Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine
Phase: EARLY_PHASE1
Conditions: Schizophrenia, Bipolar Disorder
Sponsor: Mclean Hospital

Official Title: Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine (DCS) 
 
NCT number:  NCT02304432 
 
Document Date: 4/9/2015 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
2 
 
Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
Deborah L. Levy, Ph.D. 
 
PROTOCOL TITLE 
Targeting a Genetic Mutation in Glycine Metabolism with D-cycloserine 
 
FUNDING 
NIMH 
 
VERSION DATE 
4/9/2015 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
We propose to (1) to target a triplication of GLDC by trying to normalize brain glycine levels 
using D-cycloserine augmentation of usual psychotropic drug treatment, and (2) to characterize 
the neurobiology of this mutation using neurocognitive and electrophysiology measures and 
studies of brain structure and function. 
 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
Multiple rare structural variants of relatively recent evolutionary origin are recognized as 
important risk factors for schizophrenia (SZ) and other neurodevelopmental disorders [e.g., 
autism spectrum disorders, mental retardation, epilepsy with odds ratios as high as 7-30 (Sebat 
et al. 2009; Malhotra et al. 2011; Heinzen et al. 2010; Weiss et al. 2008; McCarthy et al. 2009). 
We have found a de novo structural rearrangement on chromosome 9p24.1.  In addition to other 
genes, the duplicated region contains the gene encoding glycine decarboxylase (GLDC), which 
affects brain glycine (Gly) metabolism. Here we focus on the potential contributions of this gene 
to abnormal glycine homeostasis and N-methyl-D-aspartate receptor (NMDAR) dysfunction in 
SZ. This mutation is an obvious ‘smoking gun.’  GLDC encodes the glycine decarboxylase or 
glycine cleavage system P-protein, which is involved in degradation of Gly in glia cells.  Carriers 
of the GLDC triplication would be expected to have low levels of brain Gly, resulting in NMDA 
receptor-mediated hypofunction, which has been strongly implicated in the pathophysiology of 
SZ (Olney & Farmer, 1995; Coyle, 2006; Javitt, 2007). Individuals with mutations that lower 
brain Gly or alter other aspects of glutamatergic transmission are obvious candidates for Gly 
augmentation or complementary NMDAR modulatory strategies, which have been used with 
varying degrees of success Goff et al. 1999; Javitt et al. 2001; Lane et al. 2005; Heresco-Levy 
et al. 2004; Buchanan et al. 2007). Genetic risk factors, including variants that impact the 
synthesis and breakdown of Gly, are likely to contribute to this variability. 
 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
3 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be 
enrolled by researchers study-wide and by Partners researchers.  Provide a brief 
summary of the eligibility criteria (for example, age range, gender, medical condition).  
Include any local site restrictions, for example, “Enrollment at Partners will be limited to 
adults although the sponsor’s protocol is open to both children and adults.”
 
The total projected sample size is 2, consisting of two carriers of the 9p24.1 mutation, both of 
whom participated in the protocol entitled Neurobiology of a Mutation in Glycine Metabolism in 
Psychotic Disorders (2012P001597). The two carriers have diagnoses of bipolar disorder with 
psychotic features and schizo-affective disorder and will be recruited as outpatients.  The age 
range is 33-64 and includes one male and one female. Inclusion is restricted to these carriers of 
this specific mutation. This is a private mutation, present only in these two individuals. Exclusion 
criteria: meeting inclusion criteria but having a creatinine clearance less than 50 mL/min. 
 
Design of the study:  
Open-label DCS (daily dose of 50 mg) for 8 weeks – Treatment Arm A, followed by four 6-week 
periods of double-blind DCS or placebo with one week of washout in between. Subjects will be 
randomized to DCS-placebo-DCS-placebo or to placebo-DCS-placebo-DCS by the McLean 
Hospital research pharmacist, Laura Godfrey.  These four double-blind exposures (two each for 
DCS and placebo) will be followed by a 6-week single-blind exposure to DCS (subjects and the 
person doing the clinical assessments will not know if they are getting DCS or placebo, but Drs. 
Levy, Bodkin, and Ongur will know that they are getting DCS). After a one-week washout, this 
single-blind exposure will be followed by 6 weeks of open-label DCS. The length of each 
double-blind arm is limited to six weeks to minimize the length of symptom exacerbation 
experienced by the subjects when they are receiving placebo. The patients’ usual psychotropic 
drug regimen will not be altered as part of the study, but an attempt will be made to keep those 
medications unchanged throughout the study if possible. Both the DCS (source: The Chao 
Center) and the placebo will be dispensed by the McLean Hospital Pharmacy. Throughout the 
study, subjects will take one vitamin-B complex tablet per day. 
 
