Clinical trial NCT01695291
Conditions: Obsessive Compulsive Disorder
Keywords: Obsessive compulsive disorder
Sponsor: New York State Psychiatric Institute
Start date: 2012-05-01; Completion date: 2018-05-01
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will examine the feasibility and potential efficacy of augmenting SRIs with minocycline. The study will assess whether the addition of minocycline leads to measurable changes in striatal glutamate (Glu) levels. This study will recruit up to 45 youth ages 8-20 diagnosed with clinically significant OCD who have demonstrated no more than minimal response to SRI treatment and are currently on a stable dose of SRI medication for at least 12 weeks. Participants will be randomized to receive either 12 weeks of minocycline treatment or pill placebo. Randomization will be 2:1 so that 2 of 3 participants receive minocycline. Screening for eligibility will take place for 1-4 weeks. Participants will undergo magnetic resonance spectroscopy (MRS) scans to measure striatal Glu levels prior to randomization, and again immediately following the treatment period. During the treatment period, participants will meet initially weekly and then every other week with the study psychiatrist. All participants will be offered three months of open medication treatment following participation. The clinical trial will only be conducted at the New York State Psychiatric Institute (NYSPI) and the MRS scans may be conducted at Weill Cornell Medical Center or NYSPI.

Detailed description:
Please see the brief summary for study description.

Arms: arm 1: Participants randomized to placebo will receive pills that are identical in appearance to the study drug but contain no active medication. arm 2: Those randomized to minocycline will receive approximately 2 mg/kg/day, the FDA-approved dose for minocycline (minimum 50 mg/day and maximum 200 mg/day). After randomization, participants will receive child proofed bottles that contain enough study medication until the next visit with an additional 3 days coverage in case of scheduling issues. All participants will have a minocycline level drawn at week 12 to confirm treatment adherence. Minocycline is FDA-approved in those ages 8 and above for treatment of infections and acne and has a favorable risk-benefit profile.
Interventions: intervention 1: Minocycline intervention 2: Placebo
Intervention descriptions: intervention 1: Participants randomized to minocycline will receive approximately 2 mg/kg/day, the FDA-approved dose for minocycline. Participants will take either minocycline or pill placebo for 12 weeks. intervention 2: A placebo pill will be administered twice a day (BID) for 12 weeks.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
Official Title:  
A randomized, placebo-controlled trial of minocycline added to 
serotonin reuptake inhibitors in pediatric OCD: Examining the effects on clinical 
symptoms and on brain glutamate levels using MRS imaging 
 
 
NCT Number: 
NCT01695291 
 
 
Document Date:  
IRB Approved 03/23/2018 


Protocol Summary Form
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Simpson, Helen
Page 1 of 31
Protocol Title:
Novel Medication Strategies Targeting 
Brain Mechanisms in Pediatric OCD
Protocol Number:
6574
First Approval:
05/02/2012
Expiration Date:
04/15/2019
Version Date:
03/23/2018
Clinic:
Children's Day Unit
Contact Principal Investigator:
Helen Simpson, MD
Email: simpson@nyspi.columbia.edu
Telephone: 646-774-8110
Co-Investigator(s):
Lawrence Kegeles, MD
Research Chief:
Moira Rynn, MD
Cover Sheet
Choose ONE option from the following that is applicable to your study
If you are creating a new protocol, select "I am submitting a new protocol." As 5 Year Renewals are no 
longer required, this option remains for historical purposes.
I am submitting an annual continuation without modifications 
Division & Personnel
Division
What Division/Department does the PI belong to?
Child Psychiatry
Within the division/department, what Center or group are you affiliated with, if any? 
Pediatric Anxiety and Mood Research Clinic/Children's Day Unit
Unaffiliated Personnel
List investigators, if any, who will be participating in this protocol but are not affiliated with New York 
State Psychiatric Institute or Columbia University. Provide: Full Name, Degrees and Affiliation.
Dikoma Shungu, Ph.D., who is the co-investigator at Weill Cornell Medical Center.


Protocol Summary Form
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Simpson, Helen
Page 2 of 31
 
Moira Rynn, MD (Consulting Professor and Chair, Department of Psychiatry and Behavioral Sciences, 
Duke University Medical Center)
Application for Continuation of Research
Status
Current Status of Study: 
All research interventions were completed. Only data analysis is ongoing.
Summary of Experiences to Date
Please provide a summary of scientific progress of the study and the experience of research participants, to 
date. This requirement is designed to allow for the investigator and the IRB to reassess the study’s risks and 
benefits in terms of developments in the field, changing practice patterns, and new IRB policies and 
procedures.
We have completed recruitment and data collection for this study. In total, we enrolled 33 
participants. There are no participants in the active or 3-month follow-up phase of the study, with the 
last participant completing the 3-month follow-up phase in May 2017. The research team is 
completing data analyses at this time. 
Funding
Have there been any changes in funding status since the prior approval? 
No
Have the principal investigator and other investigators made all required disclosures of financial interest in 
the study sponsor/product?
Yes
Summary
Have there been any study findings, recent literature, or untoward events occuring here or at other sites in 
the past year which might affect the analysis of the safety, risks or benefits of study participation? 
No
Have there been any serious adverse events (serious and/or unanticipated problems involving risks to 
subjects or others at this site which occured in the past year)? 
No
Have all study staff with a significant role in the design or implementation of the human subject components 
of this study received required training in human research subject protections?
Yes
Is the study covered by a certificate of confidentiality? 


Protocol Summary Form
6574
Simpson, Helen
Page 3 of 31
No
Overall Progress
Approved sample size
45
Total number of participants enrolled to date
33
Number of participants who have completed the study to date 
24
Have there been any significant deviations from the anticipated study recruitment, retention or completion 
estimates? 
No
Comments / additional information 
Sample Demographics
Specify population
Children, adolescents and young adults
Total number of participants enrolled from this population to date 
33
Gender, Racial and Ethnic Breakdown 
Gender
-Male: 16
-Female: 17
 
Ethnicity
-White: 26
-Asian: 3
-African American: 1
-American Indian: 1
-Other: 2
Summary of Current Year's Enrollment and Drop-out 
Number of participants who signed consent in the past year
0
Did the investigator withdraw participants from the study? 
No
Did participants decide to discontinue study involvement? 
No


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Protocol Summary Form
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Simpson, Helen
Page 6 of 31
the Week 12 scan. During the treatment period, participants will meet every other week with the study 
psychiatrist. All participants will be offered three months of open medication treatment following 
participation. The clinical trial will only be conducted at NYSPI and the MRS scans may be conducted at 
Weill Cornell Medical Center or NYSPI depending on scanner availability.
Background, Significance and Rationale
Background, Significance and Rationale
With a lifetime prevalence of 2-3% and half of all cases beginning by age 19, obsessive-compulsive 
disorder (OCD) is a major health concern for children and adolescents and is a leading cause of illness-
related disability. SRI medication and cognitive-behavioral treatment represent front-line treatments for 
pediatric OCD, but lead to symptom remission in only 54% of youth with OCD. This study will examine the 
feasibility and potential efficacy of augmenting SRIs with minocycline, a drug with a novel mechanism of 
action for OCD. The study will additionally assess whether the addition of minocycline leads to measurable 
changes in striatal glutamate (Glu) levels and whether either baseline striatal Glu levels or changes in striatal 
Glu levels are associated with response to minocycline. The study will also examine minocyline as a mono-
therapy treatment for pediatric OCD in a small subset of participants that are unwilling to take SRI 
medication. The study will measure changes over time in the striatal glutamate (Glu) levels of these 
participants as well.  Minocycline is a second-generation tetracycline that has been shown to modulate 
glutamate and to have anti-oxidant and anti-inflammatory properties. There is growing evidence from 
animal studies and human clinical trials of neurological diseases (including Parkinson’s disease, 
amyotrophic lateral sclerosis, Huntington’s disease, and ischemia) that minocycline has neuroprotective 
effects.
 
Specific Aims and Hypotheses
Specific Aims and Hypotheses
Hypothesis 1: When added to SRI medication, or taken as mono-therapy, minocycline will be superior to 
pill placebo in reducing OCD symptoms.
Hypothesis 2: Adding minocycline (but not placebo) to an SRI, or taking minocycline (but not a placebo) 
without an SRI, will reduce glutamate levels in the head of caudate.
Hypothesis 3: Reduction in glutamate levels will be associated with reduction in OCD severity.
 
