Clinical trial NCT02382848
Conditions: Stress Disorders, Post-Traumatic Bulimia Nervosa
Keywords: Eating Disorders Bulimia Nervosa Nightmares Post Traumatic Stress Disorder
Sponsor: Milton S. Hershey Medical Center
Start date: 2015-07-01; Completion date: 2018-03-09
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This research is being done to find out how effective Prazosin is in the treatment of bulimic patients experiencing distressing nightmares using subjective and objective measures.

Detailed description:
To the investigators knowledge, there is no treatment trial for prazosin use in patients with bulimia nervosa struggling with nightmares, looking at either objective or subjective measures. The investigators plan to probe the effectiveness of prazosin in bulimic patients experiencing nightmares due to PTSD using both subjective and objective measures in order to improve future clinical care. The effects of prazosin on decreasing nightmares and bulimic symptoms on subjective scales and effects on sleep architecture using objective polysomnogram (PSG) measurements will help inform targeted psychopharmacologic and psychotherapeutic strategies to improve clinical care of bulimic patients struggling with distressing dreams secondary to PTSD. This study will be performed in two phases. Phase A will involve eight participants who will be tested using subjective scales (mentioned below). If Phase A data analysis leads to detection of a signal of efficacy 2 more participants will be recruited to participate in phase B of this trial using objective polysomnogram measurements. The results from this project will aid in establishing a fully powered clinical trial for treatment of nightmares in bulimic patients and improve outcomes in this high risk population.

Arms: arm 1: Participants first received Prazosin. A starting dose of Prazosin (1mg capsule) will be given at Week # 1 of this arm. Symptoms will be reassessed and medication will be adjusted by 1-2 mg increments every 7 days for 3 weeks based on clinical response and severity of night mares, to achieve maximum therapeutic benefit while monitoring adverse effects using side effects scale on weekly basis (psychiatrist will be using the scale at every visit). The end point for capping the Prazosin dose will be 6 mg daily. After a washout period, they then receive Placebo arm 2: Participants first received Placebo (matching Prazosin) for a 3 consecutive week period during the 7 week study period. After a washout period, they then received Prazosin. The starting dose of Prazosin (1mg capsule) will be given at Week # 5 of this arm. Symptoms will be reassessed and medication will be adjusted by 1-2 mg increments every 7 days for 3 weeks based on clinical response and severity of night mares, to achieve maximum therapeutic benefit while monitoring adverse effects using side effects scale on weekly basis (psychiatrist will be using the scale at every visit). The end point for capping the Prazosin dose will be 6 mg daily.
Interventions: intervention 1: Prazosin intervention 2: Placebo intervention 3: Prazosin intervention 4: Placebo
Intervention descriptions: intervention 1: A starting dose of Prazosin (1mg capsule) will be given at Week # 1 of this arm. Symptoms will be reassessed and medication will be adjusted by 1-2 mg increments every 7 days for 3 weeks based on clinical response and severity of night mares, to achieve maximum therapeutic benefit while monitoring adverse effects using side effects scale on weekly basis (psychiatrist will be using the scale at every visit). The end point for capping the Prazosin dose will be 6 mg daily. intervention 2: Prazosin-matched placebo pill intervention 3: A starting dose of Prazosin (1mg capsule) will be given at Week # 5 of this arm. Symptoms will be reassessed and medication will be adjusted by 1-2 mg increments every 7 days for 3 weeks based on clinical response and severity of night mares, to achieve maximum therapeutic benefit while monitoring adverse effects using side effects scale on weekly basis (psychiatrist will be using the scale at every visit). The end point for capping the Prazosin dose will be 6 mg daily. intervention 4: Prazosin-matched placebo pill

Protocol documents:
Prot_SAP_000.pdf: 
                                                          
HRP-591 - Protocol for
Human Subject Research
Protocol Title:   Effectiveness of Prazosin in Bulimic patients 
experiencing nightmares due to PTSD
Principal Investigator:
Name: Fauzia Mahr
Department: Psychiatry
Telephone:  717-531-8133
E-mail Address: fmahr@hmc.psu.edu
Version Date:  01/12/2018
Clinicaltrials.gov Registration #:
NCT02382848
STUDY00001746
Approval: 5/21/2018


Table of Contents
1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Data and Specimen Banking For Future Undetermined Research
9.0
Statistical Plan
10.0
Confidentiality, Privacy and Data Management
11.0
Data and Safety Monitoring Plan
12.0
Risks
13.0
Potential Benefits to Subjects and Others
14.0
Sharing Results with Subjects
15.0
Economic Burden to Subjects
16.0
Number of Subjects
17.0
Resources Available
18.0
Other Approvals
19.0
Subject Stipend (Compensation) and/or Travel Reimbursements
20.0
Multi-Site Research
21.0
Adverse Event Reporting
22.0
Study Monitoring, Auditing and Inspecting
23.0
References
24.0
Appendix
1.0
Objectives
1.1
Study Objectives
The aim of our study is to evaluate the effectiveness of prazosin in bulimic patients experiencing 
distressing nightmares secondary to PTSD. We will be testing 10 participants. 8 will be tested 
using subjective measures (Phase A). If a signal of efficacy is detected the last 2 participants will 
be tested using additional objective PSG measurements (Phase B).  Phase B will be a feasibility 
study and based on results PI will apply for external funding.
AIMS FOR PHASE A:
The Primary aim of our study is to evaluate the effectiveness of prazosin in bulimic patients 
experiencing distressing nightmares secondary to PTSD using subjective measures.
