metabolism. Alcohol Clin Exp Res, 1996. 20(9): p. 1569-76.
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Bjorn, M.K. and H.T. Northen, Effects of 2,4-Dichlorophenoxyacetic Acid on Chicks. 
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18.
Yoshida, A., I.Y. Huang, and M. Ikawa, Molecular abnormality of an inactive aldehyde 
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8.

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13 APPENDIX A - PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours.
30
Severely disabled, 
hospitalization indicated.  Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.