 
 


Protocol Summary Form
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Simpson, Helen
Page 7 of 31
Description of Subject Population
Sample #1
Specify subject population
OCD Participants
Number of completers required to accomplish study aims
45
Projected number of subjects who will be enrolled to obtain required number of completers
45
Age range of subject population
8-20 inclusive
Gender, Racial and Ethnic Breakdown
Based on our experience and the demographics of the catchment area served by our
institution, we expect the subject racial distribution to be approximately 73% White, 18% Black, 9% Asian, 
and for the ethnic distribution to be approximately 22% Hispanic. We expect the sample to be 50% female. 
Description of subject population
We plan to recruit approximately 45 individuals ages 8-20 in this study. Participants will have a current 
diagnosis of OCD and will be currently taking SRI medication. SRI dosage must be stable for at least 12 
weeks prior to study participation. 
Recruitment Procedures
Describe settings where recruitment will occur
Recruitment for this study was completed in 2016.
The study recruited participants from the Anxiety Disorders Clinic (ADC), directed by Dr. Simpson, as well 
as the CAPES Evaluation Service and the Children’s Day Unit (CDU), which are directed by Dr. Rynn. The 
ADC screens over 200 adults (≥ 18) with OCD a year. More than half are on medication (predominantly 
SRIs). The CAPES/CDU provides free expert consultation, evaluation, and treatment referrals for children 
and adolescents suffering from mood and anxiety disorders. In past years, CAPES/CDU evaluated as many 
as 30 children and adolescents with OCD, of whom approximately one-third were on SRIs only. OCD self-
help organizations such as the International OCD Foundation were contacted to further publicize the 
existence of this study.
Participants (ages 8-20) and their parent/caregiver were assessed by an IRB-approved phone screen. For 
participants ages 18-20, the research team obtained permission from the participant before speaking to 
his/her parent/caregiver. We do not communicate to families that we will destroy their screening 


Protocol Summary Form
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Simpson, Helen
Page 8 of 31
information if they do not come in for a study visit. Regardless of study participation, we enter the 
information from the phone screens into a deindentifed and password protected database.
How and by whom will subjects be approached and/or recruited? 
Research staff on the CDU and ADC may approach and discuss the research study with potential 
participants who have given permission to be contacted about research. Drs. Rynn, Simpson, and Goldberg 
will be responsible for fully explaining the details of the study, answering any questions, and consenting the 
participants if they are interested in the study.
How will the study be advertised/publicized? 
IRB-approved radio/newspaper/web advertisements and flyers were used to recruit participants 
Do you have ads/recruitment material requiring review at this time? 
No
Does this study involve a clinical trial?
Yes
Please provide the NCT Registration Number
01695291
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement
Participants may be recruited from the following ongoing studies:
· EVALUATION AT THE CHILD AND ADOLESCENT PSYCHIATRY EVALUATION SERVICES 
(CAPES) OF THE CHILDREN’S DAY UNIT (CDU),"  IRB #7058R (formally 6019R)
· “MRS Glutamate Measurement in Healthy Controls and People with OCD”, IRB #6218
Inclusion/Exclusion Criteria
Name the subject group/sub sample
OCD participants
Create or insert table to describe the inclusion criteria and methods to ascertain them
CRITERION
METHOD OF ASCERTAINMENT
1) Participants must be ages of 8-20 
at the time of consent.
Inquiry at time of consent by trained research staff
2) Participants must weigh at least 
25kg.
Weight assessed by study nurse
3) Participants and a parent/guardian 
must be able to read and 
understand English.
Inquiry at time of consent by trained research staff
4) Participants must meet diagnostic 
Clinical Interview; CYBOCS administration


Protocol Summary Form
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Simpson, Helen
Page 9 of 31
criteria for primary obsessive-
compulsive disorder with score ≥ 
16 on the Children’s Yale-Brown 
Obsessive Compulsive Scale 
(CYBOCS).
5) Participants must be on a stable 
and minimal
adequate dose of serotonin reuptake 
inhibitor
(SRI) medication as defined by the 
literature for a
minimum of 12 weeks, and have a 
documented
history of intolerable adverse effects 
at a higher dose or strong preference 
to stay at that dose.  
Congruent with the literature, 
minimal adequate
SRI doses to treat OCD are as 
follows:
Clomipramine 75 mg/day; 
Fluoxetine 20
mg/day; Paroxetine or Paroxetine CR 
20 mg/day;
Sertraline 50 mg/day; Fluvoxamine 
100 mg/day;
Citalopram 20 mg/day; Escitalopram 
10 mg/day for
a minimum of 12 weeks. If a 
potential participant
is on a minimal adequate SRI dose, 
the research
team will collaborate with the 
participant’s
treating psychiatrist to determine if 
participation in the trial is clinically 
indicated.
 
OR
 
Participants must be unwilling to 
take SRI medication due to reasons 
such as having a history of adverse 
side effects from SRI medication. 
Phone screen, Clinical interview, medical records by research 
team.


Protocol Summary Form
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Simpson, Helen
Page 10 of 31
6) If taking SRI medication, report of 
at least minimal response to 
current SRI medication to warrant 
ongoing SRI treatment.
Inquiry at time of consent by trained research staff; 
consultation with referring clinician and the CGI-I
7) For participants younger than 18, 
written informed assent by the 
participant and consent by the 
parent. For participants 19 and 
older, written consent by the 
participant and permission for 
legal guardian/parent to provide 
information.
Consent Interview by study psychiatrist 
Create or insert table to describe the exclusion criteria and methods to ascertain them
CRITERION
METHOD OF ASCERTAINMENT
1) Lifetime diagnosis of: psychotic disorder, bipolar 
disorder, eating disorder, pervasive developmental 
disorder, mental retardation, or substance/alcohol 
dependence.
Clinical Interview
2) Current diagnosis of major depressive disorder, 
Tourette’s/Tic Disorder, or substance/alcohol abuse.
Clinical Interview
3) Active suicidal ideation.
Clinical Interview
4) Females who are pregnant, nursing, or using 
hormonal birth control.
Medical evaluation conducted by study 
psychiatrist
5) Any major medical or neurological problem (e.g., 
unstable hypertension, seizure disorder, severe renal 
deficiency, and head trauma). 
Medical history obtained by study 
psychiatrist
6) Positive urine screen for illicit drugs.
 
Urine toxicology assessment
7) Presence of metallic device or dental braces.
Inquiry at time of consent by trained 
research staff
8) IQ <80
Wechsler Abbreviated Scale of 
Intelligence (WASI) administration.
9) OCD patients with primary symptoms of hoarding 
(determined by CYBOCS/ YBOCS checklist).
Clinical Interview
10) Current or past diagnosis of pediatric autoimmune 
neuropsychiatric disorders associated with 
streptococcus (PANDAS). This will be defined by 
the following criteria: abrupt onset of OCD 
symptoms (often with comorbid tics) with a  
relapsing–remitting symptom course, a temporal 
association between symptom exacerbations and a 
Group-A beta-hemolytic streptococcal (GAS) 
Clinical Interview


Protocol Summary Form
6574
Simpson, Helen
Page 11 of 31
infection, association with neurological abnormalities 
during exacerbations (adventitious movements, 
motoric hyperactivity, urinary hesitancy), and 
prepubertal age of onset.
11) Individuals who are currently receiving Exposure 
and Response Prevention therapy and are in the acute 
phase of treatment. Participants may receive ongoing 
supportive therapy and school counseling as long the 
treatment was initiated and remained stable for at 
least 6 weeks prior to enrollment in the study. The 
intensity and frequency of therapy should remain 
unchanged throughout the trial.
Inquiry at time of consent by trained 
research staff
12) Documented history of hypersensitivity or 
intolerance to tetracycline antibiotics
Medical history obtained by study doctor
13) Use of medications that are contra-indicated with 
minocycline (e.g., concomitant use of antacids, iron, 
calcium, magnesium, aluminum, zinc salts as they 
impair minocycline absorption; of anti-coagulant 
drugs as minocycline has been shown to depress 
plasma prothrombin activity; of other antibiotics or 
Accutane due to the rare side effect of Pseudotumor 
cerebri)
Medical evaluation conducted by study 
doctor
14) Inability of participant or parent/guardian to read or 
understand English.
Inquiry at time of consent by trained 
research staff
Waiver of Consent/Authorization
Indicate if you are requesting any of the following consent waivers
Waiver of consent for use of records that include protected health information (a HIPAA waiver of 
Authorization) 
No
Waiver or alteration of consent
Yes
Waiver of documentation of consent 
No
Waiver of parental consent 
No
Consent Procedures