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Hypothesis 1: 
Prazosin is associated with decrease in nightmare frequency in bulimic patients         
The secondary aim of our study is to assess changes in Cortisol levels in bulimic patients with 
PTSD before and after treatment with prazosin.
Hypothesis 2:
Prazosin use is associated with a decrease of cortisol levels.
1.2
Primary Study Endpoints
Primary outcome measure:    Decrease in frequency of nightmares (subjective measures)    
                                                   
1.3
Secondary Study Endpoints
Secondary Outcome measures:   Decrease in total CAPS score, depressed mood, bulimia 
symptoms and self-harm thoughts on depression scale
AIMS FOR PHASE B:
Phase B will involve using objective polysomnogram measurements (hypothesis 3) in addition 
to the subjective instruments used in phase A.
The Primary aim of our study is to evaluate the effectiveness of prazosin in bulimic patients 
experiencing distressing nightmares secondary to PTSD using subjective measures.
Hypothesis 1: 
Prazosin is associated with decrease in nightmare frequency in bulimic patients         
The secondary aim of our study is to assess changes in Cortisol levels in bulimic patients with 
PTSD before and after treatment with prazosin
Hypothesis 2:
Prazosin use is associated with a decrease of cortisol levels.
Hypothesis 3:
Prazosin is associated with decrease in REM density & normalization of REM disruption                         
(objective).
1.4
Primary Study Endpoints
Primary outcome measure:    Decrease in frequency of nightmares (subjective measures)    
                                                   Decrease in REM density on PSG     (objective measures)
1.5
Secondary Study Endpoints
Secondary Outcome measures:   Decrease in total CAPS score, depressed mood, bulimia 
symptoms and self-harm thoughts on depression scale
2.0
Background 
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2.1
Scientific Background and Gaps  
Nightmares are a frequent and distressing symptom in patients struggling with post-traumatic 
stress disorder (PTSD). Up to eighty percent of patients with PTSD experience nightmares which 
predominantly occur during the REM phase of sleep1. Some adult studies have also demonstrated 
association between suicidal ideation or attempt and increased REM sleep2. PTSD presents as 
common comorbidity with eating disorders and traumatic experiences often lead to development 
of Bulimia nervosa3. According to some studies up to 40 % of women with bulimia nervosa 
experience PTSD and the frequency is even higher in those with active binging symptoms3, 4.
2.2
Previous Data
PTSD has been associated with the etiology, course, and severity of Bulimia nervosa3. 
Nightmares are frequently reported by patients struggling with bulimia nervosa & PTSD. 
Clinicians managing patients with bulimia nervosa frequently report that bulimic patients 
experiencing nightmares have more serious psychopathology. However, little is known about the 
impact of nightmares on the severity and course of bulimia. Some researchers have posited that 
treatment resistance in bulimic patients may be secondary to PTSD symptomatology and 
treatment of PTSD may alleviate bulimic symptoms5. However, no studies have explored the 
impact of nightmares on bulimic symptoms, and whether their presence predicts the course or 
treatment response in bulimia nervosa. This gap in our knowledge is crucial given the high 
frequency of PTSD symptoms in bulimia.
Deregulated hypothalamic-pituitary-adrenal axis activity has been reported in both PTSD and 
Bulimia nervosa but the results of the studies are inconsistent. Some studies in PTSD report 
hypocortisolism at baseline6, 
7 while others report that women with higher cortisol 
responsiveness to stressors tend to eat more during stress. Furthermore, binging and purging 
symptoms may trigger increased release of cortisol accounting for high cortisol levels in many 
patients with Bulimia nervosa. Prazosin, an alpha-1 adrenergic receptor antagonist, affects the 
stress system, including HPA axis. Evaluating the activity of the HPA axis in bulimic patients 
with PTSD before and after treatment may help us understand the underlying pathophysiology of 
this disorder and in predicting treatment response in these patients8.
Although various psychopharmacological options are being utilized to provide symptomatic 
relief of nightmares, there is limited scientific evidence about their effectiveness in nightmare 
management. Furthermore, literature is almost non-existent about therapeutic options for patients 
with bulimia nervosa experiencing nightmares. Prazosin has been used extensively for treatment 
of nightmares in PTSD in both civilian and veteran population and has proven to be subjectively 
and objectively effective9, 10. Reversal of REM sleep disruption has been observed following 
treatment with prazosin11. Other studies have reported decrease in trauma-related distressing 
dreams with the use of prazosin, which tend to return after its discontinuation11. 
2.3
Study Rationale
To our knowledge, there is no treatment trial for prazosin use in patients with bulimia nervosa 
struggling with nightmares, looking at either objective or subjective measures. We plan to probe 
the effectiveness of prazosin in bulimic patients experiencing nightmares due to PTSD using 
both subjective and objective measures in order to improve future clinical care. The effects of 
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prazosin on decreasing nightmares and bulimic symptoms on subjective scales and effects on 
sleep architecture using objective polysomnogram measurements will help inform targeted 
psychopharmacologic and psychotherapeutic strategies to improve clinical care of bulimic 
patients struggling with distressing dreams secondary to PTSD. This study will be performed in 
two phases.  Phase A will involve eight participants who will be tested using subjective scales 
(mentioned below). If Phase A data analysis leads to detection of a signal of efficacy 2 more 
participants will be recruited to participate in phase B of this trial using objective 
polysomnogram measurements. The results from this project will aid in establishing a fully 
powered clinical trial for treatment of nightmares in bulimic patients and improve outcomes in 
this high risk population.
