Clinical trial NCT01928446
Conditions: Depressive Disorder Bipolar Disorder Suicide Suicide, Attempted
Keywords: Lithium Placebo Double-blind methods Clinical Trials, Randomized Veterans
Sponsor: VA Office of Research and Development
Start date: 2015-07-08; Completion date: 2019-08-13
Enrollment: 519 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Observational evidence and findings from clinical trials conducted for other reasons suggest that lithium, a drug used for the treatment of bipolar disorder, and, to a lesser extent, depression, may reduce rates of suicides and suicide attempts. However, this hypothesis has not yet been adequately examined in a randomized clinical trial conducted specifically to test lithium's efficacy in preventing suicides. This clinical trial fills this gap.

This study is feasible within the Department of Veterans Affairs (VA) because it is a large, integrated health system with existing programs for identifying patients at risk for suicide and delivering enhanced services. In VA, approximately 12,000 patients with depression or bipolar disorder survive a suicide attempt or related behavior each year, and 15% of them repeat within one year. Experimental treatment in this study will supplement usual care for major depression or bipolar disorder, as well as VA's standard, enhanced management for patients at high risk.

The investigators will recruit 1862 study participants, from approximately 30 VA Hospitals. Participants will be patients with bipolar disorder or depression who have survived a recent episode of suicidal self-directed violence or were hospitalized specifically to prevent suicide. Randomly, half will receive lithium, and half will receive placebo. Neither the patients nor their doctors will know whether a particular person has received lithium or placebo. The treatment will be administered and the patients will be followed for one year, after which patients will go back to usual care. Recruitment will occur over 3 years.

The investigators are primarily interested in whether lithium leads to increases in the time to the first repeated episode of suicidal behavior, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. In addition, this study will allow us to explore whether lithium decreases the total number of suicidal behaviors, and whether it has comparable effects on impulsive and non-impulsive behaviors. If there is an effect of lithium, the investigators will be interested in whether or not it could be attributed to improved control of the underlying mental health condition, or, alternatively, whether it represents a direct effect of suicide-related behavior.

Detailed description:
Objective: To test the hypothesis that lithium augmentation of enhanced usual care will reduce the rate of repeated episodes of suicidal self-directed violence (repeated suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event.

Background: The hypothesis that lithium can prevent suicide in patients with bipolar disorder and depression is based on data from observational studies and randomized clinical trials conducted to evaluate other outcomes. The question about the effectiveness of lithium for suicide prevention is one of major scientific, clinical, and public health significance. There have been no adequately powered clinical trials conducted specifically to evaluate suicide behaviors as an outcome. Two recent randomized clinical trials failed to recruit adequate numbers of subjects to be conclusive.

The VHA, as a large national healthcare system with an established program for identifying new suicide attempts, evaluating patients for underlying mental health and medical conditions, providing needed services, connecting Veterans to state-of-the-art suicide risk management, and monitoring outcomes is uniquely able to conduct a large scale clinical trial of lithium for suicide prevention.

The rationale for the study is based on the following:

* Data from observational studies and double-blind randomized clinical trials suggest that lithium can prevent suicide-related behaviors in patients with bipolar disorder and major depression.
* The high risk of suicide in Veterans receiving health care services from VHA has persisted despite extensive improvements in mental health services and in programs for suicide prevention.
* Each month, there are over 1,100 unique VHA patients with bipolar disorder or depression who attempt suicide and survive.
* Surviving a suicide attempt is the most powerful known risk factor for death from suicide in VA and elsewhere.
* Approximately 15% of VA survivors reattempt or die from suicide within one year.
* Evaluating rates of reattempts in those who have survived attempts is an established and effective method for testing interventions that may prevent suicide.
* Experimental treatment in CSP-590 would supplement usual care for major depression or bipolar disorder.
* Study procedures for the management of suicide risk would meet or exceed VA standards and requirements.
* Study procedures optimize the safety of lithium, including the potential risk of overdoses, and meet or exceed all published practice standards. The trial will utilize multiple strategies to minimize risks including frequent monitoring and assessment, determination of lithium levels during titration and at steady state, and dispensing medications in limited quantities in blister packs.
* The investigator's survey of VA psychiatrists indicates that the question is clinically important and compelling and that a clinical trial that demonstrated the hypothesized effect would transform the clinical management of suicidality.

Design: Randomized, double-blind, placebo-controlled clinical trial of lithium versus placebo augmentation of enhanced usual care.

Patient population: VHA patients with bipolar disorder or depression who have survived a recent episode of suicidal self-directed violence.

Primary outcome: Time to the first repeated episode of suicidal self-directed violence, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide

Duration: Total study duration will be 4.5 years. Recruitment will occur over 3 years. Participants will be followed for one year.

Sample size calculations and number of sites required: The design of the study is based on testing for a 37% reduction in the rate of repeated suicidal self-directed violence, a figure based on an effect size of approximately 43% observed in recent studies and then allowing for attenuation due to non-adherence. Adjusting for potential data loss due to attrition, 90% statistical power to detect a significant 37% reduction in reattempt rates at 5% overall type I error would require 1862 subjects. With recruitment of 20% of eligible subjects over a three year period, this would require approximately 9310 potentially eligible subjects. Based on current suicide surveillance data, this could be achieved with 29 sites.

Arms: arm 1: Lithium in the form of extended release lithium carbonate. Subjects will be started on 600 mg/day (300mg bid) until steady state at target plasma levels between 0.6 and 0.8 meq/liter is achieved. The lowest dose will be 300 mg/day. Lithium will be prescribed for the duration of follow-up (1 year). arm 2: Placebo tablets will be given to the subjects for the duration of follow-up (1 year). Dose adjustments will mimic the intervention arm of the study
Interventions: intervention 1: Lithium intervention 2: Placebo
Intervention descriptions: intervention 1: Lithium in the form of extended release lithium carbonate. Subjects will be started on 600 mg/day (300mg bid) until steady state at target plasma levels between 0.6 and 0.8 meq/liter is achieved. The lowest dose will be 300 mg/day. Lithium will be prescribed for the duration of follow-up (1 year). intervention 2: Oral placebo tablets will be administered for the duration of follow-up (1 year).

Protocol documents:
ICF_002.pdf: 
RESEARCH CONSENT FORM 
Version Date:  5 April 2018 
Participant Name:                                                                                     Date:  _________________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patient With Depression or Bipolar Disorder 
Local Site Investigator:  _______________________________ VA Facility:v _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                      
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:         N/A 
LSI Verification Date:              N/A 
CSP 590 ICF#1 Page 1 of 12 
 
PART ONE: SCREENING FOR ELIGIBILITY 
INTRODUCTION 
You are being invited to take part in a research study that is being funded by the Department of 
Veterans Affairs. Before you decide to take part, it is important for you to know why the research 
is being done and what it will involve. This includes any potential risks to you, as well as any 
potential benefits you might receive. 
Read the information below closely, and discuss it with family and friends if you wish. Ask one of 
the study staff if there is anything that is not clear or if you would like more details. Take your 
time to decide. If you do decide to take part, your signature on this consent form will show that 
you received all of the information below and that you were able to discuss any questions and 
concerns you had with a member of the study team. 
BACKGROUND AND PURPOSE 
Why the research is being done and why you are being asked to participate: 
The VA is doing everything it can to improve its care and learn how to prevent suicides. VA is 
doing this research to learn if lithium, a medicine used for treating bipolar disorder and 
depression, can prevent repeated suicide attempts in Veterans. There is some evidence that 
lithium may be helpful in preventing repeated suicide attempts but this has not been proven. 
This study is being done to determine whether or not lithium is effective in preventing repeated 
suicide attempts. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018 
Participant Name:                                                                                     Date:  _________________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patient With Depression or Bipolar Disorder 
Local Site Investigator:  _______________________________ VA Facility:v _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                      
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:         N/A 
LSI Verification Date:              N/A 
CSP 590 ICF#1 Page 2 of 12 
 
The complete study has two parts. Part One is to determine if you are eligible for Part Two, 
which is the actual study. Part One consists of an interview, filling out questionnaires, and a 
consultation with your mental health and an update to your primary care provider. If you meet 
the criteria for the study and you still want to participate, you go to the second part. In Part Two, 
half of the participants will get lithium and half will get a placebo (an inactive sugar pill). The 
placebo is necessary to see whether the benefits and possible harms could have happened 
anyway without the medication. All participants will be followed for one year to observe the 
benefits and harms of lithium or the placebo. 
You are being asked to consider participation in Part One because you have recently survived a 
suicide attempt, a near attempt, or other self harm behavior and because VA staff involved with 
your care let us know that you were interested in being contacted about this study. Your 
participation in Part One does not obligate you to go on to Part Two, the actual study. 
How many people will participate? 
We do not know how many Veterans we will need to screen for eligibility but the full study (Part 
Two) will include 1862 Veterans. 29 VA Medical Centers will participate; and about <insert 
number> patients will participate from this VA Medical Center. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018 
Participant Name:                                                                                     Date:  _________________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patient With Depression or Bipolar Disorder 
Local Site Investigator:  _______________________________ VA Facility:v _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                      
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:         N/A 
LSI Verification Date:              N/A 
CSP 590 ICF#1 Page 3 of 12 
 
Who is sponsoring the study and who is conducting it? 
The research is organized and sponsored by the VA Office of Research and Development. The 
lead researcher at this VA Medical Center is <insert site PI name>. 
DURATION OF THE RESEARCH   
The entire study will take 4 to 5 years to complete. Each person in the study will be in Part One 
from one day to several weeks, and in Part Two, the full study, for one year. 
If you agree to participate in Part One of this research, it would take about two to three hours of 
your time. If the results from this evaluation indicate that you are eligible for the full study, you 
would have the choice to continue or refuse testing required for Part Two of the study. You will 
have no obligation to agree to continue with Part Two. If, after reviewing all the details of the 
full study, you agree to participate, we would ask you to return for another visit and sign another 
consent form. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018 
Participant Name:                                                                                     Date:  _________________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patient With Depression or Bipolar Disorder 
Local Site Investigator:  _______________________________ VA Facility:v _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                      
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:         N/A 
LSI Verification Date:              N/A 
CSP 590 ICF#1 Page 4 of 12 
 
STUDY PROCEDURES for Part One: Screening for Eligibility  
If you decide to take part, you will be asked to complete an interview and questionnaires that 
cover your thinking and behaviors, mental health treatment, medications, use of alcohol and 
drugs, home and social supports and your understanding of the research study. You have the 
option not to answer any questions that may make you feel uncomfortable, but some responses 
are needed to see if you are able to participate in the study. We only ask questions to help us 
determine whether you are eligible. In addition, all interviews will be conducted in private. Any 
telephone discussions will be conducted once you inform us that you are in a location where 
you feel comfortable talking. You will also have information collected about your age, race, 
ethnicity, military history and contact information so that we can reach you. All this takes about 
two hours, and can be done in more than one session, in person and by telephone.  
All procedures described here are done for the purpose of research, not usual clinical care.  
After these are done we ask you to return to discuss our findings to see if you met the criteria 
and want to participate in the full study (Part Two).  
POSSIBLE RISKS OR DISCOMFORTS 
The interview and questionnaires may include questions that cause you discomfort. Although 
we encourage you to answer as best you can, you don’t have to answer any questions that 
make you feel uncomfortable. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018 
Participant Name:                                                                                     Date:  _________________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patient With Depression or Bipolar Disorder 
Local Site Investigator:  _______________________________ VA Facility:v _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                      
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:         N/A 
LSI Verification Date:              N/A 
CSP 590 ICF#1 Page 5 of 12 
 
POTENTIAL BENEFITS 
There are no benefits that can be guaranteed from your participation. You may possibly benefit 
from participation if the interview or the tests lead to new information that could help you and 
your doctors in your treatment. 
ALTERNATIVES TO PARTICIPATING IN THIS RESEARCH 
This screening process is not a treatment. If you choose not to participate, you will continue to 
receive all necessary treatment that your doctors think you need. You and your doctors may 
choose to use lithium or any other medications for your treatment. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018 
Participant Name:                                                                                     Date:  _________________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patient With Depression or Bipolar Disorder 
Local Site Investigator:  _______________________________ VA Facility:v _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                      
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:         N/A 
LSI Verification Date:              N/A 
CSP 590 ICF#1 Page 6 of 12 
 
CONFIDENTIALITY 
Taking part in Part One will involve collecting private information about you. This information will 
be protected in the following ways: 
Interviews will be conducted in private. Any telephone discussions will be conducted 
following arrangements to protect your privacy. 
Written notes related to your participation will be kept in locked files in locked offices. 
Electronic information derived from the interviews and tests will be kept in encrypted 
computer files in password protected computers in locked offices. 
Information from the interview may be shared with the doctors responsible for your 
health care. 
Information about you may be combined with information from other people taking part in 
the study to allow us to write about the combined data we have gathered. No talks or 
papers about this study will identify you. 
We will not share your records or identify you unless we have to by law. There are times 
when we might have to show your records to other people. For example, someone from 
the Office of Human Research Protections, the Government Accountability Office, the 
Food and Drug Administration, the Office of the Inspector General, the VA Office of 
Research Oversight, the VA Central IRB, our local Research and Development 
Committee, and other study monitors may look at or copy portions of records that 
identify you. 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018 
Participant Name:                                                                                     Date:  _________________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patient With Depression or Bipolar Disorder 
Local Site Investigator:  _______________________________ VA Facility:v _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                      
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:         N/A 
LSI Verification Date:              N/A 
CSP 590 ICF#1 Page 7 of 12 
 
To further help us protect your privacy, the investigators have obtained a Confidentiality 
Certificate from the Department of Health and Human Services. 
With this Certificate, the investigators cannot be forced (for example by court subpoena) to 
disclose information that may identify you in any federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings. 
Disclosure will be necessary, however, upon request of DHHS for the purpose of audit or 
evaluation. 
You should understand that a Confidentiality Certificate does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. Note however, that if an insurer or employer learns about your participation and 
obtains your consent to receive research information, then the investigator may not use the 
Certificate of Confidentiality to withhold this information. This means that you and your family 
must also actively protect your privacy. 
Finally, you should understand that the investigator is not prevented from taking steps, including 
reporting to authorities, to prevent serious harm to yourself or others. 
A description of this study is on http://www.ClinicalTrials.gov and required by U.S. Law. This 
website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018 
Participant Name:                                                                                     Date:  _________________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patient With Depression or Bipolar Disorder 
Local Site Investigator:  _______________________________ VA Facility:v _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                      
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:         N/A 
LSI Verification Date:              N/A 
CSP 590 ICF#1 Page 8 of 12 
 
COSTS TO PARTICIPANTS AND PAYMENT 
Costs to Participants: You will not be charged for any procedures that are part of this study. 
However, if you usually pay co-payments for VA care and medications, you will still have to pay 
these co-payments for VA care and medications that are not part of this study. 
Payment Offered for Participation: 
You will not be paid for participation in this study. However, if you must pay for transportation, 
parking, or other expenses related to participation, the study will reimburse you. If you travel 
less than 50 miles round trip you will receive $50, and if you travel 50 miles or more round trip 
you will receive $70. If you do not travel, but are being reimbursed for other expenses/time you 
will receive the lesser of the two amounts, $50. Reimbursement will be made available by 
<insert local info>. Payments will be made through Austin Financial Services Center and will 
generate Internal Revenue Service Form 1099 regardless of the amount. Your SSN will be used 
for this purpose in reimbursement. 
MEDICAL TREATMENT AND COMPENSATION FOR INJURY  
Every reasonable safety measure will be used to protect your well-being. If you are injured as a 
result of taking part in this study, the VA will provide necessary medical treatment at no cost to 
you unless the injury was due to your not following the study procedures. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018 
Participant Name:                                                                                     Date:  _________________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patient With Depression or Bipolar Disorder 
Local Site Investigator:  _______________________________ VA Facility:v _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                      
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:         N/A 
LSI Verification Date:              N/A 
CSP 590 ICF#1 Page 9 of 12 
 
If you should have a medical concern or get hurt or sick as a result of taking part in this study, 
call: 
 
During the day: 
 
Dr./Mr./Ms.                                                       at                                                 and  
 
 
After hours: 
 
Dr./Mr./Ms.                                            at ________________________. 
 
Emergency and ongoing medical treatment will be provided as needed. 
 
You do not give up any of your legal rights and you do not release the VA from any liability by 
signing this form. 
PARTICIPATION IS VOLUNTARY 
Participation in this study is voluntary. If you choose to participate in Part One, participation in 
Part Two remains voluntary. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018 
Participant Name:                                                                                     Date:  _________________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patient With Depression or Bipolar Disorder 
Local Site Investigator:  _______________________________ VA Facility:v _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                      
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:         N/A 
LSI Verification Date:              N/A 
CSP 590 ICF#1 Page 10 of 12 
 
Refusal to participate involves no penalty or loss of benefits. Your decision not to take part will 
not affect the relationship you have with your doctor or other staff, and it will not affect the usual 
care that you receive as a patient. If you are a VA employee or student, refusal to take part in 
the study will in no way influence your employment, ratings, subsequent recommendations, or 
academic progress. 
You may discontinue taking part in this study at any time without any penalty or loss of benefits. 
You may withdraw and still receive the same standard of care that you would otherwise have 
received. 
If you do withdraw from the study, the research team may continue to review the information 
they already collected. They cannot collect further information except from public records. 
RIGHT OF INVESTIGATOR TO TERMINATE PARTICIPATION 
The investigator may end the study if new information becomes available on lithium for suicide 
prevention. Should this happen, the research team will let you and your doctors know, and they 
will share the information they have obtained with you and your doctor to guide treatment 
planning.  
Your participation in this study may be terminated if you do not follow study procedures. 
 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018 
Participant Name:                                                                                     Date:  _________________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patient With Depression or Bipolar Disorder 
Local Site Investigator:  _______________________________ VA Facility:v _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                      
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:         N/A 
LSI Verification Date:              N/A 
CSP 590 ICF#1 Page 11 of 12 
 
PEOPLE TO CONTACT ABOUT THIS STUDY 
If you have any questions, complaints, or concerns about this study, you may contact the study 
investigator at your VA Medical Center <insert info> or the study coordinator. 
 
The investigator is Dr./Mr./Ms.                         at____________________________  
 
The <insert info> is Dr. /Mr./Ms. _____                        at ________________________. 
If you have questions about your rights as a study participant, or you want to make sure this is a 
valid VA study, you may contact the VA Central Institutional Review Board (IRB). This is the 
Board that is responsible for overseeing the safety of human participants in this study. You may 
call the VA Central IRB toll free at 1-877-254-3130 if you have questions, complaints or 
concerns about the study or if you would like to obtain information or offer input. 
FUTURE USE OF DATA AND RE-CONTACT 
After Part Two of this study ends, your study data will be stored indefinitely at the Cooperative 
Study Program, Massachusetts Veterans Epidemiology Research and Information Center 
(MAVERIC). 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018 
Participant Name:                                                                                     Date:  _________________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patient With Depression or Bipolar Disorder 
Local Site Investigator:  _______________________________ VA Facility:v _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                      
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:         N/A 
LSI Verification Date:              N/A 
CSP 590 ICF#1 Page 12 of 12 
 
AGREEMENT TO PARTICIPATE IN THE RESEARCH STUDY 
___________________________ (insert name and title of person obtaining consent) has 
explained the research study to you. You have been told of the risks or discomforts and possible 
benefits of the study. You have been told of other choices of treatment available to you. You 
have been given the chance to ask questions and obtain answers. 
By signing this document below, you voluntarily consent to participate in this study. You also 
confirm that you have read this consent, or it has been read to you.  You also give permission 
for the research team to contact family members, friends, or others who would be likely to know 
your whereabouts prior to randomization if we are unable to contact you. You will receive a copy 
of this consent after you sign it. A copy of this signed consent will also be put in your medical 
record if applicable. 
 
 
I agree to participate in this research study as has been explained in this document. 
 
 
_________________________ 
Participant’s Name 
____________________________ 
Participant’s Signature 
___________ 
Date 
_________________________ 
Name of person obtaining consent 
 
 
_____________________________ 
Signature of person obtaining consent 
____________ 
Date 

ICF_003.pdf: 
RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 1 of 19 
 
Part Two: Randomized Trial 
INTRODUCTION 
You are invited to take part in a research study that is funded by the Department of Veterans 
Affairs. Before you decide to take part, it is important for you to know why the research is being 
done and what it will involve. This includes any potential risks to you, as well as any potential 
benefits you might receive.  
Read the information below closely, and discuss it with family and friends if you wish. Ask one of 
the study staff if there is anything that is not clear or if you would like more details. Take your 
time to decide. If you do decide to take part, your signature on this consent form will show that 
you received all of the information below, and that you were able to discuss any questions and 
concerns you had with a member of the study team.  
BACKGROUND AND PURPOSE 
 
Why is the research being done? 
The VA is doing everything possible to improve the mental health of Veterans. It is a tragedy 
when someone tries to take their own life, and the VA is trying to learn how to improve our 
efforts to prevent this from happening.  
The purpose of this study is to learn if lithium, a medicine used for treating bipolar disorder and 
depression, is effective in preventing repeat suicide attempts. There are no medicines for 
preventing suicide for people with depression or bipolar disorder, but some studies indicate that 
lithium may work in people who have depression or bipolar disorder. However we do not know 
for sure whether lithium prevents suicides.  
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 2 of 19 
 
Participants in the study have a 50:50 chance of receiving either lithium or placebo (sugar pill) in 
addition to the full array of VA mental health and suicide prevention treatment we have in the VA 
currently. The placebo is necessary to see whether the benefits and harms would have occurred 
anyway.  
Why am I being asked to participate? 
You are being asked to participate in this study because you have had an experience with a 
suicide attempt, a near attempt or another form of self harm. You also have bipolar disorder or 
depression. You are thus among those people we believe lithium is most likely to help. You 
have gone through the Screening Evaluation (Part One) and may be eligible for the study. 
The research team will review this consent form with you, answer any questions, provide you 
with all the information that you want to help you decide whether or not you want to be in the 
study. 
Is the treatment used in this study approved by the Food and Drug Administration 
(FDA)? 
Lithium is approved by the FDA for treating an acute manic episode in bipolar disorder. It is also 
sometimes used for treating depression but this use is not approved by the FDA. Using lithium 
for suicide prevention is also not approved by the FDA. We are doing this study to see whether 
lithium is useful to prevent suicides.   
Who is sponsoring the study and who is conducting it? 
The VA Office of Research and Development is designing and paying for the study. The lead 
researcher at this VA Medical Center is <insert name of PI>. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 3 of 19 
 
How many people will participate in the study? 
1862 people from 29 VA Medical Centers will be involved. We think about <insert site info> 
Veteran participants will come from this Medical Center.  
DURATION OF THE RESEARCH 
You will need to have another evaluation to determine your eligibility for the study. This includes 
a physical exam, blood tests and electrocardiogram. This will take about two hours of your time. 
If you are eligible and decide to participate, your participation in the study will be for one year. 
The entire study will take 4 to 5 years to complete and to make the results available to the 
people who have participated. We will review your medical records until the study has finished; 
however, we will not need to contact you after you complete one year of participation in the 
study. 
STUDY PROCEDURES 
Determining Eligibility (2 hours) 
Before being randomized in the study, we will need to further confirm your eligibility (in addition 
to the assessments done in Part One). You will have a medical checkup, an electrocardiogram 
(heart tracing) and have a blood sample taken (about two tablespoons of blood) to check your 
kidney, liver and thyroid function. If you are a woman of childbearing age, you will be asked 
about birth control and will provide urine for a pregnancy test. Acceptable forms of birth control 
include methods of birth control which result in a low failure rate (less than 1% per year) when 
used consistently and correctly. These methods include implants, injectables, combined oral 
contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized partner.  
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 4 of 19 
 
All procedures described here are done for the purpose of research, not usual clinical care.  
After these are done we will discuss our findings with you to see if you met the criteria and want 
to enroll in the full study. This may happen on the same today or we may ask you to return at a 
later date. 
Randomization of Study Medications (1.25 hours) 
At the beginning of the study, you will be randomly (by ‘toss of the coin’) assigned to get lithium 
or a placebo, a pill that looks and tastes just like lithium but has no effect on your body. You 
have a 50:50 chance of receiving lithium or placebo. Neither you nor your doctor will know 
which pill you are getting. The lithium or placebo (both called “study medication”) will be 
given for 1 year. 
The number of pills will be adjusted until the right blood level is reached. Blood levels and 
adjusting the number of pills will be done every 5 to 14 days for about 6-8 visits. 
You will bring in old pill packages at each visit and receive new ones or by express mail. The 
packages contain a 2 week supply. 
Follow-up visits (45 minutes – 1.25 hours) 
You will come in every 5-14 days until the medications are adjusted. This usually takes 6 to 8 
visits. After that the study visits will be monthly for 1 year. You may need to be seen more if your 
health changes for any reason.  
During the year follow-up, a few visits will require an electrocardiogram, and your blood will be 
taken monthly for the first 6 months, then every 3 months until the end of the study. If you are 
taking certain blood pressure medications, your blood will be taken at every visit. At each visit 
we will check on any side effects you are having, changes in your medications or health and ask 
you to fill out questionnaires about how you are feeling. 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 5 of 19 
 
Some of the study can be done by phone. If blood tests or an electrocardiogram are necessary, 
we will try to arrange it so that it is convenient for you. There will be approximately twenty (20) 
study visits over the course of the one year. 
Your medical condition or medications (even ones where you don’t need a prescription) might 
change. If this happens, you and/or your physician should notify the study team. The study 
medication may need to be adjusted or stopped. In either situation, you may still continue in this 
study.  
In addition to the study pills, you will receive your normal medical and mental health care which 
includes the special VA care for people who have tried to commit suicide or are at high risk. We 
strongly encourage you to use this care.   
One year after randomization – Month 12/End of study participation (1.75 hours) 
The end of study medication visit will include the following procedures:  recording of all your 
current medicines, having and ECG done, Brief physical exam and the recording of vital signs 
(heart rate, temperature, breathing rate and blood pressure), completion of 5 questionnaires, 
review of any adverse side effects, collection of study medication cards and any unused study 
medication and your study medication diary. 
After the visit, the research staff will inform your VA mental health provider (psychiatrist or nurse 
practictioner) whether you were taking lithium or placebo so the two of you can decide on further 
treatment with medications. If you were on lithium and decide to stop it, it is safer to gradually 
lower the dose over a few weeks, as there is information that stopping lithium suddenly may not 
be as safe. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 6 of 19 
 
30 Day Follow-up Visit (30 minutes) 
Thirty days after 1 year of follow-up, there will be a final visit that is basically the same as the 
one you did when being screened for eligibility (Part One).  You and the research staff will 
complete 4 questionnaires.  You will also be asked about any ongoing adverse side effects. 
After study participation has ended: 
After you complete study participation (1 year) and until the study ends (up to 4-5 years), we will 
review your medical records to track how your health has been since your final study visit. To 
determine your health status, we will review your medical records and VA clinical databases. 
POSSIBLE RISKS OR DISCOMFORTS 
Any procedure has possible risks and discomforts. The procedures in this study may cause all, 
some, or none of the risks or side effects listed. Rare, unknown, or unexpected risks also may 
occur. These risks are different from any risks you might encounter from usual care. This form 
only covers risks from the research. 
The possible risks and discomforts of participation include the inconvenience of the time for 
research visits. To the extent possible, interviews will be scheduled at your convenience or by 
telephone to minimize this.  
Each blood test requires about a teaspoon of blood or about eight tablespoons over a year. This 
is not enough blood loss to cause any medical effects. However, the needle sticks may cause 
pain (like a pinch), or bruising, and, rarely, infections. Very rarely, patients become lightheaded 
or faint from having blood drawn. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 7 of 19 
 