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Protocol Summary Form
6574
Simpson, Helen
Page 13 of 31
Rynn, Moira, MD
Simpson, Helen, MD
Type in the name(s) not found in the above list
Dikoma Shungu, Ph.D., who is the co-investigator at Weill Cornell Medical Center. 
Pablo Goldberg, MD
Moira Rynn, MD
Paula Yanes-Lukin, PhD 
Study Procedures
Describe the procedures required for this study
Overview:
Children’s Day Unit:
The clinical trial will be conducted at the Children’s Day Unit (CDU). The CDU is an outpatient clinic and a 
research day treatment program that provides services for the psychiatric and educational needs of children 
and adolescents participating in research protocols at NYSPI. Most of the children have either failed or not 
completely responded to first line treatments for mood, OCD, or other anxiety disorders. School services are 
provided by PS186X, a New York City public school located on the unit during the academic year from 
September through June. In addition, during the 6 week summer program in July and August, the CDU 
provides educational tutoring. This unit provides continued clinical care for children and adolescents after 
their participation in an IRB approved protocol at no cost. Led by Dr. Rynn, the staff consists of a research 
medical director, Dr. Pablo Goldberg, a research nurse, a social worker, psychologists, and trainees. 
Although this protocol is an outpatient protocol, if an adolescent requires additional support or requires a 
higher level of care, the adolescent may be admitted to the CDU partial program that runs Monday through 
Friday from 8:30 am to 2:20 pm where the adolescent can be closely monitored, receive educational credit, 
and additional supportive services. For children under the age of 12, the CDU team is available for the child 
and the parent to come in for daily check-in visits for support and monitoring, but it does not have 
educational programming for children under 12.
Screening
Upon consenting, participants will complete all screening procedures. Screening may last from 1 to 4 weeks 
to allow sufficient time to obtain thorough medical and psychiatric history to ensure the patient’s safety and 
eligibility/ineligibility in the study. Screening procedures include: 
 Diagnostic Assessment: Anxiety Disorders Interview Schedule - Child/Parent version (The child 
version will be administered to all participants. The parent version will be administered to parents of 
all participants ages 8-17, and to parents of participants ages 18-20 with their permission); OCD 
onset form; Clinical Global Inventory – Severity Scale; Family History Screen and Isolated Tics/Tic 
Disorder Assessment questions
Feasibility and Safety Assessment: Columbia Suicide-Severity Rating Scale; Pediatric Adverse 
Event Rating Scale


Protocol Summary Form
6574
Simpson, Helen
Page 14 of 31
Efficacy Assessment: Children’s Yale-Brown Obsessive Compulsive Scale (CYBOCS)
Intelligence Assessment: Wechsler Abbreviated Scale of Intelligence (WASI)
Medical: Medical evaluation; Tanner Scale, physical exam, EKG, labs, including a Thyroid Function 
Test, and vital signs
Baseline Evaluation
After completing the screening procedures, eligible participants will proceed to the baseline evaluation. 
Baseline evaluation procedures include: 
MRS scan except for participants who have MRS incompatible dental braces
Efficacy Assessments: Children’s Yale-Brown Obsessive Compulsive Scale (CYBOCS); Child 
Obsessive-Compulsive Impact Scale – Revised (COIS-R); Hamilton Depression Scale (HAM-D)
Feasibility and Safety Assessment: Columbia Suicide-Severity Rating Scale; Pediatric Adverse 
Event Rating Scale; Medication Adherence
Randomization
Randomization to minocycline or placebo treatment will occur following the baseline evaluation. 
Randomized assignments will be generated using a random number generator in SAS. We will randomize 
minocycline versus placebo in a 2:1 ratio to gather more data about minocycline’s clinical effect. To balance 
the minocycline-placebo groups with respect to age, randomization will be stratified with respect to age 
ranges (8 to 11 years; 12 to 15 years; 16 to 20 years).
 
Post-randomization
Once randomized, the study psychiatrist will conduct the week 1 check-in via phone. After that, participants 
will be seen by the study psychiatrist every two weeks for a total of 12 weeks. Visits will last 30 minutes, 
except the first, which will last 60 minutes. The study psychiatrist will offer support and monitor the 
patient’s medication and side effects. To monitor for unexpected pregnancy, females will have a blood 
pregnancy test at screening and a urine pregnancy test at each study visit. A manual for medication 
procedures is provided in Appendix A. Clinician adherence to this manual will be formally assessed using 
the Clinician Adherence to Pharmacotherapy form as described in the manual. 
 
Ongoing SRI treatment: Participants will enter on an SRI (at a stable dose for ≥ 12 weeks). The study 
psychiatrist will continue to prescribe this SRI. To confirm ongoing SRI adherence, SRI pill counts will be 
conducted at each psychiatrist visit. In addition, SRI blood levels will be assessed at baseline and week 12 
(or early termination). For each participant and at each time point, blood will be drawn at the same time of 
day and in a constant temporal relationship to their last SRI dose. The goal is to verify a stable SRI dose in 
each participant during the trial and thereby exclude the possibility that any therapeutic effect is due to a 
change in SRI level. A small sample of participants will enroll in the study without being on a dose of SRI 
medication. For these participants, we will not monitor SRI adherence nor assess SRI blood levels.
 
At each treatment visit, medication adherence will be assessed. In addition, the C-SSRS will be 
administered at each treatment visit to assess for suicidality, the Pediatric Adverse Event Rating Scale 
(PAERS) will be administered to assess for the presence of adverse events, and the Clinical Global 
Impression Scale (CGI-S) will be administered to assess symptom severity and improvement. Vital signs 
will also be taken at each treatment visit, and pregnancy tests will be administered to female participants.


Protocol Summary Form
6574
Simpson, Helen
Page 15 of 31
 
Week 4, 8 & 12 IE Visits: Efficacy measures will be re-administered by the independent evaluator at Weeks 
4, 8, and 12 of treatment to assess for change in OCD symptoms. The following measures will be 
administered at these visits:
Children’s Yale-Brown Obsessive Compulsive Scale (CYBOCS)
Child Obsessive-Compulsive Impact Scale – Revised (COIS-R)
Hamilton Depression Scale (HAM-D)
The following staff members are designated independent evaluators for this study: Anthony Puliafico, PhD, 
Chiaying Wei, MA, Paula Yanes-Lukin, PhD. 
Post-treatment Assessment: At Week 12, in addition to the Week 12 IE assessments, the following 
assessments will be administered:
Medical Evaluation including the Tanner Scale, physical exam, EKG, labs and vital signs
Client Satisfaction Questionnaire (CSQ)
Previously endorsed modules on the ADIS-C/P
Follow-up Treatment
Upon completion of the 12-week clinical trial, participants will be offered an additional 3 months of open 
medication management as clinically indicated based on their treatment history and response during the 
study. Participants and their families will be unblinded to their treatment assignment at this point. In the 
event they prefer to be treated elsewhere, they will also be provided referrals to community providers. With 
their permission, all participants will be assessed every 4 weeks for OCD severity (using the CYBOCS and 
CGI-S by the IE) and safety (PAERS by the MD). The 1-month and 2-month follow-up assessments will be 
conducted in person, or if necessary, by phone, and the 3-month assessment will be conducted in 
person.This will be pilot data to help us evaluate patient satisfaction (e.g. proportion who choose to continue 
minocycline), ongoing safety, and maintenance of response. Participants that begin taking, and respond to, 
minocycline during the follow-up period may also have the option of undergoing a third MRS scan. 
 
Clinical Deterioration (please see Appendix A and Protection of Human Subjects)
 A clinical management issue of major significance is the referral of unimproved or deteriorating 
adolescents for a clinical evaluation. In particular, any patient who is evaluated by the study clinician to be 
much worse (CGI-I score of 6) for two consecutive visits will be discontinued from the protocol. If the 
adolescent begins to show clinical deterioration during the study and further continuation under such 
circumstances would be detrimental to the adolescent, a referral will be made for a clinical evaluation by an 
independent evaluator to determine whether the adolescent should be withdrawn from the study. If the 
adolescent is withdrawn from the protocol, the adolescent will be eligible for no cost treatment on the 
Children’s Day Unit. If the participant or the participant’s parent/guardian would prefer outside referrals, 
arrangements will be made by the research staff. The psychiatrist has full responsibility and authority to 
refer the adolescent for this clinical evaluation at any time regarding the adolescent’s suitability for 
remaining in the study. Additionally, participants who experience severe reaction to the study medication 
will be unblinded to their treatment assignment following the adverse event. 