Dr. Bodkin will be responsible for medical oversight of the d-cycloserine (DCS) augmentation 
component of the study. Dr. Ongur will serve as his back-up. Dr. Ongur will be responsible for 
medical oversight of the imaging components of the study. 
 
 
Briefly describe study procedures.  Include any local site restrictions, for example, 
“Subjects enrolled at Partners will not participate in the pharmacokinetic portion of the 
study.”  Describe study endpoints.
Before beginning the study, subjects will have an EKG and physical exam performed by their 
personal physician. This will be repeated at week 8 and week 44 at the end of the study. Blood 
work will be done at the same time and consist of the following tests: comprehensive metabolic 
profile (CMP), lipid panel, GGT, uric acid, CBC with differential, CRP-hs. Blood will also be 
drawn for large and small amino acid levels and psychotropic drug levels. 
 
Periodic blood tests and weight checks, clinical ratings (PANSS, Clinical Global Impression 
scale, Brief Psychiatric Rating Scale, Young Mania Rating Scale, HAM-D), side effect 
monitoring, movement disorder assessments (AIMS and SAS) and neurocognitive testing 
(MATRICS) – see schema for details. 
 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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At the end of week 7 of open-label DCS, subjects will undergo electroretinograms at the 
University of Minnesota. During week 8 of open-label DCS they will have a structural MRI, 
Proton 1H MRS for brain GABA, glutamate, and glycine levels, the MATRICs neurocognitive 
battery, and an EEG. 
 
For studies involving treatment or diagnosis, provide information about standard of care 
at Partners (e.g., BWH, MGH) and indicate how the study procedures differ from 
standard care.  Provide information on available alternative treatments, procedures, or 
methods of diagnosis.
Standard care usually does not involve augmentation with DCS. Otherwise, their 
pharmacological treatment is consistent with the standard of care. 
 
Describe how risks to subjects are minimized, for example, by using procedures which 
are consistent with sound research design and which do not unnecessarily expose 
subjects to risk or by using procedures already being performed on the subject for 
diagnostic or treatment purposes.
 
Subjects who meet the inclusion criteria specific above but have a creatinine clearance less 
than 50 mL/min will be excluded. 
 
DCS Augmentation has been used to augment standard psychotropic drug treatment and is well 
tolerated. At 50 mg/day, DCS is a partial agonist. It crosses the blood brain barrier readily and 
should facilitate excitation of the NMDA receptor to compensate for the accelerated degradation 
of glycine caused by the mutation. Both patients will be taking clozapine; in some patients DCS 
results in either no clinical effects or a slight worsening of negative symptoms in clozapine-
treated patients. The same applies to glycine. The fact that both patients derived considerable 
clinical benefit from glycine would suggest that DCS should have a similar therapeutic effect.  
The subjects will be monitored closely by the research team and by their own psychiatrists.  
 
The clinical assessment every two weeks includes an evaluation of suicidality (HAMS and C-
SSRS. In addition, there is an at least once-weekly call with Dr. Levy to monitor changes in 
symptoms. Should any suicidal ideation emerge, Mr. Coleman and Dr. Levy would review the 
symptoms and their acuteness with Dr. Bodkin (or Dr. Ongur). Dr. Bodkin (or Dr. Ongur) would 
talk with the subject. We would then have a conference call involving Dr. Levy, Mr. Coleman, 
and Dr. Bodkin (Dr. Ongur should Dr. Bodkin not be available) to discuss the best disposition: 
determining whether a subject need to be hospitalized, whether the subject should be 
discontinued from the study; whether emergency services (911) should be notified. We would 
confer with the subject's psychiatrist and notify the internist.  We would discuss with the subject 
what we feel is the best plan going forward and facilitate whatever disposition seems best. The 
subject's family would be informed (with written permission from the subject obtained in the 
informed consent) to help ensure prompt compliance with the disposition. 
 
The imaging procedures have been used extensively at McLean without complications. Both 
subjects will be carefully screened again for the safety of the imaging procedures. Both subjects 
have had multiple brain scans at McLean in the recent past. Baseline imaging data collected in 
the glycine study will serve as baseline data in this study. 
 
