Clinical trial NCT01172275
Conditions: Obsessive-Compulsive Disorder
Keywords: Obsessive-Compulsive Disorder OCD
Sponsor: Yale University
Start date: 2012-07-01; Completion date: 2018-02-15
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Pediatric Obsessive-Compulsive Disorder (OCD) affects 1-3% of children. The investigators currently have effective first-line interventions for pediatric OCD such as Cognitive Behavioral Therapy (CBT) and pharmacotherapy with serotonin reuptake inhibitors (SRIs). However, roughly half of children with OCD still have clinically significant OCD symptoms despite treatment with first-line pharmacological treatments and CBT interventions for OCD. Furthermore, all pharmacological treatments for OCD in children have an increased side effect burden when compared to adults. Novel treatments for children with OCD are needed.

N-acetylcysteine (NAC) is a natural supplement that acts as an antioxidant and a glutamate modulating agent. NAC has been used safely for decades in doses 20-40 times higher than in this trial as an antidote for acetaminophen overdose. The only side-effect commonly seen with NAC is nausea and this side-effect is seldom seen in the doses used in this trial.

NAC has recently been demonstrated to be effective in a double-blind, placebo-controlled trial in adults with trichotillomania (chronic hair pulling). Trichotillomania is an obsessive-compulsive spectrum disorder that is hypothesized to be closely related to OCD. In other trials NAC has evidence of some efficacy in treating diverse psychiatric conditions such as bipolar depression, schizophrenia and cocaine dependence.

The investigators are conducting this trial to determine if NAC is effective in treating OCD.

Detailed description:

Arms: arm 1: N-Acetylcysteine effervescent tablets. 1 900mg tablet once a day for 1 week, then 1 900mg tablet twice a day for 1 week and then 1 900mg tablet three times a day for the remaining 10 weeks of the trial. arm 2: Placebo effervescent tablets. 1 900mg tablet once a day for 1 week, then 1 900mg tablet twice a day for 1 week and then 1 900mg tablet three times a day for the remaining 10 weeks of the trial. Children receiving placebo will be offered the active intervention after the double-blind portion of the trial.
Interventions: intervention 1: N-Acetylcysteine intervention 2: Placebo
Intervention descriptions: intervention 1: 1 900mg tablet once a day for 1 week, then 1 900mg tablet twice a day for 1 week and then 1 900mg tablet three times a day for the remaining 10 weeks of the trial. intervention 2: 1 900mg tablet once a day for 1 week, then 1 900mg tablet twice a day for 1 week and then 1 900mg tablet three times a day for the remaining 10 weeks of the trial. Children receiving placebo will be offered the active intervention after the double-blind portion of the trial.

Protocol documents:
Prot_SAP_000.pdf: 
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YALE UNIVERSITY SCHOOL OF MEDICINE 
HUMAN INVESTIGATION COMMITTEE
Application to Involve Human Subjects in Research
DATE STAMPED-RECEIVED
PROTOCOL NUMBER
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project: Double-Blind, Placebo-Controlled Trial of N-acetylcysteine (NAC) for the 
treatment of Pediatric Obsessive-Compulsive Disorder in Children
Principal Investigator:
Michael H. Bloch, M.D., M.S.
Yale Academic Appointment:
Postdoctoral Research Fellow
Campus Address: 
Child Study Center, 230 S. Frontage Rd, PO BOX 207900, New Haven, CT 06520
Campus Phone:
 203-974-7551
Fax:  
203-785-7611
Pager: 
203-745-9921
E-mail: 
Michael.bloch@yale.edu
Protocol Correspondent Name & Address (if different than PI):
Kaitlyn E. Panza, B.A.
 Child Study Center, 230 S. Frontage Rd, PO BOX 207900, New Haven, CT 06520
Campus Phone: 203-737-
4809
Fax: 203-785-
7611
E-mail: Kaitlyn.panza@yale.edu
SECTION II: GENERAL INFORMATION
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply:
 
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)           
 NA
James F. Leckman, M.D.
Yale Academic Appointment:
Professor
Campus Address: 
Child Study Center, 230 S. Frontage Rd, PO BOX 207900, New Haven, CT 06520
Campus Phone:
 203-785-7871
Fax: 
203-785-7611
Pager: 
E-mail: 
James.leckman@yale.edu
Please refer to the HIC website for application 
instructions and information required to 
complete this application.  The Instructions are 
available at 
http://info.med.yale.edu/hic/forms/index.html.  
Submit the original application and two (2) 
copies of all materials including relevant 
sections of the grant which funds this project 
(if applicable) to the HIC.  
HIC OFFICE USE ONLY


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a. Internal Location[s] of the Study:
 Magnetic Resonance Research Center 
 PET Center
     (MR-TAC)   
 YCCI/Church Street Research Unit (CSRU)
 Yale Cancer Center
 YCCI/Hospital Research Unit (HRU)
 Yale-New Haven Hospital
 YCCI/Keck Laboratories
 Specify Other Yale Location: Yale Child Study Center, School of Medicine
b. External Location[s]:
 APT Foundation, Inc.
 Haskins Laboratories 
Connecticut Mental Health Center
 John B. Pierce Laboratory, Inc.
 Veterans Affairs Hospital, West Haven
 Other Locations, Specify: 
c. Additional Required Documents (check all that apply):
 N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)
Approval Date: 
*Pediatric Protocol Review Committee (PPRC)
Approval Date: 
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS
Approval Date: 
*Radioactive Drug Research Committee (RDRC)
Approval Date: 
 YNHH-Radiation Safety Committee (YNHH-RSC)
Approval Date: 
 Magnetic Resonance Research Center PRC (MRRC-PRC)
Approval Date: 
 YSM/YNHH Cancer Data Repository (CaDR)
Approval Date: 
 Dept. of Lab Medicine request for services or specimens form
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements.
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities. 3-4 years.
3. Targeted Enrollment: What is the number of subjects
a. targeted for enrollment at Yale for this protocol?  If this is a multi-site study, what is the total   
    number of subjects targeted across all sites? Approximately 40 subjects all from Yale.
b. expected to sign the consent form? 40 subjects
c. expected to complete some or all interventions for this protocol? 40 subjects
4. Research Type/Phase: (Check all that apply)
a. Study Type
    
 Single Center Study
    
 Multi-Center Study
Does the Yale PI serve as the PI of the multi-site study? Yes 
No 
    
 Coordinating Center/Data Management
    
 Other: 
b. Study Phase
 N/A
    
 Pilot
 Phase I
 Phase II
 Phase III
 Phase IV
    
 Other (Specify) 
c. Area of Research: (Check all that apply) Note that these are overlapping definitions and more 


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    than one category may apply to your research protocol. Definitions for the following can be found  
    in the instructions section 4c:
    
 Clinical Research: Patient-Oriented
    
 Clinical Research: Outcomes and 
    
 Clinical Research: Epidemiologic and Behavioral                 Health Services
    
 Translational Research #1 (“Bench-to-Bedside”)
    
 Interdisciplinary Research
    
 Translational Research #2 (“Bedside-to-Community”) 
 Community-Based Research
5.   Is this study required to be registered in a public database? Yes
No 
If yes, where is it registered?
Clinical Trials.gov registry 
Other (Specify) 
6. Will this research study utilize clinical care services at Yale New Haven Hospital or YMG?
Yes 
 No
If  yes, might these be billable to the subject, the sponsor, grant or other third party payer?
Yes 
No 
  
If you answered "yes", please register this study in the IDX/GE system at
http://www.yalemedicalgroup.org/pfs/forms/10000/NewStudyRequest.pdf
7. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes ___ No  X
  If Yes, please answer questions a through c and note instructions below.  If No, proceed to 
Section III.
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform?
N/A 
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure?
 N/A
c. Will a novel approach using existing equipment be applied?
 N/A
If you answered “no” to question 7a, or "yes" to question 7b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol.
 N/A
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that apply.
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant-
funded).  If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).  