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion criteria: Women struggling with bulimia nervosa (purging and non-purging 
type) between 18-45 years of age recruited via physician referrals or advertisement 
materials with complaints of nightmares secondary to PTSD. Patients may or may not be 
taking SSRIs and their use will not exclude them from the study.
3.2
Exclusion criteria: Restless leg syndrome, narcolepsy, sleep apnea, currently taking 
prazosin, neurological disorders, pregnancy, cardiac abnormalities, significant electrolyte 
abnormalities, use of steroids or Beta blockers and abuse of alcohol or other substance 
during the past three months(due to their effects on sleep parameters). Prazosin is 
commonly used to treat symptoms of PTSD and unless cardiac abnormalities are detected 
at baseline, EKGs are not routinely performed during treatment. We will exclude the 
patients with cardiac abnormalities from our study if the baseline EKG detects some 
abnormalities; they will be referred to cardiologist for further follow up. Blood work will 
be drawn to detect electrolyte abnormalities commonly seen in bulimic patients and 
patients will clinically significant electrolyte abnormalities will be excluded from the 
study. Physical examinations will not be performed as these patients follow up at the 
eating disorder clinic and those data are already available, data from the preexisting 
medical evaluations will be used to discern any major neurological or other physical 
abnormalities and participants will be excluded from the study.
3.3
Early Withdrawal of Subjects
3.3.1
Criteria for removal from study
Safety concerns, failure of subject to adhere to protocol requirements, 
subject consent withdrawal.
3.3.2
Follow-up for withdrawn subjects
A follow up phone call by the research assistant to provide instructions regarding 
the medication will be conducted. Patients will be asked to return any unused 
medication and standard care will be offered to patients if they choose not to 
participate in the research study or are withdrawn early.
4.0
Recruitment Methods
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4.1
Identification of subjects
Subjects will be identified at the Briarcrest eating disorder clinic by a therapist & additionally 
there will be flyers in the office regarding participation in the study. Study flyers will also be sent 
to other physicians and therapists in the community. The therapist will screen and identify each 
subject and obtain verbal consent.  After the initial screening, the therapist will inform the RA 
who will initially get verbal consent and schedule patient for the first day of screening 
procedures. The physical location of the evaluations will be at GCRC where the psychiatrist will 
perform the evaluations; however the initial screening by the therapist will take place at the 
Briarcrest eating disorder clinic.
4.2
Recruitment process
                                                                                   
The research assistant will contact the participants to obtain consent and avoid any form of 
coercion from healthcare providers.   The research assistant will get verbal consent via phone and 
schedule the patient for consent discussion, therapist evaluation (if not already in medical 
record), the screening lab work, pregnancy test, Salivary Cortisol collection, BMI, Vital signs, 
CMP, LFTs, UDS & EKG.                                  
Informed consent will be obtained at the GCRC by the Research Assistant.
                                            
4.3
Recruitment materials
There will be flyers in the therapist office.
 
4.4
Eligibility/screening of subjects
The potential subjects will be patients following up in the eating disorder clinic. 
They will receive initial screening from the therapist who will use the DSM-5 
based evaluation that is utilized routinely in the clinic and ascertain the diagnosis 
of Bulimia nervosa.  Patients with co-morbid  PTSD with ongoing nightmares 
(scoring 3 or above on distressing dreams item of the clinician administered 
PTSD scale (CAP) will be eligible for this study and the therapist will ask the 
patients whether they would like to be contacted by the research assistant to 
participate in the study. 
5.0
Consent Process and Documentation 
5.1
Consent Process 
. 
5.1.1 Obtaining Informed Consent
5.1.1.1
Timing and Location of Consent
The consent process will take place in the GCRC before any study 
related procedures take place. 
5.1.1.2
Coercion or Undue Influence during Consent
The PI or therapist providing care to the patient will not be 
involved in the consent process.  The therapist will ask the 
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patient about their interest in participation in the study and 
whether they would like to be contacted by the research 
assistant.  The research assistant will explore interest in 
participation via phone call and later on the written consent 
from participating subjects will be obtained at the time of the 
first blood draw. It will be emphasized that subjects do not 
have to participate. They will also be told that whatever their 
decision, their current and future care will not be affected.
5.1.2 Waiver or alteration of the informed consent requirement
N/A
5.2
Consent Documentation
5.2.1 Written Documentation of Consent
A member of the research team authorized to carry out the consent process 
will:
1. Verify that the subject has received a copy of the consent form and had 
time to review it.  
2. Review the consent form with the subject, answering any questions 
he/she may have.
3. Ask the subject to sign the consent form indicting he/she understands 
and agrees to study procedures before study procedures begin.
4. Obtain Signatures and give a signed copy of the consent form to the 
participant for his/her personal records.
5.2.2 Waiver of Documentation of Consent
N/A
Consent – Other Considerations 
Non-English Speaking Subjects
N/A
5.2.3 Cognitively Impaired Adults
N/A
5.2.3.1
Capability of Providing Consent
The patients will be adults and will have the capacity to provide 
consent. 
5.2.3.2
Adults Unable To Consent
N/A
5.2.3.3
Assent
N/A
5.2.4 Subjects who are not yet adults (infants, children, teenagers) 
5.2.4.1
Parental Permission
N/A
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5.2.4.2
Assent
N/A
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and 
Disclosures of PHI
Check all that apply:
Authorization will be obtained and documented as part of the consent 
process.