The PI has talked with all of the people involved in the study (Drs. Ongur, Bodkin, Goff, 
Visscher, Vuckovic; Mr. Coleman, Ms. Godfrey) to ascertain that they are all in agreement that 
the proposed plan for medical and/or psychiatric monitoring for the patients while they are taking 
a novel compound is adequate. Dr. Bodkin is the primary medical back-up; Dr. Ongur is back-up 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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if Dr. Bodkin is unavailable. Dr. Goff is an unpaid consult with expertise in using DCS. Drs. 
Visscher and Vuckovic are the treating psychiatrists of the subjects. Mr. Coleman is performs all 
clinical assessments. Ms. Godfrey is the research pharmacist. 
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective 
criteria for removing a subject from the study, for example, objective criteria for 
worsening disease/lack of improvement and/or unacceptable adverse events.  The 
inclusion of objective drop criteria is especially important in studies designed with 
placebo control groups.
 
FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include 
those related to drugs/devices/procedures being studied and/or administered/performed 
solely for research purposes.  In addition, include psychosocial risks, and risks related 
to privacy and confidentiality.  When applicable, describe risks to a developing fetus or 
nursing infant.
The procedures described above pose no serious physical risk to subjects and no 
psychological, social, or legal risks are anticipated.  
 
Although there are no known general risks associated with MRI scans, there are risks to 
individual subjects who have contraindications to MRI scanning, including those with metal 
implants in their body (pacemaker, aneurysm clips, metal screws and plates for orthopedic 
purposes, hearing implants, certain kinds of tattoos, sheetmetal workers with lodged metal 
fragments in the eyes).  Subjects are screened carefully and excluded if there are even 
suspected contraindications to scanning.  All subjects are asked to remove jewelry, belts and 
other metal-containing objects.  Surgical records will be retrieved prior to scan for subjects who 
have had metal placed in their body intra-operatively to ensure the hardware is MRI safe, even 
if the subject has been told the hardware is MRI-safe or if they have had MRI scans since the 
operation.  As an additional precaution, subjects are screened with a handheld metal-detection 
wand prior to the scan to ensure that no unidentified metal objects remain on the subject.  The 
noise generated by the pulsing of the gradients can lead to temporary decrease in hearing. 
The use of disposable earplugs is an easy and reliable means of preventing hearing loss. The 
risks associated with Specific Absorption Rate (SAR) are related to the fact that given a large 
enough SAR, heating of the tissue may occur. These experiments will comply with all FDA 
guidelines with regard to RF power deposition. There is also the potential risk of injury from a 
projectile (i.e., ferromagnetic objects being attracted into the magnet); and of asphyxiation due 
to large amounts of cryogenic gases generated during a quench (i.e., the event which occurs 
when a magnet makes the sudden transition from superconducting to resistively conducting). 
Routine safety procedures are in place at both scanning centers to screen subjects prior to 
scanning, maintain security of the restricted access areas, and ensure that system security 
features are in good working order. The McLean imaging center is very experienced with MRI 
scanning and has an impeccable safety record. The effects of MRI on the fetus are not well 
characterized, but are irrelevant in this study, because the female patient has had a 
hysterectomy. 
 
The scans involve use of a standard clinical MRI scanner (3T) as well as a high field (4T) MRI 
scanner. The 4T scanner is not used for routine clinical studies in children or adults, but the 
FDA has determined (July 14, 2003) that scanners with magnetic field strengths of less than 8 
Tesla do not represent a significant risk to adults, children, or infants older than 1 month. 164 
Most people experience no ill effects from 3T or 4 T scans, but some do report claustrophobia, 
dizziness, mild nausea, headaches, a metallic taste in their mouth, back tingling, double vision, 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
6 
or sensation of flashing lights.  These symptoms, if present, disappear shortly after leaving the 
scanner.  During the scan, the examiner can see and hear the subjects and will ask them to 
report any problems so the scan can be stopped if necessary.  A magnetic resonance scan may 
be uncomfortable due to claustrophobia, lying still for an hour, or loud sounds. Subjects who 
express serious concern about these will not be included. The scan will be stopped if the subject 
expresses discomfort. Total time in the scanner for the structural scan and 2 MRS scans at 
McLean is 150 minutes, with breaks occurring between scans (structural: 15 minutes; 
MEGAPRESS: 60 minutes; J-PRESS: 75 minutes).  The DCS uptake scan requires multiple 
scans over a two hour period in the scanner. Subjects will be allowed to leave the scanner 
between scans and can be re-positioned for the next scan, as described in the application. Both 
subjects have successfully completed imaging procedures. 
 