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PI 
Title of Grant
Name of Funding Source 
Funding
Funding Mechanism
Michael Bloch
Double-blind, 
Placebo-Controlled 
Trial of N-
acetylcysteine for 
Pediatric OCD
International Obsessive-
Compulsive Disorder 
Foundation -- pending
  Internal
  External
Grant-M#           
Contract# 
  Internal
  External
Grant-M#           
Contract# 
  Internal
  External
Grant-M#        
Contract# 
2. Research Team:  List all members of the research team. Indicate under the affiliation 
column whether the investigators or study personnel are part of the Yale faculty or staff, or 
part of the faculty or staff from a collaborating institution, or are not formally affiliated with 
any institution. ALL members of the research team MUST complete Human Subject 
Protection Training (HSPT) and Health Insurance Portability and Accountability Act 
(HIPAA) Training before they may be listed on the protocol.  See NOTE below.
***My signature here indicates that I have read, am in compliance with, and will continue to be in 
compliance with the HIC’s Protocol-Specific Conflict of Interest policy and the University’s policy on 
Conflict of Interest and Conflict of Commitment.
NOTE: The HIC will remove from the protocol any personnel who have not signed the application and/or 
completed required training. A personnel protocol amendment will need to be submitted when training is 
complete or signature is provided.
Name
Signature ***
Protocol-Related
 COI? 
Affiliation
Principal 
Investigator 
Michael H. Bloch, 
M.D., M.S.
 Yes  
No
Child Study Center
Role: Co-
investigator
James F. Leckman, 
M.D.
 Yes  
 No
Child Study Center
Role:  Co-
investigator
Robert E. King, M.D.
 Yes  
 No
Child Study Center
Role:  Co-
investigator
Christopher Pittenger, 
M.D.
 Yes  
 No
CMHC, Psychiatry
Role:  Co-
investigator
Angeli Landeros-
Weisenberger, M.D.
 Yes  
 No
Child Study Center
Role:  Study 
Personnel
Megan E. Smith, B.A.
 Yes  
 No
Child Study Center
Role: Study 
Personnel
Kaitlyn E. Panza, B.A
 Yes  
 No
Child Study Center


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SECTION IV:
 PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR 
AGREEMENT
As the principal investigator of this research project, I certify that:

The information provided in this application is complete and accurate.

I assume full responsibility for the protection of human subjects and the proper conduct of the
      research.

Subject safety will be of paramount concern, and every effort will be made to protect subjects’
      rights and welfare.

The research will be performed according to ethical principles and in compliance with all federal,
      state and local laws, as well as institutional regulations and policies regarding the protection of  
      human subjects.

All members of the research team will be kept apprised of research goals.

I will obtain approval for this research study and any subsequent revisions prior to my initiating the
      study or any change and I will obtain continuing approval of this study prior to the expiration date     
      of any approval period.

I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to
      participants.

I am in compliance with the requirements set by the University and qualify to serve as the
      principal investigator of this project or have acquired the appropriate approval from the 
      Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at
      Yale-New Haven Hospital.

I will identify a qualified successor should I cease my role as principal investigator and facilitate a
smooth transfer of investigator responsibilities.
_____
 
PI Name (PRINT) and Signature
Date
As the faculty advisor of this research project, I certify that:

The information provided in this application is complete and accurate.

This project has scientific value and merit and that the student or trainee investigator has the 
      necessary resources to complete the project and achieve the aims.

I will train the student investigator in matters of appropriate research compliance, protection of
      human subjects and proper conduct of research.

The research will be performed according to ethical principles and in compliance with all federal,
      state and local laws, as well as institutional regulations and policies regarding the protection of  
      human subjects.

The student investigator will obtain approval for this research study and any subsequent revisions
      Prior to initiating the study or revision and will obtain continuing approval prior to the expiration
      of any approval period.

The student investigator will report to the HIC any serious injuries and/or other unanticipated 
      problems involving risk to participants. 

I am in compliance with the requirements set forth by the University and qualify to serve as
      the faculty advisor of this project.
___________
______
_____
    Advisor Name (PRINT) and Signature
Date


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Department Chair’s Assurance Statement
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a
sponsoring company, patents, licensure) associated with this research project?
 Yes (provide a description of that interest in a separate letter addressed to the HIC.)
 No
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and
the sponsor of the research project, or its competitor or any interest in any intervention and/or method
tested in the project that might compromise this research project?
Yes, and I agree to submit the Protocol-Specific Conflict of Interest Disclosure Form.
No
I assure the HIC that the principal investigator and all members of the research team are qualified by
education, training, licensure and/or experience to assume participation in the conduct of this research
trial. I also assure that the principal investigator has departmental support and sufficient resources to
conduct this trial appropriately.
   ____________________________
   Chair Name (PRINT) and Signature  
    
 Date
   _________________________________
   Department
YNHH Human Subjects Protection Administrator Assurance Statement
Required when the study is conducted solely at YNHH by YNHH health care providers.
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that:

I have read a copy of the protocol and approve it being conducted at YNHH.

I agree to submit a Protocol-Specific Conflict of Interest Disclosure Form if I am aware of any real 
or apparent institutional conflict of interest.

The principal investigator of this study is qualified to serve as P.I. and had the support of the hospital 
for this research project.
  ______________________________________
    YNHH HSPA  Name (PRINT) and Signature       
Date
For HIC Use Only
Date Approved
Human Investigation Committee Signature


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SECTION V: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
The aim of the study is to determine if N-acetylcysteine is an effective treatment for OCD in 
children.
2.   Background: Describe the background information that led to the plan for this project. Provide
      references to support the expectation of obtaining useful scientific data. 
Pediatric OCD affects 1-3% of children (Douglass, Moffitt et al. 1995; Zohar 1999).  We 
currently have effective first-line interventions for pediatric OCD such as Cognitive Behavioral 
Therapy (CBT) and pharmacotherapy with serotonin reuptake inhibitors (SRIs) (POTS 2004).  
However, roughly half of children with OCD still have clinically significant OCD symptoms 
despite treatment with first-line pharmacological and CBT interventions for OCD (POTS 2004).  
When severe, OCD can be incapacitating with devastating consequences for children and their 
families. Augmentation strategies with antipsychotic medications can improve the effectiveness 
of SRI therapy but do not eliminate OCD symptoms (Bloch, Landeros-Weisenberger et al. 2006).  
Furthermore, all pharmacological treatments for OCD have an increased side effect burden when 
compared to adults. Novel treatments for children with OCD are needed. 
Converging lines of evidence from neuroimaging, genetic and pharmacological studies 
support the importance of glutamate abnormalities in the pathogenesis of OCD (Rosenberg, 
MacMaster et al. 2000; Rosenberg, MacMillan et al. 2001; Chakrabarty, Bhattacharyya et al. 
2005; Coric, Taskiran et al. 2005; Poyurovsky, Weizman et al. 2005; Arnold, Sicard et al. 2006; 
Dickel, Veenstra-VanderWeele et al. 2006; Lafleur, Pittenger et al. 2006; Pasquini and Biondi 
2006; Pittenger, Krystal et al. 2006; Whiteside, Port et al. 2006; Stewart, Fagerness et al. 2007).  
In magnetic resonance spectroscopy studies, elevated concentrations of glutamate and related 
compounds have been demonstrated in the caudate nucleus and orbitofrontal cortex of OCD 
patients compared to normal controls (Rosenberg, MacMaster et al. 2000; Rosenberg, MacMillan 
et al. 2001; Whiteside, Port et al. 2006).  Cerebral spinal fluid analysis has likewise demonstrated 
elevated glutamate levels compared to normal controls (Chakrabarty, Bhattacharyya et al. 2005).  
In genetic studies, single nucleotide polymorphisms within the glutamate transporter gene 
SLC1A1 have been associated with the diagnosis of OCD (Arnold, Sicard et al. 2006; Dickel, 
Veenstra-VanderWeele et al. 2006; Stewart, Fagerness et al. 2007).  Open-label, 
pharmacological treatment studies have suggested that glutamate modulating agents such as 
riluzole (Coric, Taskiran et al. 2005; Pittenger, Coric et al. 2008; Grant, Lougee et al. in press), 
N-acetylcysteine (NAC) (Lafleur, Pittenger et al. 2006) and memantine (Poyurovsky, Weizman 
et al. 2005; Pasquini and Biondi 2006) may be effective in the treatment of OCD.  However, no 
double-blind, placebo-controlled trials of glutamatergic agents have been completed in OCD.
NAC is a naturally occurring amino-acid that has been used safely for decades as an 
antioxidant agent and as an antidote for acetaminophen overdose.  Due to its benign safety 
profile, NAC is available as an over-the-counter medication at a cost of less than 25 cents a day.  
More recently, NAC has been demonstrated to be a glutamate modulating agent.  NAC is 
converted to cystine, a substrate for the glutamate/cystine antiporter located on glial cells. The 
uptake of cystine by glia causes glial release of glutamate into the extrasynaptic space, where it 
appears to stimulate inhibitory metabotropic glutamate receptors on glutamatergic nerve 
terminals and thereby reduces the synaptic release of glutamate (Moran, McFarland et al. 2005).  
NAC has been recently demonstrated in randomized, double-blind, placebo-controlled studies to 
be  effective for the treatment for bipolar depression and schizophrenia (Berk, Copolov et al. 
2008; Berk, Copolov et al. 2008).  NAC has also been demonstrated in double-blind, placebo-
controlled studies to effectively reduce the symptoms of trichotillomania, a disorder that is 
considered to be on the OC spectrum and is often comorbid with OCD (Grant, Odlaug et al. 