Protocol Summary Form
6574
Simpson, Helen
Page 16 of 31
Minocycline versus Pill Placebo
Participants will be randomized to receive the addition of either minocycline or pill placebo. The 
medications will be identical in appearance and made by the NYSPI pharmacy. Those randomized to 
minocycline will receive approximately 2 mg/kg/day, the FDA-approved dose for minocycline and the dose 
used in our pilot study (<35 kg: 50 mg/day; 35-55 kg: 50 mg BID; >55-75 kg: 75 mg BID; >75kg: 100 mg 
BID). Participants will be asked to take the tablet with food, in an upright position, and with 4 to 8 ounces of 
water in order to lessen gastric side effects. After randomization, participants will receive child proofed 
bottles that contain enough study medication until the next visit with an additional 3 days coverage in case 
of scheduling issues. Drs. Rynn and Goldberg will prescribe the study drug, which will be dispensed by the 
NYSPI pharmacy. All participants will have a minocycline level drawn at week 12 to confirm treatment 
adherence. In the absence of a laboratory that can perform a minocycline level, participants' serum and 
plasma will be collected and stored in a -80 degree Celsius freezer at NYSPI until an alternate laboratory 
can be located to do this test. Minocycline is FDA-approved in those ages 8 and above for treatment of 
infections and acne and has a favorable risk-benefit profile.
 
MR Neuroimaging Methodology
 All MR imaging data will be acquired on a GE 3T SIGNA whole-body MR system and a standard 
quadrature single-channel head coil in a total examination time of approximately 45 min, including scan 
setup. At baseline, after 12 weeks of treatment, and for a subset of the sample, after the 3-month follow-up 
period, subjects will undergo MR imaging at either NYSPI or at Weill Cornell Medical Center. Participants 
will continue to take their prescribed SRI medication (if applicable) and minocycline or placebo when they 
undergo the 12-week MR imaging. Subjects will be escorted to the imaging procedure by a project 
coordinator. Female participants will be given a urine pregnancy test prior to scanning in addition to the 
blood pregnancy test at screening. There will be a 72-hour window between pregnancy testing and MRS 
scan. The team at Cornell will receive a signed copy of the negative urine pregnancy test in order to proceed 
with the scan. First, a standard T1-weighted volumetric MRI series will be acquired for use in estimating the 
proportions of gray matter, white matter and CSF content of the head of the caudate through tissue 
segmentation. Second, glutamate (Glu) levels will be recorded from the head of the caudate using MRS. The 
recorded 4D raw data set will be processed using standard procedures. The striatal voxels will be selected 
from the spectroscopic imaging grid after acquisition and post-processing, and then analyzed for Glu 
content using versatile software, XsOSNMR, developed in Dr. Shungu’s laboratory (see Resources). The 
rationale for focusing on the striatum and the head of the caudate in particular is described above (Section 
C5.h). The Glu data will be quantified as peak area ratios relative to the robust unsuppressed water 
resonance (W) in a spectroscopic imaging data set that will be acquired in just 4 min using the same spatial 
parameters as in the PRESS SI sequence. 
You can upload charts or diagrams if any
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
Clinical deterioration (please see Appendix A and Protection of Human Subjects): A clinical management 


Protocol Summary Form
6574
Simpson, Helen
Page 17 of 31
issue of major significance is the referral of unimproved or deteriorating adolescents for a clinical 
evaluation. In particular, any patient who is evaluated by the study clinician to be much worse (CGI-I score 
of 6) for two consecutive visits will be discontinued from the protocol. If the adolescent begins to show 
clinical deterioration during the study and further continuation under such circumstances would be 
detrimental to the adolescent, a referral will be made for a clinical evaluation by an independent evaluator to 
determine whether the adolescent should be withdrawn from the study. If the adolescent is withdrawn from 
the protocol, the adolescent will be eligible for no cost treatment on the Children’s Day Unit. They will also 
have the option to attend the school program on the CDU. If the participant or the participant’s 
parent/guardian would prefer outside referrals, arrangements will be made by the research staff. The 
psychiatrist has full responsibility and authority to refer the adolescent for this clinical evaluation at any 
time regarding the adolescent’s suitability for remaining in the study.
Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
A blood sample, approximately one tablespoon (15 cc’s) of blood, will be taken at screening and at study 
completion (or withdrawal, if earlier) for a total of two tablespoons (30 cc). These samples will be used to 
measure minocycline and SRI levels and for safety monitoring, including Chemistry Screen and CBC. The 
samples for drug assay will be forwarded to a centralized laboratory for analysis. Participants may 
experience a bruise at the site of venipuncture. EMLA cream may be used to minimize the discomfort of 
venipuncture.
 
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
Diagnostic Assessments:
Anxiety Disorders Interview Schedule for Children for DSM-IV (ADIS-C/P Revised): This will be 
administered to the subject (and parent/caretaker for those <18 and those 18-20 with permission) by the 
independent evaluator (IE) at screening to confirm the diagnosis of OCD and its age of onset. At the week 
12 post-treatment assessment, previously endorsed modules on the ADIS-C/P will be administered to 
measure changes in diagnoses and symptomatology.
Wechsler Abbreviated Scales of Intelligence (WASI): This estimates Full Scale IQ with excellent reliability 
and validity for ages 6-90. It consists of four subtests: Vocabulary, Similarities, Block Design, and Matrix 
Reasoning. The Vocabulary and Matrix Reasoning subtests will be administered by the protocol manager at 
screening.
Family History Screen (FHS): This screens for the presence of 15 psychiatric disorders among the 
participant’s biological relatives. It is administered to a family informant (for those ages 8-17) or to the 


Protocol Summary Form
6574
Simpson, Helen
Page 18 of 31
subject (ages 18-20), who reports on himself/herself and on other biological relatives. It will be 
administered by the MD at screening.
 
Isolated Tics/Tic Disorder Assessment: The parent(s) of the participant will be asked five questions about 
family history of isolated tics and Tic Disorder. The questions were developed by investigator Blair 
Simpson and are administered as an addendum to the FHS. 
Medication Evaluation: The study psychiatrist and study nurse will conduct a medical history, laboratory 
tests, physical exam, (including weight, height, and EKG), pregnancy test at each visit, at screening and 
Week 12.
The Tanner Scale: This is a scale of physical development based on external primary and secondary sex 
characteristics. Participants look at pictures of pubertal stages and identify their pubertal stage.
 
Feasibility Assessments:
Pediatric Adverse Event Rating Scale (PAERS): This self-report questionnaire assesses the severity of 48 
potential adverse events, each on a five-point Likert scale (0–4). It is filled out by the participant at each 
medication visit (and parent/caretaker for those <18 and those 18-20 with permission). It is reviewed by the 
study psychiatrist to determine final severity and relationship to treatment or illness. 
Columbia Suicide-Severity Rating Scale (C-SSRS): This is a semi-structured clinician rating of suicidal 
behavior, suicide attempts, and presence and intensity of suicidal ideation. The assessment will be 
administered by study psychiatrists at screening, baseline and each study visit except the phone interview at 
week 1.
Client Satisfaction Questionnaire (CSQ): Used in prior studies, this scale includes questions about 
satisfaction with treatment condition (CSQ). It will be completed by the participant (and parent/caretaker for 
those < 18 and those 18-20 with permission) at week 12 and used to assess the acceptability of minocycline 
augmentation. For children under the age of 12, the Research Assistant (RA) will be present in case of 
reading comprehension questions.  
Medication Adherence: The participant and psychiatrist will review the dosing procedures and use of a 
dosing diary with the parent/caretaker. Adherence to medication will be assessed by: 1) direct query of the 
participant and parent/caretaker; 2) pill count; 3) review of the dosing diary that participants return at each 
study visit; and 4) SRI and minocycline blood levels (as described above). A log will document the number 
of SRI and study medication tablets provided and what is returned at the next visit, with 70% or greater 
accuracy considered adherent. Number of sessions attended will also be recorded. 
Attrition: The proportion of patients who drop out at each assessment will be used as a measure of attrition. 
Specific reasons for discontinuation will be documented. Every attempt will be made to obtain all 
assessments at all time points from all study participants, even if they terminate early from the study.
 
Efficacy Assessments:
Yale-Brown Obsessive Compulsive Scale, Child version (CYBOCS): The CYBOCS is a semi-structured 
measure of OCD severity with excellent inter-rater reliability, internal consistency, and test-retest reliability. 


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Protocol Summary Form
6574
Simpson, Helen
Page 20 of 31
(i) it is not intended to be reported to FDA in support of a new indication for use or to support any other 
significant change in the labeling for the drug;
 
We are not intending to report the results to the FDA in support of a new indication or change in labeling.
(ii) it is not intended to support a significant change in the advertising for the product; 
There will be no support to change advertising for this product. 
(iii) it does not involve a route of administration or dosage level, use in a subject population, or other factor 
that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of 
the drug product.
 