The primary risks and discomforts of participation are from the study medication. Lithium has 
been used for over 30 years and is generally safe if used as instructed and blood levels 
monitored. It should be kept out of the reach of children or others with limited capacity to read or 
understand. You should not break, chew or crush the tablet. If you experience any troubling side 
effects you should immediately contact the research team. 
Risks and Side effects 
You may experience side effects during this study regardless of whether you are taking lithium 
or placebo. If people have side effects, they usually have them when they first begin lithium. 
These are usually mild and go away after days or weeks. The most frequent side effects include 
nausea, loose stools, thirst, change in urination patterns, shakiness, headaches, sweating, 
fatigue, decreased concentration, and skin rash.  
Side effects that last are usually due to high levels of lithium in the blood. These usually go 
away with lowering the dose of lithium or changing the time it is taken. Also, some medications 
may interact with lithium. The study team will review your medications to check for known 
interactions. It is important that you notify the study team of any new medications prescribed 
before starting them so that the study team may be aware of any potential interactions with 
lithium. For some medications, the study drug dose may need adjusting and extra monitoring 
might be necessary. 
Side effects: 
Risks of the usual care you receive are not risks of the research. Those risks are not included in 
this consent form. You should talk with your health care providers if you have any questions 
about the risks of usual care. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 8 of 19 
 
Symptoms that up to 75% of people experience who start lithium and which go away in 
90 to 99% of people who continue lithium: 
 
Mild nausea 
 
Loose stools 
 
Abdominal discomfort 
 
Decreased appetite 
 
Weight change 
 
Thirst 
 
Changes in urination patterns 
Shakiness of the hand 
Headache 
Sweating 
Fatigue 
Decreased concentration 
Rash 
Dry Skin 
Hair thinning 
Fast or pounding heartbeat 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 9 of 19 
 
Adverse side effects that occur less frequently but may persist: 
Decreased activity of the thyroid gland, or increased size of the gland. This may occur in 
about 25% of people so we will monitor your thyroid function throughout the study.  
Lithium may cause worsening of pre-existing acne or psoriasis in about 50% of people 
who already suffer from these conditions. This worsening usually goes away once 
lithium is stopped. 
Adverse side effects that occur in less than 1-2% of people taking lithium: 
Lithium toxicity in which people get diarrhea, vomiting, drowsiness, weakness, lack of 
coordination, dizziness, confusion, trouble with walking or balance, blurred vision, ringing 
in the ears, and stupor, coma, seizures, blackouts, multiple organ failure, dangerous 
heart irregularity and death 
You should let us know immediately if your health changes or when you start any new 
medications.  
Certain illnesses and certain medications (particularly nonsteroidal anti-inflammatory drugs 
(NSAIDs), such as high dose aspirin, ibuprofen, and naproxen, medicines used for heart 
problems, and medicines used to treat high blood pressure) may change your lithium level even 
though you are taking the same amount of lithium. Increased lithium levels may increase side 
effects or lithium toxicity, and decreased lithium levels may be less effective.  
Lithium is dangerous when blood levels go too high. We will be closely monitoring your lithium 
blood levels, so it is unlikely that toxicity will occur if you follow directions carefully. You should 
contact the research team, your psychiatrist, or a doctor immediately if you have taken too much 
of your study medication. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 10 of 19 
 
Risks associated with suddenly stopping study medications: 
For people taking lithium for bipolar disorder, stopping the medication too quickly can lead to 
recurrences of mania or depression, and increase the risk of suicide.  
Before you discontinue your study medication for any reason, it is important that you contact the 
research team or your psychiatrist so they can help you do it safely. 
They will give you instructions on how to safely stop taking the study medication. 
Reproductive Risks: 
Lithium can cause birth defects and it is not safe to take during pregnancy. If you are pregnant, 
plan to become pregnant, or are nursing, you cannot take part in this study. You must notify us 
immediatlely if your method of birth control changes and/or you believe that it may have lapsed 
and you are at an increased risk of pregnancy. 
A pregnancy test will be performed at each study visit for those participants of childbearing 
potential.  The test will be performed by urinalysis. If you are able to become pregnant, you will 
have a pregnancy test before starting this study. While taking the study drug, you should not 
become pregnant. During the study you need to take measures to prevent pregnancy by using a 
medically accepted method of birth control. 
If you become pregnant, you need to stop taking the study medication and tell your doctor and 
the research team immediately. You will be asked to sign a separate consent form and HIPAA 
so that we may follow you during the pregnancy up and and including the pregnancy outcome. 
POTENTIAL BENEFITS 
Lithium may or may not be effective for suicide prevention. You may not benefit from taking 
study medications.  


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 11 of 19 
 
The VA and society as a whole may benefit from this research by learning more about how to 
prevent suicide. 
ALTERNATIVES TO PARTICIPATING IN THIS RESEARCH 
Participation in this research is completely voluntary. 
Whether or not you participate, you will receive safety planning and other services for Veterans 
at risk for suicide, treatments (including medications) for depression, bipolar disorder, and other 
mental health conditions, and treatment for any medical conditions you have.  
This treatment may include receiving lithium under the direction of your current doctor.  
CONFIDENTIALITY 
Taking part in this study will involve collecting private information about you. This information 
will be protected in the following ways:  
Interviews will be conducted in private. Any interviews or discussions over the telephone will be 
conducted following arrangements you choose to protect your privacy. Written notes related to 
your participation in this study will be kept in locked file cabinets in locked offices. Electronic 
information derived from the interviews and tests will be kept in encrypted computer files in 
password protected computers in locked offices.  
Information from your research participation will be shared with the doctors responsible for your 
medical and mental health care. Results from the electrocardiogram and the blood tests except 
for the lithium levels will be included in your medical records.  
During the study, we will monitor your VA medical record to see if you have had any suicide 
attempts or self-harm events. If you are also receiving care from a non-VA clinic or hospital, we 
will ask your permission to obtain those records to confirm any suicide events that you or your 
study doctor tells us about. 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 12 of 19 
 
Information about you may be combined with information from other people taking part in the 
study to allow us to write about the combined data we have gathered. No talks or papers about 
this study will identify you. 
We will not share your records or identify you unless we have to by law. There are times when 
we might have to show your records to other people. For example, someone from the Office of 
Human Research Protections, the Government Accountability Office, the Food and Drug 
Administration, the Office of the Inspector General, the VA Office of Research Oversight, the VA 
Central IRB, our local Research and Development Committee, and other study monitors may 
look at or copy portions of records that identify you.  
We will do everything we can to keep others from learning about your participation in the 
research. To further help us protect your privacy, we have obtained a Confidentiality Certificate 
from the Department of Health and Human Services. With this Certificate, the investigators 
cannot be forced (for example by court subpoena) to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings. 
Disclosure will be necessary, however, upon request of DHHS for the purpose of audit or 
evaluation. 
You should understand that a Confidentiality Certificate does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. Note however, that if an insurer or employer learns about your participation and 
obtains your consent to receive research information, then the investigator may not use the 
Certificate of Confidentiality to withhold this information. This means that you and your family 
must also actively protect your privacy. 
Finally, you should understand that the investigator is not prevented from taking steps, including 
reporting to authorities, to prevent serious harm to yourself or others. 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 13 of 19 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by 
U.S. Law. This website will not include information that can identify you.  At most, the website 
will include a summary of the completed results. You can search this website at any time. 
COSTS TO PARTICIPANTS AND PAYMENT 
Costs to Participants: You will not be charged for any treatments or procedures that are part of 
this study. However, if you usually pay co-payments for VA care and medications, you will still 
have to pay these co-payments for VA care and medications that are not part of this study. 
Payment Offered for Participation: You will not be paid for participation in this study. 
However, if you must pay for transportation, parking, or other expenses related to participation, 
the study will reimburse you. If you travel less than 50 miles round trip you will receive $50, and 
if you travel 50 miles or more round trip you will receive $70. If you do not travel, but are being 
reimbursed for other expenses/time you will receive the lesser of the two amounts, $50. 
Reimbursement will be made available by <insert site specific info>. Payments will be made 
through Austin Financial Services Center and will generate Internal Revenue Service Form 
1099 regardless of amount. Your SSN will be used for this purpose in reimbursement. 
MEDICAL TREATMENT AND COMPENSATION FOR INJURY  
 
Every reasonable safety measure will be used to protect your well-being. If you are injured as a 
result of taking part in this study, the VA will provide necessary medical treatment at no cost to 
you unless the injury was due to your not following the study procedures. 
If at some point you have thoughts of self-harm or are in emotional distress and need to speak 
to someone, please call the Veteran’s Crisis Hotline at: 1-800-273-8255 and Press 1. They are 
available 24 hours a day 7 days a week. 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 14 of 19 
 
If you should have a medical concern or get hurt or sick as a result of taking part in this study, 
call: 
DURING THE DAY: 
 
Dr./Mr./Ms. _____________________________________ at                                                 and  
 
AFTER HOURS: 
 
Dr. /Mr./Ms ________________________________________ at ________________________. 
Emergency and ongoing medical treatment will be provided as needed. 
For those who participate in this research, there are more than minimal risks associated with 
taking study medication. If you experience injuries that may be related to study medication, you 
should contact the research team or your doctors. Treatment for injuries related to study 
medication will be provided without charge to you. 
You do not give up any of your legal rights and you do not release the VA from any liability by 
signing this form. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 15 of 19 
 
PARTICIPATION IS VOLUNTARY 
Participation in this study is voluntary. Refusal to participate will involve no penalty or loss of 
benefits. Your decision not to take part will not affect the relationship you have with your doctor 
or other staff, and it will not affect the usual care that you receive as a patient. If you are a VA 
employee or student, refusal to take part in the study will in no way influence your employment, 
ratings, subsequent recommendations, or academic progress. 
You may discontinue taking part in this study at any time without any penalty or loss of benefits. 
You may withdraw and still receive the same standard of care that you would otherwise have 
received. 
You may choose to discontinue study medication while remaining in the research study. If so, 
the research team will work with you to decrease the number of pills you are receiving each day. 
Suddenly discontinuing lithium may lead to worsening of symptoms in bipolar disorder, and 
possibly an increased risk for suicidal behavior. Tapering the medication gradually is safer than 
abrupt discontinuation. 
If you do withdraw from the study, the research team may continue to review the information 
they already collected and your medical records. They cannot collect further information directly 
from you. They may continue to review VA clinical and administrative records to find out if you 
have repeated self-harm or suicidal behavior unless you withdraw your consent for them to do 
so either verbally or in written form. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 16 of 19 
 
RIGHT OF INVESTIGATOR TO TERMINATE PARTICIPATION 
The investigator may terminate this study at any time. Possible reasons include: additional 
information on the benefits versus the risks of lithium for suicide prevention; discontinuation of 
funding for this research; or problems with your ability to follow study procedures. Should this 
happen, the research team will let you and your doctors know, and they will share the 
information they have obtained with you and your doctor to guide treatment planning.  
PERSONS TO CONTACT ABOUT THIS STUDY 
If you have any questions, complaints, or concerns about this study, you may contact the study 
investigator at your VA Medical Center or the <insert info> during regular business hours.  
 
The investigator is Dr./Mr./Ms _________________________ at ______________________  
 
The <insert info> is Dr. /Mr. /Ms. ________________________ at _____________________. 
 
If you have questions about your rights as a study participant, or you want to make sure this is a 
valid VA study, you may contact the VA Central Institutional Review Board (IRB). This is the 
Board that is responsible for overseeing the safety of human participants in this study. You may 
call the VA Central IRB toll free at 1-877-254-3130 if you have questions, complaints or 
concerns about the study or if you would like to obtain information or offer input. 
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 17 of 19 
 
SIGNIFICANT NEW FINDINGS 
Sometimes during the course of a research study, new information becomes available about the 
condition or medicine that is being studied that might change a person’s decision to stay in the 
study. If new information about the treatments to prevent suicide, or about the benefits and risks 
of lithium, becomes available the study team will tell you about it and talk with you about 
whether or not you want to continue in the study. If you decide to withdraw from the study, your 
research doctor will arrange for your medical care to continue. If you decide to continue in the 
study, you might be asked to sign an updated informed consent form. Your research doctor 
could also decide it to be in your best interests to withdraw you from the study. If so, he or she 
will explain the reasons and arrange for your usual medical care to continue. 
FUTURE USE OF DATA  
After this study ends, your study data will be stored indefinitely in a research Data Repository at 
the Cooperative Study Program, Massachusetts Veterans Epidemiology Research and 
Information Center (MAVERIC).  
If you agree, the Cooperative Studies Program Coordinating Center in Boston, MA will make 
your study data available for use for other approved research studies by investigators not 
associated with this study. Researchers using the study data will not have access to your 
identifying information such as name, address, and Social Security Number.  
Researchers may link this data with the electronic medical records data from VA national data 
resources including the Suicide Prevention and Application Network (SPAN) and National Data 
Systems (NDS), but Data Repository personnel, will ensure that your data will be de-identified to 
the extend possible prio to release to other researchers.   
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 18 of 19 
 
Any use of your research data, from this study, by other researchers must comply with existing 
regulations and be approved by appropriate oversight bodies including a VA Institutional Review 
Board (IRB), a committee that protects the rights of research subjects. The oversight bodies 
may require that you be contacted for your consent prior to the use of your data in a new study if 
it decides such consent is required for your protection. 
If you would like to be included, please read the following statement and circle one answer 
below. Please initial in the space indicated below your answer. You can change your mind 
about participating at any time. No matter what you decide to do, your decision will not affect 
your medical care or your participation in the study already described.  
 
I give permission to allow researchers to store my data in the Data Repository. 
 
 
 
 
YES 
 
 
 
NO 
 
 
 
 
Please Initial: ________________  
 
 


RESEARCH CONSENT FORM 
Version Date:  5 April 2018  
Participant Name:                                                                                                    Date:  _________ 
Title of Study: CSP#590:  A Double-blind Placebo-Controlled Study of Lithium For Preventing 
Repeated Suicidal Self-Directed Violence in Patients With Depression or Bipolar Disorder 
Local Site Investigator:  ______________________________      VA Facility:  _________________  
Principal Investigator/Study Chair for Multisite Study:   Ira Katz, MD, PhD      
 
 
SUBJECT’S IDENTIFICATION 
                                                                   
VA Form    10-10-86 
MAR 2006        
VA CIRB template Nov 2012                        
 
FOR VA CENTRAL IRB USE ONLY 
PI/SC Approval Date:  May 1, 2018 
LSI Approval Date:        N/A 
LSI Verification Date:             N/A 
CSP 590 ICF#2 Page 19 of 19 
 
AGREEMENT TO PARTICIPATE IN THE RESEARCH STUDY 
 
___________________________________(insert name and title of person obtaining consent) 
has explained the research study to you. You have been told of the risks or discomforts and 
possible benefits of the study. You have been told of other choices of treatment available to you. 
You have been given the chance to ask questions and obtain answers. 
By signing this document below, you voluntarily consent to participate in this study. You also 
confirm that you have read this consent, or it has been read to you. You also give permission for 
the research team to contact family members, friends, or others who would be likely to know 
your whereabouts if we are unable to contact you. You will receive a copy of this consent after 
you sign it. A copy of this signed consent will also be put in your medical record if applicable. 
 
I agree to participate in this research study as has been explained in this document. 
 
___________________________ 
Participant Print Name 
________________________________ 
Participant’s Signature 
___________________ 
Date 
___________________________ 
Name of person obtaining consent 
_______________________________ 
Signature of person obtaining consent 
____________________ 
Date 
 

Prot_000.pdf: 
 
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Page 1 of 97 
VA COOPERATIVE STUDY # 590 
  
DOUBLE-BLIND PLACEBO-CONTROLLED STUDY  
OF LITHIUM FOR PREVENTING REPEATED SUICIDAL 
SELF-DIRECTED VIOLENCE IN PATIENTS WITH 
DEPRESSION OR BIPOLAR DISORDER 
 
 
 
 
 
 
 
STUDY CHAIR: Ira R. Katz, MD, PhD 
STUDY DIRECTOR: Matthew H. Liang, MD, MPH 
BIOSTATISTICIANS: Robert Lew PhD 
Gheorghe Doros, MA, MS, PhD 
STUDY PHARMACIST: Robert J. Ringer, Pharm.D. 
PROJECT MANAGER: Melynn Nuite, RN, BS, CCRC 
 
 
 
 
 
 
 
 
PRIVILEGED AND CONFIDENTIAL 
 
 
Not for distribution beyond the intended function 


 
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Table of Contents 
EXECUTIVE SUMMARY 
3 
ABBREVIATIONS AND DEFINITIONS 
5 
I. 
INTRODUCTION AND BACKGROUND 
7 
II. 
SIGNIFICANCE OF THE PROPOSED RESEARCH TO THE VA 
15 
III. 
PRELIMINARY RESEARCH 
16 
IV. 
STUDY OBJECTIVES and EXPERIMENTAL DESIGN 
17 
V. 
STUDY POPULATION 
18 
VI. 
STUDY MEASURES 
22 
VII. 
BIOSTATISTICAL CONSIDERATIONS 
24 
VIII. 
POTENTIAL PITFALLS OF THE PROPOSED DESIGN AND           
ALTERNATIVE DESIGN CONSIDERATIONS 
32 
IX. 
FEASIBILITY OF RECRUITMENT 
37 
X. 
POTENTIAL BARRIERS and STRATEGIES TO OPTIMIZE                
RECRUITMENT 
38 
XI. 
PATIENT ENROLLMENT 
39 
XII.  
HUMAN SUBJECTS ISSUES AND INFORMED CONSENT 
42 
XIII. 
TREATMENT REGIMENS 
46 
XIV. 
FOLLOW-UP AND TERMINATION 
51 
XV. 
MONITORING ADVERSE EVENTS 
58 
XVI. 
DATA MANAGEMENT AND DATA SECURITY PLANS 
61 
XVII. 
QUALITY CONTROL PROCEDURES 
64 
XVIII.  GOOD CLINICAL PRACTICES AND SITE REVIEW PROGRAM 
66 
XIX. 
STUDY ORGANIZATION AND ADMINISTRATION 
67 
XX. 
PUBLICATIONS 
70 
XXI. 
TABLES AND FIGURES 
72 
XXII. 
REFERENCES 
84 
  


 
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EXECUTIVE SUMMARY  
Objective:   To test the hypothesis that lithium augmentation of enhanced usual care will reduce 
the rate of repeated episodes of suicidal self-directed violence (repeated suicide attempts, 
interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide) in 
participants with bipolar disorder or depression who have survived a recent self-directed violence 
event. 
 
Background: The hypothesis that lithium can prevent suicide in patients with bipolar disorder 
and depression is based on data from observational studies and randomized clinical trials 
conducted to evaluate other outcomes. The question about the effectiveness of lithium for suicide 
prevention is one of major scientific, clinical, and public health significance. There have been no 
adequately powered clinical trials conducted specifically to evaluate suicide behaviors as an 
outcome. Two recent randomized clinical trials failed to recruit adequate numbers of subjects to 
be conclusive.  
 
The VHA, as the largest national healthcare system with an established program for identifying 
new suicide attempts, evaluating patients for underlying mental health and medical conditions, 
providing needed services, connecting Veterans to state-of-the-art suicide risk management, and 
monitoring outcomes is uniquely able to conduct a large scale clinical trial of lithium for suicide 
prevention.  
 
The rationale for the study is based on the following: 
 
• Data from observational studies and double-blind randomized clinical trials suggest that 
lithium can prevent suicide-related behaviors in patients with bipolar disorder and major 
depression. 
• The high risk of suicide in veterans receiving health care services from VHA has 
persisted despite extensive improvements in mental health services and in programs for 
suicide prevention. 
• Each month, there are over 1,000 unique VHA patients with bipolar disorder or 
depression who attempt suicide and survive. 
• Surviving a suicide attempt is the most powerful known risk factor for death from suicide 
in VA and elsewhere.  
• Approximately 15% of VA survivors reattempt or die from suicide within one year.  
• Evaluating rates of reattempts in those who have survived attempts is an established and 
effective method for testing interventions that may prevent suicide. 
• Experimental treatment in CSP-590 supplements usual care for major depression or 
bipolar disorder.  
• Study monitoring and procedures for the management of suicide risk would meet or 
exceed VA standards and requirements. 


 
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• Study procedures optimize the safety of lithium, including the potential risk of overdoses, 
and meet or exceed all published practice standards. The trial will utilize multiple 
strategies to minimize risks including frequent monitoring and assessment, determination 
of lithium levels during titration and at steady state, and dispensing medications in 
limited quantities in blister packs. 
• Our survey of VA psychiatrists indicates that the question is clinically important and 
compelling and that a clinical trial that demonstrated the hypothesized effect would 
transform the clinical management of suicidality. 
 
Design: Randomized, double-blind, placebo-controlled clinical trial of lithium versus placebo 
augmentation of enhanced usual care. 
 
Patient population: VHA patients with bipolar disorder or depression who have survived a recent 
episode of suicidal self-directed violence.  
 
Primary outcome: Time to the first repeated episode of suicidal self-directed violence, including 
suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths 
from suicide   
 
Duration: Total study duration will be 4.5 years. Recruitment will occur over 3 years. 
Participants will be followed for one year. 
   
Sample size calculations and number of sites required: The design of the study is based on 
testing for a 37% reduction in the rate of repeated suicidal self-directed violence, a figure based 
on an effect size of approximately 43% observed in recent studies and then allowing for 
attenuation due to non-adherence.  Adjusting for potential data loss due to attrition, 90% 
statistical power to detect a significant 37% reduction in reattempt rates at 5% overall type I error 
would require 1862 subjects. With recruitment of 20% of eligible subjects over a three year 
period, this would require approximately 9310 potentially eligible subjects. Based on current VA 
suicide surveillance data, this could be achieved with 29 sites. 
 
 
 


 
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ABBREVIATIONS AND DEFINITIONS 
CDC 
Centers for Disease Control and Prevention 
CRF 
Case Report Form 
CSP 
Cooperative Studies Program 
CSPCC 
Cooperative Studies Program Coordinating Center 
CSPCRPCC 
Cooperative Studies Program Clinical Research Pharmacy Coordinating 
Center 
DMC 
Data Monitoring Committee 
DTHP 
Drug Treatment and Handling Procedures 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
MAVERIC 
Massachusetts Veterans Epidemiology Research and Information Center 
MHP 
Mental Health Provider 
POC 
Point of Care 
SAE 
Serious Adverse Event 
SMART 
Site Monitoring Auditing and Resource Team 
SPAN 
Suicide Prevention and Application Network 
SPC 
Suicide Prevention Coordinator 
 
GLOSSARY OF TERMS FOR KEY PERSONNEL 
Study Chair 
Principal Investigator, blinded 
Study Director 
Blinded and directs CSP Coordinating Center component of CSP 590 
Central Psychiatrist 
/Safety Officer 
Blinded clinician independent of Study Chair’s Office and study sites.  
With Study Director, directs overall safety program with consultants in 
clinical pharmacology, nephrology, and cardiology 
Study Nephrologist 
/Safety Officer 
Blinded clinician independent of Study Chair’s Office who consult on 
renal function monitoring and individual participants  
Study Cardiologist 
/Safety Officer 
Blinded clinician independent of Study Chair’s Office who will review 
EKGs from sites and consult on QTc monitoring on an as-needed basis 
Site Investigator 
MD or PhD investigator responsible for overall study at individual site 
Site Coordinator 
Research Team member who organizes study and personnel to carry out 
the protocol at each site 
Site Physician 
Research Team member who prescribes study medication 
Research Team 
The Site Investigator, Site Coordinator, and Site Physician at each site 
Treating Mental 
Health Provider 
The clinical staff member(s) responsible for the patient’s ongoing mental 
health care not related to the study protocol.  
For purposes of study introduction this mental health provider individual 
does not have to be capable of prescribing medication.  
If a participant’s mental health provider can not prescribe,  study staff 
will ensure that a person capable of prescribing is involved, a minimum 
of 2 months, prior to  the warm handoff.  
 


 
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NOMENCLATURE 
Historically, suicide research has been hampered by ambiguity in the language used to describe 
events (Silverman et al., 2007). For precision, this proposal uses technical language based on 
current CDC nomenclature for suicide-related events when specifying hypotheses, outcomes, and 
inclusion criteria (Crosby et al., 2011; see section V of this proposal). When describing findings 
from previous research, it uses the language of those studies. In other contexts, it uses common 
language. 


 
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I. 
INTRODUCTION AND BACKGROUND 
 
Suicide and suicide attempts are persistent and growing public health problems for America and 
for Veterans. There are few evidence-based approaches for their prevention; and, given the 
importance of the problem, there have been relatively few randomized clinical trials of potential 
treatments (Dolgin, 2012).   
 
According to estimates from the Centers for Disease Control and Prevention (CDC) (Karch et al., 
2006), Veterans account for approximately 22% of the deaths from suicide in the United States 
(Bossarte, 2013). Applying these proportions to the 36,900 suicides that occurred in the United 
States in 2009 and the 38,600 that occurred in 2010 leads to estimates that 18 to 22 Veterans die 
from suicide each day.  
 
It is not clear whether suicide rates in the entire population of Veterans are higher than the 
overall US population after controlling for relevant variables (Gibbons et al., 2012; Kaplan et al., 
2007, 2012; Miller et al., 2009, 2012). In 2006, rates in OEF/OIF Veterans were similar to those 
of other Americans after controlling for age, sex, and race, but in 2007 they were higher (Kang & 
Bullman, 2008; Kang, 2012). Whether this trend will continue or will be a time-limited increase 
similar to that observed after Veterans returned from Vietnam (Wantanabe & Kang, 1996) is not 
clear.  
 
Whether or not all Veterans are at increased risk, suicide rates are substantially increased among 
those who use VHA health care services.  Information from the Office of Mental Health 
Operations on causes of death for all Veterans who use VHA healthcare services since 2000 
demonstrates that rates among users are higher than those of the general population (McCarthy et 
al., 2009; Katz et al., 2012).  Rates of suicide among users of VHA services   are approximately 
36 per 100,000 patient years, 38 per 100,000 among men, and 15 per 100,000 among women 
(McCarthy et al., 2009, VA MH Operations to Under Secretary, 2011). Among the deaths from 
suicide, approximately half have had a mental health diagnosis in the year prior to their deaths; 
in those with a mental health diagnosis the rate of suicide is 70 per 100,000 (Ilgen, et al., 2010). 
The highest rates are 113 per 100,000 patient years among Veterans with bipolar disorder where 
suicide accounts for approximately 110 deaths per year. The highest numbers of deaths among 
those with mental health conditions are for those with depression where rates are 82 per 100,000 
and there are approximately 400 suicides per year. Altogether, diagnosed affective disorders 
account for about 500 deaths from suicide each year in VHA, or about 25-30% of all suicides 
among VHA patients.  
 