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2009).  NAC has also demonstrated to be safe without significant side effects in a recent double-
blind, placebo-controlled trial in children with autism (Posey, Erickson et al. 2009).
3.   Research Plan: Provide an orderly scientific description of the study design and research procedures
as they directly affect the subjects. 
Subjects: Children with OCD will be recruited through the TS/OCD Clinic at the Yale Child 
Study Center.  Inclusion and Exclusion Criteria are listed below.
Intervention:  Subjects will be randomized in a ratio of 1:1 to receive treatment with NAC or 
placebo.   NAC (or placebo) will be titrated up to a maximum dose of 2400mg/day over the 
course of 1 week. Subjects will take a single 600mg tablet twice a day for 1 week, and then 
increase to two 600mg tablets twice a day for the remainder of the 12 week study.  After 
completion of the study all subjects receiving placebo will be offered NAC treatment for the 
following 12 weeks.
Subjects, their parents, investigators, staff, and persons performing the assessments will 
remain blind to treatment assignment from the time of randomization until their completion of 
the study after 12 weeks. Randomization data are kept strictly confidential until the time of 
unblinding and are accessible only to authorized persons. The identity of the treatments will be 
concealed by the use of study drugs that are identical in packaging, labeling, schedule of 
administration and appearance. Placebo and study drug will be prepared in a like fashion at the 
Yale-New Haven Hospital Investigational Drug Service pharmacy.   
NAC is an altered form of the amino acid cysteine, which is commonly found in food and 
synthesized by the body.  N-acetylcysteine (NAC) is generally well tolerated and has been 
extensively used in the treatment of acetaminophen overdose/toxicity at high doses for many 
years. The dosage in acute acetaminophen overdose is a 140mg/kg loading dose, followed by a 
maintenance dose of 70mg/kg administered every 4 hours for 17 consecutive doses.  The dose 
used to treat acetaminophen overdose in children is approximately 10-fold greater than the 
maximum dose we will use in this study.  Although generally well-tolerated, the PDR indicates 
that adverse reactions reported with oral NAC include nausea, vomiting, diarrhea, headache 
(especially when used along with nitrates) and rashes when used at higher doses (Cheng, Lin et 
al. 2007). There are rare reports of renal stone formation and cases of bronchospasm with 
intravenous use only.  The long-term use of NAC has been well-studied in the treatment of 
Chronic Obstructive Pulmonary Disease and was extremely well-tolerated (Grandjean, Berthet et 
al. 2000).  NAC has been well-tolerated in the treatment of adults with OCD and trichtillomania 
(TTM) at a maximum dose of 3000mg (Pittenger, Krystal et al. 2005; Lafleur, Pittenger et al. 
2006).  
Assessment:  Pre-study screening procedure: After an initial phone screen to rule out obvious 
exclusions from the study protocol, potential subjects will have an initial evaluation that will be 
performed by a multidisciplinary clinical team.  Exclusions in screening would include (1) 
Comorbid bipolar disorder, psychotic disorder, substance use disorder, developmental disorder 
or mental retardation (IQ<70), (2) asthma diagnosis requiring treatment in the last 3 months, and 
(3) a change in psychotropic medications or behavioral treatment for OCD within the last month.  
In addition to a standard clinical evaluation consisting of history, and mental status exams, 
subjects will receive a clinical diagnostic interview using the Kiddie-Schedule for Affective 
Disorders and Schizophrenia (K-SADS) (Kaufman, Birmaher et al. 1997). Additional baseline 
ratings will be conducted for OCD, tic, depression and anxiety severity using:  1) Children’s 
Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) (Scahill, Riddle et al. 1997), (2) 
Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS).Additional baseline ratings 


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will be conducted for OCD, tics, trichotillomania, depression and anxiety severity using (3) Yale 
Global Tic Severity Scale (YGTSS) (Leckman, Riddle et al. 1989), (4) ADHD Rating Scale 
(ADHD-RS) (DuPaul, Power et al. 1998), (5) Multidimensional Anxiety Scale for Children 
(MASC) (March, Parker et al. 1997), (6) Children’s Depression Inventory (CDI) (Kovacs 1985), 
(7) Massachusetts General Hospital – Hairpulling Scale (MGH-HPS) (Keuthen, O'Sullivan et al. 
1995), (8) Clinical Global Impression (CGI) scale (Guy 1976) and (9) Pediatric-Adverse Events 
Rating Scale (PAERS) (March, Karayal et al. 2007).  The pediatric adverse events rating scale 
will be used to monitor safety throughout the trial.  A medical assessment including vital 
signs, physical exam and urine drug screen and pregnancy test will be completed prior to study 
enrollment.  The measures utilized in this study are outlined below.
Baseline Assessments
K-SADS
Psychiatric History
General Medical History
Medical Assessments
Vital Signs
Physical Exam
Mental Status Exam
Urine Toxicology
Urine Pregnancy Test
Rating scales
CY-BOCS    DY-BOCS
YGTSS         ADHD-RS 
CDI             MASC
MGH-HPS  CGI 
           PAERS              
The table below indicates the clinical ratings scheduled planned for the trial.  If subjects’ 
have significant ADHD, tic, anxiety or depression symptoms at screening, ratings of these 
symptoms will be followed regularly at study assessments.  Subjects will be encouraged to 
continue outside therapy and will be required to continue all concurrent medications during 
the course of this trial.  Subjects will also be asked about the number of missed doses of 
medications at each study visit.
Measure
Screening/ 
Baseline
Week 2
Week 4
Week 8
Week 
12
CY-BOCS
x
x
x
x
x
DY-BOCS
x
x
x
x
x
YGTSS
x
 
x
x
x
ADHD-RS
x
 
x
x
x
CDI
x
 
x
x
x
MASC
x
 
x
x
x
MGH-HPS
x
 
x
x
x
CGI
x
x
x
x
x
PAERS
x
x
x
x
x
 
 
 
 
 