There is no change in the route of administration or dosage level in this subject population and does not 
increase the risks for this specific population or decrease the acceptability of the risks associated with the 
use of the drug product for this particular disorder. 
(iv) it is conducted in compliance with the requirements for IRB review and informed consent [21 CFR 
parts 56 and 50, respectively]; 
Yes
(iv) it is conducted in compliance with the requirements concerning the promotion and sale of drugs [21 
CFR 312.7];
Yes
(vi) it does not intend to invoke 21 CFR 50.24.
Yes
Research Related Delay to Treatment
Will research procedures result in a delay to treatment?
Yes
Maximum duration of delay to any treatment 
For all enrolled participants, the maximum delay in initiating augmentation treatment will be 14 weeks. 
Participants will be randomized to either minocycline or placebo upon completing the baseline evaluation. 
Two of every three participants will be randomized to minocycline and will begin treatment immediately 
after randomization, and approximately 1-4 weeks after the screening process began. Participants who are 
randomized to placebo will be offered medication management at no cost following the 12-week acute 
treatment phase of the study. All participants will be advised of their alternatives to participation (e.g., 
seeking alternative SRI augmentation treatments such as the addition of cognitive-behavioral therapy, an 
atypical antipsychotic, or clomipramine) before consenting to participate.
Maximum duration of delay to standard care or treatment of known efficacy
For enrolled participants, the maximum delay in beginning a treatment of known efficacy is 14 weeks. 
Participants in both the minocycline and placebo groups will be offered medication management following 


Protocol Summary Form
6574
Simpson, Helen
Page 21 of 31
the 12-week acute treatment phase of the study.
Treatment to be provided at the end of the study
Upon completion of the acute treatment period, participants will be offered three additional months of 
medication management at no cost. Medication management will be offered to all participants regardless of 
response during the acute study treatment period because all participants will enter the study on a stable SRI 
dose. For participants requiring continued medication management following this three-month follow-up 
treatment period, the research staff will refer the patient to his or her previous psychiatrist or will assist the 
participant and his/her family in identifying a psychiatrist.
Clinical Treatment Alternatives
Clinical treatment alternatives
Currently cognitive-behavioral treatment involving exposure and response prevention (CBT/ERP) and 
serotonin reuptake inhibitor (SRI) medication are considered the first line treatments for OCD. However, 
pharmacotherapies have relatively modest effects in OCD. CBT/ERP treatment is the mainstay of the 
treatment for OCD. Yet, CBT/ERP alone results in response rates of anywhere between 60% and 80%, and 
fear of non-adherence to ERP is hypothesized to contribute to the lack of ERP efficacy across age groups.
Risks/Discomforts/Inconveniences 
Risks that could be encountered during the study period
1) Distress from discussion about emotional symptoms; 2) blood sampling; 3) delay in initiation of other 
medication augmentation options for OCD patients; 4) medication-related adverse events and side effects 
for those randomized to minocycline; 5) placebo risks; 6) risks from chronic SRI treatment; 7) risks 
associated with MR imaging. 
1) Distress from thoughts or discussion about emotional symptoms: Some participants may experience 
distress or anxiety related to participating in these procedures. Participants will be monitored throughout the 
procedures, and they will be encouraged to report any concerns. A psychiatrist will be available to assist the 
participant if needed, and participants will be removed from the protocol if their distress or anxiety becomes 
intolerable. Participants and their legal guardians will be informed that their continued treatment at NYSPI 
will not be impacted if at any point they choose to no longer participate. 
2) Risks of blood sampling: A blood sample, approximately one tablespoon (15 cc’s) of blood, will be taken 
at screening and at study completion (or withdrawal, if earlier) for a total of two tablespoons (30 cc). These 
samples will be used to measure minocycline and SRI levels and for safety monitoring, including Chemistry 
Screen and CBC. The samples for drug assay will be forwarded to a centralized laboratory for analysis. 
Participants may experience a bruise at the site of venipuncture. EMLA cream may be used to minimize the 
discomfort of venipuncture.
3) Delay in Initiating Other Augmentation Treatment for Participants: All participants must be on active 
treatment, an SRI, which has known efficacy from the beginning of the study and all patients must have 
experienced at least minimal response to this SRI. Participants will be randomized to minocycline or 


Protocol Summary Form
6574
Simpson, Helen
Page 22 of 31
placebo (2:1). We do not expect pill placebo to have effects. Therefore, for all the participants enrolled, the 
maximum delay in initiating augmentation treatment will be 14 weeks. All subjects will be advised before 
entering of their alternatives to participation (e.g., seeking alternative SRI augmentation treatments such as 
the addition of cognitive-behavioral therapy, an atypical antipsychotic, or clomipramine).
Because minocycline may not benefit participants and placebo is assumed to have no effects, there is the 
potential for participants to not improve from baseline or even to experience a worsening of symptoms. 
Participants will be monitored closely for the development of depressive symptoms, intolerable suicidal 
thinking or behaviors, and/or a decline in function. If, at any time it is clinically determined that it is unsafe 
for a participant to continue in the study (e.g., no longer meets inclusion/exclusion criteria that are focused 
on safety), the participant will be discontinued from the study and provided three months of treatment at no 
cost.
4) Minocycline Risks: Minocycline is a semi-synthetic derivative of tetracycline with a large volume of 
distribution. The drug is completely absorbed from the gastrointestinal tract and 60-75% is bound to plasma 
proteins. Food does not interfere with the absorption of minocycline. Most of minocycline is concentrated in 
the liver and excreted, by way of the bile, into the intestine, from which the drug is partially reaabsorbable. 
Its half life is about 18 hours. Approximately 11% of minocycline is excreted by the kidneys. Minocycline 
is highly lipid soluble and penetrates the CNS. It is found in high concentration in the tears, saliva and 
breast milk. Drug interactions with minocycline include various antacids, calcium, and iron supplements. It 
is active against many tetracycline resistant strains of bacteria like staphylococci, streptococci, and E. Coli. 
Minocycline is commonly used to treat acne and is available for prescription to children and adolescents 
aged 8 years and older. It is generally well tolerated both acutely and chronically. Minocycline is not 
recommended for use for under the age of 8 because it may lead to permanent tooth discoloration. The most 
common side effects in children and adolescents are nausea, headache, and dizziness.
In a study of 700 patients (ages 13 to 48) receiving minocycline for acne, 13% reported adverse effects, all 
of which were rated as mostly benign. Gastrointestinal disturbances and vestibular disturbances were the 
most common, each occurring in about 2% of patients. Vestibular adverse effects including dizziness or 
vertigo may occur particularly in women. Participants will be advised not to drive or operate machinery if 
affected. Chronic administration of minocycline over two years to Huntington’ Disease patients revealed no 
side effects related to long term administration. Unlike other tetracyclines, minocycline does not appear to 
accumulate in those with impaired renal function. However, when used in individuals with impaired renal 
function, the recommendation is to reduce the dose or extend the time intervals between doses. 
Skin pigmentation may occur in up to 4% of patients. Three patterns of skin pigmentation have been 
described: blue-black macules occurring in areas of inflammation and scarring and possibly due to an iron 
chelate of minocycline within macrophages; blue-grey macules or hyperpigmentation affecting normal skin 
and which may be due to a breakdown product of minocycline; or a grayish-brown discoloration occurring 
particularly in sun-exposed areas of skin ('muddy skin syndrome'), apparently due to melanin deposition. 
Skin pigmentation appears to resolve slowly upon discontinuing the drug, although recovery may be 
incomplete. Diffuse pigmentation tends to occur at doses greater than 100 mg and may resolve with 
reduction of dose; however, localized pigmentation does not appear to be dose related. There are rare reports 
of photosensitivity, which is manifested by an exaggerated sunburn; participants will be advised to avoid 
extensive exposure to sunlight. Study participants will be carefully monitored for the development of any 