Partial waiver is requested for recruitment purposes only (Check this box if 
patients’ medical records will be accessed to determine eligibility before 
consent/authorization has been obtained)
Full waiver is requested for entire research study (e.g., medical record 
review studies) 
Alteration is requested to waive requirement for written documentation of 
authorization
6.2
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
N/A
6.2.1 Access, use or disclosure of PHI representing no more than a minimal 
risk to the privacy of the individual
6.2.1.1
Plan to protect PHI from improper use or disclosure
6.2.1.2
Plan to destroy identifiers or a justification for retaining 
identifiers 
6.2.2 Explanation for why the research could not be practicably be 
conducted without access to and use of PHI
6.2.3 Explanation for why the research could not practicably be conducted 
without the waiver or alteration of authorization
6.3
Waiver or alteration of authorization statements of agreement
7.0
Study Design and Procedures
7.1
Study Design 
Study Design: We plan to conduct a 7 week prospective, double blind, placebo controlled 
crossover study.  Each patient, in a randomized design will receive three weeks of prazosin and 
three weeks of placebo separated by 1 week washout period. A 1-week washout period is 
considered sufficient, given that the half-life of prazosin is 2-3 hours, and previous studies have 
demonstrated that the clinical effects of prazosin are eliminated within a week10, 11.  The subjects 
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will be blinded and the randomization list will be sent directly to the research pharmacy. 
Methylcellulose will be used as placebo.
7.2
Study Procedures (PHASE A)

Subjective Scales: EDI-3 (eating pathology), PCL –C (PTSD checklist- civilian 
version), CAPS (Clinician administered PTSD scale), PSQI (Pittsburg sleep 
quality index), HDRS (Hamilton Depression Rating Scale) & 5 relevant questions 
from sleep-50 questionnaire.

Other parameters: Salivary Cortisol (5 diurnal samples), BMI, Vital signs, EKG, 
CMP, LFTs, UDS.  Saliva samples will be analyzed in our departmental lab using 
ELISA kits (Alpco).  Blood samples will be sent to Quest Diagnostics Lab for 
analysis. The Biological Safety and Recombinant DNA Committee registration 
number is FUM15-01p-2.

Upon completion of the intervention period, participants will return to the Milton S. 
Hershey Medical Center and repeat the exact same procedures as completed during 
the Baseline period including the vital sign measurements, blood, urine, & saliva 
collection, sleep lab recordings, and questionnaire completion. Any unused 
medication and/or the empty medication bottle will be collected at the end of both 
interventions.
7.2.1
Day 1 
The first day of the study will involve Consent, standard evaluation by therapist, 
if not done previously, initial blood draw, urine pregnancy test and EKG.  Patients 
will be referred to cardiologist, if needed based on EKG results and will be excluded 
from the study.
7.2.2
Day 2
On the second day of the study participants meeting eligibility criteria based on 
EKG & labs, will be assessed by the psychiatrist and 5 diurnal salivary samples will 
be collected from the participants. Patients will be randomly assigned to one of the 
treatment arms.  The two treatment arms with Prazosin and Placebo will be monitored 
similarly. Rating scales will also be collected by RA that day at baseline, as well as 
on the last day of the first and second treatment arms and the last day of washout 
period (Total 4 times). Vital signs will be checked that day and on each physician 
visit. Prazosin will be prescribed by the PI (psychiatrist) at 1 mg (taken by mouth 
once or divided BID) after the initial assessment on the second day of the study.
7.2.3
Weekly Visits
Symptoms will be reassessed and medication will be adjusted by 1-2 mg 
increments every 7 days based on clinical response and severity of night mares, to 
achieve maximum therapeutic benefit while monitoring adverse effects using side 
effects scale on weekly basis (psychiatrist will be using the scale at every visit). A 
phone contact by RA will be made on the morning after dose initiation and after each 
increment to monitor adverse events. The end point for capping the Prazosin dose will 
be 6 mg daily. The psychiatrist will administer adverse events rating scale and 
nightmare assessment using Sleep-50 Questionnaire at every psychopharmacologic 
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visit after initiation of medication in addition to the initial visit. Vital signs will be 
checked at each visit as well. The participants will have a total of 7 visits with the 
psychiatrist (1 for initial evaluation and 3 for the dose titration during each study 
arm).  Research pharmacy and RA will determine and track the sequence and random 
allocation of the medication to ensure blind randomized trial.  RA will also gather 
salivary samples from the patient at end of each study arm (5 diurnal samples for each 
arm) After 3 weeks on one treatment arm, a wash out period of 1 week will be given 
prior to starting the second study arm.  The same sequence will be repeated for the 
second study arm and study questionnaires will be repeated on the last day of the 
washout period. Blood work will be drawn thrice, once at baseline and once at the 
end of each study arm.  5 Diurnal salivary samples will be collected thrice, once at 
baseline and once at the end of each study arm. All sets of cortisol level will be 
collected at the same time points as the baseline level to allow accurate comparisons. 
All Rating scales will be completed 4 times, once at baseline, once at end of wash out 
period and once at the end of each study arm. At the end of each study arm, any 
unused medication will be collected from the participant.  Upon completion of the 
study, participants may want to continue taking the study medication if they 
experienced positive results. The PI will discuss with each participant if it is 
appropriate to continue taking the medication.
Study Procedures (PHASE B)
Objective Measure:    PSG (Polysomnogram) will be conducted at baseline for 3 
consecutive nights and the last 3 nights of each treatment arm for a total of 9 nights/ 
person during Phase B of the study. 2 participants will be enrolled in this phase. All 
other procedures will be the same as described under Phase A.                                        
7.3
Duration of Participation
The study duration is 7 weeks.