 
NAC dose
600mg BID
1200 mg 
BID
1200 mg 
BID
1200 mg 
BID
1200 mg 
BID
3. Statistical Considerations: Describe the statistical analyses that support the study design. 
We will use the CY-BOCS as our primary outcome measure.  Our primary analysis will 
involve a mixed effects modelusing weekly CY-BOCS ratings from baseline to 12 weeks with 
treatment (NAC/placebo) as a fixed factor and time as a within-subject factor. We will adhere to 
intention-to-treat principles in our analysis.  We powered our study to have 80% power to detect 
a large effect of NAC (d=0.9) assuming =0.05. Given a similar variance in the Cy-BOCS 
scores in previous placebo-controlled trials of pediatric OCD, we would expect this effect size to 
correspond to a 6.5 point difference in Cy-BOOCS between the NAC and placebo groups (POTS 


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2004).  By comparison, the effect size of NAC in the treatment of adults with trichotillomania, 
using the MGH-HS (d=1.2, N=50), and in bipolar depression, using the Montgomery-Asberg 
Depression Rating Scale (MADRS) (d=0.8, N=80) was considerably larger  (Grant, Odlaug et al. 
2008).
As a secondary outcome we will examine the safety and tolerability of NAC.  Given our 
sample size of 40 we will have limited power to detect adverse events of low frequency.  That 
being said, assuming that we do not see a side-effect in the placebo group, we will have 80% 
power to detect NAC related side-effect, if it occurs in one-third of NAC treated subjects.  
Frequency of side-effects will be measured with the PAERS as discussed in the assessments 
section.
SECTION VI: RESEARCH INVOLVING DRUGS, DEVICES, BIOLOGICS & PLACEBOS
1. Identification of Drug, Device or Biologic: What is (are) the name(s) of the drug(s), device(s) or
biologic(s) being used? Identify whether FDA approval has been granted and for what indication(s). 
N-Acetylcysteine (USP grade) is FDA approved for the pediatric population in oral form to 
reduce the extent of liver injury after an acetaminophen overdose. N-acetylcysteine (NAC) is 
an altered form of the amino acid cysteine, which is commonly found in food and 
synthesized by the body. NAC is generally well tolerated and has been extensively used at 
high doses in the treatment of acetaminophen overdose/toxicity for many years. The NAC 
dosage for acute acetaminophen overdose, in both adults and children, is a 140mg/kg loading 
dose, followed by a maintenance dose of 70mg/kg administered every 4 hours for 17 
consecutive doses. The long-term use of NAC has also been investigated in six-month to 
three-year studies. These studies examine the efficacy and tolerability of NAC (dosed 
between 600-1200mg per day) in the treatment of chronic obstructive pulmonary disease 
COPD (Pela, Calcagni et al. 1999; Grandjean, Berthet et al. 2000; Stey, Steurer et al. 2000; 
Kasielski and Nowak 2001; Poole and Black 2001; Chikina, Iagmurov et al. 2002; Decramer, 
Rutten-van Molken et al. 2005). NAC helps the body synthesize glutathione, an important 
antioxidant. In animals, the antioxidant activity of NAC protects the liver from the adverse 
effects of exposure to several toxic chemicals. NAC also protects the body from 
acetaminophen toxicity and is used, at very high levels, in hospitals for patients with 
acetaminophen poisoning. It has also been shown to be effective at treating liver failure from 
causes other than acetaminophen poisoning (e.g., hepatitis, and other drug toxicity) and at 
preventing kidney damage caused by injections of iopromide, a contrast medium used in 
people scheduled to undergo computerized tomography (CT) imaging.
All protocols which utilize a drug, device or biologic not approved by, but regulated by, the FDA must 
provide the following information:  
 Not applicable to this research project
   i.   What is the Investigational New Drug (IND) or Investigational Device Exemption (IDE) number 
   assigned by the FDA? 
   ii.   For IDE’s: Did the FDA approve this IDE as a Category A (experimental/investigational) or as a  
         Category B (non-experimental/investigational)? 
iii. Who holds the IND or IDE? 


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The clinical investigation of a drug product that is lawfully marketed in the United States may be
exempt from the requirements for filing an IND. If there is no IND and an exemption is being sought,
complete the following:
i.   Is the intention of the investigation to report to the FDA as a well controlled study in support of a
     new indication for use or to be used to support any other significant change in the labeling for the
     drug?  
 Yes  
 No
ii. If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, is
      the intention of the investigation to support a significant change in the advertising for the product?
      
 Yes  
 No
iii.  Does the investigation involve a route of administration or dosage level or use in populations or   
      other factor that significantly increases the risks (or decreases the acceptability of the risks)   
      associated with the use of the drug product? 
 Yes  
 No
The NAC dosage for acute acetaminophen overdose is a 140mg/kg loading dose, followed by a 
maintenance dose of 70mg/kg administered every 4 hours for 17 consecutive doses. The dose 
used to treat acetaminophen overdose in children is approximately 10-fold greater than the 
maximum dose we will use in this study.  
iv. Will the investigation be conducted in compliance with the requirements for institutional (HIC)   
      review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50  
and 21 CFR Part 56)? 
Yes  
 No
v.   Will the investigation be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs? 
Yes  
 No
2. Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 
influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models. 
N-acetylcysteine (NAC) is generally well tolerated and has been extensively used at high 
doses in the treatment of acetaminophen overdose/toxicity for many years. The NAC dosage for 
acute acetaminophen overdose is a 140mg/kg loading dose, followed by a maintenance dose of 
70mg/kg administered every 4 hours for 17 consecutive doses. The long-term use of NAC has 
also been investigated in six-month to three-year studies examining the efficacy and tolerability 
of NAC (dosed between 600-1200mg per day) in the treatment of chronic obstructive pulmonary 
disease COPD (Pela, Calcagni et al. 1999; Grandjean, Berthet et al. 2000; Stey, Steurer et al. 
2000; Kasielski and Nowak 2001; Poole and Black 2001; Chikina, Iagmurov et al. 2002; 
Decramer, Rutten-van Molken et al. 2005). A recent study by Decramer and colleagues in 2005 
concluded that there were no adverse events thought to be drug related in their study examining 
the use of 600mg/day of NAC in over 500 patients with COPD. Additionally, Chikina and 
colleagues found that the most effective dose of NAC in the treatment of COPD was 
1200mg/day (the study examined doses of NAC ranging from 600-2400mg/day). A meta-
analysis examining the efficacy of NAC in COPD, performed in 2000, revealed that NAC was 
well tolerated without significant adverse effects (Grandjean, Berthet et al. 2000). Although 
generally well-tolerated, the PDR indicates that adverse reactions reported with oral NAC 
include nausea, vomiting, diarrhea, headache (especially when used along with nitrates) and 
rashes. There are rare reports of renal stone formation.  It is also important to note that rare 
reports of bronchoconstriction have occurred with intravenous NAC (but no reports of 
bronchospasm related to the oral use of NAC). Although there are no known contraindications to 