Since 2008, the Office of Suicide Prevention has maintained a registry of VHA suicide attempts 
and deaths reported by the Suicide Prevention Coordinators (SPCs) in each Medical Center. This 
active surveillance registry, VA-Suicide Prevention and Application Network (SPAN), was 
established to coordinate the identification and reporting of suicide-related events within and 
across facilities, to facilitate the identification of individuals at high risk to target interventions, 
and to support both program planning and evaluation. It has served as an important resource for 
planning the proposed study. Between April 1, 2010 and March 30, 2012, SPCs reported suicide 
attempts or deaths from suicide that became known to the facility in almost 30,000 Veterans 
utilizing VA services. Of these, 94% had a primary or secondary diagnosis of depression or 
bipolar disease documented in their medical records before the attempt or during the evaluation 


 
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of the attempt, and approximately half were first time attempters. Of these Veterans, 0.06% died 
within one week. Among those who survived, 15% reattempted suicide within a year, and 
approximately 3-5% died from natural or unnatural causes within one year. Suicide attempt 
survivors have a very high risk for repeated attempts and death.   
 
Current VA Management of Suicidality 
 
The VA’s activities in suicide prevention constitute a comprehensive program that includes 
public health activities, ready access to high-quality health and mental health care services, and 
interventions targeting individuals at high risk. For those at risk, the program requires 
supplementing evidence-based treatment for underlying mental health conditions with 
interventions that directly address the risk of suicide. Documents defining the program are 
included as Appendix A. 
 
The VA standard of care for the prevention-focused care of patients at high risk is specified in     
“Patients at High-Risk for Suicide,” from the Principal Deputy Under Secretary for Health and 
the Deputy Under Secretary for Health for Operations and Management, April 24, 2008. This 
memo requires the Suicide Prevention Coordinator (SPC) at each facility to maintain a list of 
patients at high-risk for suicide, including, but not limited to those who have survived a suicide 
attempt. It includes specific language outlining requirements for the care for those at high-risk: 
 
1. Patients at high-risk for suicide must be placed on the high risk list for at least 3 months 
after discharge. They must be evaluated at least weekly during the first 30 days after 
discharge. 
 
2. Other patients surviving a suicide attempt and those placed on the high-risk list for other 
reasons should be evaluated at least weekly for at least the next month. 
 
3. When a Veteran attempts suicide or is identified as being at high risk and placed on the 
facility’s high risk list, the SPC will make personal contact with the Veteran, establish a 
US mail contact, and contact the Veteran’s primary care and mental health provider to 
ensure that: 
 
a. The Veteran’s mental health diagnoses and care plan have been reviewed in light of the 
risk of suicide and that the care plan appropriately addresses the Veteran’s conditions and 
functional limitations. 
 
b. Specific treatments with the potential for reducing suicide risk have been considered. 
These include clozapine for schizophrenia and lithium for bipolar disorder. 
 
c. The plan includes ongoing monitoring for suicidality and plans for addressing periods 
of increased risk. These plans must include specific processes of follow-up for missed 
appointments. 
 
d. There is an individualized discussion about means reduction that should address issues 
such as medication storage, gun safety, and high-risk behaviors. 
 


 
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e. A family member or friend has been identified, either to be involved in care or to be 
contacted, if necessary. 
 
f. There is a safety plan in the medical record and the Veteran has a copy of the plan. 
 
(1) The plan should be specific and behaviorally oriented. It should be designed to 
help the Veteran identify times when he or she is at increased risk, and to act to 
preserve his or her life. It should list situations, stressors, thoughts, feeling, 
behaviors, and symptoms that suggest periods of increased risk, and step-by-step 
descriptions of coping strategies and help-seeking behaviors that can be used at 
these times. 
  
(2) The plan is developed by the Veteran with guidance and support from his or 
her provider or from the SPC. 
 
(3) The safety plan must include directions for the Veteran about how to get help 
24/7, including local VA numbers available and the National Crisis number (1-
800-273-TALK). 
 
(4) Periodic review of the plan and discussion of its use in times of stress should 
be included in the Veterans ongoing care. 
 
A memorandum “Safety Plans for High Risk Veterans” from the Under Secretary for Health to 
the VISN Directors (July 13, 2010) provided additional information about safety planning. 
Specifically, it stated that safety plans should: 
 
1. Be developed with participation of patients/families 
 
2. Be provided to patients 
 
 
3. Include five elements: 
 
 
a. Identification of the warning signs that precede a crisis 
 
b.   Identification of internal coping strategies 
 
c. Indication of when to contact family/others for support or to help resolve a crisis 
 
 
 
d.   Identification of when professional agencies should be contacted 
 
 
 
e.   Provision of ways to get help, including the phone number for the Veterans Crisis 
Line 
 
4. Be completed in a timely manner, prior to a Veteran being discharged from an inpatient 
facility or at the next scheduled appointment for Veterans followed as outpatients 
 
5. Be the focus of the required weekly follow-up visits 


 
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Other policies and guidance were specified in VHA Directive 2008-036, “Use of Patient Record 
Flags to Identify Patients at High Risk for Suicide” released on July 18, 2008, and a 
memorandum “Standardized Suicide Nomenclature (Self Directed Violence Classification 
System)” from the Deputy Under Secretary for Health Operations and Management to the VISN 
Directors on April 19, 2010.  
 
The policy requirements reviewed here were supplemented by the Suicide Prevention 
Coordinator Orientation Manual issued in August, 2009 and updated July, 2011. 
  
VA provides an array of services that complement the clinical programs specified in these 
documents. These include the national telephone Crisis Line, 800-273-TALK, the text messaging 
and internet chat services linked with it, and firearm safety programs required at each Medical 
Center. There are also ongoing demonstration and research programs for ensuring follow-up and 
continuity of care for those who come to emergency departments for problems related to suicide, 
but for whom hospital admission is not necessary. 
 
Focused clinical interventions that may be available in certain facilities include three specific 
psychotherapies: Cognitive Therapy for Suicide Prevention (Brown et al., 2005), an evidence-
based psychotherapy found to be effective for suicide prevention across mental health 
conditions; Dialectical Behavioral Psychotherapy (Linehan et al., 2006), an evidence-based 
suicide prevention program for patients with borderline personality disorder and related 
conditions; and  Collaborative Assessment and Management of Suicidality (CAMS) (Ellis, et al. 
2012), a  promising behaviorally oriented psychotherapy. Other ongoing research, within VA 
and outside, is evaluating motivational interviewing strategies to enhance safety planning. 
Specific targets for new research include strategies for promoting firearm safety and other ways 
to delay access to lethal means, and methods for identifying reasons for living that can be used to 
inform coping strategies.  
 
The April 24, 2008 memorandum that requires providers to “consider” lithium treatment for 
patients with bipolar disorder at high risk for suicide was based on the available evidence at the 
time, as reviewed by VA leadership. However, this recommendation was criticized by a Blue 
Ribbon Panel convened by the Secretary to review VA’s suicide prevention program who argued 
that, in the absence of any direct data from randomized clinical trials designed to evaluate 
lithium for suicide prevention, it could not be supported by the available evidence (Hoge et al., 
2008). These differences reflect the importance of further research in this area.  In fact, the 
conduct of focused research on suicide prevention is consistent with the vision expressed in the 
April 24, 2008 memorandum, “VHA strongly encourages research, clinical demonstrations, and 
the development of best-practices in the care of those at high risk. The activities identified here 
should be the focus for ongoing innovations.”  
 
 
Clinical Pharmacology of Lithium for Suicide Prevention 
 
Lithium is FDA-approved for treating acute mania and preventing recurrent episodes for patients 
with bipolar disorder. Other uses supported by evidence from controlled clinical trials, but not by 
FDA approval, include preventing relapses in major depressive disorder and adjunctive therapy 
for treatment-resistant major depression (Bauer & Dopfmer, 1999; Bauer et al., 2003; Burgess et 
al., 2001; Fava & Rush, 2006; Nierenberg et al., 2006; Prien et al., 1984).  


 
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Even in the absence of randomized clinical trials, the 2003 American Psychiatric Association 
Practice Guideline for the Assessment and Treatment of Patients with Suicidal Behaviors stated, 
“There is strong evidence that long-term treatment with lithium salts is associated with major 
reduction in the risk of both suicide and suicide attempts in patients with bipolar disorder, and 
there is moderate evidence for similar risk reductions in patients with recurrent major depressive 
disorder.” The Guideline recognized the potential dangers of overdosing on lithium and 
recommended appropriate clinical management when it was used for suicide prevention. More 
recently, the 2013 VA-DoD Clinical Practice Guideline for the Assessment and Management of 
Patients at Risk for Suicide (Department of veterans Affairs, Department of Defense, 2013) 
stated, “Lithium should be considered for patients diagnosed with bipolar disorder who do not 
have contraindications to lithium as it has been shown to reduce the increased risk of suicide 
associated with this illness.”  
 
A 2001 Cochrane review of lithium for maintenance treatment for bipolar disorder (Burgess et 
al., 2001) updated in 2009 found the evidence for lithium to be inconclusive. However it stressed 
the importance of the issue, saying, “Low suicide rates in lithium-treated patients have led to 
claims that lithium has a specific anti-suicidal effect. If so, this is of considerable importance as 
treatments for mental disorders in general have not been shown convincingly to be effective in 
suicide prevention.” This conclusion is echoed in the September 10, 2012 release of the US 
National Strategy for Suicide Prevention, “… clozapine has been found to be effective in 
reducing suicidal behaviors among patients with schizophrenia, and lithium shows promise in 
patients with mood disorders.” 
 
The effect sizes reported for observational studies and meta-analyses of lithium for the 
prevention of suicide and suicide attempts are, in general, large in depression, bipolar disorder, 
and mixed populations of those with affective disorders  (Ahrens et al., 1993, 1995a, 1995b; 
Baldessarini et al., 1999a, 1999b, 2001, 2003, 2006; Brodersen et al., 2000, 2001; Coppen et al., 
1992, 1998, 2000; Dunner, 2004; Goodwin et al., 2003; Guzetta et al., 2007; Hanus & Tuma, 
1992; Isometsa et al., 1992; Kallner et al., 2000; Kessing et al., 2005; Modestin et al., 1992; 
Muller-Oerlinghausen et al., 1991, 1992a, 1992b, 1994, 1996, 2003, 2005; Tondo et al., 1997, 
1998, 2000, 2001; Vestergaard & Aagaard, 1991. Key studies are summarized in Table 2). 
Moreover, observational studies suggest that the preventive effect may be independent of other 
symptom-related outcomes (Ahrens, 2001; Muller-Oerlinghausen, 2001).  
 
However, some observational studies of lithium for suicide prevention are negative. These 
include studies on attempt rates from a single psychiatric practice, from a single VA site, and 
from a pharmaceutical claims database (Collins & McFarland, 2008; Yerevanian et al., 2003, 
2007).  Secondary analyses from two large observational studies, Collaborative Depression 
Study and the Systematic Treatment Enhancement Programs for Bipolar Disorder did not 
demonstrate protective effects from lithium (Coryell et al., 2001; Marangell et al., 2008).   
 
Findings from two recent randomized clinical trials of lithium for managing symptoms of bipolar 
disorder were negative for suicide-related outcomes. The LITMUS study (Nierenberg et al., 
2013) evaluated “optimized personalized therapy” for bipolar disorder with or without moderate 
doses of lithium in an open-label, flexible-dose randomized clinical trial to determine whether 
lithium led to improved symptom outcomes. Findings for the primary outcomes, the control of 
affective symptoms, were largely negative. Other findings included the absence of differences 


 
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between groups in the emergence or persistence of suicidal ideation. The publication stated that 
there were no differences between groups in the frequency of suicide-related behaviors or in the 
rate of hospitalizations to avoid them; however, no data related to these outcomes were 
presented. The BALANCE study (2010) evaluated lithium plus valproate versus lithium alone 
versus valproate alone for the prevention of relapses in patients with bipolar disorder in an open-
label randomized clinical trial. For the primary outcome, relapse prevention, lithium plus 
valproate or lithium alone were more effective than valproate alone.  Using the investigators’ 
terminology, the frequency of deliberate self-harm ranged from 2% on lithium alone to 5% on 
valproate alone, but the study was not powered to test for differences.  
 
In addition, two recent observational studies have reported negative findings in VA patients. In 
one study, Ahearn and her colleagues (in press) evaluated medical record data on suicide 
attempts in patients with bipolar disorder at five VA medical centers from 1999 to 2004 and 
found no significant differences between those taking lithium and valproate as mood stabilizers; 
however, the number of attempts in patients taking either medication was relatively low, and 
there was limited power for detecting even moderate to large differences. Important observations 
were that a majority of VA patients with bipolar disorder were taking a second generation 
antipsychotic medication, often in combination with lithium, valproate, or other mood stabilizers, 
and that those taking antipsychotic medications had higher rates for suicide attempts than those 
taking mood stabilizers alone. There have been significant changes in the usual care for bipolar 
disorder since the time of the earlier observational studies. In a second recent study, Smith 
(2012) compared deaths from suicide in patients taking lithium or valproate in a case control 
study with propensity score matching. The basic finding from the primary analysis was that there 
were no significant differences between the two agents. However, secondary analyses 
demonstrated that those who were discontinued from lithium were at greater risk than those who 
remained on lithium, those who were discontinued from valproate, and those who remained on 
valproate. (Issues related to discontinuation and withdrawal of lithium are addressed in Sections 
XII Human Subjects and Informed Consent and XIV Follow-up and Termination). 
 
In reviewing this literature, it is important to recognize that the positive findings from 
observational studies could, in principle, reflect bias by indication (Bowden & Fawcett, 2004; 
Johnston, 2001; Yerevanian et al., 2004). Given concerns about the safety of lithium, providers 
may be less likely to prescribe lithium for those patients perceived as being at higher risk for 
suicide. To the extent that the providers’ perceptions are valid, this could lead to an apparent 
protective effect for lithium.  
 
The most robust evidence for a lithium effect comes from a 2005 meta-analysis by Cipriani and 
colleagues of 32 clinical trials with 1389 patients randomized to lithium and 2069 patients 
randomized to other pharmacological treatments for affective disorders (Cipriani et al., 2005). 
Because the findings were derived from randomized clinical trials, the results were not subject to 
bias by indication. The meta-analysis demonstrated significant protective effects for death from 
suicide (Peto odds ratio=0.26, 95% CI 0.09-0.77) and for both deaths and (non-fatal) attempts 
(Peto odds ratio =0.21, 95% CI 0.08 to 0.50).  These effects, a 74% decrease in deaths from 
suicide and a 79% decrease in suicide-related behaviors, are comparable to the effect-sizes 
estimated in the observational studies. Similar findings were reported from a reanalysis of 
findings from a study of lithium and carbamazepine in preventing recurrences in bipolar disorder 
that was not included in the Cipriani meta-analysis (Thies-Fletchner et al., 1996).  


 
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More recently, Cipriani and colleagues updated and extended their meta-analysis (and included 
the Lauterbach et al (2008) and the Oquendo et al (2011) studies discussed below). The findings 
from planned analyses were that lithium was significantly more effective than placebo in 
reducing the number of suicides (Peto odds ratio= 0.13, 95% CI 0.03-0.66) and deaths from any 
cause (Peto odds ratio 0.38, 95% CI 0.15-0.95), but not episodes of deliberate self harm (Peto 
odds ratio =0.60. 95% CI 0.27-1.32). Other findings from planned analyses were that there were 
no significant differences between lithium and other medications in effects of suicide or deaths 
from any cause. Lithium was more effective than carbamazepine in reducing the number of 
deliberate self-harm events (Peto adds ratio 0.14, 95% CI 0.02-0.83), but there was no significant 
differences for other medications.   
 
There have been two recent randomized clinical trials of lithium for preventing suicide attempts 
in patients who survived an initial attempt. Both were unable to enroll their target number of 
participants. As a result, both were inadequately powered and neither was definitive. One study 
evaluated adjunctive treatment for preventing repeated suicide attempts in depression, but it was 
terminated prematurely after only 167 of the planned 468 subjects were enrolled. In this study, 
Lauterbach and colleagues (2008) reported a hazard ratio for lithium of 0.517 that, as expected 
given the reduced sample size, was not significant (95% CI 0.18-1.43). In the second study, 
Oquendo and co-investigators (2011) evaluated lithium versus valproate for treatment of bipolar 
disorder in patients with previous suicide attempts. It reported negative results for the prevention 
of repeated attempts after 2.5 years for 98 of a planned 232 randomized subjects. Post-hoc 
sample size calculations showed the study had 80% power for detecting an 85% reduction for 
lithium relative to valproate. Additional post-hoc calculations by CSP-590 investigators 
demonstrate that the study would have had only 14.4% power for detecting a 50% effect, and 
only 9.3% power for a 40% effect. The negative results provide evidence against only a very 
large effect. The raw data indicate that 16% of the valproate group reattempted over 2.5 years; 
reattempts for those on lithium were 33% lower at 1 year and 25% lower at the conclusion of the 
study.  
 
Most recently, the United States Preventive Services Task Force (USPSTF) summarized research 
in this area in a draft recommendation, “Screening for Suicide Risk in Adolescents, Adults, and 
Older Adults: US Preventive Services Task Force Recommendation Statement.” It stated, 
“Minimal data are available on the effectiveness of medications in preventing suicidal 
behaviors,” and, referring to the Lauterbach study, “The lone study was a short-term fair-quality 
trial that assessed the use of lithium. The study reported hazard ratios that suggest a possible 
benefit for lithium, but were not statistically significant. There was a statistically significant 
lower rate of suicide deaths per patient year in the intervention group; however, the study had 
high attrition rates and there were only three suicide deaths.” It went on to state, “In the one 
medication trial that evaluated treatment with lithium, a higher percentage of patients in the 
treatment group withdrew from the study due to adverse effects compared with the placebo 
group (13% vs. 2%), though the statistical significance was not reported and the overall dropout 
rates were similar between the two groups.” (USPSTF, 2013)  
 
Conceptual Models for the Hypothesized Effects of Lithium on Suicide Behaviors 
 
The mechanisms through which lithium controls symptoms and prevents recurrences in bipolar 
disorder and depression are not completely understood.  Even less is known about the 


 
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mechanisms that may underlie its putative effect in preventing suicide. One of the strategies used 
to investigate mechanisms for the treatment of bipolar disorder has been to evaluate actions that 
are common to both lithium and mood-stabilizing antidepressants. However, this is not 
applicable for studies related to suicide prevention. First, the effect on suicide prevention is 
unique to lithium, and, second, it may not be directly related to the effect associated with control 
of affective symptoms (Ahrens, 2001; Muller-Oerlinghausen, 2001). In the absence of a 
mechanism of action, it is useful to review the conceptual models that could inform research. 
 
Empirical Models based on Suicidality as a Treatment Target:   
 
This proposal is based on a “target symptom” conceptual model for the use of lithium for suicide 
prevention that views the risk of suicide as a potential target for treatments to be provided in 
addition to treatments focused on specific disorders. In this model, the value of defining 
suicidality as a target follows from observations that it does not uniformly respond to treatments 
directed toward the underlying affective disorders even when they reduce symptoms. A similar 
approach underlies clinical use of antipsychotic medications to target delusions when they occur 
in depression or bipolar disorder (Meyers et al., 2009; Kunzel et al., 2009), and ongoing research 
on strategies for augmenting treatment with antipsychotic medications with agents that could 
target the cognitive deficits observed in schizophrenia (Marder, 2011).  
 
Impulsivity and/or Aggression as Mediators: 
 
A number of studies suggest that increased impulsivity, aggression, and other forms of 
behavioral dyscontrol may occur in patients with mental health conditions, including depression 
and bipolar disorder, and that they may contribute to the risk of suicide in these conditions 
(Brodsky et al., 2001; Brent et al., 1994; Dougherty et al., 2004; Grunebaum et al., 2006; Mann, 
1999, 2003; McGirr et al., 2009; Oquendo et al., 2004; Perroud et al., 2011; Swann et al., 2005).  
 
The evidence for an effect of lithium on impulsivity and/or aggression is suggestive. Small 
clinical trials suggest benefits of lithium for aggression in prison populations (Sheard, 1971, 
1976) and children with conduct disorders (Campbell et al., 1984, 1995; Malone et al., 2000). 
However, a meta-analysis identified substantial limitations in the evidence that lithium was 
effective for managing “impulsive or repetitive aggression” in patients without intellectual 
disability, organic brain disorder, or psychosis, and determined that the available evidence 
provided comparable support for certain anticonvulsants as well as lithium (Jones et al., 2011).  
Other small trials of lithium for impulsivity suggested effectiveness in patients with “emotionally 
unstable character disorder,” (Rifkin et al., 1972) and in those with pathological gambling 
(Hollander et al., 2005). 
 
A model in which impulsivity and aggression can serve as endophenotypes (deconstructed 
components of complex behavioral phenotypes) (Gottesman & Gould, 2003; Kovacsics et al., 
2009, 2010; Mann et al., 2009; Ohmura et al., 2011; Turecki, 2005) for suicide underlies 
research on neurobiological mechanisms underlying suicide and the effects of lithium. 
Aggression and impulsivity can be evaluated in humans and animals; the same behaviors and 
traits that could serve as mediators in clinical populations could, from a different perspective, 
support the design of animal research on questions that are fundamentally human.   
 


 
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Although the proposed study is designed to improve suicide prevention and to decrease the 
public health burden of suicide, a rigorous test of the effectiveness of lithium could also   
catalyze research to probe mechanisms and to develop alternative agents.  
II. 
SIGNIFICANCE OF THE PROPOSED RESEARCH TO THE VA 
Suicide in Veterans is a major public health problem, a source of considerable anguish to 
families and communities, and a challenge to a health care system that already devotes 
substantial efforts and resources to solve the problem. The high rate of suicides and suicide 
attempts has persisted despite every effort to track the problem, enhance awareness and increase 
access to specialized mental health services and programs for veterans.  
 
Each year, approximately 9,000 VA patients with bipolar disorder or depression who would be 
eligible for lithium treatment attempt suicide and survive. Based on data from SPAN and the 
CDC, 15% of those who survive attempts make a reattempt within one year, and approximately 
0.5% die from suicide within one year (see below). The rate for reattempts is comparable to 
estimates from community studies, but the rate of deaths may be somewhat lower in VA (0.5% 
versus approximately 2%; Owens et al., 2002). 
 
If lithium treatment prevented approximately 40% of repeated attempts in patients with 
depression or bipolar disorder during the year after an attempt (see Section VII below), it would 
prevent almost 600 reattempts. If it prevented approximately 40% of deaths, it would save on the 
order of 20 lives each year. These estimates (and the others included below) are limited to the 
effects that would occur during one year of preventive treatment; they do not estimate the 
potential benefits of longer term maintenance treatment. However, the potential effect of lithium 
could be far larger. As discussed above, there are approximately 500 deaths from suicide each 
year in VA patients with depression or bipolar disorder. If lithium treatment were utilized in 
these patients, it could, in principle, lead to approximately 200 fewer deaths from suicide per 
year. 
 
In considering the impact of lithium treatment, it is important to consider the potential effects on 
all-cause mortality among those who have survived a suicide attempt. There is substantial 
literature demonstrating that individuals who have survived a suicide attempt are at increased 
risk for death, not just from suicide, but from other forms of unnatural, external, or accidental 
deaths as well (Bergen et al., 2012; Cooper et al., 2005; Hawton et al., 1988, 2003, 2006; 
Karasouli et al., 2010; Nordentopf et al., 1993; Owens et al., 2002; Ostamo & Lonnqvist, 2001). 
One possible explanation for this finding may be that medical examiners and coroners may 
under-diagnose suicide; another is that there may be shared risk factors for suicide attempts and 
for death from unnatural causes.  
 
In one preliminary investigation in the VA, 2276 patients who attempted suicide in the first 
quarter of 2009 were identified from the SPAN data set. Based on CDC data, 3.0% died during 
the subsequent year, 0.44% of the total died from suicide, and 1.30% from other unnatural 
causes.  In another investigation in VA, 39,803 individuals were identified from medical record 
data as having survived a suicide attempt between 2000 and 2008. Based on CDC data, 14.8% 
had died by the end of 2009. 4.7% died within one year after their attempt, 0.80% from suicide 


 
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and 0.96% from other unnatural causes. For the 8331 Veterans identified from medical records 
as attempting suicide in 2008, 0.54% died from suicide in 1 year and 0.71% from other unnatural 
causes.  
 
There are also epidemiological findings demonstrating increased mortality from natural causes 
among those who have survived suicide attempts (Hawton et al., 1988, 2006; Nordentopf et al., 
1993; Ostamo & Lonnqvist, 2001). This could reflect the reaction to a medical diagnosis as a 
precipitant of suicide (Fang et al., 2012; Johnson et al., 2012).  Other explanations include bias 
against reporting suicide on the part of medical examiners, shared risk factors (e.g., smoking), or 
non-adherence with medical care as a means for suicide. Regardless, these findings suggest that 
counts of suicide as a cause of death probably underestimate the total burden in the VA and in 
the nation.  
 
Translating these findings suggests that if this study were positive and the findings were 
implemented in the target population, the lives saved could go beyond the number who died from 
suicide to include a proportion of those who survived attempts who died from other causes. 
III. 
PRELIMINARY RESEARCH 
Survey of Potential End-users of the Study: Importance of the Study Question 
 
In preparing this proposal, all VA psychiatrists, the potential users of the study results, were 
queried about a number of issues. 879 VA psychiatrists (an overall response rate of 31.8%) 
responded to an online anonymous survey. 93.3% of the responders currently prescribed lithium 
for patients with bipolar disorder and 72.7% for patients with major depression who did not 
respond to antidepressants.   
 
Providers were asked to: “Assume your patient:  
• Has bipolar disorder or major depression  
• Has survived a recent suicide attempt  
• Has no contraindications to lithium  
• Is first stabilized medically and psychiatrically  
• Is receiving clinical care per VA requirements for managing patients at high-risk for 
suicide.” 
 
Under these assumptions, respondents were asked: “Would you refer such a patient to a 
randomized, double-blind, placebo-controlled study of adjunctive lithium treatment for suicide 
prevention? (Lithium will be carefully monitored),” and 74.2% answered “Yes”, 16.8% were 
unsure, and 8.9% answered “No”.  
 
Finally, psychiatrists were asked “What overall percentage of reduction in suicide attempts 
would convince you to prescribe lithium for your own patient after a recent attempt?” Options 
between 10-100% were given in 10% increments. 78.5% of the respondents answered this 
question. The mean response was 38% and the mode, 50%. Sixty-one percent of the respondents 
would prescribe lithium if it reduced suicide attempts by at least 40% and eighty-three percent if 
it reduced attempts by at least 50%. These findings support the effect size used for this trial; and 


 
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that the effect size estimated from recent studies used for our sample size calculations would lead 
a majority of psychiatrists to change their practice to prescribe lithium for appropriate patients 
with bipolar disorder or depression who survive a suicide attempt. 
 
Overall, the responses demonstrate that respondent VA psychiatrists are experienced in the use 
of lithium, strongly supportive of the proposed study, and would change their practice if effect 
sizes we targeted were documented. 
IV. 
STUDY OBJECTIVES and EXPERIMENTAL DESIGN 
The proposed study is a double blind, placebo controlled, randomized clinical trial testing the 
effectiveness of lithium augmentation of enhanced  usual care for prevention of repeat episodes 
of suicidal self-directed violence including suicide attempts, interrupted attempts, 
hospitalizations for the prevention of suicides, and deaths from suicide, as determined by the 
Outcomes Adjudication Committee, over a one year period. The study sample will include 
patients with depression or bipolar disorder, with or without non-psychotic comorbid conditions, 
who have survived a suicide attempt, experienced an interrupted attempt, or were hospitalized to 
prevent suicide within six months prior to enrollment.  
 