Phase A (No PSG Recordings)
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Consent
x
Blood Collection, Urine Pregnancy Test, &EKG
x
Screening
Standard Evaluation by Therapist
x
Psychiatric Assessment & Randomization
x
Saliva Collection (8a, 12p, 3p, 6p, 9p)
x
Rating Scales (RS) and Vitals
x
Baseline 
Procedures
Start Treatment
x
Psychiatrist Visit
x
Vitals, Adverse Event Rating Scale 
(AERS), Sleep-50 
x
Week 1
Research Assistant Phone Call
x
Intervention 
Arm 1
Week 2
Psychiatrist Visit
x
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Vitals, AERS, Sleep-50
x
Research Assistant Phone Call
x
Psychiatrist Visit
x
Vitals, AERS, Sleep-50
x
Research Assistant Phone Call
x
Week 3
Saliva/Blood Collection & RS
x
Washout
Week 4
Rating Scales
x
Psychiatrist Visit
x
Vitals, AERS, Sleep-50
x
Week 5
Research Assistant Phone Call
x
Psychiatrist Visit
x
Vitals, AERS, Sleep-50
x
Week 6
Research Assistant Phone Call
x
Psychiatrist Visit
x
Vitals, AERS, Sleep-50
x
Research Assistant Phone Call
x
Intervention 
Arm 2
Week 7
Saliva/Blood Collection & RS
x
Phase B (2 subjects have PSG Recordings)
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Consent
x
Blood Collection, Urine Pregnancy Test, &EKG
x
PSG Recording
x
Screening
Standard Evaluation by Therapist
x
Psychiatric Assessment & Randomization
x
Saliva Collection (8a, 12p, 3p, 6p, 9p)
x
Rating Scales (RS) and Vitals
x
PSG Recordings
x
x
Baseline 
Procedures
Start Treatment
x
Psychiatrist Visit
x
Vitals, AERS, Sleep-50
x
Week 1
Research Assistant Phone Call
x
Psychiatrist Visit
x
Vitals, AERS, Sleep-50
x
Week 2
Research Assistant Phone Call
x
Psychiatrist Visit
x
Vitals, AERS, Sleep-50
x
Research Assistant Phone Call
x
Saliva/Blood Collection & RS
x
Intervention 
Arm 1
Week 3
PSG Recordings
x
x
x
Washout
Week 4
Rating Scales
x
Intervention 
Arm 2
Week 5
Psychiatrist Visit
x
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Vitals, AERS, Sleep-50
x
Research Assistant Phone Call
x
Psychiatrist Visit
x
Vitals, AERS, Sleep-50
x
Week 6
Research Assistant Phone Call
x
Psychiatrist Visit
x
Vitals, AERS, Sleep-50
x
Research Assistant Phone Call
x
Saliva/Blood Collection & RS
x
Week 7
PSG Recordings
x
x
x
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8.0
Data and Specimen Banking For Future Undetermined Research
N/A
8.1
Data and/or specimens being stored 
8.2
Location of storage
Duration of storage
8.3
Access to data and/or specimens
.
8.4
Procedures to release data or specimens
8.5
Process for returning results
9.0
Statistical Plan (Phase A)
9.1
Sample size determination
Statistical Plan & Sample size determination
Power Calculation: Our plan is to recruit 10 patients with Bulimia nervosa and PTSD in this 
trial. Here we show our power calculations for the Hypothesis 1 and 2 based on our best 
knowledge. It should be noted that we assume no carry-over therapeutic effect in the calculation 
(see Study Design).
We choose the CAPS distressing dream item as the primary measure of nightmare frequency. 
Based on previous studies in similar patient populations, we assume the baseline nightmare score 
equals to 6.5, regardless of the treatment period. We anticipate the mean (SD) nightmare score of 
6.0 (1.5) after being administered placebo for 3 weeks, and the endpoint mean (SD) for after be 
treated with Prazosin would reduce to 3.5 (2.5). We assumed that the correlation between two 
scores for the same patient equals to 0.3. With a sample size of 10 patients, we will have 80% 
power to detect the treatment effect, at 2-sided alpha level of 0.05. Other scenarios are presented 
in the table below.
CAPS Nightmare score
Correlation coefficient
Power
Baseline
Placebo
Prazosin
6.5
6.0 (1.5)
3.5 (2.5)
0.3
80%
6.5
6.0 (1.5)
3.5 (2.5)
0.4
85%
6.5
6.5 (1.5)
3.5 (2.5)
0.3
92%
6.5
6.5 (1.5)
3.5 (2.5)
0.4
95%
6.5
6.5 (1.5)
4.0 (2.5)
0.3
81%
6.5
6.5 (1.5)
4.0 (2.5)
0.4
85%
9.2
Statistical methods
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Statistical methods
The initial analyses of the data will include univariate exploration of all variables, using 
histograms, statistical summaries, and other graphical techniques. Expected ranges for all of the 
variables will be defined a priori, and out of range values, or values identified as outliers will be 
checked for errors, including going back to the original data forms. In addition to data cleaning, 
this initial analysis will serve the purpose of describing the patients’ characteristics.
Our main objective is to identify the treatment effect. We hypothesize that there will be a 
reduction in cortisol levels and other subjective scores after being treated with Prazosin, whereas 
no significant change after being administered with placebo. To examine the treatment effect, 
both univariate and multivariable methods will be used. The analytic plan for hypothesis 1 and 2 
will be similar, except the outcome measurements.
Univariate: T-tests will be used to analysis the mean difference of nightmare score, cortisol 
level, and other subjective scores.