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skin pigmentation, and if it were to develop, the participant will be withdrawn from the study. 
Rare adverse effects include erythema nodosum, hepatitis, and systemic lupus erythematosus and have been 
usually in patients taking the drug long-term for acne. Rare hypersensitivity reactions may include 
arthralgia, myalgia, pulmonary infiltration, and anaphylaxis. Other rare adverse effects include alopecia, 
myocarditis, vasculitis, pseudotumor cerebri and decreased hearing. Esophageal ulceration has occurred 
rarely and may be a particular problem if capsules or tablets are taken with insufficient fluid or in a 
recumbent posture. The true incidence of these rare adverse events and whether minocycline directly causes 
any of them is not clear given the widespread use of this drug. Adverse events due to minocycline treatment 
are being followed by the FDA Adverse Event Reporting System (AERS) to determine if there is any link 
between the chronic use of minocycline and autoimmune-like symptoms in pediatric patients. 
Pregnancy: Minocycline should not be used in pregnancy as the tetracycline class of drug is able to cross the 
placenta and can have toxic effects on the developing fetus. For this reason, pregnant females are excluded 
from the study. Any female patient who has reached menarche must demonstrate a negative human chronic 
gonadotrophin (HCG) test at screening and a negative urine pregnancy test at each study visit. Results will 
be shared with the participant’s parent(s)/legal guardian(s). Females in the study who are capable of 
becoming pregnant must either be abstaining from sexual intercourse for the duration of the study or be 
using a medically acceptable form of contraception. Acceptable methods of birth control are the double 
barrier methods (condom and spermicide) and intra-uterine devices. Given that minocycline can potentially 
render oral contraceptives less effective, use of oral contraceptive without the additional use of the double 
barrier method or an intra-uterine device is not considered acceptable as a contraceptive method. Because 
minocycline may be excreted in human milk, nursing females are also excluded from this study. A negative 
pregnancy test is required to start, and continue in, the study. In addition to the study required pregnancy 
tests, confidential pregnancy testing is available outside of our clinic, and referrals will be provided if the 
participant prefers this, however, the participant would not be able to continue in the study. Although highly 
unlikely given the careful screening monitoring for pregnancy if a study participant is determined to be 
pregnant, appropriate antenatal counseling will be offered to the participant for the purpose of explaining the 
risks to the fetus and risks and benefits for the prospective mother. The pregnant participant will be 
withdrawn from study participation. The participant will also be referred to appropriate antenatal medical 
care. The study clinician will continue to offer routine clinical treatment until the participant is carefully 
transitioned to a mutually agreed upon clinician for longer-term care. If the participant decides to continue 
with the pregnancy, further referrals, as appropriate for the neonate and mother, will be made. The outcome 
of the pregnancy will be reported to the IRB and DSMB board.
Minocycline is bacteriostatic and may interfere with the bactericidal action of penicillin. Participants will be 
advised to immediately inform study doctors about any additional antibiotics prescribed and that the use of 
penicillin is not advised. Absorption of minocycline is impaired by antacids containing calcium, 
magnesium, aluminium, zinc salts and iron preparations. Participants will be advised against the use of 
Accutane, given both compounds have the rare side effect of causing pseudotumor cerebri. Minocycline has 
been shown to depress plasma prothrombin activity and participants who are treated with anticoagulants 
may need to have this medication adjusted. 
Participants will be monitored closely for adverse events and will be withdrawn from the study if there is 
evidence of developing these more serious events. In the clinical judgment of the study team, if the 


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participant has significant neurological complaints, assessment by a pediatric ophthalmologist should be 
considered. In the event that the study participant can not tolerate the more common side effects (e.g., 
nausea, dizziness, and headaches) the participant will be withdrawn from the study.
Given the wide spread use of minocycline over the past 30 years and the extensive safety data available for 
its use for acute and chronic treatment of acne and infections in children and adolescents, it is anticipated 
that most side effects will be limited and manageable. Those participants randomized to minocycline will 
receive approximately 2 mg/kg/day, the FDA-approved dose for minocycline and the dose used in our pilot 
study (<35 kg: 50 mg/day; 35-55 kg: 50 mg BID; >55-75 kg: 75 mg BID; >75kg: 100 mg BID). Participants 
and their parents/care giver will be instructed to take the tablet with food and with 4-8 ounces of water in 
order to lessen gastric adverse effects and in an upright position well before retiring to bed. Additionally, 
participants will be instructed and reminded of the adverse events to be aware of at each study visit such as 
developing skin pigmentation, always using birth control, avoiding intense direct sun light, and informing 
the study doctor when prescribed any type of medication such as other antibiotics. Additionally, participants 
will be advised that they can not take the following: anti-coagulant drugs, antacids containing iron 
preparations, calcium, magnesium, aluminum, and zinc salts and Accutane. If a participant experiences 
adverse event or a common side effect that does not resolve and is intolerable, the study doctor will 
discontinue participant from the study and the patient will be referred for open treatment.
5) Placebo risks: One risk for participants who are randomized to inactive treatment is that they may 
experience no change from baseline and/or worsening of clinical symptoms. Participants will be monitored 
by safety evaluations for the development of depressive symptoms, intolerable adverse events, suicidal 
behaviors, and/or decline in functioning. If, at any time it is clinically determined that it is unsafe for a 
participant to continue in the study (e.g., no longer meets inclusion/exclusion criteria that are focused on 
safety), the participant will be withdrawn from the study. 
6) Risks from chronic SRI treatment: A review in 2004 by the Food and Drug Administration (FDA) of all 
pediatric placebo-controlled randomized studies of antidepressant medications found an increased incidence 
of suicidal thoughts and behaviors in the medication group (4%) versus the placebo group (2%). There were 
no completed suicides. Based on this finding, the FDA issued a “black-box” warning on all antidepressant 
medications, stating that their use may increase suicidal thinking and behavior in youth. This has led to the 
FDA to develop guidelines recommending frequent follow up and careful monitoring for the development 
of new or worsening of symptoms such as insomnia, increased agitation, anxiety, and depression symptoms, 
as well as the development of suicidal ideation/ behaviors. 
Long-term adverse effects with antidepressants, including SRIs, are similar to those reported in acute trials, 
including gastrointestinal disturbance, insomnia, and headache. Overall, these adverse effects were mild in 
severity, diminished as treatment continued, and did not lead to study withdrawal from clinical trials. 
Discontinuation syndromes associated with SRIs are headache, gastrointestinal distress, dizziness, and 
irritability or agitation. The participants in this study must be on a stable tolerable dose with at least minimal 
response for the 12 weeks, and thus should be experiencing minimal to no adverse events. 
 
Adverse events will be carefully tracked with the appropriate medical monitoring with lab work, vital signs, 
and safety measurement as designated in the research strategy. All adverse events spontaneously reported by 
the individual throughout the study will be documented and rated in intensity, relationship to study drug and 


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outcome by the study doctor. The Pediatric Adverse Event Rating Scale (PAERS) will also be used to 
evaluate for adverse events reported by parent (for those <18) and adolescent (for all 8-20) at every study 
visit. The PAERS rates the severity of 48 adverse event items on a five-point Likert scale (0–4). It will be 
reviewed by the clinician at each visit to determine final severity and relationship to treatment or illness. 
In addition, suicidal ideation and behaviors will be systematically monitored during study visits using the 
Columbia Suicide-Severity Rating Scale (C-SSRS) which evaluates and tracks suicidal ideation, suicidal 
acts, seriousness of acts, medical lethality of act, thoughts of death, and non suicidal self injury. 
 
7) Risks associated with MRI Scanning: There are no known long-term biological risks from the use of MRI 
scanners per se, including the GE 3T scanner for use in this proposal. The 3T GE system proposed in this 
study is a nonsignificant risk device (per FDA website, U.S. Food and Drug Administration, Center for 
Devices and Radiological Health, "Guidance for the Submission of Premarket Notifications for Magnetic 
Resonance Diagnostic Devices", http://www.fda.gov/cdrh/ode/95.html, Nov., 1998). Human studies have 
been carried out under IRB approval in the US since 1990 under this same evaluation at a variety of 
institutions throughout the US. More recently, field strengths of 7T and 8T have been approved for research 
studies in humans at the University of Minnesota and Ohio State University. All MRI studies follow 
guidelines set by the FDA with regard to specific absorption ratio (SAR), limits on gradient slew rate 
(dB/dt), and noise. At the same time, possible risks associated with MRI scanning can be classified into one 
of six areas: a) acoustic noise levels; b) physical discomfort; c) fetal exposure; d) static magnetic fields 
(leading to the attraction of ferromagnetic metal objects); e) gradient or time‑varying magnetic fields 
(leading to the possible stimulation of peripheral nerves); and f) radiofrequency (RF) magnetic fields 
(leading to the possible risk of tissue heating).
a) Acoustic Noise Levels: The acoustic noise associated with MR imaging is related to the mechanical 
movement of the gradient coils during the scanning process.
 