The primary hypothesis is that lithium is superior to placebo for the prevention of episodes of 
suicidal self-directed violence over time.   The primary outcome measure is time from 
randomization for treatment allocation to the first episode, either a suicide attempt, an interrupted 
attempt, a hospitalization specifically to prevent suicide, or death from suicide.  
 
As secondary objectives of the study, the efficacy of lithium will be evaluated for the prevention 
of subtypes of suicidal self-directed violence, for all suicidal self-directed violence events (even 
after the first recurrence), for the prevention of repeated events in subgroups as well as the entire 
sample, and to identify potential mediators. 
 
The tertiary objective of the study is to extend the follow up period using electronically available 
data to describe patterns of lithium use following active participation in the study participants, as 
well as to evaluate rates and determinants of suicide reattempts and all cause mortality over a 
longer follow up period. 
 
The study will enroll and randomize 1,862 patients to receive either lithium or placebo with 
enhanced usual care. The study is projected to run a total of 4.5 years with 3 years of 
recruitment, 1 year of follow-up on lithium or placebo, and time for start-up and closeout as 
indicated in the study budget. We expect to enroll, on average, 65 patients per site at 29 VA 
medical centers.   


 
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V. 
STUDY POPULATION  
Inclusion Criteria  
 
Admission of patients to CSP590 will require that: 
 
1. 
They have survived an episode of suicidal self-directed violence (including suicide 
attempts and interrupted attempts; see below) that occurred within six months of initial 
consent to the study, or they were admitted to a mental health inpatient unit specifically 
to prevent suicide within six months of initial consent to the study.  
 
2. 
They have a diagnosis of an affective disorder meeting DSM-IV-TR (2000) criteria for 
Bipolar I Disorder, Bipolar II Disorder, or current or recurrent Major Depressive 
Disorder.  Meeting the diagnosis for a current Major Depressive Disorder requires the 
presence of a Major Depressive Episode (see below). 
 
3. 
They are able and willing to identify one or more family members, friends, or other 
contacts and give permission for both clinical providers and the Research Team to 
contact them if the patient cannot be reached.  
 
4. 
They are able to provide informed consent 
 
5. 
There is concurrence from the patient’s mental health provider about inclusion/exclusion 
criteria and confirmation of the providers’ willingness to work with the research team in 
managing the patient during the course of the study (see below). The provider responsible 
for the patient’s general medical care has been made aware of the participation 
 
Rationale: 
 
This study will be implemented in FY2015, when the mental health field in VA and the 
remainder of the United States is transitioning from use of DSM-IV-TR (American Psychiatric 
Association, 2000) to DSM-5 (American Psychiatric Association, 2013) to guide the diagnosis of 
mental disorders. To maximize compatibility of research diagnoses with the clinical diagnoses 
available through VA electronic medical records, inclusion and exclusion criteria for this study 
will remain based on DSM-IV-TR. However, procedures for diagnosis and assessment of key 
disorders will be modified, as needed, to allow characterization of patients in terms of both 
DSM-IV-TR and DSM-5 diagnostic criteria.  
 
For inclusion in this study, suicide attempts must meet the definition for a suicide attempt based 
on the CDC’s document, “Self Directed Violence and Surveillance: Uniform Definitions and 
Recommended Data Elements” (Crosby et al., 2011). This system was developed in 
collaboration with VA, and was subsequently adopted by both DoD and VA as a means for 
defining attempts on the basis of behavior, reports or judgments about intent, and context.  
According to the CDC definition, an attempt is, “A non-fatal self-directed potentially injurious 
behavior with any intent to die as a result of the behavior. A suicide attempt may or may not 


 
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result in injury.” It includes suicidal self directed violence, “Behavior that is self-directed and 
deliberately results in injury or the potential for injury to oneself. There is evidence, whether 
implicit or explicit, of suicidal intent.” The CDC definition includes interrupted self-directed 
violence-by self or by other.  
 
“By self” (in some documents, termed “abortive” suicidal behavior) means a person takes steps 
to injure self but is stopped by self prior to fatal injury,” when there is implicit or explicit 
evidence of suicidal intent. “By other” means a person takes steps to injure self but is stopped by 
another person prior to fatal injury. The interruption can occur at any point during the act such as 
after the initial thought or after onset of behavior.  
 
Finally, the inclusion criteria go beyond the CDC definition to include cases where patients were 
hospitalized to prevent suicide. To summarize, the goal in defining the inclusion criteria related 
to suicidal self-directed violence is to ensure that they are representative of those clinically 
considered to have attempted suicide or have been at imminent risk.  
 
The mental health diagnosis used in this study will be based primarily on information from the 
structured diagnostic assessments conducted during the eligibility evaluation (See Section VI, 
Table 1 and Table 6). Any apparent discrepancies between these diagnoses and those in the 
medical record will be resolved by further inquiries to the patient (and, where appropriate, the 
family) about current and previous symptoms and further discussion with the patient’s mental 
health provider. The Research Team will establish a final diagnosis on the basis of the structured 
diagnostic assessments, the medical record, and other available data. Inclusion will require a 
Research Team diagnosis of bipolar disorder or current or recurrent major depression and the 
absence of exclusionary diagnoses together with the mental health provider’s concurrence with 
the validity of these diagnoses. 
 
Procedures for the diagnosis of a current or recurrent Major Depressive Disorder are designed to 
identify lifetime diagnoses. For patients for whom the current attempt has occurred within the 
context of an initial episode of depression, admission will require that the criterion symptoms for 
a Major Depressive Episode are fully met, either at the time of the interview or when the episode 
was at its worst. For those with recurrent episodes, admission will require that the criterion 
symptoms were met at the times of screening, the baseline assessment, or when the current 
episode was at its worst.  
 
Mental health comorbidities that are not exclusions include PTSD, panic disorder, generalized 
anxiety disorder, and personality disorders.   
 
A potential concern about inclusion of individuals with personality disorder is that they may 
exhibit multiple, repeated episodes of suicide attempts or other forms of self-destructive 
behaviors, and that, in this context, attempts and self-destructive behavior may become less valid 
as surrogate measures for suicide. This possibility is addressed through the exclusion criterion 
related to multiple attempts (see below). 
 
A medical record diagnosis of schizoaffective disorder may not be an exclusion when there is 
also documentation of bipolar disorder. As emphasized in DSM-5 (p. 138), “Schizophrenia, 
schizoaffective disorder, and delusional disorder are all characterized by periods of psychotic 


 
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symptoms that occur in the absence of prominent mood symptoms.” Inclusion of patients with 
chart diagnoses of schizoaffective disorder will require documentation of symptoms and a 
history consistent with a diagnosis of bipolar disorder, the absence of a history of psychotic 
symptoms in the absence of prominent mood symptoms, and the judgment of both the Research 
Team and the patient’s mental health provider that the most appropriate diagnosis is bipolar 
disorder, not schizoaffective disorder.  
 
Participation will also require concurrence from the patient’s mental health provider and a 
notification to the provider responsible for the patient’s general medical care. The rationale for 
this requirement is to ensure that the mental health providers concur with the Research Team’s 
evaluations related to inclusion/exclusion criteria, that they are not aware of additional 
information not included in the medical record that may affect eligibility, that treatment with 
study medication is compatible with any planned modifications in treatment, and that the 
providers are committed to working with the Research Team to manage the patient during the 
course of the study.  
 
If there is a prescribing mental health provider (MHP) we will require that concurrence is 
obtained from that mental health provider.  However, if there is no prescribing mental health 
provider involved with the participant at the beginning of the study or if one is lost during the 
study, a mental health provider who is able to prescribe medications and who is able to assume 
care of the participant at Month 12/End of Study will be identified. At end of study at a “warm 
handoff”, the mental health provider is un-blinded. With the participant, they can continue or 
taper off lithium or start lithium (in the event they have been on placebo). The research team 
ensures that a prescribing mental health provider is involved prior to the warm handoff and that a 
mental health provider will be identified prior to study Month 10 
Notification to the provider responsible for the patient’s general medical care alerts the provider 
to the patient’s involvement in the study. In addition, it should acknowledge the presence of any 
medical conditions or medications that may require additional monitoring during the course of 
the trial. 
 
Exclusion Criteria 
 
Potential subjects will be excluded if they have: 
 
1. Schizophrenia 
 
2. A history of psychotic symptoms (hallucinations or delusions) in the absence of prominent 
mood symptoms attributable to Major Depressive or Manic Episodes, delirium, or substance 
use/withdrawal (see rationale above) 
 
3. Cognitive impairment defined as a Brief Orientation Memory and Concentration Test 
(Katzman et al., 1983) score > 10 
 
4. Lack of decision-making capacity to evaluate the risks versus the benefits of participation as 
determined by a score of <14 out of a possible 20 on up to 2 assessments using the Jeste 
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Assessment of Capacity to Consent (UBACC) (Jeste et al., 2007), or adjudication of 
incompetence and the appointment of a guardian or conservator 
 
5. Six or more previous lifetime suicide attempts as ascertained through SPAN, reports from 
family, or patient self-report   
 
6. Current or recent (within six months) use of lithium   
 
7. History of significant adverse effects of lithium as ascertained through the medical record or 
self-report 
 
8. Unstable medical conditions or specific medical comorbidity: 
 
a. Congestive heart failure by Framingham criteria (McKee et al., 1971) 
b. QTc greater than or equal to 450 ms for men or  
QTc greater than or equal to 460 ms for women (Measurement of the QT interval and 
the risk associated with QTc interval prolongation: A review. Moss et al.,1993).    
c. Chronic renal disease as defined by national Kidney Foundation Disease Outcome 
Quality Initiative (KDOQI) criteria (2000) with a estimated GFR less than 60 
mL/min/1.73m2. 
 
9. Any possibility of being pregnant or not on appropriate birth control   
 
10. Women who are lactating and breast feeding 
 
11. Concurrent medications: 
 
a. All diuretics except amiloride 
b. Haloperidol 
c. Clozapine   
 
12. Active substance abuse: 
 
a. Active alcohol or opiate dependence requiring medically supervised withdrawal and 
stabilization 
b. Active cocaine, methamphetamine, other stimulant, hallucinogen, or cannabis abuse 
requiring stabilization  
 
13. Enrollment and active participation in another randomized interventional clinical trial 
 
Rationale: 
 
Most diuretics and ACE inhibitors decrease renal excretion of lithium, potentially increasing 
lithium levels. The only diuretic allowed in the study is amiloride. Subjects on ACE 
inhibitors/AR blockers and amiloride can be admitted. 
 


 
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The starting dose of lithium will be 300 mg. Subjects on antihypertensive medications will need 
to be on a stable dose, defined as being on the same does of antihypertensive medication for at 
least one week  while achieving adequate blood pressure control.  Monitoring will be intensified 
with lithium levels obtained monthly throughout the study once they are at steady state. Patients 
starting diuretic( amiloride) and ACE inhibitors/AR blockers may continue study medication at a 
reduced dose and increased monitoring as described in “Ongoing Dose Adjustments” in Section 
XIII). 
 
Patients taking haloperidol are excluded because there are concerns of specific interactions with 
lithium in the central nervous system. Patients taking clozapine are excluded because its 
indications, treatment-resistant schizophrenia and reducing recurrent suicidal behavior in 
schizophrenia or schizoaffective disorders, are not compatible with the inclusion criteria.  
VI. 
STUDY MEASURES 
The baseline assessment will collect basic information including race, ethnicity, educational 
attainment, period of military service, combat exposure, and marital status. Tables 1 and 6 
summarize the other data to be collected, their source, and the estimated time required of the 
participant.  
 
Primary Outcome 
 
The primary outcome will be time to the first repeated episode of suicidal self directed violence 
including (non-fatal) suicide attempts and deaths from suicide over the one year follow-up 
period.  Interrupted attempts and hospitalizations specifically for the prevention of suicide will 
be considered equivalent to attempts. To minimize variability and bias in identifying episodes of 
suicidal self-directed violence, the Outcomes Adjudication Committee will review all potential 
outcome events, and make final determinations about which should be considered.  
 
The nomenclature and definitions for suicide-related behaviors will follow CDC definitions 
(Crosby et al., 2011).  By definition, an attempt must be accompanied by a wish to die, either 
reported by the patient, or inferred on the basis of his or her behavior. Repeated suicide attempts 
are clinically significant outcomes and a proxy for death from suicide.   
 
The study will utilize all available sources of information about repeated suicide attempts 
including the medical record and VA-Suicide Prevention and Application Network (SPAN) data. 
As proposed in the  draft FDA guidelines for clinical trials in suicide (FDA Suicidal Ideation and 
Behavior Draft Guidance, 2012), the study will utilize the Columbia Suicide Severity Rating 
Scale (CSSRS; Posner et al., 2011) , supplemented with additional information about preparatory 
behavior, interrupted attempts, and other forms of self-directed violence (e.g., whether the events 
was a suicide attempt, an event of undetermined intent, or non-suicidal self-directed violence) to 
align the CSSRS with the recently adopted CDC classification system (Crosby et al., 2011). The 
need for additional information to allow cross-walking between the Columbia and CDC 
approaches has been documented by the Matarazzo et al. (2013).  
 


 
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For reports of suicide attempts, self-report data from the CSSRS will be supplemented with 
information from the Suicide Intent Scale (Beck et al., 1974) to allow further characterization of 
attempts, and to distinguish impulsive from non-impulsive attempts (Spokas et al., 2012). For 
these analyses, attempts will be considered to be impulsive when the patient reports no 
premeditation on the Suicide Intent Scale.   
 
Adjudication of Primary Outcome 
 
An Outcomes Adjudication Committee will review redacted documents of possible attempts and 
related events, analogous to the procedures used in the InterSept study of clozapine for 
preventing suicide-related behaviors in patients with schizophrenia (Meltzer et al., 2003). 
Reports using a modification of the template of Brown and Holloway (Brown & Holloway, 
2005) for use in clinical trials of Cognitive Therapy for Suicide Prevention (Brown et al., 2005) 
will be submitted to the Outcomes Adjudication Committee for each episode considered to be a 
possible suicide attempt, an interrupted attempt, another form of self-directed violence, a death 
from suicide, or an accident.  
 
There will be at least 3 members of the Outcomes Adjudication Committee. Two members will 
classify endpoints for each case. Cases will be regularly sent to the committee and reviewed 
independently and blinded to treatment assignment. A third review will be conducted if there is 
disagreement. The Committee will classify events as suicide attempts, interrupted suicide 
attempts, hospitalizations where patients were admitted specifically to prevent suicide, and 
deaths from suicide, all considered as primary outcomes, or as other types of events. 
 
To determine whether an event is an outcome, the Outcomes Adjudication Committee will 
review all available information. The reports from the study sites will include a narrative of the 
event from the patient’s perspective, information about the method used; the lethality of the 
method; mood, thoughts, and feelings prior to the event; the nature of planning and preparatory 
behaviors prior to the event; external triggers; location; whether or not the patient notified 
anyone prior to and/or after the event; and the nature of the path that led from the event to 
clinical care.  For events that are interrupted by others or by the patient, the report will provide 
details about what triggered the interruption.  
 
To allow them to determine whether inpatient admissions were done to prevent suicide attempts 
or to reduce the risk for suicide, the materials to the Outcomes Adjudication Committee will 
include the patient’s explanation of the reason for admission, VA medical records, and discharge 
summaries from non-VA facilities using authorizations obtained from the patient as part of the 
consent process. 
 
One of the most important judgments to be made by the Outcomes Adjudication Committee will 
be whether there was lethal intent.  For this purpose, the reports assembled by the Research 
Teams at the study sites will include information about intent in the patient’s own words. The 
Committee will review all available information, including copies of relevant notes from the 
medical records, rather than the relying solely on the opinion of the investigator or the patient’s 
clinician.  To minimize drift over time, the Outcomes Adjudication Committee will review and 
rate the training materials on the CSSRS as described in “Training on Study Measures” in 
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Other Outcomes 
 
In addition to repeated episodes of suicidal self-directed violence, the study will obtain data on a 
number of secondary outcomes within the 12 month follow up period. These will go beyond the 
time to the first outcome event to include the total numbers of suicide attempts, interrupted 
attempts, hospitalizations for the prevention of suicide, emergency department visits, non-
suicidal self-directed violent behaviors, and deaths from suicide, unnatural deaths, and all-
causes. To support exploratory analyses on subtypes of suicide attempts, the study will obtain 
data on impulsive and non-impulsive attempts.  
 
Following the total number of suicide attempts and time to the first attempt will allow 
comparison of our findings with other studies that used rates of attempts as an outcome. 
Following the impact of the study treatment on other forms of self-directed violence will allow 
us to explore the specificity of the observed treatment effects.  The proposal to evaluate 
treatment effects on all unnatural deaths and on all-cause mortality follows from concerns that 
deaths from other causes in patients who have survived suicide attempts may represent suicide-
equivalents or cases misclassified by medical examiners or coroners. However, we recognize that 
the observed rates of all-cause of mortality in persons who have attempted suicide are lower than 
reattempt rates, and, therefore, the study would not be powered to detect a treatment effect on 
overall mortality. Finally, exploratory analyses on impulsive versus non-impulsive attempts, 
defined on the basis of reports of the absence or presence of premeditation on the Suicide Intent 
Scale, may provide further insights into whether any observed effects of lithium could be related 
to a decrease in impulsive behaviors.  
 
Covariates  
 
Measures of potential effect modifiers will include traits of impulsivity and aggression.  
Measures of potential mediators will include symptoms of the patients’ affective disorders 
(including suicidal ideation). 
VII. BIOSTATISTICAL CONSIDERATIONS 
Overview 
 
The primary hypothesis is that lithium is superior to placebo for the prevention of episodes of 
suicidal self-directed violence, including suicide attempts, interrupted attempts, hospitalizations 
to prevent suicide, and deaths from suicide over the ensuing year.  The primary outcome measure 
is time from randomization for treatment allocation to the first episode. The results for event-free 
survival will be analyzed by means of a two-sided log-rank test. The study will have one interim 
analysis and one final analysis. 
 
The duration of the study will be 4.5 years total, which allows for 3 years of recruitment, 1 year 
of follow-up for all enrollees, and time for start-up and closeout as indicated. A total of 1,862 
patients will be enrolled and randomized to receive either lithium or placebo, both in addition to 


 
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enhanced usual care. We expect to enroll an average of 65 patients per site at 29 VA medical 
centers.  All subjects will be followed for 12 months after randomization.  Section IX describes 
site identification and recruitment plans.  
 
Estimated Incidence of Primary Endpoint 
 
We posit a 1-year event rate of 15% in the placebo group for the primary outcome based on data 
from the literature on lithium and SPAN data.  
 
Lauterbach et al. (2008) reported a 12% 1-year reattempt rate in the placebo group in a cohort 
primarily of women, slightly younger than the VA cohort, and predominantly with major 
depressive disorder. This rate is slightly lower than that projected for the current study possibly 
because hospitalizations to prevent suicide were not included.  Oquendo et al. (2011) evaluated 
suicide attempts and suicide events separately. Reattempt rates at 1 year were approximately 
12% and 18% in the lithium and valproate groups respectively. In spite of their small samples 
and a more rigid definition of the endpoint, these two trials provided point estimates of outcome 
event rates between 12% and 18%. 
 
To obtain a more precise estimate of the event rate in the Veteran population, we used VA SPAN 
data from second half of FY 2010 through the first half of FY 2012 (24 months), to characterize 
the target Veteran population potentially eligible for the proposed study.  Detailed analysis of 
this cohort is presented in Section IX and selected characteristics of this target population are 
included and compared to the participant profiles of prior studies in Table 2. 
 
Overall, there were 27,128 veterans with bipolar or major depressive disorder, who survived an 
attempted suicide between 4/1/2010 - 3/31/2012, a 24 month period.  After considering 
exclusions for 6+ prior attempts, co-morbid conditions of schizophrenia, congestive heart failure, 
renal failure, lithium therapy within the past year, or use of medications that may interact with 
lithium, approximately 17,656 subjects (65%) remained potentially eligible for CSP590.  
According to SPAN data for a subset of the eligible cohort with at least one year of follow-up, 
15.2% had repeated episodes of suicidal self-directed violence. 
 
Using event rates from SPAN and the literature, we used a 12 month estimate of a 15% repeat 
rate in the control population to estimate our sample size and to determine feasibility. 
 
Estimated Effect of the Intervention 
In Table 2, we summarize key studies that provide estimates for the efficacy of lithium in 
reducing suicide rates in depression and bipolar populations. In their prospective cohort study of 
approximately 20,000 subjects with bipolar disorder, Goodwin et al. observed a 41% to 60% 
reduction in suicidal events for those on lithium compared to other pharmacological agents.  In 
their meta-analyses of lithium studies, Cipriani and Guzetta demonstrated larger effect sizes 
ranging from 74% to 88%.  Together, these studies support estimates of effect sizes for lithium 
for reduction of suicide events of 50% or greater and we expect to observe a similar reduction in 
CSP590. 
 


 
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For the proposed study, however, Lauterbach’s placebo-controlled clinical trial in a sample with 
a large proportion of patients with depressive disorders and Oquendo’s valproate-controlled 
clinical trial in a sample of bipolar patients are also relevant. A reduction of 48% in 1-year 
reattempt rates in the lithium group relative to placebo was reported in the Lauterbach study, and 
approximately a 33% reduction in the lithium group relative to valproate group was observed in 
the Oquendo study.   
 
To be conservative, our sample size estimate is based on an initial estimate of a 43% effect, the 
weighted average of the 48% reduction effect observed in the Lauterbach study and the 33% 
reduction effect observed in the Oquendo study. We adjusted for a potential attenuation of the 
effect due to non-adherence; estimating 15% non-adherence leads to a final estimated effect size 
of 37%.  As discussed below, correction for the loss of data from patients who dropout is 
addressed through estimates of the sample size requirement, not the effect size for the 
intervention.  
 
Missing Data from Attrition  
 
In randomized clinical trials, Lauterbach (2008) and Oquendo (2011) reported overall attrition 
rates of 58% and 50% in the lithium group respectively, of which 21% and 11% were treatment 
related.  Moreover, Lauterbach reported a similar rate of attrition for the placebo group, 
suggesting that there was no differential dropout. 
 
The proposed study, unlike the previous trials, allows for continued enrollment of subjects who 
discontinue study medications. The sample size calculations are based on a dropout rate during 
the course of the study of approximately 40%, or assuming that the dropout rate is uniform, a 
reduction in the effective sample size of approximately 20%.  Allowing for up to 40% dropout or 
approximately a 20% loss of data for reasons unrelated to treatment, the statistical power 
calculation is based on an effective sample size of 1,490 evaluable patients from a total of 1,862 
enrolled. For the primary time to event analysis, we will censor follow up at the first occurrence 
of the primary endpoint event, death, or withdrawal from the study for any reason.  
 
We will test the missing at random assumption using a Bayesian Pattern Mixture Missingness 
approach (Rybin et al., 2013), to validate the results and identify potential bias from possible 
non-random patterns of missing data.  For secondary longitudinal analyses, we will evaluate 
missingness patterns and perform sensitivity analysis based on multiple imputation methods.   
 
Non-Adherence to Study Protocol  
 
Estimates of the extent of full or partial non-adherence to lithium range from 20-60% (Goodwin 
& Jamison, 1990; Lingam & Scott, 2002).  Findings from a long term follow-up study of patients 
in a lithium clinic (Maj et al., 1998) and from two large studies using pharmacy data are within 
this range (Johnson & McFarland, 1996; Kessing et al., 2007).  In recent studies, Nierenberg et 
al. (2013) studied optimized personalized treatment with and without lithium in bipolar subjects 
and observed that 21% of the participants discontinued lithium prematurely during a six month 
trial; the BALANCE group (2010) observed that 40% discontinued prematurely in a two year 
trial.  
 


 
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The most relevant information on tolerability and adherence in a population similar to CSP 590 
is from the two studies of lithium for the prevention of suicide.  The overall discontinuation rates 
for the Lauterbach (2008) study (including discontinuations related to suicide and suicide 
attempts) were 9.5% for the lithium group and 16.7% for placebo at 1 month, 27.3% and 32.5% 
at 3 months, 32.5% and 35.7% at 6 months, and 57.1% and 59.0% at 1 year. When 
discontinuations due to suicide and suicide attempts were excluded, the rate for discontinuation 
during the year was 50%.  Because these occurred throughout the year, and because informative 
data after randomization were obtained on almost all patients, the decrease in the effective 
sample size was approximately 25%. Dropouts due to the subject’s discontinuing treatment were 
only 10.9% and 12.5%.  For planning CSP590, we allowed for potential attenuation of the 
treatment effect from non-adherence in 20% of the sample. This is reflected in the sample size 
calculations as an attenuation of the effect size for lithium. 
 
Randomization Plan 
 
The MAVERIC Cooperative Studies Program Coordinating Center (MAVERIC CSPCC) will be 
the coordinating center for the trial. The Albuquerque VA Cooperative Studies Program Clinical 
Research Pharmacy Coordinating Center (CSPCRPCC) will manage drug inventory and 
accountability.  Patients will be randomized to lithium or placebo by the MAVERIC CSPCC in 
Boston, in coordination with the CSPCRPCC in Albuquerque.  
 
Both stratification and blocking will be utilized to control for potential imbalances in 
randomization.  The randomization scheme will be stratified by participating site in addition to 
diagnosis (bipolar vs. depression) and history of prior attempts other than the index attempt 
(none vs. 1+ attempt).  Stratification by site is necessary because of possible regional differences 
in clinical practices.  Participants will be randomized to either lithium or placebo within 
permuted random blocks of 4 so that the treatment arms are balanced after every 4th 
randomization within the 4 strata at each site: bipolar with prior attempt, bipolar without prior 
attempt, depression with prior attempt, and depression without prior attempt.  Breaking the blind 
at the end of each participant’s time in the study is not expected to provide information about the 
treatment assignment of participants remaining in the study as block randomization is within 
multiple strata.  Regardless, an extra treatment assignment will be inserted to each stratum of 
four to disrupt the blocks and make block size harder to discern. 
 
A web-based randomization program validated by the MAVERIC CSPCC will be provided to 
study sites. At subject enrollment, Site Coordinators will enter the patient ID number, study site, 
and eligibility information into the randomization program to confirm that all eligibility criteria 
are met.  If met, the program will select the first unused entry from the pre-specified list of 
random treatment assignments for the particular site. The lists will be stored on a secure server at 
MAVERIC CSPCC.  In case the electronic system is down, the identical process can be followed 
manually and the randomization scheme telephoned or faxed to the site.  
 
This CSP clinical trial is a double-blinded study in which neither the patient nor the site 
investigator knows to which of the two study arms the patient has been assigned. Emergency 
drug code envelopes will be prepared by the CSPCRPCC and shipped with the study drugs to the 
Pharmacy Service of the participating medical center prior to the study starting. Each envelope is 
numbered with a unique patient randomization number and contains the treatment assignment for 


 
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that patient. These envelopes are placed in the custody of the Pharmacy Service for the duration 
of the study. The blind (or treatment assignment) will only be broken if knowledge of the 
specific drug is essential to the medical management of the patient (See DTHP Section 11 for 
further information on emergency unblinding of a participant during the study), or at the 
completion of the study and transfer of care to primary providers (See Section XIV).  
 
The emergency drug code envelope and its contents must be returned to the CSPCRPCC within 
72 hours of the code break. Upon receipt of the code envelope, the CSPCRPCC will immediately 
inform the study biostatistician via telephone or email and send the envelope, which will be filed 
with the study documents at the MAVERIC CSPCC. When the study has been completed (or 
terminated early) the unopened envelopes must be returned to the CSPCRPCC. The CSPCRPCC 
will verify that the envelopes were or were not intact and notify the study biostatistician of their 
status. 
 