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NAC use, individuals with asthma will be excluded from the study given the rare, but potential, 
adverse effect of bronchospasm. 
The safety and tolerability of chronic NAC at higher doses has been evaluated in a number of 
contexts.  In a double-blind, placebo-controlled randomized trial of oral NAC in HIV-infected 
patients, subjects were treated with 8,000mg per day of NAC for 8 weeks (De Rosa et al, 2000). 
Adverse effects in this trial were minimal and some subjects reduced the dose due to side effects, 
with the average dosage by the end of the trial being 6.3 grams/day; however, the reduction in 
"dose" was similar for the placebo arm. In another double-blind, placebo-controlled randomized 
trial involving 43 Alzheimer's patients, subjects were given placebo or 50 mg/kg/day orally 
(Adair, Knoefel et al. 2001). In that study, there were no adverse effects more common than in 
placebo (except perhaps headache).
In acetaminophen overdose, the dose of NAC is 140 mg/kg load followed by 70 mg/kg every 4 
hours for 17 consecutive doses. At this dosage, NAC can cause nausea, vomiting and sometimes 
generalized urticaria. In normal volunteers the dose that the vast majority of patients were able to 
tolerate was 3200 mg/m2/day. Common toxicities at higher doses were bad taste and 
gastrointestinal disturbances (Pendyala and Creaven. et al).
Severe toxicity is rare and occurs at doses an order of magnitude higher than what we will be 
using in this study.  In a single case report, a 16-kilogram child received 39,207 mg of 
intravenous NAC due to a medical error; she developed cerebral edema with uncal herniation 
(Bailey, Blais et al. 2004).  The lethal oral dose of NAC is 4400 mg/kg in mice and 5050 mg/kg 
in rats (RTECS 2001).
According to the PDR: “NAC is rapidly absorbed from the gastrointestinal tract and transported 
to the liver via the portal circulation, where it undergoes extensive first-pass metabolism. Peak 
plasma concentrations are observed approximately 0.5 to 1 hour following oral administration of 
doses of 200 to 600 milligrams. NAC is metabolized to N-acetylcysteine, N, N-diacetylcystine 
and L-cysteine. L-cysteine itself is metabolized to glutathione, protein, taurine and sulfate. NAC 
has low bioavailability, probably because of its extensive first-pass metabolism in the liver. The 
terminal half-life of total NAC is approximately 6.25 hours after ingestion. Use of supplemental 
NAC along with carbamazepine may cause reduced serum levels of carbamazepine.”
NAC helps the body synthesize glutathione, an important antioxidant. In animals, the antioxidant 
activity of NAC protects the liver from the adverse effects of exposure to several toxic 
chemicals. NAC also protects the body from acetaminophen toxicity and is used at very high 
levels in hospitals for patients with acetaminophen poisoning. It has also been shown to be 
effective at treating liver failure from causes other than acetaminophen poisoning (e.g., hepatitis, 
and other drug toxicity) and at preventing kidney damage caused by injections of iopromide, a 
contrast medium used in people scheduled to undergo computerized tomography (CT) imaging.
Supplementation with NAC has been shown to reduce the proliferation of certain cells lining the 
colon and may reduce the risk of colon cancer in people with recurrent polyps in the colon.
There have been several case reports of oral NAC producing dramatic improvements in 
Unverricht-Lundborg disease, an inherited degenerative disorder involving seizures and 
progressive disability. One study used up to 3 grams of NAC per day.
Oral supplementation with NAC has been used successfully in two cases to treat a rare syndrome 
that complicates kidney dialysis. This condition, known as pseudoporphyria, has no other known 
treatment. Controlled clinical trials are needed to confirm these preliminary observations.


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Our choice of using 2400 mg daily in this study stems from our preliminary experience with 
NAC in trichotillomania and refractory OCD (Lafleur, Pittenger et al. 2006; Grant, Odlaug et al. 
2008).  Although a dose of 2400mg has demonstrated efficacy for treating adults with TTM, 
higher doses of NAC are routinely used in the treatment of other psychiatric conditions.  This 
dose has been well tolerated in this case report and in several other clinical observations 
(Pittenger, Krystal et al. 2005).
3. Source: a) Identify the source of the drug, device or biologic to be used. 
      N-Acetylcysteine will be obtained from the Yale-New Haven Hospital Investigational Drug 
Service pharmacy through a commercial supplier
b) Is the drug or device provided free of charge? 
 Yes  
 No
    If yes, by whom? 
4. Preparation and Use: Describe the method of preparation, storage, stability information, and for 
parenteral products, method of sterilization and method of testing sterility and pyrogenicity. 
NAC will be stored at the YNHH IDS pharmacy. Placebo will be placed in the same capsules as NAC, 
thus NAC and placebo will look and smell identical. 
5. Use of Placebo: 
 Not applicable to this research project
Provide a justification which addresses the following:
a.   Describe the safety and efficacy of other available therapies (if any). 
b.   State the maximum total length of time a participant may receive placebo while on the study. 
c.   Address the greatest potential harm that may come to a participant as a result of not receiving    
  
   effective therapy (immediate or delayed onset.) 
d.   Describe the procedures that are in place to safeguard participants receiving placebo. 
(a) Pharmacotherapy with SSRIs and cognitive behavioral therapy are both relatively 
safe and effective treatments for pediatric OCD (POTS 2004).  We will recommend 
to all subjects considering enrollment in this trial that they engage in adequate trials 
(>3 months) of each of these interventions prior to enrolling in this trial.  Assuming a 
child has significant residual OCD symptoms despite engaging in both these 
treatments, additional options include (1) antipsychotic augmentation, (2) switching 
SSRIs and (3) continuing on their current treatments.
1. Antipsychotic Augmentation – Randomized, placebo-controlled studies in 
adults with OCD indicate that antipsychotic addition to ongoing SSRI 
monotherapy is a modestly effective treatment for refractory OCD.  Estimates 
indicate that the Number needed to treat for this intervention is 5 with an 
outcome measure of treatment response.  However, antipsychotic treatment is 
associated with significant side-effects including sedation, weight-gain, 
metabolic side effects such as diabetes and lipid abnormalities and the risk of 
extrapyramidal side effects such as tardive dyskinesia and akathisia.  The risk 
of these side effects appears more pronounced in children than adults and no 
controlled studies for OCD have been conducted in these medications.
2.   For children who have tried only 1 SSRI an additional option is to switch to 
a different SSRI  or SNRIs such as venlafaxine and clomipramine.  There are 
no controlled studies assessing efficacy of medication switches in children 
with OCD.  Data in adults suggest that if a patient has not responded to 1 
SSRI the likelihood of responding to a different one is 25% and if they have 
not responded to 2 SSRIs, the likelihood of responding to a third is 10%.  


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There is no significant evidence that the rate of response to switching to a 
serotonin norepinephrine reuptake inhibitor (SNRI) such as venlafaxine or 
clomipramine is any different.  SSRIs are associated with side effects such as 
insomnia, sedation, nausea, diarrhea, sexual dysfunction, behavioral activation 
and suicidal ideation.
3. Continuing current therapies – current evidence suggests that the treatment 
response to SSRIs or CBT plateaus by 3 months after the initiation of 
treatment.  The risk of continuing their current therapy varies based on the 
nature of that therapy, but does not contain the additional risks associated with 
NAC.
(b) 12 weeks.
Since the study medication is added to the children’s current medications, the risk of 
symptoms worsening is not significantly greater in this clinical trial than it would be 
if the patient’s medications were changed as part of standard clinical care. The only 
additional risks in this study are potential adverse effects of N-acetylcysteine or no 
response in the placebo group.  We will monitor subjects carefully for these changes 
during the course of the study and discontinue the study and provide or refer subjects 
for appropriate treatment as necessary. Subjects assigned to placebo will have the 
opportunity to receive active NAC after the 12 weeks. 
(c) If a child is discontinued from the study because of the worsening of symptoms, the 
child, if receiving active medication, will be referred for appropriate behavioral and 
pharmacological treatment, and if on placebo will be offered active medication in 
addition to the above therapy.  
6. Use of Controlled Substances:
Will this research project involve the use of controlled substances in human subjects?
 Yes  
 No See instructions to view controlled substance listings. 
7.   Continuation of Drug Therapy After Study Closure   
 Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended? 
 Yes  
 No
If yes, describe the conditions under which continued access to study drug(s) may apply as well as 
conditions for termination of such access. 
Subjects receiving placebo with receive NAC free of charge for the next 12 weeks of the protocol.  
They will continue clinical sessions as needed for the next 12 weeks.  After receiving 12 weeks of 
NAC, they will be instructed on how to obtain NAC over-the-counter but encouraged to receive 
continued psychiatric care.  We will make appropriate clinical referrals as necessary at the end of 
the trial.  We will offer continued consultations to outside practitioners throughout the study 
period.
SECTION VII: HUMAN SUBJECTS 
1. Recruitment Procedures: How will potential subjects be identified, contacted and recruited? 
Attach copies of any recruitment materials that will be used.
 Flyers
 Internet/Web Postings
 Radio
 Posters
 Mass E-mail Solicitation
 Telephone
 Letter
 