Multivariable regression model: The mixed effects model will be used to examine the 
differences of the objective measures and subjective scores between two treatment arms. In these 
models, we will account for the period effect (period 1 or 2) and sequence effect (sequence 
Placebo-Prazosin or Prazosin-Placebo). The sequence effect will be treated as a random effect. 
Demographic characteristics and baseline measures will be treated as confounders and adjusted 
in the models as well. We expect no significant differences in the outcome variables will be 
observed between baseline and placebo. Therefore, the analysis will focus on the Prazosin vs. 
Placebo. Least squares mean, standard error of the mean, and p value for the differences will be 
presented as the final results.
Statistical Plan (Phase B)
Protocol B is only a feasibility study using 2 subjects therefore statistical support is not required.
10.0
Confidentiality, Privacy and Data Management 
10.1
Confidentiality
10.1.1 Identifiers associated with data and/or specimens
Participant names, addresses, telephone/fax numbers, email addresses, 
date of birth, medical record numbers, social security numbers, etc. can be 
collected as part of this research study.  All study data will be identified 
only by a code number rather than a name.  The list linking the code 
number with any of the other identifiers is password protected and limited 
staff has access to it. Social security numbers are collected only for 
payment purposes and will not be stored after payment check is issued to 
the participant. 
10.1.1.1 Use of Codes, Master List
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All data will be identified only by a code number rather than a name.  
The list linking the code number to any other identifiers is stored in a 
password protected database, located on the Department of Psychiatry 
private network.  
10.1.2 Storage of Data and/or Specimens
Paper files are stored in a locked filing cabinet in C5600D.  Electronic data is 
stored on the Psychiatry server (Microsoft Server 2003) with active directory 
limiting access established by the Primary Investigator.
10.1.3 Access to Data and/or Specimens
Only the PI and 1-2 key research team members have access to the 
data/specimens.
10.1.4 Transferring Data and/or Specimens
     N/A                                                                                                                                     
10.2
Privacy
The research team has access only to information about the subjects provided by the 
subject during the research study.  The Department of Psychiatry is extremely concerned 
about all issues related to privacy and confidentiality and is experienced in procedures of 
maintaining it effectively.  
All study procedures including phone conversations, obtaining consent, and clinic visits 
will be conducted in private offices or exam rooms within the General Clinical Research 
Center.  Participants are volunteers and may discontinue the research procedures at any 
time with no penalty or loss of benefits to which they are entitled.
11.0
Data and Safety Monitoring Plan
Although prazosin is routinely used in clinical settings in bulimic patients experiencing 
PTSD and nightmares and thus does not pose more than minimal risk for the patients, the 
research team will have the following data and safety monitoring plan to ensure safety 
and prevent any untoward outcomes.
11.1
Periodic evaluation of data
Subjects will be monitored weekly by a board certified psychiatrist to evaluate 
safety.  The PI and co-investigators will be looking at the date monthly to further 
ensure safety of subjects.
11.2
Data that are reviewed 
Vital signs, lab work, side effects and scales of symptom severity will be 
reviewed periodically to ensure safety.
11.3
Method of collection of safety information
The information will be collected at study visits and if needed, follow up phone 
calls will also be used.
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11.4
Frequency of data collection
Data collection will be as described in the methods and recruitment section. Vital 
signs will be collected at every visit; similarly adverse events will be monitored 
on a weekly basis. Scales of symptom severity will be collected 4 times during the 
duration of the study.
11.5
Individual’s reviewing the data
The data will be reviewed by PI and co-investigators, the findings will be reported 
to the IRB by PI.
11.6
Frequency of review of cumulative data
Monthly reviews of the data will be conducted
11.7
Statistical tests
N/A
11.8
Suspension of research
Any life threatening adverse events or outcomes endangering subject safety will 
trigger immediate suspension of research.
12.0
Risks
There may be discomfort associated with removing blood by venipuncture (by needle from a 
vein). A slight pinch or pin prick may be felt when the sterile needle enters the skin. The risks 
include mild discomfort and/or a black and blue mark at the site of puncture. Less common risks 
include a small blood clot, infection or bleeding at the puncture site, and on rare occasions 
fainting during the procedure. 
There is no risk involved with the collection of saliva for diurnal cortisol testing.
There is a minimal risk associated with the discomfort of having standard clinical EEG paste 
electrodes applied to the scalp and EKG Stickers applied to the chest when performing 
polysomnography.  Rarely, we have had an individual who has had a mild allergic reaction to 
the tape applied over electrodes. This risk is minimized by using hypoallergenic tape. If a 
sleep disorder is discovered, the participant will be referred to a sleep specialist or family 
doctor for further follow up as needed.
There is no risk or real discomfort associated with an EKG, however body hair can 
sometimes interfere with the signal recording and at times a small patch of hair may need to 
be shaved in order to place the electrode. Abnormal findings will be reviewed by a physician 
and referred to cardiologist for further follow up, if needed.
There is a risk of loss of confidentiality if medical information or identity is obtained by 
someone other than the investigators, but precautions will be taken to prevent this from 
happening.
The most common side effect of low-dose Prazosin when administered at bedtime may cause 
orthostatic hypotension especially after first dose. Other common side effects of Prazosin 
include palpitations, headache, dry mouth, blurred vision, dizziness, fatigue, constipation, 
diarrhea and nausea.  
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The risks to an unborn baby or a nursing child from the study drug are largely unknown, 
though some animal studies suggest adverse events. Limited use in pregnant women has not 
demonstrated any fetal abnormalities or adverse events.  Women who are pregnant or are 
nursing a child may not participate in this research study.  Participant must agree to take 
reasonable and necessary precautions against becoming pregnant during the period of the 
investigation.  The investigator will discuss appropriate precautions with participant.  If at 
any point during the research participant believes there is any possibility of pregnancy, they 
must notify the investigator immediately.