Primary Data Analysis Plan 
 
The primary analysis will be an intention-to-treat survival analysis of all subjects who were 
randomized and received at least one dose of study medication.  The primary hypothesis to be 
tested is that lithium augmentation of enhanced usual care is superior to enhanced usual care plus 
placebo for the prevention of repeated episodes of suicidal self-directed violence over time. We 
posit a one-year repeat rate of 15% in the placebo group and a 37% reduction of events in the 
intervention group. 
 
The null hypothesis is that the two treatment groups do not differ in their hazard rates.  The 
alternative hypothesis is that the group on lithium augmentation has a lower hazard rate than the 
placebo augmentation group.  
 
The primary hypothesis can be stated as follows. 
 
Under the null hypothesis: The 1-year event rate will be 15%.  
 
Under the alternative hypothesis for patients treated with lithium: The 1-year event rate 
will be 9.45%.  
 
The reductions attributed to treatment may be viewed in several ways.  The absolute reduction 
from 15% to 9.45% is 5.55%, the relative reduction is (15 – 9.45)/15 = 37%, and the hazard ratio 
(treatment hazard rate/control hazard rate) of 0.61 is approximately midway between the simple 
odds ratio, [9.45(100-15)] / [15(100-9.45)] = 0.59 and the risk ratio 9.45/15 = 0.63. 
 
The formal hypothesis test is two-sided allowing for lithium augmentation therapy to be either 
more or less effective than placebo augmentation of enhanced suicide prevention management.  
However, the study of lithium will only be viewed as successful if patients augmented with 
lithium have a significantly lower hazard of repeated events than patients not treated with 
lithium.  
 
We will test this hypothesis with a log rank test, followed by Cox proportional hazards 
regression modeling to provide the hazard rates, their ratio and the 95% confidence interval 


 
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about the ratios.  We will also fit a random effects or frailty model to investigate potential 
heterogeneity of effect due to site variability (Glidden et al., 2004; Hougaard, 1991).  
 
Interim Analysis 
 
We will conduct one interim analysis after half of the participants have completed their 12 month 
follow up.  Assuming a uniform rate of enrollment, it will take 1.5 years to enroll half the 
sample. Allowing for the last patient to accrue 12 months of follow-up, the interim analysis 
should take place approximately 2.5 years after initiation of enrollment, at which time, after 
adjusting for attrition, there should be a sample of 746 evaluable subjects, (373 in each group). 
 
Projecting the same event rate in this sub-sample we expect a 15% repeat rate or 112 events (56 
events in each group) under the interim null hypothesis that event rates are equal in the 
intervention and placebo groups.  Under the interim alternative hypothesis, the absolute 
reduction from 15% to 5.3% is (15-5.3) = 9.7%, the relative reduction is (15-5.3)/15 = 65%, and 
the hazard ratio (treatment hazard rate/control hazard rate) is 0.34.  
 
Using the O'Brien-Fleming procedure, (Turnbull & Jennison, 2000), this analysis will have a 
Type I error of 0.2%, which negligibly decreases the overall Type I error for the study and has 
virtually no effect on the power for primary analysis. The interim analysis is two-sided, and the 
interim null hypothesis will be rejected if the hazard ratio exceeds 1/0.34= 2.94 or falls below 
0.34.  
 
We considered earlier times for interim analyses, but rejected this idea because we would have 
only modest power to detect very large effects with even smaller sample sizes.  Of note, the 
effects reported by Cipriani and Guzetta (Table 2) are similar or greater than the effects to be 
tested in the interim analysis. We will confer with the Data Monitoring Committee members and 
the program leadership for potential stopping guidelines based on efficacy findings from the 
interim analysis. 
 
Sample Size and Statistical Power Considerations for the Primary Hypotheses 
 
The results for the primary outcome measure will be analyzed by a two-sided log-rank test to 
detect either a hazards ratio that exceeds 1/0.61=1.64 or is less than 0.61.   The test will have a 
two-sided 5% type I error overall.  The test has 90% power to detect a hazard ratio of 1.64 or 
larger or 0.61 or less with a total of 1,862 patients, 931 per study arm which reduces to 1490 
evaluable patients. This allows for 40% of subjects lost to follow-up resulting in a 20% complete 
data loss while on study before a repeat suicide event is observed.  
 
Tables 3a, b, and c below consider three scenarios for possible shift in statistical power, 
specifically (1) in the event that an intervention effect different from the projected 37% reduction 
is observed (Table 3a), (2) in the event that the sample size for the study falls either above or 
below the targeted 1490 evaluable subject mark (Table 3b), and (3) in the event that the event 
rate is below the expected 15% in the placebo group. This study will have greater than 80% 
statistical power at 5% overall error if the observed effect is as low as 33% reduction, if the final 
evaluable sample is as low as 1200 subjects, or if we observe an event rate as low as 12% in the 
placebo group. 


 
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Secondary Data Analysis Plan 
 
Our secondary analyses are intended:  
 
(a) To explore the effectiveness of lithium augmentation of enhanced suicide 
prevention management in preventing separately: 
1. all-cause mortality 
2. impulsive suicide reattempts 
3. non-impulsive suicide reattempts 
4. self-directed violence 
 (b) To explore heterogeneity of response to treatment in subgroups including: 
1. categories of age, race/ethnicity, and gender 
2. diagnosis of depression vs. bipolar disorder  
3. impulsive index attempt vs. non-impulsive index attempt 
4. substance use vs. absence of substance use  
5. individuals with and without trait impulsivity  
6. individuals with and without trait aggression 
7. subjects who have vs. have not received evidence based psychotherapies 
(c)  To explore the effect of lithium augmentation of enhanced suicide prevention 
management on total occurrence of all event types combined and individual event 
type as follows:  
1. all suicide attempts  
2. all suicide attempts plus interrupted attempts 
3. all hospitalizations for the prevention of suicide  
4. all self-directed violence 
5. all emergency department visits   
(d)  To explore longitudinally the effect of lithium augmentation of enhanced suicide 
prevention management on symptoms of bipolar disorder and depression and suicidal 
ideation 
(e) To explore mediators of the effect of lithium augmentation on prevention of 
episodes of suicidal self-directed violence, specifically improved control of symptoms 
and lithium plasma levels 
 
Secondary objective (a) will use a time to event, survival analysis to determine whether there is a 
treatment difference in event rates for each of the defined endpoints. The null hypothesis for each 
endpoint is that the two treatment groups do not differ in their hazard rates.  The alternative 
hypothesis is that the intervention group on lithium has a lower hazard rate than the placebo 
group.  The log-rank test and Cox proportional hazards models will be used. 
  
 
For secondary objective (b), the null hypothesis for each of the factors is that treatment effect 
does not differ over levels of the factor.  The alternative hypothesis is that there is differential 
treatment effect over levels of the factor.  Effect modification will be tested through the use of 
interaction terms in the Cox proportional hazards regression model with main effects of 
treatment and factor and an interaction of the two.  A forest plot will be used to display the 
results. 


 
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Secondary objective (c) will be evaluated using Poisson regression to model for grand total 
numbers of events and for total number of each event type controlling for follow up time.  The 
null hypothesis for this objective will be that total event rates do not differ by treatment 
assignment.  The alternative hypothesis is that there is a difference in total event rates across 
treatment groups. 
 
Secondary objective (d) will be evaluated using mixed effect models allowing for random 
variation in symptoms of bipolar disorder and depression at baseline. The null hypothesis for this 
objective will be that change in symptoms and suicidal ideation in the lithium group is similar to 
that of the placebo group. The alternative hypothesis is that there is a difference in change across 
treatment groups over time. 
 
Secondary objective (e) will be evaluated by regression analysis method comparing regression 
coefficients for treatment effect in the models with and without the mediator (Sobel, 1982), as 
well as by bootstrapping methods, (MacKinnon et al., 2002; Preacher & Hayes, 2008; Tein & 
MacKinnon, 2003). 
 
Tertiary Data Analysis Plan 
 
These exploratory objectives (explained further in Section XIV) are to analyze electronically 
available data over the extended follow up period to:  
(a) describe pattern of Lithium use following active participation in the study 
participants,  
(b) evaluate suicide reattempt and all cause mortality over a longer follow up period, 
both for the study population and patients who were evaluated for enrollment under 
HIPAA waiver (“pre-screen” population), and 
(c) evaluate all cause mortality over a longer follow up period. 
 
Tertiary objective (a) will be evaluated by descriptive analysis on duration of lithium use, and by 
regression modeling to determine factors associated with any lithium use within one month 
following active study participation.  
 
Tertiary objectives (b) and (c) will be evaluated using time to event survival analysis and Cox 
regression modeling to determine correlates of suicide reattempts and all cause mortality in the 
study population. 
 
Data Repository 
 
The Boston CSP Coordinating Center will create a data repository under the Boston IRB 
oversight for research purposes. Data will be housed at the Boston Cooperative Studies Program 
Coordinating Center and will be made available to appropriately credentialed researchers 
conducting studies related to suicide, lithium, or other health questions, in accordance with the 
Repository Protocol and relevant SOPs.  


 
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VIII. POTENTIAL PITFALLS OF THE PROPOSED DESIGN AND 
ALTERNATIVE DESIGN CONSIDERATIONS 
 
Potential pitfalls of the trial include the threats to internal and external validity inherent in any 
clinical trial and those of particular concern to this study question. 
 
A. Defining inclusion/exclusion criteria and the “indication”: The study includes patients 
with depression or bipolar disorder who have survived an episode of suicidal self-directed 
violence, and allows enrollment of patients with psychiatric comorbidities other than 
psychotic disorders, active substance abuse, and dementia. Basically, the proposal is to 
test the effectiveness of lithium for prevention of suicide-related behaviors rather than the 
treatment of any specific condition. The study population for this clinical trial is similar 
to that of the Lauterbach study (2008) while the Oquendo study (2011), in contrast, 
studied only patients with bipolar disorder. There may be adequate numbers of patients in 
VA to support a study limited to depression, but not for one limited to bipolar disorder. 
Nevertheless, the decision to include all potential subjects with an affective disorder was 
based on the available evidence and was intended to maximize the potential impact of 
findings, both for VA and beyond. 
 
B. Potential limitations in the accuracy of estimates for the number of suicide attempts and 
reattempts: 
 
1. Attempt rates: The number of suicide attempts and the number of unique 
individuals who have survived attempts are identified in real time by the SPCs. 
The SPCs also report on deaths from suicide when they become aware of them. 
Comparing these reports of deaths with those identified through the CDC’s 
National Death Index (after a lag of 2-3 years) demonstrate that facilities are 
aware of somewhat less than half of all suicides in their population. It is possible 
that similar limitations in ascertainment apply to suicide attempts as well as 
deaths, and that the SPC reports may underestimate the number of attempts and 
the number of survivors. However, ongoing review of the reported attempts has 
repeatedly demonstrated that there are few, if any, false positives. Therefore, the 
estimates used for planning this study must be viewed as lower limits for the true 
numbers of potentially eligible subjects. 
 
2. Repeat rates: The proportion of attempt survivors reattempting suicide within one 
year has remained stable in the VA over the past several years. The reported rates 
are well within the range of those for other studies of preventive interventions 
(Section VII). Nevertheless, there are two potentially counterbalancing effects 
that may affect the reattempt rate for study participants. One is that the increased 
attention and support due to study participation may decrease the rate of 
reattempts. The other is that supplementing VA’s current methods of surveillance 
with repeated inquiries using the CSSRS may lead to increased rates. There is no 
way to estimate the magnitude of these effects, separately or in combination, or 
even to estimate which is likely to be the larger effect. Uncertainty about these 


 
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effects must be viewed as a limitation in the calculations of statistical power for 
the proposed study.   
 
C. Non-adherence with study medication: The study is designed to minimize the number of 
subjects who would not be able to tolerate lithium. First, the study’s standard operating 
procedures includes a protocol for reducing the dose of study medication to a minimum 
of 300 mg/day, and maintaining subjects on the highest tolerable plasma level not to 
exceed the target of 0.6-0.8 meq/liter. Second, the Site Physician may modify the timing 
of the daily dose, e.g., recommending lithium with meals to decrease rates of absorption, 
or shifting larger proportions of the dose to the evening to minimize the impact of fine 
tremor during the day. In addition, as discussed in Section VII, the sample size 
calculation allows for a moderate degree of non-adherence. The study tests for an effect 
of lithium of approximately 43% based on the observed effects in the Lauterbach (2008) 
and Oquendo (2011) studies. The effect size is lower than most of the observational 
studies and the meta-analysis of randomized clinical trials conducted for other outcomes. 
The sample size calculations also assume that up to 20% of subjects would discontinue 
taking study medications, and that this would attenuate the apparent effect of treatment. 
To summarize, the proposal to test for an effect size of 37% represents a test for a 43% 
effect attenuated by non-adherence.  
 
D. Feasibility of blinding lithium treatment: We reviewed the literature on lithium to 
determine the feasibility of maintaining blinding in a placebo-controlled, randomized 
clinical trial. Searching of the Medline database using the key words lithium AND 
clinical trials AND the text word placebo identified 18 relevant reports of primary or 
secondary analyses of placebo controlled randomized clinical trials (Aggarwal et al., 
2010; Amado et al., 2005; Bauer et al., 2000; Bell et al., 2005a, 2005b; Bowden et al., 
2003, 2005a, 2005b, 2006; Calabrese et al., 2006; Gyulai et al., 2003; Hirschfeld et al., 
2003; Nierenberg et al., 2003; Swann et al., 2001, 2002, 2004; Weisler et al., 2011; 
Willson et al., 2005). Of these 11 were in subjects with bipolar disorder, 2 in depression, 
and 1 in amyotrophic lateral sclerosis. There were also four reports of studies that 
evaluated the psychological and physiological effects of lithium in normal subjects. This 
search did not identify the Lauterbach paper on suicide prevention. Including it, we 
identified 19 relevant reports. None of them commented on difficulties in maintaining 
blinding. None of them reported on the subjects or investigators guesses on treatment 
assignment and tests of their validity. 
 
As another way to evaluate the literature, we reviewed the rationale for the non-blinded 
study design in two recent open-label randomized clinical trials of lithium, LITMUS and 
BALANCE. The primary outcome paper for LITMUS (Nierenberg et al., 2013) did not 
present a rationale for the open-label design. However, the earlier design paper 
(Nierenberg et al., 2009) stated, "We chose to not blind the clinicians to treatment 
because the goals of LITMUS are to evaluate treatments that are used in the community 
and to study the impact of treatment decisions that are relevant to every day clinical 
practice. Another factor that supports the open design of the study is that because no one 
knows the effectiveness of flexibly-dosed lithium added to other mood stabilizers, 
clinicians should be in equipoise..."  The primary report of the BALANCE study (2010) 
stated, "Investigators and participants were aware of treatment allocation because of the 


 
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complexities of masking of lithium therapy and the concern that concealment would 
restrict participation and generalisability." The earlier design paper (Rendell et al., 2004) 
stated, "In principle psychiatrists espoused double-blind methodology and it was only 
when they began to contemplate the possibility of not knowing whether a particular 
patient was on lithium that blind of treatment emerged as a major disincentive to 
recruitment." To summarize, the investigators in both studies used non-blinded designs 
primarily because they were concerned that a double-blind design could be a barrier to 
recruitment and that it might compromise their goals for recruiting representative patients 
samples, and drawing inferences about effectiveness. Other reasons were, for 
BALANCE, the difficulties in the logistics of conducted a blinded, flexible dose study of 
lithium, and, for LITMUS, the presumed lack of any reason for bias. Most significantly, 
neither of the study reports stated that their decision to conduct a non-blinded studies was 
a response to the futility of blinding. 
 
Planning members questioned whether the high frequency of side effects in lithium users 
would compromise blinding but the consensus of the planning group was that the impact 
of side effects would be minimized by the proposed schedule for titrating doses. 
Moreover they concluded that difficulties in maintaining blinding could emerge as an 
issue for a meaningful subset of subjects in a study of monotherapy with lithium versus 
placebo in patients who are physically healthy and not taking other medications. 
However, with the complexity of the patient population with its extensive comorbidity 
and medications for treatment of coexisting conditions, this would occur only rarely in 
the proposed study.   
 
E. Dropouts, especially differential dropout between the active and placebo agents are 
always a concern.  
 
1. Minimizing dropouts: Several methods will be used to minimize dropouts. The 
study will maintain contact with study participants and reach out to those who do 
not follow-up. Contacts with treating physicians will be maintained and clinic 
appointment logs will be scanned to identify when participants will be visiting a 
VA facility for any reason. In addition, written permission to contact family 
members, friends, or others who would be likely to know the whereabouts of 
study participants will be obtained at enrollment.  Study staff may arrange home 
visits to conduct interviews, when necessary, or offer assistance with 
transportation arrangements, and meal tickets. 
2. Participants who cannot tolerate study medication, even at reduced doses, will be 
encouraged to continue study assessments to allow their inclusion in the intention 
to treat (ITT) analyses and to allow our continued access to their electronic VA 
records.  
3. Analytic considerations: Estimates for dropout, and the probability of differential 
dropout are discussed in Section VII. For each secondary outcome, all data 
collected will be used in the repeated measures analyses.  If missing data are 
determined to be informative, sensitivity analyses will be conducted to examine 
their influence on the treatment comparisons.   
 


 
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F. Safety concerns: Safety, obviously, is a primary concern. Our Safety Program has X 
essential elements 
 
1. Lithium level monitoring that meets and/or exceeds what is done in usual care 
practice and VA practice. Labs are done centrally and reported as soon as they are 
done to the Safety Officer and pari passu to sites. 
2. 24/7 availability of a Safety Officer, a senior psychiatrist, backed by a team with 
internal medicine, nephrology, cardiology experts – all blinded, are available for 
consultations on a case by case basis.  
3. Safety first is the study’s priority. This operationalizes a risk-adverse, 
conservative approach to study drug dosing. Summarized, when there is any 
doubt, we assume the subject is on active agent (lithium), treat reported or 
observed symptoms as potential lithium excess, and lower, or hold, or stop study 
medication (lithium/placebo) when there is any uncertainty or lack of data (lack of 
contact with subject, lab results, etc.)    
 
The risk of overdosing from lithium can be estimated from the Lauterbach (2008) and 
Oquendo (2011) studies which found that approximately 1% of participants overdosed on 
study medication during the course of one year. To decrease the probability of overdoses, 
study medications will be dispensed in blister cards because this strategy may reduce the 
frequency of impulsive (though not planned) overdoses.  Another strategy will be to limit 
the amount of study medications dispensed at any one time.  
 
We propose to dispense two one-week blister cards of study medication at a time and to 
require the return of used blister cards at the next study visit. Study visits for clinical 
evaluations and blood tests will be after a minimum of 5 days and a maximum of 30 days 
at a constant dose of study medication (see section XIV for more detail on dosing 
intervals). Decisions about dose adjustments would be made, and medications would be 
dispensed, in general by express mail, to allow starting on the new dose approximately 3-
4 days after the study visit. 
 
The ideal would be to require exchanging new blister cards for old ones every 3 or 4 
days, but this is not feasible. While planning this study, we evaluated the possibility of 
accelerating the cycles of blood tests, dose recommendations, and dispensing of new 
medications to allow weekly visits, and dispensing of only one week’s medication at a 
time. However, to do this, it would have been necessary to obtain blood levels after as 
little as 3 days, too short a time to ensure that steady state was achieved. Although this 
may have led to some decrease in the risk of serious overdose, it would have been at the 
expense of less reliable estimates of plasma levels, and an increased risk for dose-related 
adverse reactions. 
 
To summarize, the protocol as proposed focuses on minimizing the risks of overdosing 
by dispensing medications in blister cards and in limited amounts, and by requiring the 
return of old blister cards. The decision to dispense two-weeks’ medication at a time 
reflects a compromise: limiting the amount dispensed and allowing enough time at each 
dose to achieve steady state while maintaining the burden of repeated study visits at a 
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G.   Procedures for monitoring and adjusting lithium levels: Lithium levels will be 
determined by a Central Lab to ensure consistency as well as prevent accidental 
unblinding of the local study staff. By contract, the results will be accessible to the 
MAVERIC data coordinating center within 36 hours of the blood draw, wherein 
simulated lithium levels for those participants randomized to receive placebo will be 
calculated. If lithium level results are not available within 72 hours to the local site, 
consultation with the Central psychiatrist / CSP590 Safety Officer is required.  
 
The MAVERIC data coordinating center will provide the lithium levels (actual level for 
participants in active group and simulated level for participants in placebo group) to the 
Site Physician and the Central Psychiatrist/Safety Officer. The Site Physician, after 
consultation with the Central Psychiatrist/Safety Officer as needed, will make the final 
dose adjustments and document the dose, using the provided lithium level and all the 
clinical information available. 
 
Simulated levels will be calculated as outlined in Section XIII.  
 
The planning group considered an alternative proposal in which all dose adjustments 
would be done by the Central Psychiatrist/Safety Officer on the basis of lithium levels 
from the laboratory and clinical information from the study site. In this approach, the Site 
Physician would execute the recommendation by prescribing the recommended dose 
unless there was a compelling clinical reason to modify it. The principle advantage of this 
might be less variability between sites in decision-making about dose adjustments. 
However, the planning consultants felt this process for titration of the medication would 
be complicated and cumbersome. Specifically, there was a consensus that it would limit 
the study’s ability to respond to what might be subtle indicators about minor side effects 
or discomforts with the study medication. Accordingly, there were concerns that it might 
increase the risk of more significant side effects or dropouts. 
 
Other designs were considered including:   
 
1. A randomized controlled trial (RCT) comparing active treatments: This possibility was 
rejected because, other than lithium, there is no justification for use of any other 
medication as adjunctive treatment for patients with depression or bipolar disorder.   
2. A clinical trial without a placebo comparison: This possibility was rejected because the 
planning group viewed it as likely that knowledge of whether or not patients were 
receiving lithium would affect their providers’ decisions about other components of 
treatment and management.  
3. Point of Care (POC) Randomization (Fiore et al., 2011): A POC design with 
randomization to lithium or another psychoactive agent was rejected on ethical grounds. 
There is no justification for use of any other medication as adjunctive treatment for 
patients with depression or bipolar disorder.  POC with randomization to lithium or to no 
lithium was judged fatally flawed in that that knowledge of whether or not patients were 
receiving lithium would affect their providers’ decisions about treatment and 
management. POC was also judged not to be feasible as maintaining safety would require 


 
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titrating lithium and monitoring of plasma levels, all procedures that were beyond the 
scope of a POC study.   
IX. 
FEASIBILITY OF RECRUITMENT 
Eligible Veterans Population 
 
For evaluating the feasibility of successfully completing CSP590, we used the VA-SPAN data to 
identify veterans with bipolar or depressive disorder, who survived a suicide attempt during the 
24 month period from the second half of fiscal year 2010 to the first half of fiscal year 2012. The 
flow chart in Section XXI (Figure 1) describes the process by which we determined the eligible 
cohort.  
 
During this 24 month period, 28,934 veterans survived an attempted suicide and of this cohort, 
17,656 subjects (65%) were potentially eligible for CSP590. Table 4 gives the 50 VA sites with 
the largest number of potentially eligible subjects for a one year period. 
 
Assuming we are able to recruit approximately 1 out of 5 eligible subjects, full enrollment would 
require evaluating a total of 9310 potential subjects. Estimates of the number of study sites 
required to achieve this target are given in Table 4. Assuming participation of all sites with high 
numbers of potentially eligible subjects, the minimum number of sites that would be required is 
21. A more conservative estimate used the actual sites that agreed to participate and the estimate 
that 20% of potentially eligible subjects would be recruited. Based on these calculations, we are 
proposing to include 29 sites. 
 
 
Also in support of the feasibility of our protocol which calls for titration and blood collection, we 
have data (not shown) that approximately 70% of those who survive suicide attempts live within 
60 miles of a VA medical center. 
 
When identifying the 29 VA sites, we will utilize the CSP Network of Dedicated Enrollment 
Sites (NODES) whenever possible.  As a consortium of VA medical centers   dedicated to the 
multi-site clinical research mission of CSP, it represents sites that should be well-equipped to 
conduct this study. Eight of the NODES sites (San Diego, Houston, Minneapolis, Dallas, Hines, 
Palo Alto, Salt Lake City, and Portland) are in the 50 top sites for potentially eligible subjects for 
this proposed study. Together, they would contribute approximately 2707 potentially eligible 
subjects over three years, or almost 30% of the total required.   
 
Site Selection 
 
To assist with site selection for CSP590, a survey was conducted on a total of 70 sites comprised 
of the top 50 sites identified in Table 4, 3 additional CSP NODE sites that were not in the top 50 
list, and 17 sites which independently expressed interest. From the 40 sites that returned the 
survey, the top 29 with the largest pool of potentially eligible subjects have been identified. In 
addition, 2 VISN1 Clinical Research sites have been added to maintain the enrollment estimate 
needed for CSP590, but will be included in the Boston site.  
 


 
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Experience with the SAFEVET Program 
 
The experience of VA’s Center of Excellence for Suicide Prevention in Canandaigua addresses 
the feasibility of recruiting suicidal Veterans. The SAFEVET program was implemented from 
2009 to 2012 as a demonstration project to evaluate a model for providing follow-up services for 
Veterans who came to VA emergency departments after a suicide attempt but did not need 
inpatient care.  
 
During the 3-year project, 1781 Veterans came to participating VA emergency departments after 
a suicide attempt and were not admitted directly to inpatient units. Of these, 95 (5.3%) refused to 
participate in SAFEVET; 46 (2.6%) were excluded for other reasons, and 30 (1.7%) were 
admitted to an inpatient unit within 24 hours of the initial emergency department visit. 388 
(21.8%) did not participate for reasons that were not reported to the project’s Principal 
Investigator. Overall, 1222 Veterans (68.6% of the population) enrolled in the project. The 
outcomes of the program are being evaluated. 
 
Most relevant to the proposed trial, the proportion of potentially eligible Veterans who refused 
participation in SAFEVET was between 5.3%, the proportion refusing, to 27.1%, the percentage 
refusing and not enrolled for unknown reasons. The SAFEVET program is substantially different 
from the proposed trial but shows it is possible to enroll a substantial majority of Veterans who 
survive suicide attempts to participate in an evaluation of a program aimed at suicide prevention.  
X. 
POTENTIAL BARRIERS and STRATEGIES TO OPTIMIZE 
RECRUITMENT 
Only two randomized trials have been conducted to determine whether lithium can prevent 
suicide. Both failed because they were unable to recruit adequate numbers of patients. In both 
studies, subjects were recruited from a small number of hospitals and clinics, and surveillance for 
potential subjects was established de novo for the study. Moreover, many potential subjects had 
no ongoing connection with the hospitals or mental health providers associated with the study.  
 
In contrast, our study would be conducted within a large comprehensive health care system with 
an electronic medical record, an established patient population, a highly organized and 
standardized system for the management of suicide risk and a unique system for active case-
finding of patients who have attempted suicide. All of these factors should increase the 
likelihood of accomplishing our recruitment targets and should overcome most of the barriers 
that limited recruitment in the prior studies. Put in another way, since 2007, the VA has 
developed the infrastructure for studies such as the one proposed here as it established VA’s 
program for suicide prevention.   
 