 Departmental/Center Website
 Television


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 Medical Record Review
 Departmental/Center Research Boards
 Newspaper
 Departmental/Center Newsletters
 Web-Based Clinical Trial Registries
 Other (describe):
 Clinicaltrials.gov Registry (do not send materials to HIC)
1. a. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject? 
 Yes, all subjects
 Yes, some of the subjects
 No
If yes, describe the nature of this relationship. 
We may recruit subjects who come to be seen at our clinic. Some children may be referred for 
psychopharmacology consult. Other subjects may come specifically because of interest in the 
study. No subjects will be taken off current medication or withdrawn from ongoing therapy in 
order to participate in the trial, unless the current medication is ineffective or causing 
unacceptable adverse effects. Families of children who are not interested in the study will be 
treated in the usual clinical manner.
2. Subject Population Provide a detailed description of the targeted involvement of human subjects 
for this research project. 
In many cases subjects will be screened via telephone. The telephone screen will be used to 
inform the parent (primary caretaker) about the nature of the study, the duration of the study, 
number of visits, randomization, etc. The telephone screen will include collecting a brief history 
to exclude subjects that are unlikely to be eligible. People may not be eligible because of an 
ongoing medical problem (asthma or pregnancy), presence of an excluded psychiatric diagnosis 
(see exclusion criteria), or because they are unable to attend scheduled study visits. Interested 
subjects will be scheduled for a screening visit.  The screening visit will occur over one visit. 
The overall purpose of the screening is to confirm that the subject meets all entry criteria. The 
first step in the screening visit will be to review the consent form, answer questions about the 
protocol and to obtain written informed consent. All procedures will be described to the subject 
in a developmentally appropriate manner.
2. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or exclusion? 
How will eligibility be determined, and by whom? 
Subjects will be well-characterized and must meet selection criteria to be enrolled. The measures 
used in the baseline assessment will be used by the principal investigators to determine if 
subjects meet inclusion/exclusion criteria.
  
Inclusion Criteria:
1. Children aged 8-17 years.
2. Primary diagnosis of OCD.  
3. Duration of OCD greater than 6 months.
4.  Significant Current OCD symptoms: Current CY-BOCS score greater than or equal to 
16.
Exclusion Criteria:
1. Comorbid bipolar disorder, psychotic disorder, substance use disorder, developmental 
disorder or mental retardation (IQ<70).
2. Recent change (less than 4 weeks) in medications that have potential effects on OCD 
severity (such as Selective Serotonin Reuptake Inhibitors, clomipramine, naltrexone, 
lithium, psychostimulants, anxiolytics, or antipsychotics).  Medication change is defined 


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to include either dose changes or medication discontinuation. 
3. Asthma requiring medication use within the last 3 months (case reports have linked 
intravenous NAC administration with asthma exacerbation)
4. Known hypersensitivity or previous anaphylactoid reaction to acetylcysteine or any 
components in its preparation.
5. Positive pregnancy test or drug screening test.
6. Previous use of N-acetylcysteine (dose greater than 600mg for more than 2 weeks).
       3.a. Will email or telephone correspondence be used to screen potential subjects for eligibility
        prior to the potential subject coming to the research office? 
 Yes  
 No
3.b. If yes, will identifiable health information be collected during this screening process and 
retained by the research team? 
 Yes  
 No
4. Subject Classifications: Check off all classifications of subjects that will be invited to enroll in 
the research project. Will subjects, who may require additional safeguards or other 
considerations, be enrolled in the study? If so, identify the population of subjects requiring special 
safeguards and provide a justification for their involvement.
  Children
 Healthy
Fetal material, placenta, or dead fetus
 Non-English Speaking
 Prisoners
 Economically disadvantaged persons
 Decisionally Impaired
 Employees
 Pregnant women and/or fetuses
 Students 
 Females of childbearing potential
For children, we will obtain consent from their parent (legal guardian) before enrolling them in the 
study.  We will also require childhood assent for participation.  A simple quiz testing the 
understanding of the protocol and important elements of informed consent is in place at the end of the 
consent form.  
For females of child bearing potential we will conduct a urine pregnancy test prior to enrollment in the 
study. If the pregnancy test is positive we will refer people to appropriate treatment and will exclude 
them from participation in the trial until completion of their pregnancy.  For sexually active females, 
we will provide contraceptive counseling and refer them for contraceptive treatment if indicated.  The 
acceptable methods of contraception will include oral birth control pills (OTCs), IUD, transdermal 
preparations, parenteral preparations, barrier contraceptive methods (i.e. condoms and diaphragm) and 
abstinence.  Because full confidentiality regarding pregnancy cannot be entirely guaranteed, these 
testing requirements and the limited scope of confidentiality will be made known to all subjects during 
the consent procedure. In this manner, young women who would not be comfortable with pregnancy 
testing or sharing the results of such testing can “opt out” of the study at the time of the initial consent, 
without having to declare specific reasons.
Since subjects will also be screened for drugs, it would be advisable to explain that these results will 
also be kept confidential. However, if subjects exhibit any behaviors that could be an immediate 
danger to themselves or others and/or other serious medical conditions, subjects will be excluded, 
parents will be advised of these findings, and subjects will be referred for the appropriate evaluation. If 
subjects or parents are uncomfortable with the provisions surrounding drug testing, then, they may 
also opt out of participating. 


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a. Is this research proposal designed to enroll children who are wards of the state as potential 
subjects? 
 Yes  
 No (If yes, see Instructions section VII #4 for further requirements) 
SECTION VIII: CONSENT/ ASSENT PROCEDURES
1. Consent Personnel: List all members of the research team who will be obtaining consent/assent. 
Michael H. Bloch, MD, MS, Angeli Landeros-Weisenberger MD, James F. Leckman, MD, 
Robert E. King, MD, Kaitlyn E. Panza, BA, Megan E. Smith, BA
2. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will 
be obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making. 

The research team (PI, his designee or research coordinator) will explain the study to the 
child and legal guardian.

Understanding of the study will be tested using a brief questionnaire (see consent and 
assent form) of the key elements of the study. 

The research team will discuss the child’s participation in the study with the patient’s 
primary clinician and/or pediatrician. The clinician’s opinion about the patient’s 
participation and ability to provide informed consent will be documented.  
3. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed. 
Subjects will be minors (ages 8-17) and the consents will be obtained from the parent 
(guardians).  We will also obtain assent from minors participating in our trial.  The consent 
documents will be reviewed verbally with both parent and child.  A brief questionnaire will be 
used to assess their basic understanding of our protocol – random assignment, need for regular 
visits, and the need for twice daily medication use. If for any reason, it becomes clear that either 
the parent or child can not comprehend trial design or procedures they will not be enrolled in this 
study.
4. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects.
Parental Consent Form, young child assent Form, adolescent assent form. 
5. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. Translated copies of all consent materials must 
be submitted for approval prior to use. 
This protocol will not involve Non-English speaking subjects. 
6. Waiver of Consent: Will you request either a waiver of consent, or a waiver of signed consent, for 
this study? If so, please address the following:
This section is not applicable to this research project
Waiver of consent: (No consent form from subjects will be obtained.)
a.
Does the research pose greater than minimal risk to subjects? 
 Yes  
 No
b.
Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No