FDA Guidelines: "The acoustic noise levels associated with the device must be shown to be below the level 
of concern established by pertinent Federal Regulatory or other recognized standards setting organizations. 
If the acoustic noise is not below the level of concern, the sponsor must recommend steps to reduce or 
alleviate the noise perceived by the patient." Current FDA guidelines follow the regulations of the 
International Electrotechnical Commission (IEC) Standard 601-2-33, which stipulate that for MR equipment 
used in medicine, hearing protection is required when the system can produce acoustic sound levels above 
99 dBA (maximum A weighted r.m.s.) and that the protection should be able to reduce noise levels to below 
99 dBA. The FDA has approved systems for which noise levels have been quantified, ranging up to 105 dB 
RMS for scanners operating at field strengths of 1.5 Tesla. It is important to note that the static magnetic 
field strength is only one factor, and not necessarily the most important one, in determining acoustic noise. 
Among the factors listed above, the design and construction of the gradient coils plays a major role in the 
noise level that MRI scanning produces. Therefore, noise levels are not necessarily greater when scanning at 
3.0 T compared with 1.5 T field strengths. It is nevertheless possible that, in some circumstances, our 
system could produce noise levels higher than 99 dB, as do many clinical systems operating at lower field 
strengths.
 


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Summary: The acoustic noise levels perceived by human subjects when undergoing MRI examination in our 
3.0 Tesla magnet constitutes a non-significant risk; specifically, our system will not be operated in a way 
that will present more noise to human subjects than is recommended by the FDA.
 
Plans to Minimize Risk: As suggested by the FDA, we will take steps to reduce the noise levels experienced 
by subjects. The easiest and most reliable means of preventing hearing loss is to use disposable earplugs, 
which we will do for all scans. We will also be using acoustically shielded headsets, which further attenuate 
noise. 
b) Physical Discomfort: The physical confinement and isolation produced by the scanner could cause mild 
to moderate emotional distress, although participants in previous trials, including participants diagnosed 
with OCD, generally tolerate the procedures remarkably well. All subjects will be able to communicate 
directly with technologists and study staff to inform them of any emotional or physical distress during the 
scanning procedure. If they wish, the scan will be terminated immediately and the subject will be removed 
from the scanner.
c) Fetal Exposure: The risk of MR imaging to the fetus is unknown. Pregnant women are excluded. While 
there is no known risk of MR scans to the fetus, it is standard practice to exclude women who are pregnant 
from research MR scans. Therefore to implement this exclusion a pregnancy blood test will be performed at 
screening and, in addition, a urine pregnancy test will be performed on the day of each MR scan for all 
female participants.
d) Static Magnetic Fields: The possible risks of static magnetic fields have received much attention in the 
lay press, but scientific consensus on these risks has yet to be fully reached. The FDA has deemed that 
systems operating at 8.0 Tesla or less do not pose a significant risk. Moreover, experience with thousands of 
clinical studies over the past decade, and with multiple human investigations carried out at higher field 
strengths over this period, have not revealed risks of exposure to higher static magnetic fields. The most 
significant risk associated with static magnetic fields is that ferromagnetic objects, such as aneurysm clips or 
heart valves, can interact with the magnetic field of an MRI scanner, causing the device to malfunction or to 
move, and injuring the subject.
 
FDA Guidelines: “Studies conducted at 8T or less are not considered significant risk" (FDA Center for 
Devices and Radiological Health, memorandum 7-14-03).
 
Summary: This category of risk applies to work conducted around superconducting magnets of any kind 
(including standard clinical diagnostic MRI units). It is not unique to our 3.0 Tesla facility, which will 
maintain a safety policy to safeguard subjects and staff members from these incidental risks. Systems with 
static magnetic field less than 8 Tesla have been considered to represent a nonsignificant risk by the FDA. 
The static magnetic field of our system (3.0 Tesla) is therefore to be classified as posing nonsignificant risk 
to human subjects.
Plans to Minimize Risk: The risks outlined above are the same as in other commercially available clinical 
systems. Like clinical MRI centers, our facility has a complete range of procedures to assure security of the 
restricted access area, careful screening of potential subjects before they enter the restricted access area, and 
a metal detector positioned at the doorway leading into the magnet room within the MRI suite. In addition, 


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access is tightly controlled, allowing only those personnel and research subjects who have legitimate reason 
to be there. Doors to the unit will be securely locked, with only MR technologists, physicists, or physicians 
controlling entry of ferromagnetic and other materials that could possibly cause injury to patients, research 
subjects, personnel, or equipment. In addition, entry-ways to the unit will be labeled with clear visible signs 
warning of the presence of the magnetic field and the exclusion from entry by individuals with implanted 
metal objects such as prostheses, pins, clips, IUD’s, etc.
e) Time‑Varying Magnetic Fields/nerve stimulation: The concern about the time-varying magnetic fields 
used in MRI is that these can, in some instances, induce stimulation of peripheral nerves, thereby producing 
sensations such as 'twitching' or 'tingling'. In very rare instances, this nerve stimulation can be painful. 
Nerve stimulation is particularly likely when subjects are physically positioned in a way that increases the 
likelihood of inducing stimulation, such as with hands clasped or arms folded. It should be noted that the 
parameter of interest here, dB/dt (the rate of change in the magnetic field per unit time), is not a function of 
the strength of the static magnetic field, so evaluating risk in a 3T MRI scanner involves the same 
considerations as evaluating other MRI systems operating at lower magnetic field strengths (i.e., the same 
issues apply to all the commercially available, FDA approved scanning systems). Thus, it is the gradient 
system only that needs to be evaluated to determine the risk of producing nerve stimulation.
 
FDA Guidelines: The FDA Guidance of 1995 was developed specifically to consider the fact that many 
clinical systems were capable of exceeding levels of dB/dt that could produce nerve stimulation. It was 
originally considered that a warning level should be implemented to guard against peripheral nerve 
stimulation, but the FDA finally concluded that: '... this warning level is not considered critical since there 
are no harmful effects associated with mild peripheral nerve stimulation.’ The current guidelines therefore 
include monitoring procedures to help avoid painful peripheral nerve stimulation, and without specific dB/dt 
limitations.
 
Summary: The gradients used in our 3.0 Tesla MRI system will typically be operated at levels below those 
considered to be negligible according to FDA guidelines. Our system, like most commercially available, 
FDA-approved systems, does have the capacity to exceed this level, but it will include the same safeguards 
that are included in other FDA-approved clinical systems. Furthermore, policies and procedures will be 
implemented according to FDA guidelines to avoid the possibility of painful peripheral nerve stimulation. 
Therefore, in all circumstances the system will be operated in a way that poses nonsignificant risk to the 
participant.
 
Plans to Minimize Risk: The consent form will provide information about this risk. A record of dB/dt value 
will also be included with the imaging data to help in analysis of levels of peripheral nerve stimulation 
possibly perceived by subjects. In addition, we will conduct detailed calculations of the changes in magnetic 
field over time that our gradient system is capable of, and conservative values will be selected as limits that 
will be used to determine when special additional monitoring is indicated. In these cases, we will use the 
monitoring procedures recommended by the FDA. The gradient switching times and strengths will also be 
monitored together with the routine assessment of all electrical components of the system, as described 
previously.
 
In addition, MR technologists receive special training to prevent peripheral nerve stimulation. Before any 
scanning procedure that might stimulate peripheral nerves, a technologist will inform the subject that 


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peripheral nerve stimulation may occur; describe the nature of the sensation to the subject; instruct subjects 
not to clasp their hands, since this may create a conductive loop which will increase the possibility of 
stimulation; maintain constant verbal contact with the subject; instruct subjects to inform the MR 
technologist if they experience discomfort or pain; terminate the scan if the subject complains of discomfort 
or pain; complete a report of any incidents involving severe discomfort or pain, including describing the 
associated circumstances (imaging parameters, dB/dt value, level of pain, etc.), and submit this report 
immediately to the IRB.
f) Specific Absorption Rate (SAR): MRI scanning induces some heating of body tissues. This specific 
absorption rate (SAR) that determines heating is the amount of radiofrequency (RF) energy deposited 
(typically by a coil or “helmet”-like apparatus placed over the subject’s head) per unit volume of tissue per 
unit time. The SAR for RF radiation is primarily related to the amplitude of RF power, duration of the RF 
pulse, type of RF coil, frequency of RF radiation, resistivity of the tissue, configuration of the anatomical 
region, and several other parameters.
 
FDA Guidelines: "The following are levels of concern: A) If SAR 0.4 W/kg whole body; and if SAR 8.0 
W/kg spatial peak in any 1 gram of tissue; and if SAR 3.2 W/kg averaged over the head: below level of 
concern. Or B) If exposure to radiofrequency magnetic fields is insufficient to produce a core temperature 
increase in excess of 1°C and localized heating to greater than 38°C in the head, 39°C in the trunk and 40°C 
in the extremities: below level of concern. The parameter SAR cited above must be shown to fall below 
either of the two levels of concern by presentation of valid scientific measurement or calculation evidence 
sufficient to demonstrate that SAR is of no concern."
 