Additionally, study visits and blood draws may take place at Community-Based Outpatient 
Clinics (CBOCs) under the same Federal Wide Assurance as the approved participating medical 
center to allow more flexibility and convenience for the participants.  Thus, selected sites that are 
able to meet the requirements of the protocol will utilize VA telehealth (VTel) at CBOCs for 
study visits - both titration and steady state - and laboratory monitoring.  
 


 
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The director of the CBOC will provide a letter of support to conduct study visits at the CBOC.  
CBOC staff will provide standard-of-care/practice services they would normally provide and  
have have the capacity to carry out the procedures required by the protocol (e.g. vital signs, 
phlebotomy, EKGs, etc). It is expected that study sites may have different work flows to meet 
the requirements of the protocol.  
 
The number of unique survivors of attempts by facility is information only available within VA. 
Unlike previous research, planning of this study went beyond the use of basic epidemiological 
findings to estimate the availability of potential subjects; it utilized counts of specific subjects in 
specific facilities rather than estimates from the literature or similar populations. 
 
In addition, the study will use the SPAN database to identify potentially eligible patients at each 
site. Participating sites will send the Boston Coordinating Center their screening logs on a 
monthly basis. The Coordinating Center will compare those patients already screened by the sites 
against new persons recorded in the SPAN database to increase the pool of potential participants.    
 
Our survey of VA psychiatrists (Section III) also demonstrates strong support for the study from 
clinicians in the field.  Findings from SAFEVET (Section IX) suggest that those patients who 
have attempted suicide will at least consider participation. These findings can inform estimates 
of the magnitude of provider-related barriers, and at least the initial component of patient-related 
barriers. They suggest that the estimate that 20% of eligible patients can be recruited should 
provide a margin of safety adequate to ensure that this study can meet targets for enrollment. 
 
The study is built upon recognition that an attempted suicide and related behaviors are highly 
emotionally charged events in the lives of veterans and their families, and that the processes for 
obtaining consent, establishing eligibility, randomizing treatment, and maintaining subjects 
under double blind conditions for a full year are major challenges. Preliminary discussions with 
survivors within the VA have suggested that participation in research can, to some extent, 
represent an opportunity for individuals to transcend their suffering and to use their experience to 
help others. Nevertheless, the investigators recognize that staffing for the study and its 
implementation must reflect sensitivity, cultural competence, and caring for Veterans in a high 
degree of distress and for those who would prefer to deny the significance of their attempt. These 
issues will be addressed during site selection and staff training. In addition, we will have regular 
telephone conferences for Site Coordinators to review the issues that have arisen during 
recruitment, to share lessons learned, and to engage the broader group in problem-solving. 
XI. 
PATIENT ENROLLMENT 
Maintaining Awareness 
 
In this, as other clinical trials, it is important to ensure that mental health and medical providers 
maintain awareness of the study so they can consider referring patients who are potentially 
eligible for participation. Members of the Research Team will be encouraged to conduct rounds 
or academic detailing on a regular basis in mental health and primary clinics, pain clinics, 
emergency departments, inpatient units and other relevant settings. Research Teams will also 
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to identify patients who may be eligible, determine whether they have been referred for study 
participation, and engage in problem-solving to identify and overcome any barriers. 
 
Recruitment, Screening, and Evaluation Procedures  
 
Recruitment: Case identification and recruitment will proceed through the following steps, 
generally in two or three visits: 
 
1. Veterans who have survived suicide attempts may come to the attention of the 
Suicide Prevention Coordinators from providers, SPAN, or the Veterans Crisis Line. 
SPCs will refer the patient to the Research Team at the site.  
 
2. Site Coordinators may also become aware of potential participants through outreach 
such as scanning admissions and ER logs for events, and IRB approved posters and 
pamphlets advertising the study.  
 
3. During pre-screening, the research team will review the medical record for 
information about the recent episodes, diagnoses, and medications.  
 
4. Before contacting a patient directly, the site coordinator must ensure that a member of 
the patient’s mental health care team  has introduced the study to the patient and the 
patient agrees to be contacted by the study team.  The method used by the provider to 
document the permission of the participant to be contacted can be done in the 
following ways: 1) the provider can document via an encrypted email or 2) a non-VA 
Mental Health provider can send to a secure faxline or by US mail to study site with 
permission granted by patient to have the study team contact the potential pariticpant. 
 
Should a potential participant contact the research team directly to learn more about 
the research study, a research team member can speak with the potential participant 
about  the study.    
 
5. When a patient appears eligible, consent will be sought.  Contact with the patient’s 
mental health provider and provider responsible for the patient’s general medical care 
will be made.  
 
After ICF 1 (see section XII Human Subjects Issues and Informed Consent) and prior 
to randomization, documentation of VA MH provider concurrence will be obtained 
by  
1) an encrypted email, or  
2) secure fax, or 
3) signed CPRS note.   
 
A non-VA Mental Health provider can send to  
1) a secure faxline or  
2) by US mail, to study site, concurrence of study participation.   
 


 
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6. After obtaining ICF 1 and prior to randomization, documentation of the participant’s 
general medical care provider’s  (primary care provider’s) awareness will be required.  
This awareness can documented by  
1) CPRS co-signed note, or  
2) read receipt of encrypted email, or 
3) documentation of awareness (e.g. phone or in-person) conversation.  
 
 
Screening and Evaluations:  
 
First consent [ICF 1]:  This consent is limited to screening procedures, describing the purpose 
and what is involved in the study, and answering any questions the participant may have. It will 
be made absolutely clear that the screening is not treatment and that going through screening 
does not obligate the person to participate in the actual study. 
 
During screening, the Research Team will conduct a complete review of the medical record, and, 
if the patient meets preliminary inclusion/exclusion criteria, the patient’s health care providers 
will be contacted to inform them that the patient is being considered for the study. 
 
 
 
The Research Team will conduct evaluations to: 
 
• Confirm that the patient has attempted suicide, experienced an interrupted 
attempt, or was hospitalized specifically to prevent suicide within the 
previous six months 
• Obtain a history of previous psychiatric diagnoses and previous attempts 
from the patient and from available medical records  
• Conduct structured diagnostic interviews with MINI and the SUD module 
of the SCID  
• Evaluate cognitive status with the OMC 
• Evaluate decision-making capacity/competency for consent using Jeste’s 
brief instrument for assessing decisional capacity (UBACC) 
• Identify and obtain contact information for family member(s), friend(s), or 
other contact that could provide information about the participant’s 
whereabouts if the participant cannot be reached by the research team. 
• Document all medications (prescribed and over-the-counter) including 
those prescribed within and outside of the VA . 
• If the Veteran agrees, the Research Team will include family members and 
significant others in discussions about the study and the Veteran’s 
participation. 
 
Second Consent [ICF 2]: Before randomization, the Research Team will seek the final consent 
for the individual’s participation in the randomized trial, after discussing the consent form with 
the patient (and others as appropriate), to be sure that the participant is fully aware of the 
procedures, the meaning of randomization, the potential benefits and risks of participation, and 
that they want to participate.  
 


 
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To avoid unnecessary costs and inconvenience screening laboratory tests and screening EKG 
will only be done if the person consents to the actual trial. Final screening procedures that are 
done after ICF 2 is obtained include labs (CBC, TSH, creatinine, electrolytes, and calcium 
levels), EKG and Physical Exam.  (If the EKG and / or Physical Exam have been done within the 
past 30 days, they will not have to be repeated.)  Research staff who routinely perform medical 
or physical exams under their scope of practice are allowed to perform these exams for this 
research study.  
 
A urine pregnancy test will be performed at each study visit for those participants of childbearing potential.  
XII.  HUMAN SUBJECTS ISSUES AND INFORMED CONSENT 
Process for obtaining informed consent 
 
There are two Informed Consent documents for this study: 
1. ICF 1: [Part One: Screening for Eligibility] seeks consent to screen the patient for 
eligibility for the clinical trial, and  
 
2. ICF 2: [Part Two: Randomized Trial] seeks consent to further evaluate the patient 
for eligibility with a physical exam, EKG, and laboratory tests, and ask potential 
subjects who meet inclusion and exclusion criteria after preliminary screening 
whether they consent to study participation if they continue to be eligible. 
 
The initial phase (under ICF 1) of the consent process will focus on the details of the evaluations 
and a general outline of the treatment study. The second phase (under ICF 2) will focus on the 
details of the actual clinical trial. 
 
Overall, the consent process will explain the purpose of the study and describe the treatments. 
The randomization process, the necessity of blinding, the timeline, and what is expected of the 
patient will be reviewed. The risks associated with lithium and study procedures (e.g., 
venipuncture) will be addressed.  The procedures and safeguards for maintaining strict 
confidentiality will be described.  
 
If the patient consents to participate in the study, each phase of informed consent  (ICF 1 and 
ICF 2) will be documented per VA guidelines. The original documents will be placed in the 
Local Site Investigator’s Master Consent Binder. Copies of signed Informed Consent documents  
will be provided to the participant, placed in the participant’s study file, and securely transmitted 
to the MAVERIC CSPCC.  
 
Informed consent requires that the participant understand the details of the study and agree, 
without coercion, to participate in the study. To obtain informed consent, the following 
information shall be provided to each participant: 
 
1. 
Name of the study 
2. 
Name of  Site Investigator(s) 
3. 
Explanation that the study involves research 
4. 
Explanation of the purpose of the study 


 
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5. 
Explanation of the study procedures 
6. 
Description of randomization 
7. 
Description of the risks and benefits of participation in the study 
8. 
Description of alternatives to participation in the study 
9. 
Explanation that all records will be kept confidential, but that records may be 
examined by representatives of the VA and/or the FDA 
10. 
Whom to contact for questions about the research and about subjects' rights 
11. 
Whom to contact in the event of a research-related injury 
12. 
A statement that participation in the study is voluntary and that a decision not to 
participate or to withdraw from the study after initially agreeing involves no 
penalty, loss of benefits, or reduction in access to medical care 
13. 
A statement that the treatments provided as part of this study are free 
 
Merely obtaining signed consent from the patient does not constitute informed consent. 
However, the use of a standardized consent form aids in assuring that participants receive 
adequate and consistent information about the trial and that they have consented to participate. 
 
In conjunction with the informed consent procedure, participants will review and be asked to 
sign the Authorization for Release of Protected Health Information From as required by HIPAA. 
As with the informed consent forms, The original HIPAA documents will be placed in the Local 
Site Investigator’s Master Consent Binder and copies of the signed HIPAA forms will be 
provided to the participant, placed in the participant’s study file, and securely transmitted to the 
MAVERIC CSPCC. 
 
Benefits 
 
General: The information from this study will be of scientific and public health value, helping to 
guide treatment of individuals at risk for suicide. 
 
For participating subjects: Participants may benefit from the increased monitoring that is related 
to study participation and through early identification of exacerbations of their mental health 
condition and periods of increased risk for suicide. 
 
Reimbursement 
 
Participants will receive reimbursement to defray their travel/time based on the distance from 
their residence to the study site.  
 
Risks  
 
The risks of study participation are related primarily to the risks of lithium administration, 
including the side effects or adverse reactions that can occur during treatment or when someone 
stops taking lithium, drug-drug, and drug-disease interactions, and intentionally taking too much 
of the medication. They also include the risks associated with drawing blood for various tests. 
 
All medications have potential risks. Lithium may cause all, some, or none of the side effects 
listed below. Rare or unknown risks may also occur. Each study participant will be informed of 


 
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any information that becomes known during the course of the study regarding risks of the 
interventions that might affect their willingness to continue to participate.   
 
Side Effects and Adverse Reactions: 
 
The incidence and severity of adverse reactions from lithium are related to its serum 
concentrations and to individual patient sensitivity, generally occurring more frequently and with 
greater severity at higher lithium concentrations.  According to the American Hospital Formulary 
Service (AHFS) Drug Information Service (2012), about 75% of people experience some side 
effects when they begin lithium.  The most frequent side effects include nausea, loose stools, 
thirst, increase in urination, shakiness of the hand, headaches, sweating, fatigue, decreased 
concentration, rash, and dry skin. For most people, these are mild and limited to beginning of 
lithium treatment. The prevalence of some side effects is described below: 
Nervous system: Lithium can cause a hand tremor in almost 50% of people who start 
taking the medicine, but it persists for one year in less than 10%. Feelings of weakness or 
a loss of strength can occur in about 30% of people who start lithium, but it persists in 
about 1%. 
Gastrointestinal effects: Symptoms like nausea or vomiting, decreased appetite, loose 
stools or diarrhea and abdominal discomfort occur in 10-30% of people who start lithium; 
they persist for up to 1-2 years in 1-10%.  
Kidney effects: Increased urination with increased thirst and fluid intake occurs in 30-
50% of people who start lithium. By 1-2 years, these symptoms decrease to between 10-
30%. 
Metabolic effects: Lithium can lead to increases in Thyroid Stimulating Hormone in 
about 30% of people, clinically significant decreases in thyroid function in 1-4% and 
goiter in about 5%.  
Heart effects: Lithium can cause changes in the electrocardiogram in about 20-30%, but 
these are usually of no clinical significance.  Rarely, lithium can cause arrhythmias or 
changes in cardiac conduction, usually in people with preexisting cardiac disease.  
Skin effects: Dry skin is the most common skin-related side effect of lithium. Rashes 
occur in about 1%. 
A recent meta-analysis of adverse effects observed during long term administration of lithium 
(McKnight et al., 2012) should be noted even though the study drug is intended for only one 
year. The synthesis found decreases in glomerular filtration rate and in renal concentrating 
ability, increases in TSH and clinical hypothyroidism, increases in calcium, in PTH, and weight. 
It found no increased hair loss or skin disease. Contrary to FDA and other warning sources, it 
found no increase in congenital malformations but the number of cases was too few to be 
definitive.  
 
 


 
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Discontinuation and Withdrawal 
 
That lithium might prevent suicide and suicide-related behaviors is suggested by comparisons of 
patients currently receiving lithium and those who have discontinued lithium (Muller-
Oerlinghausen et al., 1992; Nilsson, 1990, 1999; Schou, 1998; Tondo et al., 2000, 2001), 
comparisons of behaviors before, during and after lithium treatment (Tondo et al., 1997, 1998), 
and comparisons of patients taking lithium and other medications.  Suicide related behaviors may 
be more frequent during the first year after discontinuation of lithium than afterwards (Tondo et 
al., 1997, 1998). The available data do not allow a distinction between an unmasking of suicide-
related behavior when lithium is discontinued versus a withdrawal phenomenon. However, there 
have been suggestions that the increase in the onset of mania, depression, and suicide-related 
behaviors is lower when lithium is discontinued gradually, over a period of two weeks or longer 
(Baldessarini et al., 1999a; 1999b).       
 
These issues will be addressed by including information about discontinuation in the consent 
form, gradual tapering of lithium whenever subjects discontinue treatment, and individualized 
clinical management at the end of the study. 
 
Drug-Drug Interactions 
 
Potential drug-drug interactions are listed on Table 5 (”Lithobid”, n.d.). These can result either 
from effects on the renal excretion of lithium and modifications in lithium levels, or from effects 
on end-organ sensitivity to other drugs. With most medications with potential drug-drug 
interactions, a patient may be on a drug with potential interaction with lithium as long as there is 
close monitoring and regular lithium levels obtained. 
 
Drug-Disease Interactions 
 
Lithium may affect the cardiac conduction system and these effects can be of increased 
significance in those with pre-existing cardiac disease. Lithium may also affect thyroid function 
in those with thyroid disease; and affect renal physiology in those with mild to moderate kidney 
disease. These are compatible with study participation with close monitoring for adverse effects 
as proposed.  Patients with renal failure and heart failure are excluded because these conditions 
are associated with a high degree of variability in lithium clearance. 
 
Toxicity   
 
The concentrations of lithium that may be toxic (1.5 mEq/L or greater) are close to the 
concentrations that are generally considered to be within the therapeutic range (0.6 to1.2 mEq/L).  
Diarrhea, vomiting, drowsiness, weakness, and lack of coordination may be signs of lithium 
intoxication. They are most common at lithium concentrations of 2.0 mEq/L or above, but they 
can occur at low levels. At higher concentrations, giddiness, ataxia, blurred vision, and tinnitus 
can occur. Serum lithium concentrations above 3.0 mEq/L often lead to severe, dangerous 
adverse reactions affecting multiple organ systems. 
 
No antidote for lithium is known and treatment for lithium toxicity is supportive. Mild symptoms 
of lithium toxicity are treated by holding the dose or reducing the drug for 1 to 3 days. In 


 
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poisoning, the treatment is: 1) elimination of lithium by gastric lavage, 2) correction of fluid and 
electrolyte imbalance, and 3) stabilizing renal function. Urea, mannitol, and aminophylline 
increase lithium clearance. Hemodialysis can be used to remove lithium rapidly in severely toxic 
patients.  
 
Two studies of lithium in suicide prevention were used in estimating the risks of overdose in this 
study. In the Lauterbach study (2008), 17 suicide-related events (3 suicides and 14 non-fatal 
attempts including 13 overdoses) occurred. Two of the overdoses were with study medication, 
neither fatal, and represented 1.2% of those randomized. In the Oquendo study (2011), there 
were 18 non-fatal suicide attempts over the 2.5 years of the study. Three of these were with study 
medication; and represented 2.0% of those randomized.  
XIII. TREATMENT REGIMENS 
Study medications 
 
Lithium will be provided as extended-release lithium carbonate (or placebo) in 300 mg tablets. 
Subjects will be started on 600 mg/day (300 mg bid), unless there are clinical indications for 
starting at a lower dose (300 mg/day). Lithium (or placebo) plasma levels will be determined (by 
send-out central lab testing) after each dose adjustment (see section XIV, Titration Visits, for 
more detail) until steady state at target plasma levels between 0.6 and 0.8 mEq/L is achieved. 
Steady state is defined as a serum lithium level between 0.6 and 0.8 mEq/L, over 2 consecutive 
visits, at the same dose, and with the second level the same or 0.1 mEq/L lower than the first 
level. The target range will be operationalized by providing guidance to Site Physicians that they 
should stop titrating the dose upwards if proportional increases in plasma levels would exceed 
0.8 mEq/L, that is, if the steady state plasma level on a dose of 300 mg/day exceeds 0.40 mEq/L 
or the level of a dose of 600mg/day exceeds 0.53 mEq/L. After steady state levels within the 
target range are achieved, the frequency of plasma level determinations will be decreased to 
monthly until the end of six month’s participation, and then quarterly unless they are on an ACE 
inhibitor or a diuretic, in which case monthly monitoring will continue; they will be done more 
frequently when medically indicated in either the lithium or the placebo group.  
 
The target plasma levels are within the range considered effective for other lithium indications. 
The 2010 VA-DoD Clinical Practice Guideline for Bipolar Disorder recommends target levels of 
0.6-1.0 mEq/L for maintenance treatment; the 2009 VA-DoD Clinical Practice Guideline for 
Major Depressive Disorder recommends 0.5-1.0 mEq/L for the augmentation of antidepressant 
responses; and the 2002 American Psychiatric Association Guideline on Bipolar Disorder 
recommends 0.5-1.2 mEq/L. A 1998 observational study by Tondo et al. found an 85-90% 
reduction in suicide risk for patients on lithium with average plasma levels of 0.624 ± 0.134 
mEq/L. Based on these data, target plasma levels for the Lauterbach study (2008) were 0.6-0.8 
mEq/L, similar to those proposed for this study.  
 
On the basis of studies that examined associations between suicide rates and lithium 
concentrations in drinking water, it has been suggested that lithium may have a preventive effect 
even at very low plasma levels (Helbich et al., 2012; Kabacs et al., 2011; Kapusta et al., 2011; 
Ohgami et al., 2009; Schrauzer & Shrestha, 1990). Based on these reports and absence of data 


 
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for what constitutes a lower limit for effective plasma levels, dose (and plasma-level) reductions 
will be allowed for patients who are unable to tolerate 0.6-0.8 mEq/L. The lowest allowable dose 
of lithium for continued treatment will be 300 mg/day. All patients able to tolerate that dose will 
be maintained at the highest tolerable plasma level not to exceed 0.6-0.8 mEq/L. 
 
Blinding 
 
This is a double blind placebo-controlled study in which the participant, treating clinicians, and 
all study personnel, including the Central Psychiatrist/Safety Officer, are blinded to treatment 
assignment.  
 
All investigators and Outcomes Adjudication Committee members will only see blinded interim 
reports. Members of the DMC will receive unblinded reports in that they will view study results 
by treatment group (e.g. A versus B) and these designations will be randomly assigned within a 
report. The placebo will be produced by the CSPCRPCC and be nearly identical in appearance to 
the active agent and have similar taste and odor.  
 
Breaking the blind, to the patient’s mental health provider, at the end of a participant’s time in 
the study should not compromise the blind for the personnel at the study site nor influence 
outcome assessments of participants remaining in the study. All ratings and assessments will be 
completed before the blind is broken.  To ensure that the breaking the blind on those who 
complete the study does not reveal information about the assignment of the last subjects, block 
randomization is within multiple strata and an extra treatment assignment will be inserted to each 
stratum of four to disrupt the blocks and mask block sizes, as described in Section VII. 
 
Titrating study medication 
 
The process for titrating study medication at the initiation of study treatment and for maintaining 
them during the course of the study will be based on real or simulated plasma levels. To ensure 
local site blinding and standardization of measurements, some blood samples will be sent to a 
Central Laboratory for analysis. Lithium levels, TSH, T4, and creatinine will be analyzed by the 
Central Laboratory, while other samples, for complete blood count (CBC) and electrolytes will 
be sent to the local VA laboratories for analysis.   
 
Lithium levels, creatinine, eGFR, and summary of side effects will be sent to the MAVERIC 
data coordinating center which will send real or simulated plasma levels and dosage adjustment 
recommendation to the Site Physician and  to the Central Psychiatrist/Safety Officer. A lithium 
level of 1.2 or above will be considered a potentially dangerous situation and will be 
automatically sent to the Site Physician as well as the Coordinating Center and Central 
Psychiatrist/Safety Officer.  
 
The Site Physician will use these levels and a check list review of symptoms at the time of the 
blood draw to make dose adjustments. During the initial dose adjustments, the Site Physician 
will typically decide between increasing doses by one pill per day, or maintaining the current 
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Participants will have titration visits until they reach the target steady state: a serum lithium level 
between 0.6 and 0.8 mEq/L, over 2 consecutive visits, at the same dose, and with the second 
level the same or 0.1 mEq/L lower than the first level. It is expected that most patients will titrate 
within 4-6 visits, but the process may take fewer visits, or may take up to 8. If steady state is not 
achieved after 8 visits, the Central Psychiatrist/Safety Officer will work with the site on a case-
by-case basis to determine a prescribing plan. If participants are not able to tolerate the dose 
needed to achieve the target level, they will be prescribed their maximum tolerated dose.  
 
If it has been fewer than 60 days from randomization to achieving steady state, the participant’s 
next visit will be a steady state follow-up visit 2 months after randomization (within the window 
allowed for steady state visits). If it takes more than 60 days, the next visit will be the 3 month 
steady state visit, and the month 2 visit will be ommitted. 
 
For added safety, the site physician has the capacity to hold study medication for up to three days 
or decrease the dose as the clinical circumstances warrant. When determining the initial dose of 
study medication; if the site physician has concerns that factors such as aging, potential drug-
drug interactions, or potential drug-disease interactions would decrease the tolerability of an 
initial dose of 600 mg of study medication, he or she could can reduce the starting dose to 300 
mg/day for the first interval. 
 
During the course of the study,  there may be unanticipated changes in the patient’s medical 
condition, side effects or adverse reactions to study medication, new prescriptions of medications 
with potential drug-drug interactions, or other events associated with volume depletion or 
dehydration  that could lead to adverse events through increased the serum level or increased 
tissue sensitivity. If any of these occur, the site physician may decrease the dose of study 
medication.  
 
Whenever the site physician holds study medication or prescribes a reduced dose for reasons of 
safety, he or she will document the reason, and the duration of the “hold” or the actual dose 
prescribed. Also, at these times, the site physician will monitor the patient closely, e.g., through 
increased contact by telephone. Depending on the patient’s clinical condition, further dose 
decreases may be necessary; decreases down to 300 mg/day are allowed by the protocol. If the 
patient is stable, the reduced dose will be maintained for approximately 5-7 days at which time 
another lithium level will be obtained and used to guide further dose adjustments, as appropriate. 
 
When each patient is entered, the Research Team will forward information on physiological 
parameters including age, sex, height, weight, medications, medical conditions, and creatinine to 
the MAVERIC data coordinating center to allow estimations of the lithium clearance using 
empirical algorithms (e.g., Abou-Auda et al., 2008). At the time that blood levels are determined, 
the Research Team at the study site will provide the MAVERIC data coordinating center with 
updated information on laboratory parameters, information about changes in the patient’s 
medications and medical status, and reports from the patient on adherence for study medications 
and side effects. To calculate the simulated lithium level, the MAVERIC data coordinating 
center will: 
 
1) Calculate a plasma level for the current dose using the method of Abou-Auda (2008).  


 
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2) Adjust the plasma upwards if there are reports of side effects, and downward, if there 
are reports of non-adherence; these adjustments are intended to ensure that the 
simulated plasma levels appear plausible and realistic in light of the patient’s clinical 
status. 
3) Multiply the adjusted value by a random factor. This is necessary to ensure that there 
is a realistic degree of week to week variability for simulated plasma levels and that 
the reported values cannot signal the Research Team at the study site about whether 
the plasma levels are real or simulated. 
 
During the course of the study, the study biostatistician will periodically compare the 
distributions of real and simulated plasmas levels to ensure that there are no significant 
differences. Should there be trends suggesting they are diverging, the biostatistician will work 
with the MAVERIC data coordinating center to revise the parameters for calculating simulated 
measures. 
  
All participants will have flags in their VA electronic medical records in accordance with local 
policy. This study falls under the 1200.05 2012 version, however, we recommend that the flags 
state that the participants are enrolled in a research study and any medication changes or drug 
level testing be done only after consulting the Site Physician. The amount of information 
provided within the flags may vary by site according to local policies and procedures. 
 
The processes for dispensing medication from a VA pharmacy or by mail will be developed for 
each patient, depending upon whether patients are inpatients (at the start of the study) or 
outpatients, and whether or not they have convenient access to a VA facility.  Medications will 
be dispensed in blister cards containing medication for two weeks. Some participants may be 
dispensed one week of medication at a time if the investigator determines this is more 
appropriate for the safety of the participant. Participants will be asked to return unused blister 
cards at the next study visit to perform tablet counts to assess adherence. 
 
In general, blood samples, updated medical and psychiatric history, and review of side effects 
will be obtained on approximately the 7th day (± 2 days) of the dosing interval (see section XIV, 
Titration Visits, for more detail). Findings will be reported to the Central Psychiatrist/Safety 
Officer and lithium levels (actual or simulated) under ideal circumstances will be communicated 
to the site within 48-72 hours.   
 
Once the Site Physician decides on dose adjustments and orders the study medication, the blister 
card containing the prescribed amount of tablets will be dispensed in person or by express mail. 
  
If, for any reason, the scheduled blood tests are missed, the process for dose adjustment will need 
to be modified. However, the scheduled assessments will still be completed to guide patient 
management as well as to ensure ongoing study assessments.  The Site Physician may either hold 
the current dose if there are problems or continue the current dose but may not, to be cautious, 
increase the dose. If necessary, the subject will be mailed enough blister-packed tablets to cover 
the time until the next scheduled dose adjustment. 
 