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c.
Why would the research be impracticable to conduct without the waiver? 
d.
Where appropriate, how will pertinent information be returned to, or shared with subjects
at a later date? 
Waiver of signed consent: (Verbal consent from subjects will be obtained.)
 This section is not applicable to this research project
a.
Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No
b.
Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes  
 No
OR
c.
Does the research pose greater than minimal risk? 
 Yes  
 No AND
d.
Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No
7.  Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the HIPAA 
Privacy Rule. Indicate which of the following forms are being provided:
 Compound Consent and Authorization form
  HIPAA Research Authorization Form
8. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA 
Authorization for either the entire study, or for recruitment purposes only)
Choose one: For entire study: ______ For recruitment purposes only: x___
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data;
ii. If requesting a waiver of signed authorization, describe why it would be impracticable 
to obtain the subject’s signed authorization for use/disclosure of this data;
i.
We are requesting a waiver of HIPAA authorization for recruitment 
purposes only.  Subjects will be initially recruited through word of mouth, 
OCD advocacy organizations, physician referrals and internet ads.  We will 
need to use PHI such as name, telephone number and email addresses to 
schedule initial screening interviews.  It would be impractical to coordinate 
initial subject enrollment and recruitment without this data.
ii.
Signed authorization is impractical because initial screening of patients 
recruited through advertisements or referral may occur over the telephone 
or email.
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB.
SECTION IX: PROTECTION OF RESEARCH SUBJECTS


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1. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, discomforts, 
or inconveniences associated with subjects participating in the research. 
The risks in this study include: 
1) drug side effects of N-Acetylcysteine, 
2) worsening of symptoms 
3) length of research protocol and time required to complete study instruments  
4) unanticipated side effects like nausea 
Drug side effects
N-acetylcysteine (NAC) is an altered form of the amino acid cysteine, which is commonly 
found in food and synthesized by the body.  N-acetylcysteine (NAC) is generally well 
tolerated and has been extensively used in the treatment of acetaminophen overdose/toxicity 
at high doses for many years. The dosage in acute acetaminophen overdose is a 140mg/kg 
loading dose followed by a maintenance dose of 70mg/kg administered every 4 hours for 17 
consecutive doses. The long-term use of NAC has also been investigated in six-month to 
three-year studies examining the efficacy and tolerability of NAC (dosed between 600-
1200mg per day) in the treatment of chronic obstructive pulmonary disease COPD (Pela, 
Calcagni et al. 1999; Grandjean, Berthet et al. 2000; Stey, Steurer et al. 2000; Kasielski and 
Nowak 2001; Poole and Black 2001; Chikina, Iagmurov et al. 2002; Decramer, Rutten-van 
Molken et al. 2005). A recent study by Decramer and colleagues in 2005 concluded that there 
were no adverse events thought to be drug related in their study examining the use of 
600mg/day of NAC in over 500 patients with COPD. Additionally, Chikina and colleagues 
found that the most effective dose of NAC in the treatment of COPD was 1200mg/day (the 
study examined doses of NAC ranging from 600-2400mg/day). A meta-analysis examining 
the efficacy of NAC in COPD performed in 2000 revealed that NAC was well tolerated 
without significant adverse effects (Grandjean, Berthet et al. 2000). Although generally well-
tolerated, the PDR indicates that adverse reactions reported with oral NAC include nausea, 
vomiting, diarrhea, headache (especially when used along with nitrates) and rashes. There are 
rare reports of renal stone formation.  It is important to note that rare reports of 
bronchoconstriction have occurred with intravenous NAC (but no reports of bronchospasm 
related to oral use of NAC). Although there are no known contraindications to NAC use, 
individuals with asthma will be excluded from the study given the rare, but potential, adverse 
effect of bronchospasm. 
We have treated a number of adult  psychiatric patients with NAC at higher doses, up to 3000 
mg/day, without side effects beyond mild nausea (Pittenger, Krystal et al. 2005; Lafleur, 
Pittenger et al. 2006). 
Worsening of symptoms
Since N-Acetylcysteine is added to the patients’ current medications, the risk of symptoms 
worsening in this study is probably not greater than it would be if the patient continued on 
their current medication. The only additional risks in this study are potential adverse effects 
of N-Acetylcysteine.  
Ratings
Patients may find the battery of behavioral and movement ratings tedious. 
Unanticipated side effects
NAC is commonly used in acetaminophen overdose as well as COPD. Although NAC has 
been shown to be effective and without adverse effects in adults with trichotillomania, 


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schizophrenia and bipolar disorder, the use of this medication in children with OCD might be 
associated with unforeseen risks, such as worsening of existing symptoms or emergence of 
new symptoms. All medications can be associated with allergic reactions. Any clinical trial 
involves risks and side effects that cannot be predicted. Subjects will be told of any important 
new information that might affect their decision to continue in the study. In addition, the HIC 
will be notified regularly of any new information about the safety of the study medication
2. Minimizing Risks: Describe the manner in which the above-mentioned risks will be minimized. 
Subjects will be seen regularly during dose titration to monitor increases in the medication dose. 
Adverse effects will be systematically evaluated and documented with respect to severity and 
duration. Evaluation of adverse effects and dose are closely tied in so that the medication schedule 
is set up, such that decisions about dose increases occur at study visits. The treating clinician is 
free to delay an increase or reduce the dose at any time to manage a suspected medication-related 
adverse effect.
3. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make the 
final determination of the risk to subjects.) For more information, see the Instructions, page 24.
a. 
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study? 
b.
If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study? 
c.
Data and Safety Monitoring Plan: 
a)  This trial is greater than minimal risk to the child, but presenting the prospect of direct benefit 
to the individual subjects.
b)  This trial is greater than minimal risk to the child, but presenting the prospect of direct benefit 
to the individual subjects 
c) 
Data Management: 
All data obtained during the course of the study will be stored both electronically and in hard 
copy. The study coordinator will be responsible for ensuring completion of all study forms and 
collection of all data materials. Study data will be entered into an electronic spreadsheet by 
dedicated data managers and/or study coordinators. Double data entry procedures will be used to 
ensure accuracy and completeness.
To protect the privacy of subjects, all information will be kept confidential and only members of 
investigative team, and the HIC will have access to the study data. All paper data will be 
maintained and secured in locked file cabinets. To further safeguard privacy, a numbering 
system will be used to assign a unique identifier to each subject. Each subject will have the same 
unique identifier for both paper and electronic spreadsheet. Only individuals with appropriate 
Human Research Subjects Protection training will be permitted to handle study subject data 
forms.  
Safety Monitoring Plan:
Since this is a placebo-controlled, double-blind, study of children with OCD, we believe the risks 
involved in this study are greater than minimal risk to the child, but presenting the prospect of 
direct benefit to the individual subjects. However, assessment of adverse events, including 
grading of severity and attribution to research will be conducted at each visit. We will use the 
Pediatric Adverse Events Rating Scale (PAERS) to specifically track possible adverse events 