DCS Augmentation Clinical Trial: Pharmaceutical grade DCS (The Chao Center) will be used. 
The dose will be 50 mg/d, which is well within the range of doses that were well tolerated in 
previous patient studies (Goff et al. 1999a, b, 2005, 2008; Heresco-Levy et al. 1998, 2002). No 
adverse effects on kidney, liver, hematology or blood chemistry values have been reported. The 
subjects will be monitored closely by the research team and by their own psychiatrists. Blood 
chemistries, including liver/kidney function tests, will be monitored at baseline and monthly 
during the open-label DCS treatment arm as well as every 6 weeks after that. As mentioned 
above, at the low dose of DCS that we plan to use, the only reported psychiatric side effect was 
a modest and time-limited worsening of negative symptoms in a small minority of patients who 
were taking clozapine; this effect may be related to having a high DCS plasma level (Goff et al. 
1996, 1999a, b). Interestingly, this mild worsening was not “particularly distressing to patients or 
clinicians” (Goff et al. 1999a). Subjects will also take one vitamin B-complex tablet/day to ensure 
that they do not develop B12 and folate deficiency. These are unlikely at the low dose of DCS 
(50 mg) that will be used. 
 
Periodic blood samples involve the slight discomfort of a needle stick and the small risk of a 
bruise. Every attempt is made to have the subject feel comfortable and at ease with the 
environment and the staff. Subjects are debriefed at the end of the day by the study coordinator 
at which time they can ask questions and express their reactions to the study. Subjects who 
wish to discontinue the study may withdraw at any time. 
 
Risks to privacy and confidentiality are minimal. All subjects are assigned a random 4-digit ID 
number, which is used to code all material.  
 
EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
 
The general goal of this study is to clarify the neurobiology of a mutation in glycine metabolism 
and to determine whether carriers of this mutation may preferentially benefit from DCS 
augmentation of their medication regimen. Although subjects receive no immediate benefit from 
the brain imaging procedures beyond contributing to important research, the potential scientific 
yield could have a major impact on identifying causal mechanisms in psychotic disorders. If the 
DCS augmentation is beneficial, these two subjects may experience a significant reduction in 
psychotic symptoms and improvement in neurocognition, which may also help other subjects 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
7 
with mutations impacting the glycine metabolic pathway. Since both subjects responded well to 
glycine, which is a cumbersome to use and an unrealistic long-term treatment, DCS, which is 
available in a once daily pill would be a helpful long-term clinical adjunct if it is shown to be 
effective.  
 
EQUITABLE SELECTION OF SUBJECTS 
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
The only scientific and ethical justification for including subjects in this study is if their 
participation can help to clarify the neurobiology of a mutation in glycine metabolism and if they 
might benefit from DCS augmentation. All other subjects are excluded. Therefore, the only 
eligible participants at the present time are two carriers of this specific genetic mutation who 
also have a diagnosis of a psychotic disorder and have participated in the Neurobiology of a 
Mutation in Glycine Metabolism in Psychotic Disorders (2012P001597) protocol. To our 
knowledge, this is a private mutation although different mutations in the same gene have been 
reported in other individuals with psychotic disorders and with autism spectrum disorders. These 
individuals may be potentially eligible for a similar augmentation intervention. 
 
When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so.  Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present.
N/A 
 
For guidance, refer to the following Partners policy: 
          Obtaining and Documenting Informed Consent of Subjects who do not Speak English
          https://partnershealthcare-public.sharepoint.com/ClinicalResearch/Non-
English_Speaking_Subjects.1.10.pdf
 
 
 
RECRUITMENT PROCEDURES 
Explain in detail the specific methodology that will be used to recruit subjects.  
Specifically address how, when, where and by whom subjects will be identified and 
approached about participation.  Include any specific recruitment methods used to 
enhance recruitment of women and minorities.
The subjects will be selected on the basis of having a triplication of the GLDC gene, a mutation 
involving an abnormality in glycine metabolism that may be implicated in psychotic disorders, a 
psychotic disorder, and having participated in the Neurobiology of a Mutation in Glycine 
Metabolism in Psychotic Disorders (2012P001597) protocol. Prior to beginning the study, the PI 
will call the subjects and review all of the procedures and time frames. The subjects will be 
flown to Boston for the McLean procedures and to Minneapolis for the UMN procedures. Other 
procedures will be carried out in the subjects’ city of residence. The procedures will be 
scheduled well in advance to minimize inconvenience to the subjects and to optimize successful 
data collection at McLean.  