When participants are in the group that receives placebo, their condition will go without 
active treatment for three weeks in addition to the one-week washout period and their 
symptoms may get worse.
13.0
Potential Benefits to Subjects and Others
13.1
Potential Benefits to Subjects
The subjects will have no direct benefits. During the active treatment arm, symptoms 
may get better.
13.2
Potential Benefits to Others
There is no previous study demonstrating the benefits of the Prazosin use in Bulimic 
patients for treatment of night mares related to PTSD.  This project will provide insight 
into the effectiveness of this medication and aims to decrease the distress associated with 
nightmares.
14.0
Sharing Results with Subjects
The individual results will not be shared with the subjects or their healthcare providers. If 
a condition is discovered, the participant will be referred to their family physician for 
appropriate follow up care.
15.0
Economic Burden to Subjects
15.1
Costs 
N/A
15.2
Compensation for research-related injury
The research involves no more than minimal risk to subjects that they may incur as part 
of routine treatment with Prazosin. It is the policy of the institution to provide neither 
financial compensation nor free medical treatment for research-related injury.  In the 
event of injury resulting from this research, medical treatment is available but will be 
provided at the usual charge.  Costs for the treatment of research–related injuries will be 
charged to subjects or their insurance carriers.
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16.0
Number of Subjects
Subjects: 15 patients will be identified and screened for participation in the study.  Only 10 
patients with Bulimia nervosa and PTSD will complete the study and be included in the final 
analysis.  The additional 5 participants will allow for screen failures or participant withdrawal 
after consent is obtained. This sample size has been derived from the previous studies in PTSD 
that have investigated the role of Prazosin in alleviating nightmares and other PTSD symptoms.
17.0
Resources Available
17.1
Facilities and locations
Briarcrest Clinic & GCRC– For recruitment and enrollment as well as follow up 
with psychiatrist to monitor symptoms.
17.2
Feasibility of recruiting the required number of subjects
The potential subjects are the patients who already follow up with the eating disorders 
clinic; the therapist will screen all patients following up with her for potential suitability 
to participate in the study until the proposed number of subjects has been recruited.
17.3
PI Time devoted to conducting the research
PI will devote 10% of time to this project to ensure that it is completed in the 
projected time frame. 1% of this time will be unfunded effort supported by 
Psychiatry.
17.4
Availability of medical or psychological resources
A therapist will be available for the assessment and screening as well as providing routine 
support for any ongoing issues.  A referral to cardiologist will be made for any patients 
where cardiac assessment is indicated to ensure the cardiac stability of these patients.
17.5
Process for informing Study Team
The PI will meet with each team member separately to inform them of their 
expected participation and duties.  The PI will also send a copy of the written 
protocol after IRB approval to each team member to ensure accurate 
understanding of procedures and will be available to answer questions by the 
research team.
18.0
Other Approvals
Approval from the departmental review committee and GCRC advisory committee will be 
obtained.
19.0
Subject Stipend (Compensation) and/or Travel Reimbursements
Subjects will be paid $500 for participation in the 7 week study. The 2 subjects who also 
participate in phase 2 (Protocol B) will receive an additional $500.
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20.0
Multi-Site Research
20.1
Communication Plans
N/A
20.2
Data Submission and Security Plan
20.3
Subject Enrollment
20.4
Reporting of Adverse Events and New Information
20.5
Audit and Monitoring Plans
21.0
Adverse Event Reporting
21.1
Reporting Adverse Reactions and Unanticipated Problems to the Responsible 
IRB
In accordance with applicable policies of The Pennsylvania State University Institutional 
Review Board (IRB), the investigator will report, to the IRB, any observed or reported 
harm (adverse event) experienced by a subject or other individual, which in the opinion 
of the investigator is determined to be (1) unexpected; and (2) probably related to the 
research procedures. Harms (adverse events) will be submitted to the IRB in accordance 
with the IRB policies and procedures.
21.2
Auditing and Inspecting
The investigator will permit study-related monitoring, audits, and inspections by the Penn 
State quality assurance program office(s), IRB, the sponsor, and government regulatory 
bodies, of all study related documents (e.g., source documents, regulatory documents, 
data collection instruments, study data etc.).  The investigator will ensure the capability 
for inspections of applicable study-related facilities (e.g., pharmacy, diagnostic 
laboratory, etc.).
22.0
Study Monitoring, Auditing and Inspecting
22.1
Auditing and Inspecting
The investigator will permit study-related monitoring, audits, and inspections by the Penn 
State quality assurance program office(s), IRB, the sponsor, and government regulatory 
bodies, of all study related documents (e.g., source documents, regulatory documents, 
data collection instruments, study data etc.).  The investigator will ensure the capability 
for inspections of applicable study-related facilities (e.g., pharmacy, diagnostic 
laboratory, etc.).
23.0 References
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1. Best Practice Guide for the Treatment of Nightmare Disorder in Adults ,Standards of 
Practice Committee: R. Nisha Aurora, M.D.1; Rochelle S. Zak, M.D.2; Sanford H. 
Auerbach, M.D.3; Kenneth R. Casey, M.D.4; Susmita Chowdhuri, M.D.5; Anoop 
Karippot, M.D.6; Rama K. Maganti, M.D.7; Kannan Ramar, M.D.8; David A. Kristo,  
Journal of Clinical Sleep Medicine, Vol.6, No. 4, 2010
2. Subjective and objective sleep and self-harm behaviors in young  children : A general 
population study Ravi Singareddy a,n, Venkatesh B. Krishnamurthy a, Alexandros N. 