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throughout the trial (March, Karayal et al. 2007).  Serious and unanticipated and related adverse 
events will be reported immediately to the HIC (using HIC form 6A), and any appropriate 
funding and regulatory agencies. Also, serious anticipated adverse events will be reported 
immediately to the HIC and others whenever their magnitude or frequency exceeds expectations. 
Dr. Bloch will evaluate the adverse event and determine whether the adverse event affects the 
Risk/Benefit ratio of the study and whether modifications to the protocol (at Risks to Subjects) or 
consent form (at Risks and Inconveniences) are required.
Personnel responsible for the safety review and its frequency.
Dr. Bloch will conduct a review of all adverse events at least quarterly and if any serious adverse 
events occur. He will evaluate the frequency and severity of the adverse events and determine if 
modifications to the protocol or consent forms are required. During the review process Dr. Bloch 
will evaluate whether the study should continue unchanged, require modification, continue or 
close enrollment.
Since this is a study of a FDA-approved medication in children with OCD, we believe the risks 
involved in this study are greater than minimal risk to the child, but presenting the prospect of 
direct benefit to the individual subjects. However, assessment of adverse events, including 
grading of severity and attribution to research, will be conducted at each visit indicated below.
1. Attribution of Adverse Events
Clearly: The adverse event is clearly related to the intervention
Likely: The adverse event is likely related to the intervention
Possibly: The adverse event may be related to the intervention
Unlikely: It is unlikely that the adverse event is related to the intervention
Not: The adverse event is clearly not related to the intervention
2. Plan for Grading Adverse Events
The FDA's definition of serious adverse events (21 CRF 312)
SAEs include any untoward medical occurrence that at any dose results in death or the 
immediate risk of death, hospitalization or the prolonging of an existing hospitalization, 
persistent or significant disability/incapacity or congenital anomaly/birth defect (NOH Guide- 
6/11/99)
Grades of Risk:
0 = No Adverse Event or within normal limits
1 = Non-Serious Adverse Event
2 = Serious Adverse Event
3. Plans for reporting serious and unanticipated and related adverse events, anticipated adverse 
events occurring at a greater frequency than expected, and other unanticipated problems 
involving risks to subjects or others to the HIC:
Serious and related unanticipated adverse events will be reported immediately to the HIC (using 
HIC form 6A), and any appropriate funding and regulatory agencies. Other unanticipated 
problems involving risks to subjects or others will also be reported to HIC.
Serious anticipated adverse events will be reported immediately to the HIC and others whenever 
their magnitude or frequency exceeds expectations.  Dr. Bloch will evaluate the adverse event 
and determine whether the adverse event affects the Risk/Benefit ratio of the study and whether 
modifications to the protocol (at Risks to Subjects) or consent form (at Risks and 
Inconveniences) are required.  For the current study, the following individuals, funding, and/or 
regulatory agencies will be notified: 


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a.
All co-investigators
4. Plans for reviewing and reporting non-serious anticipated and unanticipated adverse events:
Dr. Bloch will conduct a review of all adverse events at least quarterly. He will evaluate the 
frequency and severity of the adverse events and determine if modifications to the protocol or 
consent forms are required.
4.    Confidentiality & Security of Data:
a.    What protected health information about subjects will be collected and used for the research?   
       
b.    How will the research data be collected, recorded and stored? 
c.    How will the digital data be stored? 
 CD  
 DVD  
 Flash Drive  
 Portable Hard   
       Drive  
 Secured Server  
 Laptop Computer  
 Desktop Computer  
 Other
d.    What methods and procedures will be used to safeguard the confidentiality and security of    
       the identifiable study data and the storage media indicated above during the subject    
       participation in the study? 
e.    What mechanisms are in place to ensure the proper use and continued protection of these   
       data after the subject participation in the study has ceased? 
f.    What will be done with the data when the research is completed? Are there plans to destroy 
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. 
If no, describe how the data and/or identifiers will be secured.
g.   Who will have access to the protected health information? (such as the research sponsor, the  
investigator, the research staff, all research monitors, FDA, QUACS, SSC, etc.)
h.   Which external or internal individuals or agencies (such as the study sponsor, FDA, QUACS,
       SSC, etc.) will have access to the study data? 
i.    If appropriate, has a Certificate of Confidentiality been obtained? 
j    Are there any mandatory reporting requirements? (Incidents of child abuse, elderly abuse,
      communicable diseases, etc.) 
(a) Private identifiable information will be collected but will be kept confidential and will not be 
divulged in any publication emanating from this work
(b) Clinical data, outcomes of diagnostic instruments, and research data will be collected by the 
principal investigator and other study personnel and stored in a locked file cabinet in a 
locked office.  Data will be entered into a database on a password-protected computer in a 
locked office, by study personnel.
(c) Above
(d) All data will be coded and stored in locked cabinets/password protected computer in an 
office that is locked. Information that will breach subject confidentiality will not be shared. 
Rather, data will only be released upon written consent of the subject and will be available 
for review by the Yale human Investigation Committee.
(e) The consent form will ask families to provide consent to contact them in the future. This 
request will make it clear that participation in the study is not contingent on granting this 
permission. Furthermore, granting permission to be re-contacted does not obligate the family 
to participate in any future project.  Published reports will contain only aggregate data and 
will be free of personal identifiers.
(f) We will hold paper files for seven years at which point they will be destroyed. As noted 
above, archived computer files will not have any identifying information.
(g) Principal investigator, co-investigator and study personnel.


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(h) The International Obsessive-Compulsive Disorder Foundation is a potential sponsor of this 
project and could have access to trial data if they come to Yale to monitor the conduct of this 
research study.
(i) We will not preserve drug screening data after completion of tests so we will not apply for a 
certificate of confidentiality.
(j) Yes. Evidence of child abuse or situations in which the subject is deemed a danger to self or 
others will be reported.
5. 
Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.) 
Children may benefit from the thorough medical and psychiatric evaluations that they will 
receive while participating in the study. During the study, subjects will also receive a higher level 
of evaluation and care than routine treatment.  Additionally, subjects may benefit from the study 
medication. 
         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.     Alternatives: What other alternatives are available to the study subjects outside of the research?
1) Continuing patient’s current medications or therapy, which might include various SSRIs 
or clomipramine) or cognitive behavioral therapy.  Both these interventions have 
demonstrated efficacy for the treatment of pediatric OCD.  All subjects will be 
recommended to engage in adequate trials of both these interventions before enrolling in 
the trial.  
2) Antipsychotics in addition to SSRIs have shown some benefit for the treatment of 
refractory OCD in adults.  These medications are associated with a significantly greater 
side effect burden than NAC.  Families will be made aware of this additional treatment 
option prior to enrolling in this study.
3) Since N-Acetylcystiene is FDA approved for use to reduce the extent of liver injury after 
acetaminophen overdose, the patient’s doctor might feel comfortable prescribing it off 
label to the patient.
 
2. 
Payments for Participation (Economic Considerations): Describe any payments that will be 
made to subjects and the conditions for receiving this compensation. 
Subjects will be paid a total of $150 for participation in the study -- $50 screening assessment, 
$25 for each of the 4 follow-up visits. .
3.
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects.     
Families will not be charged for the study medications, clinical assessments, services or 
laboratory tests directly related to the study. As noted above, some subjects may be seen for a 
clinical consultation prior to study entry. This clinical consultation will be charged as part of 
standard of care in the usual manner.
4.
In Case of Injury: This section is required for any research involving more than minimal risk.


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a.     Will medical treatment be available if research-related injury occurs? 
b.     Where and from whom may treatment be obtained? 
c.     Are there any limits to the treatment being provided? 
d.     Who will pay for this treatment? 
e.     How will the medical treatment be accessed by subjects? 
(a)
Yes
(b)
Initial assessment and appropriate referral will be carried out by the research team. The 
PI (Michael H. Bloch, MD) will conduct assessment under the supervision of Dr. King and Dr. 
Pittenger. Whether these events were considered "related to the study treatment" or not, our 
research team will participate in the assessment and appropriate disposition of the case. The 
disposition has taken many forms: in some cases, we assume ongoing clinical care of the subject; 
in other cases, we secure appropriate referrals and are no longer involved in the patient's care; 
other cases may involve a combined approach in which we provide care in collaboration with 
appropriate specialists. In all cases, the disposition is guided by the family's preference and 
clinical judgment regarding the subject's best interest. Every reasonable effort will be made to 
involve the subject's primary care provider.
(c)
Our intervention will focus on assessment and securing an appropriate referral in 
collaboration with the family and the primary care provider.
(d)
We will provide our assessment and referral services without charge. Ongoing care will 
be paid by the family or family's insurance carrier.
(e)
As noted in 4b, the occurrence of an adverse event requiring care outside the confines of 
the study will be initially assessed by the research team. Referrals to the family's primary care 
provider or other specialists will be made in accordance with the nature of the subject's problem.  


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