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
8 
 
Provide details of remuneration, when applicable.  Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation.  Investigators may wish to consider providing reimbursement for such 
expenses when funding is available
Each subject will be paid $1,000 for completing the open-label DCS study and $1,000 for 
completing the entire double-blind DCS-placebo study. They will each be paid $200 for the 
UMN procedures. The imaging, electrophysiology procedures will involve at least 1 week 
away from work other responsibilities. All expenses incurred as part of participating (e.g., 
travel, hotel, local transportation, and meal costs) will be paid for by the grant supporting this 
study. Subjects will be paid a pro-rated amount if unable to complete all procedures based 
on the proportion of the study that was completed. For example, if a subject completes 80% 
of the procedures, that subject would be paid $800. Any additional expenses related to 
participation, such as gas or taxis, up to $500.00 in year 1 and up to $300 in year 2, will be 
reimbursed based on submitted receipts. 
 
For guidance, refer to the following Partners policies: 
          Recruitment of Research Subjects 
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Recruitment_Of_Research_Subjects.pdf
 
          Guidelines for Advertisements for Recruiting Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Guidelines_For_Advertisements.1.11.pdf
 
          Remuneration for Research Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Remuneration_for_Research_Subjects.pdf
 
 
CONSENT PROCEDURES 
Explain in detail how, when, where, and by whom consent is obtained, and the timing of 
consent (i.e., how long subjects will be given to consider participation).  For most 
studies involving more than minimal risk and all studies involving investigational 
drugs/devices, a licensed physician investigator must obtain informed consent.  When 
subjects are to be enrolled from among the investigators’ own patients, describe how 
the potential for coercion will be avoided.
The PI and Dr. J. Alexander Bodkin, a licensed physician who provides medical back-up for the 
study, will obtain written informed consent after reviewing the purposes of the study, detailing 
the procedures and explaining the informed consent documents. The subjects will have several 
weeks to consider participation. The subject will be given an opportunity to ask questions after 
which written informed consent is obtained. Competence to give informed consent will be 
determined by the PI based on the subject’s understanding of the purpose of the study and 
procedures, what they involve, how long they take, and risk and benefits. The subject receives a 
copy of the Informed Consent for his/her own files.  
 
NOTE: When subjects are unable to give consent due to age (minors) or impaired 
decision-making capacity, complete the forms for Research Involving Children as 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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Subjects of Research and/or Research Involving Individuals with Impaired Decision-
making Capacity, available on the New Submissions page on the PHRC website: 
      https://partnershealthcare.sharepoint.com/sites/phrmApply/aieipa/irb 
 
For guidance, refer to the following Partners policy: 
     Informed Consent of Research Subjects:
     https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Informed_Consent_of_Research_Subjects.pdf
 
 
 
DATA AND SAFETY MONITORING 
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief description of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and complexity of the 
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity.        
 
NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care. 
 
The scientific integrity of the study and protection of participant safety will be monitored by the 
investigators using an Adverse Event Tracking Log, including the detection and reporting of 
adverse events. The safety data include all imaging procedures, the neurocognitive function 
battery, as well as the double-blind placebo-controlled and open-label DCS augmentation trials. 
Efficacy data includes all DCS-related procedures.  
 
All adverse events will be promptly reported to the Partners Human Research Committee 
(PHRC) and NIMH as appropriate. At a minimum, the investigators will review all adverse 
events at the end of each treatment arm, but more often if needed. Unanticipated problems 
involving risks to subjects or others including adverse events will be reported to the PHRC in 
accordance with PHRC unanticipated problems reporting guidelines. 
 