 
 


 
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Ongoing dose adjustments 
 
During the course of double-blind treatment a number of events may indicate the need for 
additional clinical assessments, blood level determinations, other laboratory tests, and, possibly, 
dose adjustments. These may, for example, include reports of side effects, observations of 
possible adverse reactions, laboratory measures, changes in medical status, or modifications in 
medications. When these occur, the Site Physician will conduct clinical evaluations, obtain blood 
for lithium level and other determinations as needed using the same procedures for planned dose 
adjustments. Decisions about clinical management of dosing will be the responsibility of the Site 
Physician. He or she may ask the patient not to take study medications for up to three days, 
modify the dose on a temporary basis, or modify the dose from that time onward. In general, he 
or she will continue to monitor the patient with repeated contacts, assessments, blood levels, and 
other tests as appropriate until the patient’s medical status and blood levels stabilize.  
 
Enhanced usual care for preventing suicide 
 
Enhanced usual care is detailed in Section I, Introduction and Background. Each patient’s 
management will meet VA policies and practice guidelines. Patients will be evaluated regularly 
for titration visits until they reach the target steady state range, then monthly(see section XIV, 
Titration Visits, for more detail). Management will include safety planning, directions for 
seeking help on a 24/7 basis, and identification of family members and/or friends who could 
inform the Research Team about side effects, recurrences, or treatment emergent events.  
Completion of study visits will meet requirements of enhanced usual care. 
 
Concurrent care for psychiatric and medical conditions 
 
To ensure patient safety, the protocol includes provision for more detailed clinical evaluations 
and additional blood tests to determine lithium levels (or simulated lithium levels) when there are 
significant side effects or treatment emergent events. There is also provision for additional 
evaluations and needed modifications of concomitant treatments whenever there are recurrences 
or exacerbations of mental health conditions. 
 
Participants receive four types of care: (a) study treatment, (b) management of the risk of suicide, 
(c) treatment of the depression or bipolar disorder and coexisting mental health conditions, and 
(d) routine primary care/treatment of coexisting medical conditions. 
 
Treatment with study medications will be the responsibility of the Research Team. Treatment of 
the depression or bipolar disorder and comorbid mental health conditions will be the 
responsibility of the patient’s mental health providers. Routine primary care and treatment of 
coexisting medical conditions will be the responsibility of the patient’s medical providers. Study 
procedures, including the requirement for concurrence with participation from the patient’s 
mental health provider, are designed to ensure coordination of the study with clinical care.  
 
The research team will share responsibilities with the participant’s mental health provider(s) 
including the Suicide Prevention Coordinator (SPC) for managing the risk of suicide. Research 
team members will also share timely information about side effects of medications, changes in 
mental and medical health and current medications with the participant’s mental health and 


 
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medical providers as appropriate. The Research Team will follow-up on questions about suicide 
related symptoms and behaviors by reminding the particpant about the suicide prevention safety 
plan.  When necessary, research staff will contact the SPC and the mental health provider(s) 
about the need for revising the plan. All research visits will be considered research encounters 
and no participant or his/her insurance will be billed or charged a copay for these encounters.   
 
The research team will inform a participant’s mental health and medical care providers about 
significant changes in a participant’s status. To ensure patient safety, the patient’s providers will 
be asked to communicate changes in the patient’s medical status, and any and all new 
medications prescribed before these medicines are started, to the Research Team. Should the 
treating mental health provider decide that lithium or haloperidol treatment is essential, the 
participant will be withdrawn from the trial but be included in the intention-to-treat analysis.  In 
other situations, they will discuss strategies for optimizing the patient’s safety in light of possible 
drug-drug and drug-disease interactions. For example, if patients have new onset hypertension, 
the physicians will discuss use of medications that minimize drug-drug interactions with lithium 
(e.g., certain beta blockers or amiloride rather than other diuretics). Other drug choices may call 
for increased monitoring for plasma levels and side effects and a lowering of lithium doses 
because lithium clearance may decrease.  
 
When there are new signs, symptoms, or diagnoses of cardiac, thyroid, or renal disease, the 
provider responsible for the patient’s general medical care and Site Physician will jointly 
evaluate the possible contribution of lithium. Decisions about discontinuing the study medication 
versus continuation with increased monitoring and modifications in the dose of study 
medication, as appropriate, will be made on a case by case basis by the Site Physician, and the 
provider responsible for the patient’s general medical care in consultation with the Study Chair 
as appropriate. 
XIV. FOLLOW-UP AND TERMINATION 
Titration Visits 
 
All participants will be followed from randomization until the completion of the study (one year 
of lithium/placebo treatment).  Participants will be followed as described in the Schedule of 
Visits (Table 6).  Study assessments will be done at screening, baseline, every 10-14 days during 
the titration phase (in general, for up to six visits), and monthly until the end of study.  
 
During the titration phase, participants will take the same dose of study medication for a 
minimum of 5 days prior to having their levels reassessed. Results from the blood draw are 
available to sites within approximately 3 days of the blood shipment, at which point a new dose 
may be selected and shipped to the participant if they are unavailable to pick up the prescription. 
Based on the dispensing of 2 weeks of study medication at a time and that it is necessary to allow 
a minimum of 4 days after a study visit for processing blood samples, communicating findings to 
the Central Psychiatrist/Safety Officer, communicating actual or simulated plasma levels to the 
study site, prescribing, and dispensing medications, there is a window of 10 to 14 days between 
titration visits. The Site Coordinator can conduct all assessments unless a physical exam is 


 
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required. Additionally, it is possible for participants to have unscheduled check-in visits at any 
time.  
 
During titration phase, each new dose of study medication must be taken for a minimum of five 
days before collecting and sending another Lithium blood sample.  
 
Steady State Visits 
 
Once participants have reached steady state, study visits will occur every month, with a window   
from one week before the target date to one week afterwards. For the completion of the study, 
the window will be between one week before the target date to one month afterwards. 
 
Ongoing Considerations and Special Circumstances 
 
Additional visits will be completed as necessary for emergent events.   
 
Pregnancy testing: At every visit post-randomization, participants of childbearing potential will 
be reminded of the potential dangers of lithium during pregnany, review acceptable birth control 
methods, document what method of contraception is being used, and update all medications as 
well as over-the-counter medications, supplements being used.. If  there is reason to doubt the 
participant’s judgment, a pregnancy test will be done. Women of childbearing potential will have 
pregnancy testing at each study visit.  
 
Participant Pregnancy:   
Upon learning of a possible participant pregnancy, the study medication should be held STAT, 
and the Safety Officer, CSP Coordinating Center (Boston, MA) and local site investigator 
notified.The pregnancy will be confirmed and the participant will be informed. 
 
Upon confirmed pregnancy,  the LSI, participant, and MH provider will be unblinded. As the 
medical necessity for knowing the identity of the study drug is ultimately the responsibility of 
the participant’s obstetrical and medical providers.  The CSP Coordinating Center, Safety 
Officer, Study Chair and VA Central IRB will remain blinded. The LSI or designee shall, in turn 
communicate the pregnancy status with both mental health and primary care providers. 
 
If the subject is on lithium, the LSI will ensure that her mental health provider(s), primary care 
physician, and obstetrician will be made aware of her situation.  LSI and study team will 
recommend that she have ultrasound at 16 weeks of the pregnancy to screen for Ebstein’s 
anomaly. The understanding is that the decision to have an ultrasound is ultimately a decision of 
the participant in consultation with her pre-natal care providers.   
 
The outcome of the pregnancy and the health of the newborn especially with regard to the 
presence or absence of Ebstein’s anomaly is an area of concern for lithium usage.  The CSP 
Coordinating Center  and LSI will follow the individual until the end of pregnancy and the status 
of the newborn is established. As the delivery will likely occur in a non-VA facility, the review 
will require all other (e.g. obstetric, neonatal and/or pediatric) medical records be gathered after 
signed permission.The participant will also be invited for an end of study visit to close out her 
study record. 


 
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Special Circumstances - Involuntary Psychiatric Hold:  
In the event that a study participant is placed in an involuntary psychiatric hold (i.e., 5150 in 
California) outside of the VA Facility, the following would occur: 
1) Missed study visits – The Study Coordinator will follow study protocol on locating the 
participant and obtaining all the details for the missed visit, including any details from the 
hold. 
2) The Study Coordinator will complete CRFs that were missed during the hold. 
3) The participant will be asked to provide any documentation from the hold and asked to 
allow for permission to get records from the facility where the hold occurred using our 
Release of Information form. 
4) The LSI may require additional documentation in addition to what is provided above, 
and those instances will be handled on a case-by-case basis. 
 
Special Circumstances – Medical or Psychiatric Emergency Involving a Study Participant:  
In the event that a study participant experiences a medical or psychiatric emergency during the 
course of their participation in CSP 590, the well-being of the participant will be the primary 
focus. Participating sites will follow their local practices for mental health or medical 
emergencies occurring during a study visit. Emergencies occurring outside of the study visit will 
also be handled according to local site practices with the well-being of the participant as the 
primary focus of the incident. Study procedures will continue or resume at a clinically 
appropriate time. 
 
Special Circumstances – Incarceration:   
Participants will be withdrawn upon discovery of an ongoing incarceration, and re-enrollment 
may be possible after release. Re-consent is required at the time of re-enrollment. If the 
incarceration occurred in the past when discovered, and no immediate future risk of incarceration 
is present, then continuation of participation is reasonable.  
 
Neither the Safety Officer/Central Psychiatrist nor the local site research team will have control 
of study medication during a participant’s incarceration.  No new prescriptions for study 
medication will be written during the incarceration. No CRADO waiver is sought as we treat and 
document all incarcerations on VA Central IRB Form 119, Report of Serious Adverse Event 
(SAE) and Unanticipated Problem (UAP) Involving Risks to Participants or Others. 
 
 
Special Circumstances – Participant Death:  
If a participant dies while participating in the study, this will be treated as an early termination; 
however, as continuity of care and patient safety is no longer an issue, unblinding to the MH 
Provider will not occur. 


 
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Disclosure of study information under Special Circumstances: No information about 
participation in the study will be disclosed under any circumstances, unless required by 
law, in accordance with HIPAA authorization and Certificate of Confidentiality.  
 
Notifications and Procedures in the Event of a Participant Death 
 
Unblinding should never occur in the event of a participant death, given that: 
1) The protocol states unblinding only occurs due to continuation of care at the warm hand-
off at end of study 
2) There are no impending safety issues posed to the participant after his or her death that 
would otherwise require unblinding 
 
Release of information regarding study-related matters should never occur with any 
persons outside the study team, given that: 
1) A Certificate of Confidentiality is in place for CSP 590.  This protects participants’ 
privacy by withholding information from anyone not connected with the conduct of the 
research study to avoid disclosure of information that may have adverse consequences.  
Because of this, the research team is not compelled in any Federal, State, or local civil, 
criminal administrative, legislative or other proceedings to provide information about the 
participant. 
2) The HIPAA authorization form that participants sign at the beginning of the study 
protects their privacy and does not allow us to release information. 
3) No written consent to disclosures is provided by the participant in conjunction with study 
participation. 
 
 
 
 
 
 
 
 
 
 
 


 
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See tables below for specific detail on Notifications and Procedures for Participant Deaths. 
NOTIFICATIONS 
Activity 
Responsible  
Party 
Considerations/ 
Requirements 
Recommendation 
Notification of 
Coordinating Center 
Site Study Staff 
Protocol 
Reported via EDC system within 72 hours of the Site 
Investigator being made aware of the event. Email 
notification of the submission is relayed by the EDC 
system to the study Biostatistician, Clinical Research 
Pharmacist, Study Director and Study Chair. 
Notification of CSPCC 
Study Staff and Director 
Study Director, 
Clinical Research 
Pharmacist 
 
 
Notification of VA 
Central Office 
CSPCRPCC, CSPCC 
CSP SOP 3.6 
Reported via email by Close of Business the next day 
after becoming aware of the event with a full report 
sent via email within 15 business days of the initial CO 
notification. 
Notification of VA 
Central IRB 
Site Study Staff, 
Chair’s Office 
CIRB Table of 
Reporting 
Requirements 
-If suicide, expedited reporting is not required as this is 
an anticipated outcome.  These SAEs are reported at 
continuing review. 
-If “unanticipated *and* related” to research, 
expedited reporting is required (within 5 business days 
of becoming aware of the occurrence). 
-Otherwise SAE is reported at continuing review. 
Notification of Local 
Hospital Leadership 
Site Study Staff 
HIPAA, VHA 
Directive 1605.01, 
VHA Handbook 
1200.05, Certificate 
of Confidentiality 
Remind local hospital leadership that release of 
information regarding study-related matters, 
including unblinding, with any persons outside the 
study team is prohibited. 
Disclosure of 
information about 
mental health care, but 
not information about 
research participation, 
to the family 
Mental Health 
Provider (Note: this 
activity occurs 
outside of the study 
protocol, but is 
provided as a 
recommendation). 
HIPAA, VHA 
Directive 1605.01, 
Certificate of 
Confidentiality 
Local policies and procedures will vary. Consult 
Privacy Officer and other hospital leadership.  Provide 
forms and assist family in completing the forms to 
facilitate their information seeking.  Do not provide 
any information regarding study-related matters, 
including unblinding, with any persons outside the 
study team. 
 
PROCEDURES 
Activity 
Responsible  
Party 
Considerations/ 
Requirements 
Recommendation 
Completion of SAE 
forms 
CSPCRPCC Study 
Staff 
Protocol  
Any other outstanding SAE forms should be closed out 
with the resolved option. 
Completion of study 
forms 
Site Study Staff 
Protocol 
Complete end of study form 
Study visit entry into 
CPRS 
Site Study Staff 
Protocol, VHA 
Handbook 1200.05, 
Certificate of 
Confidentiality 
-Include clinically relevant information (e.g., 
“participant expired”) 
-Do not to include information about the study (e.g., 
“participant completed suicide”) 
-Cause of death should be ascertained by medical 
records and/or death certificate (should not entered into 
CPRS, should be entered into DataLabs) 
 


 
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Determination of lithium levels: Close surveillance is essential to patient safety. This includes 
determination of lithium levels, renal function, thyroid function, hematological measures, 
electrolytes, and electrocardiograms (EKGs)  and meticulous attention to concomitant drugs 
which might increase toxicity. Our protocol meets or exceeds published guidelines for 
monitoring patients on lithium.  
 
QT Corrected (QTc) Interval:  Due to potential lengthening of the QTc, all randomized 
participants will receive an electrocardiogram (EKG) on a minimum of four study time points: 
1. at screening, 
2. once during the titration phase, 
3. once during steady state, and 
4. at the end of study or early termination.  
 
If the QTc is greater than or equal to 450 ms for men or 460 ms for women but less than 500 ms 
at any point during titration or during the subsequent course, the EKG will be repeated. If 
lengthened QTcc is confirmed, Consultation with Study Cardiologist/Safety Officer and the 
Central Psychiatrist/Safety Officer will occur  to develop an individualized plan for that patient. 
If after adjustment, the QTc remains prolonged,  the  subject’s study drug will be held and the 
subject withdrawn from the study.  
 
If the QTc interval rises above 450 ms (for males) or 460 ms (for females) this will report this as 
an AE to the appropriate committees and individuals.  
 
If the QTc is equal to or greater than 500 ms at any point, the site will notify the CSPCC, 
CSPCRPCC, Central Psychiatrist/Safety Officer and Study Cardiologist/Safety Officer STAT. 
The participant will be terminated from the study and appropriate medical care will be provided. 
 
Lithium levels will be determined according to the Titration Visits section (above) until steady 
state is achieved, then monthly until the end of the first six months of study participation, then 
quarterly. 
 
To insure the highest quality, reliability, subject convenience, and timeliness of the lithium level 
determinations, all lithium level determinations will be made by a Central Lab.   
 
By contract, lithium levels will be analyzed by a Central Lab and results will be uploaded to a 
database within 36 hours of receipt of sample by the Central Laboratory. Given that there could 
be delays in shipping and blood sample processing, the study will allow an additional 36 hours 
before requiring action i.e., consultation with the safety officer.  The data will be accessible to 
the MAVERIC data coordinating center, which will calculate simulated lithium levels as 
described in XIII above. The results will be forwarded to the local site investigators as well as 
the Central Psychiatrist/Safety Officer.   
 
 
 
 


 
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Completion of the Study and Transfer of Care to Primary Providers 
 
Patients who complete 1 year of study treatment 
 
At the conclusion of the 1-year study treatment, participants will be referred to their treating 
mental health provider for continued management. There are data to suggest that suicidality and 
mood disturbances may be increased after stopping lithium. To insure continuity, the 
appointment with the subject’s providers will be scheduled well before completion of the study. 
The Research Team will maintain responsibility for the subject until they have been seen by their 
treating clinician in a face-to-face encounter; the goal will be to provide warm-hand-offs through 
encounters that include the Research Team, the clinical provider, and the patient whenever 
possible. The research team will ensure that each study participant has a prescribing mental 
health provider assigned to him/her prior to study Month 10. 
 
At the End of Study visit, the participant and the treating mental health provider will be informed 
of the treatment assignment. They will be reminded about the possible risks associated with rapid 
withdrawal of lithium and the need for a slow taper if lithium is to be discontinued. Patients will 
be asked to return for a 30-day follow-up study visit. 
  
Patients who withdraw consent 
 
Participants withdrawing consent will be asked to participate in a final study assessment. The 
blind will be broken at the time of this assessment and no further data will be collected. The 
Research Team will contact the participant’s treating mental health provider to recommend 
gradual tapering of lithium as needed.  
 
Patients who discontinue study treatment prior to 1 year 
 
The investigator may discontinue the study medication for any reason, including adverse effects, 
safety concerns or protocol violations. In addition, participants may elect to discontinue study 
medication at any time.  Discontinuation of study medication will not automatically result in 
withdrawal of the participant from the trial, nor unblind the study treatment. The investigators 
will encourage the participant to continue with study assessments but they will not be required to 
complete EKGs, blood draws or vital signs except for the 30 day follow-up visit (see Table 7). If 
a participant does not agree to continue assessments, the blind will be broken, to the participant’s 
mental health provider, at the time they are tapered or discontinued. All ratings and assessments 
will be completed before the blind is broken.   
 
When study medication is discontinued by the investigator or the patient opts for discontinuation, 
the investigator will ask the patient to return blister cards, study medication will be tapered 
gradually, and the facility’s treating mental health providers will assume responsibility for 
further treatment.  
 
Participants who prematurely discontinue treatment due to an adverse effect or other event will 
be evaluated 30 days after the last dose of study drug to complete the safety assessments. 
 
 


 
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Unblinding during treatment 
 
A participant may be inadvertently or intentionally unblinded by medical personnel not involved 
with the study. A provider, for instance, may feel that it is medically necessary for the patient’s 
treatment to determine a lithium level. This may occur even though participants will have flags in 
their electronic medical record indicating that they are enrolled in a research study  
 
If and when the blind is broken, research and clinical ethics requires us to inform the participant 
of the assignment to lithium or placebo.  This will not automatically result in withdrawal of the 
participant from the trial, and the participant will be included in all intention to treat (ITT) 
analyses.  
 
See DTHP Section 11 for further information on emergency unblinding of a participant during 
the study. 
 
Extended Follow-up 
 
At the end of the study period, we will perform an electronic data sweep to collect passive 
follow-up data on lithium use and suicide related behaviors following active participation in the 
study for all subjects that had been randomized. In addition, death rates for individuals who were 
considered as part of pre-screening activities will be obtained by linking SSN with SPAN, 
BIRLS and the National Death Index. By the end of the 4 year study period, average follow-up 
including both active and passive follow up for the study subjects will be 2.5 years (first subject 
enrolled will have 4 years of follow up and last subject enrolled will have 1 year of follow up). 
However, subjects terminated from the protocol before they completed a full year of 
participation will have somewhat longer periods of passive follow-up. Data on lithium use and 
clinical and administrative data related to primary study endpoints over the extended observation 
period will be obtained by linking the study database to SPAN data, VA Electronic Medical 
Records data, VA Pharmacy Benefit Management data, the VA Beneficiary Identification and 
Records Locator System database, and the VA-DoD data repository for suicide-related data that 
will include data on causes of death from the National Death Index.  Linkage for most variables 
will be through the VHA Corporate Data Warehouse, a national repository of data from VA 
Electronic Medical Records and several other VHA clinical and administrative systems. 
 Hospital admission records and discharge summaries will be collected to determine if a subject 
was hospitalized to prevent suicide.   
XV. MONITORING ADVERSE EVENTS 
Role of the Site Investigator and Research Team in Adverse Event Monitoring  
 
The site Research Team is responsible for the following:  
 
1. Closely monitoring all subjects for new adverse events (AEs) and/or serious adverse 
events (SAEs);  
2. Reviewing accuracy and completeness of all AEs and/or SAEs reports.  


 
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3. Complying with Cooperative Studies Program policies for reporting AEs and/or SAEs. 
4. Complying with local Research & Development Committee (R&DC) policies for 
reporting AEs and/or Serious AEs. 
5. Complying with: 
a. VA Central IRB (http://www.research.va.gov/vacentralirb/)  
b. VHA Handbook 1058.01 Research Reporting Compliance Requirements  
6. Notifying VA Central IRB and local R&DC of safety issues reported to the investigator 
by the CSP.  
7. Managing or reporting of adverse events or serious adverse event, and when questions 
arise, in consultation with the Site Physician, Clinical Research Pharmacist, Study Chair, 
or  Study Director.  
 
Definitions  
 
For CSP#590, AE and SAEs will be collected using the International Conference on 
Harmonisation (ICH) Clinical Safety Data Management (ICH-E2A) and CSP Global Standard 
Operating Procedure (SOP) 3.6.2 definitions as follows:  
 
Adverse Events: An AE is any untoward physical or psychological occurrence in a 
human subject participating in research. An AE can be any unfavorable and unintended 
event, including an abnormal laboratory finding, symptom, or disease associated with the 
research or the use of a medical investigational test article. An AE does not necessarily 
have to have a causal relationship with the research. 
  
Serious Adverse Events: An SAE is an adverse event that results in:  
 
• Death  
• A life-threatening experience,  
• Inpatient hospitalization  
• Prolongation of hospitalization,  
• Persistent or significant disability/incapacity,  
• Congenital anomaly/birth defect, or  
• Requires medical, surgical, behavioral, social, or other intervention to prevent 
such an outcome.  
 
Relatedness: Relatedness involves an assessment of the degree of causality between (or 
attributed to) the study intervention and the event. Site investigators are charged with 
making an assessment of relatedness based on their clinical judgment and experience. 
The assessment of relatedness provided by the site investigator is used by the sponsor 
(CSP) to determine if an AE/SAE represents an alteration or change in the safety profile 
of the study intervention. All AE/SAEs with a reasonable causal relationship to the 
investigative treatment may be considered “related”. A definitive relationship does not 
need to be established.  
 
Adverse Events and Serious Adverse Events Reporting Requirements 


 
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Adverse Events: Only adverse events possibly or definitely related to the study intervention will 
be reported. Documentation of this assessment may be recorded on a worksheet or source 
document. The lithium carbonate formulation used in CSP #590 is a commercially available 
product prescribed for bipolar disorder. Lithium has a well characterized adverse effect profile 
and there is no evidence suggesting this agent will demonstrate a different adverse event profile 
in CSP#590 from the one already known.  
 
Serious Adverse Events: All SAEs shall be collected for CSP #590 regardless of relatedness; 
however, the Site Investigator must still make an assessment of whether or not the event is 
related to the study intervention.  All SAEs will be recorded on the appropriate case report form. 
SAEs that meet the criteria for an endpoint should be reported as such. 
 
Adverse Event and Serious Adverse Event Monitoring 
  
Patients will be actively monitored at each clinic visit and telephone contact for AEs and SAEs. 
All AEs and SAEs will be recorded on the appropriate event form(s). Per CSP policy, active and 
passive monitoring of AEs and SAEs will begin when a participant signs the Randomization 
Informed Consent. Monitoring of AEs and SAEs will continue through to 30 days past the “end 
of study” for each study subject. (No SAEs should be collected for participants after withdrawal 
of consent). 
 
Expedited Reporting of Serious Adverse Events to CSP 
  
All SAEs will be promptly reported by reporting the event via the CSP #590 Electronic Data 
Capture (EDC) system within 72 hours of the Site Investigator or other study personnel being 
made aware of the event. Email notification of the submission is relayed by the EDC system to 
the study Biostatistician, Clinical Research Pharmacist, Study Director, and Study Chair. The 
CSP #590 Clinical Research Pharmacist (CRP) is responsible for evaluating all SAEs for 
immediate patient safety concerns. A back-up CRP will evaluate the event in if the primary CRP 
is not available. 
 
Reporting of Serious Related and Unexpected Events 
 
The determination of the expectedness of an event is the responsibility of the CSP. The source of 
information used in the determination of expectedness includes the CSP #590 Drug Information 
Report, the Informed Consent form, and published literature. SAEs determined by the CSP to be 
both related to the study intervention and unexpected after review by the CRP, the Study Chair, 
and consultants as needed will be reported to the VA Chief Research and Development Officer, 
the FDA, and site investigators. 
 
Reporting of Adverse and Serious Adverse Events to the DMC  
 
The Coordinating Center and CSPCRPCC will summarize blinded and unblinded AE and SAE 
data for the DMC in a format and on a schedule requested by the DMC. The DMC will receive 
results by treatment group (e.g. A versus B) but will not receive fully unblinded reports until all 
data collection has been completed. 


 
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Reporting Requirements of the VA Central IRB 
  
Sites investigators are responsible for following the VA Central IRB policy in submitting safety 
data and protocol deviations as detailed in the VA Central IRBs’ most recent policy including 
Table of Reporting Requirements, instructions, and forms 
(http://www.research.va.gov/vacentralirb/). 
XVI. DATA MANAGEMENT AND DATA SECURITY PLANS 
The MAVERIC CSPCC will manage the trial data using a web-based Electronic Data Capture 
(EDC) system. The EDC system allows direct entry of case report forms (CRF) into a web-based 
study database and thus allows site coordinators to manage their participants, handle data 
clarifications, and correct data online. This system makes patient data management easier, 
timelier, and more efficient.  The electronic system will be used to create, modify, maintain and 
retrieve clinical data for CSP#590 during each step of the data collection process. The EDC 
system will be validated by the MAVERIC CSPCC Quality Assurance department to ensure the 
integrity of the data capture software. 
 
Paper source documents will be provided to site coordinators as a primary means of collecting 
data. Data entered on paper CRFs will be used as source documentation for EDC entries. All 
paper-based study records will be kept under lock and key.  
 
The Study Chair and Study Director will prepare an Operations Manual. A training session at the 
study kick-off meeting for all site investigators and site coordinators will be conducted to assure 
uniformity in patient management, data collection, and study procedures. At this training, site 
coordinators will be provided with reference materials on the software tool and tasks. Formal 
training on the use of the EDC system for clinical study management will also be conducted at 
investigator meetings and on an as-needed basis for new study personnel. 
 
For CSP#590, EDC designers will create a specific database that includes case report forms, the 
interview schedule, and data queries. The purpose of data clarifications (DCFs) or data queries is 
to draw attention to data that are inconsistent or potentially erroneous. DCFs will be managed in 
two ways. Certain queries will be programmed into the forms that are designed to activate upon 
data entry if data is missing or discrepant with study parameters. Additional DCFs will be 
programmed using other data analysis tools such as SAS and will be uploaded into the system for 
study coordinators to address. Furthermore, the system will allow manual DCFs to be entered 
into the forms by the coordinating center as needed. Updates to the electronic forms and database 
can be generated during the study without impacting collected data. Study reports can be 
generated from exported data in order to track the study progress and to monitor adverse events, 
particularly Serious Adverse Events. Study reports will be circulated to appropriate individuals, 
including the Site Investigators, the Study Chair, the Study Director, and the DMC. 
 