This guideline is based on the calculation of a system that has no thermoregulatory response, and thus it is a 
very conservative estimate compared with the temperature change that would be experienced in any living 
subject. Normal diurnal temperature variations in humans, for example, are about +/-1°C from the normal 
set point 37°C, and healthy people with normal thermoregulatory responses can easily dissipate any excess 
(or, in this instance, deposited) heat by increasing their peripheral blood flow or sweat rate. Thus, the 
heating effect of MRI with the SARs used in accord with these guidelines is extraordinarily unlikely to 
cause any acute effects in healthy human subjects. Furthermore, our scanner console calculates SAR based 
on the subject’s body weight before running any pulse sequence and prohibits running of the sequence if 
exceeds the FDA-approved limit.
 
Summary: Because all experiments performed on the 3.0 Tesla system will comply with FDA guidelines 
with regard to SAR, and because appropriate RF power safety checks are in place, this criterion for 
classification of nonsignificant risk is satisfied.
 
Plans to Minimize Risk: The magnitude of temperature increase during MRI scanning is minimal. Increases 
are always within FDA guidelines, which include core temperature increases less than 1°C , as well as 
localized heating to less than 38°C in the head, 39°C in the trunk, and 40 °C in the extremities. Our 3.0 
Tesla system has in place a means to monitor RF power levels and ensure that energy deposition is 
sufficiently low to stay well within these guidelines for temperature increases. First, a "system security" unit 
is employed to integrate the output of the RF amplifiers. This integration takes into account the amplitudes 
and duty cycle of the transmitter. If system security detects an output that might exceed the guidelines noted 
above, it automatically shuts down the entire RF power system. Secondly, all pulse sequences are evaluated, 


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based on calculations and sound scientific measurements, to ensure that SAR remains within FDA-approved 
guidelines, prior to their use in humans. Any experiment performed on our 3.0 Tesla system will comply 
with all FDA guidelines with regard to RF power deposition. Proper and routine monitoring of all RF 
electronics (e.g., coils, transmitters, system security, etc.) will be performed on a regular basis. All pulse 
sequences will be evaluated (by calculation and by valid scientific measurement) prior to use in humans.
Describe procedures for minimizing risks
All efforts will be made to minimize risks and to ensure participant safety. Participants will be encouraged 
to relay the emergence of any adverse events to the study team, who will attend to it appropriately.
Methods to Protect Confidentiality
Describe methods to protect confidentiality
Confidentiality will be maintained by assigning unique identifying code numbers to each participant and 
his/her family. Code numbers, rather than names, will be used on all documents pertaining to the 
participants. All data will be kept in locked files or on Windows 2003 servers or XP workstations with 
password access, to which only researchers will have access. These operating systems provide multi-level 
security restrictions and privileges will only be granted by Drs. Rynn, Simpson and Shungu to others 
working on the project. All individuals granted access to the database will be issued a password. The portion 
of the database that connects a person’s identifying information and the code numbers will be maintained 
separately and require a higher level of security clearance on the system. No individual will be named or 
described with information that could allow him/her to be identified in published reports. 
Once the MR data are analyzed, Dr. Shungu will provide Drs. Simpson and Rynn a hard copy of a 
deindentified database of the key MRS variables for each subject. These MRS variables will be merged by 
the study data manager into the clinical database to create the final data file that will be stored on a network 
server securely located behind the NYSPI firewall.
Clinical data will be entered twice into a Microsoft Access relational database, checked for consistency, and 
merged with MRS data. This database is stored on a network server securely located behind the NYSPI 
firewall; a username and password are required to access the server and a separate password to access this 
database. Subjects are identified by numeric codes consistent with HIPAA guidelines; hard copies of data 
are stored in locked rooms with restricted access. The data manager will perform random data audits to 
further ensure the integrity of the data. Server backups of study databases are performed nightly; database 
copies on CD-ROM archive disks are stored separately for safety. Drs. Simpson and Rynn will oversee the 
operation and scientific integrity of the clinical trial and ensure that the protocol design, instrumentation, 
patient recruitment, data collection and analysis yield information that achieves the major objectives of the 
study. 
The MR imaging data will be transferred from the scanner to a secure network-attached file storage server, 
which can be accessed to retrieve the data for further processing. Consistent with HIPAA guidelines, 
subjects will only be identified by numeric codes. Dr. Shungu is responsible for the scientific integrity of the 
MR imaging data. Dr. Shungu will provide Drs. Simpson and Rynn the de-identified database of the 
relevant MRS variables. The MRS data will be merged with the clinical data by the study data manager (Dr. 
Van Meter, see Personnel) prior to the analyses. This merged file will constitute the final datafile and will be 


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stored on a network server securely located behind the NYSPI firewall.
Will the study be conducted under a certificate of confidentiality?
No
Direct Benefits to Subjects  
Direct Benefits to Subjects
The potential benefit of this study is that the subject may be randomized to minocycline augmentation and 
may respond to this novel treatment strategy for OCD. In addition, each participant will be receiving a 
psychiatric evaluation and will be carefully followed in the study. Participants will continue on SRI 
medication and will only be included in the study if he/she have experienced at least a minimal response to 
SRI treatment. Participants and their legal guardians will be informed of any clinically significant findings 
from the clinical assessments and from the MR imaging. 
The MRS measurements will not be of direct benefit to subjects. The indirect benefit is the knowledge the 
study will provide about minocycline’s potential effects on the brain and/or about potential biomarkers that 
might predict who will respond to this novel treatment strategy. Although the risks are greater than minimal 
given the randomization to placebo and the unknown efficacy of minocycline as an augmentation option, at 
this time there are no proven medication augmentation treatment strategies for children and adolescents with 
OCD who continue to have clinically-significant symptoms despite an adequate SRI. Available compounds 
to augment SRI treatment include stimulants, antipsychotics, or clomipramine, but the data supporting the 
efficacy of these compounds in pediatric OCD are limited and some have the potential for significant 
adverse event burden. Moreover, low risk methods for examining putative brain mechanisms of these 
compounds (e.g., changes in dopamine or serotonergic neurotransmission) are not yet feasible in pediatric 
populations. Minocycline is FDA approved for children 8 years and older and is well tolerated. MRS 
methods can be used in pediatric populations to assess the effects of minocycline on striatal glutamate (Glu) 
levels, one of minocycline’s possible mechanisms of action. Thus, it would seem the potential benefits of 
this study make the potential risks a reasonable consideration for participants suffering from this impairing 
disorder.
Compensation and/or Reimbursement 
Will compensation or reimbursement for expenses be offered to subjects?
Yes
Please describe and indicate total amount and schedule of payment(s). 
Include justification for compensation amounts and indicate if there are bonus payments.
Participants will be compensated for $125.00 for each MRI scan and $50 for the evaluations done at the 
time of the scan. The compensation takes into account the time involved, travel costs and parking in New 
York City, and meals or snacks.


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References
References
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SAP_001.pdf: 
 
 
 
 
 
 
Title:  
A randomized, placebo-controlled trial of minocycline added to 
serotonin reuptake inhibitors in pediatric OCD: Examining the effects on clinical 
symptoms and on brain glutamate levels using MRS imaging 
 
 
NCT Number: 
NCT01695291 
 
 
Document Date:  
Updated 01/07/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Baseline characteristics were compared between groups using two-sample t-test for 
continuous variables and chi-squared tests for categorical variables. Pre-specified primary 
(CYBOCS) outcome and secondary outcomes (CGI-IE Severity, CGI-IE Improvement, HAM-D, 
ADIS OCD CSR, COIS-C, COIS-P) at baseline and end of treatment (week 12) were 
summarized by mean, standard deviation, and frequencies. Pre-specified brain measures 
(glutamate and glutathione at striatum) were collected and summarized by mean and standard 
deviation.  
 
All analyses were performed under intention-to-treat (ITT) principle. Linear mixed 
effects models with subject-specific random intercepts and covariates (race and history of CBT) 
were fitted to primary and secondary clinical measures and brain measures separately to assess 
treatment effects. Each model contained the main effect of treatment group (Minocycline + SRI 
versus PBO + SRI) and time (categorical for clinical measures and continuous for brain 
measures), and their interaction to examine within treatment group change over time and 
between-group treatment effects. Pre-planned moderation analysis tested interaction effect 
between baseline brain measures and treatment on clinical outcomes. Sensitivity analyses of 
comparing post-treatment dichotomized CYBOCS (week 12 CYBOCS change from baseline 
>25% or >35%) and CGI improvement (with improvement defined as either at least minimally 
improved) between groups were conducted by fisher exact tests. Exploratory analyses were 
performed for other brain measures. All analyses were performed using SAS version 9.4 (SAS 
Institute) and all tests were two-sided with a significance level of 0.05.