The research will be altered or stopped if subjects have adverse reactions to any of the 
procedures (e.g., claustrophobia in the scanners) or significant side effects to DCS. The dose of 
DCS used in the augmentation trials (50 mg/d) is well tolerated and is a standard dose used in 
clinical trials. Dr. Goff, a consultant on this project, has a great deal of experience in using DCS 
to augment the therapeutic effects of antipsychotic medication. Dr. Goff will be available to 
discuss ongoing clinical states, side effects, and to address any relevant management issues. 
At least once every week, the subjects will receive a phone call from Dr. Levy to discuss how 
they are feeling and to review side effects. At the end of the first week of DCS, the subjects will 
also be called by a study physician (Dr. Bodkin) to assess how they are reacting to the DCS or 
placebo. Both subjects’ psychiatrists will also be monitoring their clinical states and side effects 
throughout the study.  Subjects will be told that if they experience any side effects, they must 
report them to Dr. Levy or any of the other co-investigators immediately (phone and page 
numbers through the McLean Hospital operator will be provided).  
 

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Partners Collaborative Media (PCM) will provide oversight (for a fee) to ensure that the clinical 
assessments taking place every two weeks using skype-like video conferencing are secure. 
Specific web cameras recommended by PCM will be used by McLean staff and by the subjects. 
All calls will be initiated from McLean using a Partners computer. This computer will have the 
Cisco program, “movi” [mobile video], installed. PCM will create generic credentials for the 
subjects such that they will not be using their own actual skype credentials. Thus, if the skype 
material is stolen, it cannot be linked to the subjects themselves.  A McLean clinician will call the 
subjects by clicking on customized phone numbers and allow the McLean caller to lock the 
virtual meeting room. 
 
A technical statement about how the secure connection will be implemented has been 
uploaded. 
 
Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  When the investigator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites.   
 
NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the Partners Human Research Committee guidelines for Adverse Event 
Reporting
 
Subjects will be discontinued from the study if the BPRS shows a 25% worsening or severity of 
specific symptoms changes by two additional points (compared with baseline). Any adverse 
events will be immediately reported to the IRB. 
 
MONITORING AND QUALITY ASSURANCE 
Describe the plan to be followed by the principal investigator/study staff to monitor and 
assure the validity and integrity of the data and adherence to the IRB-approved 
protocol.  Specify who will be responsible for monitoring, and the planned frequency of 
monitoring.  For example, specify who will review the accuracy and completeness of 
case report form entries, source documents, and informed consent.   
 
NOTE: Regardless of monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for ensuring that the study is conducted at his/her 
investigative site in accordance with the IRB-approved protocol, and applicable 
regulations and requirements of the IRB.
The PI will monitor the validity and integrity of the data and ensure that all appropriate forms 
(e.g., consent forms) have been thoroughly completed and that all blood samples are collected 
and shipped in accordance with the approved protocol. Monitoring will be done on an ongoing 
basis in close collaboration with the co-investigators. 
 
For guidance, refer to the following Partners policies: 
          Data and Safety Monitoring Plans and Quality Assurance
            https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/DSMP_in_Human_Subjects_Research.pdf  

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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          Reporting Unanticipated Problems (including Adverse Events)
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Reporting_Unanticipated_Problems_including_Adverse_E
vents.pdf
 
 
 
PRIVACY AND CONFIDENTIALITY 
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected.  This typically includes such practices as substituting codes for names and/or medical 
record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location.   
 
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of 
sensitive data, such as sexual, criminal or illegal behaviors.
 
Each subject will be assigned a 4-digit randomly generated ID number. All scans and blood 
samples will be labeled with this ID number. Signed consent forms and demographics forms 
with identifying information will be kept in locked file cabinets stored in a secure location with 
access limited to Drs. Levy, Ongur, or Bodkin. Computer databases are password protected.   
 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects.
 
Blood samples will be sent to Dr. Raymond Suckow, Analytical Psychopharmacology 
Laboratory at the Nathan Kline Institute, for amino acid and psychotropic drug levels. Samples 
will be labeled with a 4-digit randomly generated ID number for each subject, a date and a time 
of day. The identity of the subjects will not be known to Dr. Sukow. 
 
Specifically address whether specimens/data will be stored at collaborating sites outside 
Partners for future use not described in the protocol.  Include whether subjects can withdraw 
their specimens/data, and how they would do so.  When appropriate, submit documentation of 
IRB approval from the recipient institution.
N/A 
 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
12 
RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
When specimens or data collected by research collaborators outside Partners will be 
sent to Partners investigators, indicate from where the specimens/data will be obtained 
and whether the specimens/data will contain identifiers that could be used by Partners 
investigators to link the specimens/data to individual subjects.  When appropriate, 
submit documentation of IRB approval and a copy of the IRB-approved consent form 
from the institution where the specimens/data were collected.
N/A