Vgontzas a, Julio Fernandez-Mendoza a, Susan L. Calhoun a, Michele L. Shaffer b, 
Edward O. Bixler  Psychiatry Research 209(2013)549–553
3. The National Women's Study: relationship of victimization and posttraumatic stress 
disorder to bulimia nervosa. Dansky BS, Brewerton TD, Kilpatrick DG, O'Neil PM. Int J 
Eat Disord. 1997 Apr;21(3):213-28.
4. Comorbidity of partial and subthreshold ptsd among men and women with eating 
disorders in the national comorbidity survey-replication study (pages 307–315) Karen S. 
Mitchell, Suzanne E. Mazzeo, Michelle R. Schlesinger, Timothy D. Brewerton and Brian 
N. Smith Article first published online: 18 OCT 2011 | DOI: 10.1002/eat.20965
5. Scope and significance of posttraumatic symptomatology among women hospitalized for 
an eating disorder. Gleaves DH1, Eberenz KP, May MC. IntJ Eat Disord. 24(2):147-56, 
1998 Sep
6. Salivary cortisol and dehydroepiandrosterone sulfate in adolescent rape victims with 
post-traumatic stress disorderIva A E Bicanic, Riemke M Postma, Gerben Sinnema, 
Carlijn De Roos, Miranda Olff, Floryt Van Wesel, Elise M Van de Putte 
Psychoneuroendocrinology  Volume 38, Issue 3 , Pages 408-415, March 2013
7. Chronic insomnia and activity of the stress system: a preliminary study.Vgontzas AN1, 
Tsigos C, Bixler EO, Stratakis CA, Zachman K, Kales A, Vela-Bueno A, Chrousos GP.J 
Psychosom Res. 1998 Jul;45(1):21-31.
8. Symptom fluctuation in bulimia nervosa: relation to menstrual-cycle phase and cortisol
      levels.Lester NA1, Keel PK, Lipson SF. Psychol Med. 2003 Jan;33(1):51-60.
9. REM sleep inhibition by desipramine: Evidence for an alpha-1 adrenergic mechanism. 
Ross RJ, Gresch PJ, Ball WA, Sanford LD, Morrison AR. Brain Res 1995;701:129–34. 
[PubMed: 8925274]
10. Prazosin Effects on Objective Sleep Measures and Clinical Symptoms in Civilian Trauma 
PTSD: A Placebo-Controlled Study Fletcher B. Taylor, MD, Patti Martin, Charles 
Thompson, MD, Judi Williams,Thomas A. Mellman, MD, Christopher Gross, MD, 
Elaine R. Peskind, MD,Murray A. Raskind, MD Biol Psychiatry. 2008 March 15; 63(6): 
629–632.
11. Placebo-controlled comparison of prazosin and cognitive-behavioral treatments for sleep 
disturbances in US Military Veterans.Germain A1, Richardson R, Moul DE, Mammen O, 
Haas G, Forman SD, Rode N, Begley A, Nofzinger EA.J Psychosom Res. 2012 
Feb;72(2):89-96. doi: 10.1016/j.jpsychores.2011.11.010. Epub 2011 Dec 20.
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24.0 Appendix
24.1
Test Article(s) (Study Drug(s) and/or Study Device(s))
24.1.1Description
Prazosin is an FDA approved medication indicated for the treatment of 
hypertension.  A common off-label use of the medication is PTSD-related nightmares 
and sleep disruptions.  Prazosin is supplied in capsule form.
24.1.2Treatment Regimen
In this study, prazosin capsules and placebo capsules will used for 3 weeks each.  
Capsules are taken by mouth at bedtime.  The starting dose will be 1 mg and titrated by 
1-2 mg each week as needed to achieve maximum therapeutic benefit while 
monitoring any adverse effects.
24.1.3Method for Assigning Subject to Treatment Groups
All subjects will receive prazosin and placebo as a treatment at separate 
intervals during the study.  The randomization process will determine which subjects 
receive prazosin first and which subjects will receive placebo first. We will use 
computer generated random numbers for randomization process.
24.1.4Subject Compliance Monitoring
 
Subjects will be see by the psychiatrist each week during the study duration and 
will be asked to bring along their pill bottle so any remaining capsules can be counted 
and collected. The research assistant will also call the participants after each dosage 
increase to inquire about usage and side effects. 
24.1.5Blinding of the Test Article
The research pharmacy will provide the drug capsules which will be over 
encapsulated to maintain the same size as the capsules containing placebo.  
24.1.6 Receiving, Storage, Dispensing and Return 
24.1.6.1
Receipt of Test Article 
We will obtain the drug and placebo from the Research Pharmacy.  
24.1.6.2
Storage
The Research Pharmacy will store the drug and placebo according to their 
standard practice.
24.1.6.3
Preparation and Dispensing
Both the medication and placebo will be prepared by the Research 
Pharmacist experienced in drug research studies.  The drug capsules will 
contain 1 mg prazosin and will be over encapsulated.  Methylcellulose will 
be used in the placebo capsules.
24.1.6.4
Return or Destruction of the Test Article
At the conclusion of each study arm, the participant will return their pill 
bottle, so that any remaining capsules can be counted and collected and 
will be destroyed on site.  
24.1.6.5
 Prior and Concomitant Therapy
Prazosin is the only treatment being offered in this study.  Subjects cannot 
be taking steroids or beta blockers and will be excluded from the study if 
used.  
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