 
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Study data is housed on secure VA servers, encrypted and protected in accordance with VA 
policies compliant with FDA requirements, Federal Information Security Management Act and 
the HIPAA Privacy and Security rules.  MAVERIC CSPCC personnel manage the data access 
request process for the EDC system to ensure that data access is appropriate for each individual 
and the level of the individual access.  VA’s Office of Information & Technology (OI&T) is 
responsible for managing other VA system access and ensuring the security and integrity of VA 
information systems, including the databases and servers housing study data.  In accordance with 
VA Handbooks and Directives, OI&T is responsible for ensuring that appropriate firewalls and 
data security is implemented and maintained, that data backups are performed and that data may 
be restored in the event of a system malfunction. 
 
Hard copy data will be sent via a traceable mail system (i.e., FEDEX), via a courier, or via 
secure fax. Faxes are electronically routed to document management systems housed on VA 
protected servers located at the Regional Data Center in Philadelphia, PA. Access to these secure 
fax servers is restricted to the Coordinating Center personnel with approved access to the system. 
All secure fax servers are compliant with VA directive 1605.1 and 6500. All data security 
incidents will be reported in accordance with VA policy within one hour of discovering the 
incident to: 
 
1. The District (local) Information Security Officer (ISO) 
2. The MAVERIC CSPCC Quality Assurance department 
3. The VA Central IRB 
 
Study data will be coded and stored using a unique study identifier for each participant. 
Identifiable information will be collected for patient tracking and safety purposes, and kept in an 
encrypted, password protected file to which a small number of people will have access. Access 
to the cross-walk file linking the participant's identifiers and their study data will be restricted to 
the clinical site and to the approved personnel at the CSP coordinating center. This file will be 
destroyed according to CSP policy well after the close of the study. 
 
Access to the study data is restricted to individuals with CSP approval. Individuals must be 
properly credentialed research staff and must be compliant with VA security trainings (e.g. 
HIPAA, Rules of Behavior, and Good Clinical Practices). Once formal training is completed, 
user accounts utilizing a URL specific to the study to access and use the system and enter patient 
data will be activated. Accounts will be password protected and unique to the each user. The 
account permissions will correspond with the users' functional study group (i.e., those for a site 
coordinator would differ from those of the coordinating center or site monitors).  Furthermore, 
the permissions of the electronic systems are structured such that individual sites can only see the 
data for their study participants. They cannot see or access the data for another clinical site or for 
another participant. Research data will be stored on VA secure servers with restricted 
permissions for copying and exporting data. Only properly approved Coordinating Center 
personnel will have the ability to copy and export data. These individuals have received training 
on the local SOP governing their permissions.  
 
Access to protected health information (PHI) will be restricted to individuals approved by CSP to 
have access to the data. 
 


 
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At the Study Sites, between three and five FTE staff positions (depending on staffing allocations 
at each particular site) will have access to PHI. Individuals in these positions will be able to 
access all forms of PHI: 
1. Site Investigator 
2. Site Physician 
3. Site Coordinator 
4. Research Assistants (up to 2) 
 
At the MAVERIC CSPCC nine staff positions will have access to all forms of PHI: 
1. Center Director 
2. Study Director 
3. Project Manager/Project Coordinator 
4. Data Manager 
5. Primary Biostatistician 
6. Secondary Biostatistician 
7. Quality Assurance Officer 
8. SAS Programmer 
9. Research Assistant 
 
At the CSPCRPCC four staff positions will have access to PHI. Individuals in these positions 
will be able to access de-identified forms of PHI: 
1. Clinical Monitors 
2. Study Pharmacist 
3. Adverse Event Specialist (Regulatory Affairs and Safety Officer)  
4. Pharmacy Project Manager 
 
 Periodic access control assessments will be made by Coordinating Center Quality Assurance 
personnel to verify that access is controlled and appropriate for personnel. In addition, the 
clinical monitors (SMART) will provide continuing education on good clinical practices 
compliance and will evaluate clinical site operations for violations of VA policies including VA 
data security policies and GCP. 
 
At the end of the study, the data for CSP#590 will remain property of the Cooperative Studies 
Program and be stored and shared according to CSP guidelines and procedures. Retention and 
destruction of data will be conducted according to CSP operating procedures and federal and 
local VA regulations. This will include paper and electronic data stored at the study sites, the 
MAVERIC CSPCC, and at the VA facility housing our servers. Participating medical centers 
must retain study files and records after the study is completed in accordance with National 
Archives and Records Administration requirements as indicated in the VHA Records Control 
Schedule (at the time of this printing, such records must be held indefinitely until further notice). 
Research data forms are to be kept in accessible files for at least five years after the end of 
subject follow-up.  These files can be retained for a longer period if required by applicable 
regulatory requirements or as agreed with an industry sponsor/partner, or if needed by the CSP.  
Identifiable data will be kept according to CSP policy as outlined in the "CSP Guidelines for the 
Planning and Conduct of Cooperative Studies”. 


 
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XVII. QUALITY CONTROL PROCEDURES  
A. Training on Study Measures 
 
Prior to the initiation of the study, all site investigators and site coordinators will meet to review 
the governance and management of the study, study procedures and receive training on 
collecting data for the study.  Much of this will take place during the study kickoff meeting.  The 
protocol and case report forms will be sent to site investigators and coordinators to review prior 
to the meeting.  During the meeting, study personnel will receive training on obtaining and 
maintaining source documents, and completing study assessments and case report forms. Verbal 
feedback and discussion will follow to ensure that each coordinator comprehends the proper 
methodology for assessment. This will include a training exercise to measure and maximize 
inter-rater reliability of clinical assessments. Any differences in the results will be discussed so 
that a consensus can be reached. The meeting will also cover an in-depth review of the study 
operations manual. Such a review will serve to reinforce the training described above and will 
orient the study personnel to the reference guides for the study. 
 
During the study itself, we intend to maintain the highest inter and intra-reliability of the clinical 
assessment, especially the Columbia Suicide Severity Rating Scale (CSSRS) by having data 
collectors rate common simulated interviews on a monthly basis with feedback and discussion. 
Most of the other measures are self-reported. 
 
B. Protocol deviations 
 
Strict adherence to the protocol will be expected of every participating center and monitored by 
the DMC, the Executive Committee, and the Study Group. Any protocol violations will be fully 
documented on the Protocol Deviation form developed by the MAVERIC CSPCC. Protocol 
deviations will be summarized for review at each DMC meeting. Any medical center or 
participant with repeated protocol violations, and after remedial action, may be recommended for 
termination to the Director of the Cooperative Studies Program after discussion with the CSPCC 
Director, Study Chair, Executive Committee, and DMC. If any member of the DMC or of the 
monitoring bodies for CSP#590 feels that adherence to the protocol will be detrimental to a 
participant's health or well-being, the interest of the participant will take precedence and the 
subject withdrawn after consultation with the Executive Committee. Site coordinators will be 
responsible for reporting protocol deviations to the IRB of record as required.  
 
C. Enrollment or Termination issues 
 
I. Guidelines for Early Termination of a Study Site 
 
During the course of a study, it may be necessary to drop one or more participating medical 
centers from the study. Such action must have the prior approval of the CSPCC Director and the 
Director of CSR&D. Early termination is usually based on recommendations from the Executive 
Committee and the Data Monitoring Committee and most often reflects inadequate patient intake 


 
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or serious noncompliance with Good Clinical Practices. This action should always be based on 
the best interests of the study and study participants and does not necessarily imply poor 
performance on the part of the site investigator or the medical center. Termination will be 
conducted per CSP guidelines and performance measures defined below.  
 
II. Enrollment Issues and Site Performance Measures 
 
The Study Chair and the study biostatistician will monitor the intake rate and operational 
aspects of the study. Participating medical centers will continue in the study only if adequate 
participant intake is maintained. The Executive Committee may take action leading to the 
discontinuation of enrollment at a center with the concurrence of the CSPCC Director. If 
recruitment is not proceeding at an appropriate rate, the Study Chair and study biostatistician will 
scrutinize the reasons for participant exclusions and other barriers to recruitment.  Based on this 
information, the Executive Committee may choose, with the approval of the DMC and the 
Director, VA CSR&D, to drop centers, add additional centers, make minor modifications to the 
inclusion/exclusion criteria, or extend the recruitment period.  
 
The following performance measures will be used to determine whether sites are at risk of being 
placed on probation or should be placed on probation.  
 
1. Noncompliance with the protocol, ICH, or applicable federal regulations. 
 
2. Recruitment rate: Recruitment rate will be calculated by dividing the number of 
randomized patients by the number of expected patients where the number of expected 
patients is based on prior SPAN and administrative data. This measure will be 
continuously monitored and sites between 75% and 90% of expected recruitment may be 
subject to remediation such as action plans or mentoring. Sites under 75% cumulative 
recruitment after a 3-month ramp-up period maybe recommended for probation. 
Assessment for probation will occur on a monthly basis. 
 
3. Follow-up rate:  Follow-up rate will be calculated by dividing the number of patients 
with follow-up forms completed by the expected number of patients with visits due.  
Both the numerator and denominator will be subject to a 4-week delay in order to allow 
for scheduling of visits and completion of forms. Sites with cumulative follow-up rates 
below 90% may be recommended for probation. Assessment for probation will occur on 
a monthly basis. 
 
4. Forms completion rate: Forms completion rate will be calculated by dividing the 
number of completed forms by the number of expected forms, excluding forms marked 
“not collected”. Forms completion rates will be calculated both by patient and by form. 
Sites with cumulative forms completion rates under 90% may be recommended for 
probation.  Assessment for probation will occur on a monthly basis. 
 
If a medical center is placed on probation, the Study Chair will confer with the site personnel and 
may visit the site, if necessary, to help improve the rate of recruitment. Once a site is placed on 
probation, failure to meet the requirements specified by the end of the probation period will 
result in a recommendation for termination.  Additionally, sites that fail to meet two or more of 


 
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the above performance measures, and sites that habitually under-perform by any of these 
measures, will be at risk of termination. 
 
To plan for the possible termination of a site(s) and the addition of a new site(s), back-up sites 
with IRB approval will be identified prior to study initiation to minimize the delay in adding a 
new site. The Executive Committee will take actions leading to discontinuation of a site only 
with the concurrence of the CSPCC Director. If a site is terminated from the trial, resources will 
be reallocated to other medical centers or used to start up a back-up site. 
 
III. Premature Termination of the Study 
 
The Director, CSP, can terminate a cooperative study before completion. The DMC makes 
recommendations as to whether the study should continue or be terminated. The decision to 
terminate a study prematurely is a complex one involving many factors. The DMC may consider 
the following circumstances as grounds for early termination: 
1. If patient accrual falls far below that which is predicted (e.g., 75% of expected 
accrual), it will be necessary to reassess the study design and the potential value 
of its continuation. 
2. If patient accrual far exceeds the predicted, this study could be completed at an 
earlier date. 
3. If serious adverse events or mortality are noted to be excessive in either treatment 
group.  
4. If interim analyses indicate a trend in the data which is unlikely to change prior to 
study completion. 
5. If, during interim analyses on the primary end point, the significance level crosses 
the efficacy boundary established by the DMC. 
Termination by recommendation of the DMC will be carried out as outlined in CSP guidelines. 
XVIII. GOOD CLINICAL PRACTICES AND SITE REVIEW PROGRAM  
Role of GCP  
This trial will be conducted in compliance with Good Clinical Practice (GCP) regulations.  The 
intent of these regulations is to safeguard subjects’ welfare and assure the validity of data 
resulting from the clinical research. Study site personnel will receive GCP training at the study 
kickoff meeting.  Subsequently, the VA Cooperative Studies Program will assist Site 
Investigators in complying with GCP requirements through its Site Monitoring, Auditing and 
Resource Team (SMART) based in Albuquerque, NM.  SMART serves as the Quality Assurance 
arm of CSP for GCP compliance. SMART will assist study personnel in organizing study files 
and will be available throughout the trial to advise and assist Site Investigators regarding GCP 
issues. Further details of the SMART monitoring plan will be provided in the study-specific 
Operations Manual. 
 
Summary of Monitoring and Auditing Plans: 
 
Monitoring Visits  
1. Initiation visits at each site soon after patient enrollment begins 


 
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2. Additional monitoring visits may be conducted as deemed necessary by study 
leadership or SMART. 
 
Audits  
1. Routine audits – independent site visits to one or more sites per year as determined by 
SMART.  
2. For-Cause audits –independent audit of a site as requested by study leadership or CSP 
Central Office.  
3. Audits may be scheduled or unannounced. 
XIX. STUDY ORGANIZATION AND ADMINISTRATION 
A. Administration 
 
The administrative structure of this study is similar to others in CSP and includes: 
 
The Cooperative Studies Program (VA Central Office) establishes overall policies and 
procedures that are applied to all VA cooperative studies through the Study Chair’s office and 
the CSPCC. 
 
The CSPCC and the Study Chair’s office jointly will perform the day-to-day scientific and 
administrative coordination of the study. These include developing and revising the study 
protocol, Operations Manual, and case report forms; ensuring the appropriate support for the 
participating centers; scheduling meetings and conference calls; answering questions about the 
protocol; conducting site visits; publishing newsletters. The CSPCC will also prepare interim and 
final progress reports; and archive study data at the end of the study. Study progress reports will 
be produced every 6 months. Patient accrual, patient safety, and data quality will be monitored 
closely by the CSPCC to ensure that the study is progressing satisfactorily. Further delineation of 
responsibilities will be documented in communications with the Study Chair’s office. 
 
The Central Psychiatrist/Safety Officer will be an experienced VA-credentialed blinded 
psychiatrist responsible for reviewing clinical data from the sites and serving as a resource to 
sites for lithium dosing and other relevant clinical matters. 
 
The Study Cardiologist/Safety Officer is a senior cardiologist with specialty in 
electrophysiologyand EKG interpretation 
 
The CSP Clinical Research Pharmacy Coordinating Center (CSPCRPCC) manages the 
pharmaceutical aspects of multicenter pharmaceutical and device clinical trials including patient 
safety monitoring. CSPCRPCC acts as a liaison between the study participants, the FDA, and the 
manufacturers of the study drug(s) or device(s) in all VA Cooperative Studies that involve drugs 
or devices. The CSPCRPCC develops Drug Treatment and Handling Procedures, obtains and 
distributes the study drug(s), prepares a Drug Information Report for the study drug, and 
provides advice and consultation about drug-related matters during the study. CSPCRPCC is 
responsible for monitoring and reporting the safety of trial participants through the review, 
assessment, and communication of adverse events and serious adverse events reported by study 


 
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personnel with reviewing responsibilities occurring through ongoing communication with the 
Study Chair, Executive Committee, CSPCC, and CSP Central Office. The reporting activities 
include filing regulatory documents involving adverse events with the FDA and manufacturers to 
meet federal regulations and CSP policies. In conjunction with the CSPCC, the CSPCRPCC 
trends and analyzes safety data to prepare reports for various committees including the DMC, 
VA Central IRB (CIRB), Executive Committee(s), and Study Group meetings.  
 
Each participating VA medical center will designate a site investigator (SI) to be responsible 
administratively and scientifically for the conduct of the study at the center. SIs will be expected 
to attend all annual Study Group meetings, as well as to hire and supervise personnel. By 
agreeing to participate in the study, the medical center delegates responsibility for global 
monitoring of the ongoing study to the DMC, the CSPCC Human Rights Committee, and the 
CSSEC.  
  
The Cooperative Studies Scientific Evaluation Committee (CSSEC) reviews the scientific 
merit of all new cooperative study proposals and all ongoing cooperative studies every 3 years. 
The committee is composed of both VA and non-VA clinical research scientists, most of whom 
have had experience in managing their own cooperative studies. 
 
The Study Group will be composed of the SIs from each participating center, the Study Chair, 
Study Director,  and CSP staff (biostatistician, project manager, clinical research pharmacist, and 
others). The Study Chair will head the group, which will meet once a year to discuss the progress 
of the study, any problems that the investigators have encountered, and any suggestions for 
improving the study. 
 
B. Monitoring 
 
The following groups monitor the various aspects of the study.  These committees will meet 
according to current Cooperative Studies Program guidelines. In addition, the CSP SMART will 
monitor the trial for GCP compliance as indicated above.  
  
The Executive Committee is responsible for the operations of the study, including protocol 
amendments, and overall management of the study. It will be headed by the Study Chair and 
Study Director and consist of the study biostatistician, study project manager, clinical research 
pharmacist, CSP Center Director, selected participating investigators, and outside consultants as 
needed. This committee will meet regularly to review blinded data (not broken down by 
treatment group), decide upon changes in the study, determine the fate of hospitals whose 
performance is substandard, initiate any subprotocols, and discuss publication of the study 
results.  This Committee must grant permission before any study data may be used for 
presentation or publication. 
 
The Data Monitoring Committee (DMC) will review the progress of the study and will 
monitor patient intake, outcomes, adverse events, and other issues related to patient safety, 
including review of study participants with lithium levels of ≥ 1.3 to determine if there is an 
association with concomitant hypertensive medications and whether the participants’ age or 
eGFR may play a role. Interim, independent, and unbiased reviews of the study's ongoing 
progress will be provided. The DMC will consist of experts in the study’s subject matter field(s), 


 
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clinical trials, biostatistics, and ethics. These individuals will not be participants in the trial and 
will not have participated in the planning of the protocol. The DMC will consider safety or other 
circumstances as grounds for early termination, including either compelling internal or external 
evidence of treatment differences or the unfeasibility of addressing the study hypothesis (e.g., 
poor patient intake, poor adherence to the protocol).  
At each of its meetings during the study period, the DMC will review the randomization rates 
and assess the difference between the actual and the projected rates, as well as the impact of 
these assessments on overall trial size. If the study enrollment is inadequate, the reasons for 
exclusion may be scrutinized and actions may be suggested. An assessment of whether the trial 
should be continued will be made followed by recommendations, as appropriate. All serious 
adverse events will be reported regularly to the DMC for review. Unexpected, related serious 
adverse events will be reported to the DMC as soon as they become known based upon the 
consensus of the Study Chair, the study biostatistician, the Study Director, and the study 
pharmacist. The study biostatistician will provide the appropriate data to the DMC at specified 
intervals for this purpose. Conditional power estimates may be provided to the DMC to assist 
them in making their decisions and recommendations at their request. To help them make their 
assessment, the Study Chair and study biostatistician will furnish the Data Monitoring 
Committee with appropriate monitoring data before each meeting.  The DMC makes 
recommendations after each meeting to the Director of the Clinical Science Research and 
Development (CSRD) Service about whether the study should continue or be stopped.  
 
The VA Central IRB will be the IRB of record for all VA sites.  They will monitor the study’s 
serious adverse events on a continual basis.  They will conduct annual reviews of the study.  In 
addition, some study materials (such as subject correspondence and protocol changes) will have 
to be reviewed by the VA CIRB, and approved prior to implementation.  
 
The CSPCC Human Rights Committee (HRC) is composed primarily of lay people and is 
responsible for ensuring that patients' rights and safety are upheld prior to study initiation and 
during the conduct of the study. The committee reviews all new protocols, periodically makes 
site visits to participating centers to monitor firsthand the progress of the study, and may be 
asked to review any ethical and human rights issues that arise during the conduct of the study.    
 
The CSP Site Monitoring, Auditing and Resource Team (SMART), located at the 
CSPCRPCC in Albuquerque, will monitor the trial for compliance with Good Clinical Practices. 
GCP reviewers from SMART will visit participating sites shortly after enrollment is initiated and 
as needed thereafter to monitor investigator regulatory compliance, protocol adherence, and 
overall research practices. SMART will conduct initiation visits at all sites. It also will conduct 
GCP site review and a for-cause audit of a participating site if requested by any of the 
monitoring bodies. If an IND is required by the FDA, the frequency of follow-up monitoring 
visits will be based on the CSP standard for regulated trials. At a minimum, each site will be 
visited at least once during the study by SMART.  
 
 
 
 
 


 
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XX. PUBLICATIONS 
 
Publication policy 
 
It is the policy of the CSP that outcome data will not be revealed to the participating 
investigators until the data collection phase of the study is completed. This policy safeguards 
against possible biases affecting the data collection.  
 
All presentations and publications from this study will be done in accordance with current CSP 
Guidelines, including the Authorship Policy. The most current version of the Guidelines should 
be referenced when planning any study publication. 
 
The presentation or publication of any or all data collected by participating investigators on 
patients entered into the VA Cooperative Study is under the direct control of the study's 
Executive Committee. No individual participating investigator has any inherent right to perform 
analyses or interpretations or to make public presentations or seek publication of any or all of the 
data other than under the auspices and approval of the Executive Committee. 
 
The Executive Committee has the authority to establish one or more publication subgroups of   
investigators and members of the Executive Committee for producing scientific presentations 
and publications. Authors with VA appointments must list their VA affiliation first. The VA 
contributions to the research project should be acknowledged in all written and oral presentations 
of the research results, including scientific articles, news releases, news conferences, public 
lectures, and media interviews.   
 
All study reports and journal manuscripts must be reviewed and approved by the MAVERIC 
CSPCC Director prior to submission for publication.  After approval for submission is granted 
by the MAVERIC CSPCC Director, VA Central Office must be notified upon acceptance of any 
publications.  This includes minor publications such as abstracts and poster presentations.   
 
Planned Publications 
 
A list of planned publications is provided below. The design paper will be completed during the 
conduct of the study. The manuscript detailing the main study results will be completed within 
six months of the study's completion.   
 
1. Efficacy of lithium in the prevention of repeated suicide attempts in high risk 
subjects with affective disorders: A VA Cooperative Study (main publication that 
will present clinical outcomes) 
2. Design, rationale and methodological challenges in a randomized placebo-
controlled trial of lithium and enhanced usual care of persons with recent suicide 
attempts. 
 
3. Determinants of treatment adherence to lithium in participants who recently 
attempted suicide.   
4. Predictors of impulsive and non-impulsive suicide attempts. (Secondary aim b). 
5. Predictors of repeated suicide attempts and suicide events (secondary aim c and 
d). 


 
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6. Effect of adjunctive lithium in managing symptoms of bipolar disorder and 
depression in patients who have survived a suicide attempt (secondary aim e) 
7. Mediators and moderators of lithium augmentation on prevention of suicide 
reattempts (secondary aims b,f) 
8. Relationship between lithium plasma levels and repeated suicide attempts in 
patients who have survived a suicide attempt 


 
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XXI. TABLES AND FIGURES 
Table 1: Instruments and scales for data acquisition 
Domain 
Measure  
Abbreviation 
Description 
Source 
# items 
 
 
Study 
Purpose 
Time 
(minutes) 
Suicidality 
Columbia Suicide 
Severity Rating Scale- 
lifetime version, 
supplemented (Posner et 
al., 2011; Matarazzo et 
al., 2013) 
CSSRS-
lifetime-supp 
History of suicide-
related behaviors 
Interview 
39 (6 item 
screen) 
 
Eligibility 
20 
  
Columbia Scale -since 
last visit version, 
supplemented (Posner et 
al., 2011; Matarazzo et 
al., 2013) 
CSSRS-last 
visit-supp 
Interim history of 
suicide related 
behaviors 
Interview 
Variable (6 
item 
screen) 
 
Monitoring 
10 
 
Suicide Intent Scale 
(Beck et al., 1974) 
SIS 
Context and 
characteristics of 
suicide attempts 
Interview 
15 
 
Monitoring 
8 
Psychiatric 
Diagnosis 
Mini-International 
Neuropsychiatric 
Interview (Sheehan et al., 
1998) 
MINI 
Structured interview 
to elicit psychiatric 
symptoms and 
determine diagnoses 
Interview 
Variable 
 
Eligibility 
20 
 
PTSD Checklist 
(modified to allow DSM-
IV-TR and DSM-5 
diagnoses); Blanchard et 
al., 1996) 
PCL 
Self-rating scale to be 
administered as a 
structured interview 
Self or 
Interview 
22 
Potential 
covariate 
for 
exploratory 
analyses 
6 
  
Substance use disorders 
module from Structured 
Clinical Interview for 
DSM-IV-TR Axis 1 
Disorders (First et al., 
2002) 
SCID SUD 
Supplementary 
questions related to 
substance use 
diagnoses 
Interview 
Variable 
 
Eligibility 
10 
Cognition 
and 
Decision-
Making 
Capacity 
Orientation Memory 
Concentration Test 
(Katzman et al., 1983) 
OMC 
Cognitive screening 
instrument 
Interview 
6 
 
Eligibility 
6 
  
The Jeste Decision-
Making Capacity 
Assessment – University 
of California, San Diego 
Brief Assessment of 
Capacity to Consent 
(UBACC) 
UBACC 
Evaluation of 
decision-making 
capacity 
Interview 
Variable 
 
Eligibility 
5 


 
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Mental 
Health 
Symptoms  
Patient Health 
Questionaire-9 (Kroenke 
et al., 2001) 
PHQ-9 
Symptoms of 
depression 
Self or 
Interview 
10 
Secondary 
Outcome 
7.5 
  
Internal State Scale 
(Bauer et al., 2000)  
ISS 
Symptoms of bipolar 
disorder 
Self or 
Interview 
15 
Secondary 
Outcome 
7.5 
  
Alcohol Use Disorders 
Identification Test-C 
(Bradley et al., 2007)  
Audit C 
Quantity-frequency 
data on alcohol use  
Interview 
3 
Secondary 
Outcome 
3 
Moderators 
Buss-Perry Aggression 
Scale (Buss & Perry, 
1992) 
Buss Perry 
Aggression as a  trait 
Self 
29 
Secondary 
Outcome 
10 
  
Barratt Impulsiveness 
Scale (Patton et al., 1995) 
Barratt 
Impulsivity as a trait 
Self 
30 
Secondary 
Outcome 
10 
Lithium side 
effects 
Lithium side effects 
checklist  
  
Systematic review of 
possible lithium side 
effects 
Interview 
8 
 
Monitoring 
5 
Use of VA 
and non-VA 
health and 
mental health 
services 
Sirey et al., 
2005) 
Self-report log based on 
the Cornell Services 
Index (Sirey et al.,2005) 
 
Use of health and 
mental health services 
to include patient’s 
report of reasons for 
hospitalization or 
emergency 
department visits 
Log 
maintained by 
subject and 
reviewed by 
research staff 
at each visit 
Variable 
 
 
 Monitoring 
 
5 minutes 
for review 


 
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Table 2: Comparison of select prior studies of lithium with CSP590 
 
  
Cipriani (2005) 
Guzzetta (2007) 
Goodwin (2003) 
Lauterbach (2008) 
Oquendo (2011) 
Proposed 
CSP590  
Design 
Meta-analysis of 
32 RCTs 
conducted to 
evaluate other 
outcomes 
Meta-analysis of 
8 studies   
Observational study in two 
health plans 
RCT (Terminated 
prematurely due to 
low recruitment) 
RCT (Terminated 
prematurely due to 
low recruitment) 
Randomized 
Clinical Trial 
Period 
1968-2002 
1976-2006 
1994-2001 
2001-2006 
2000-2007 
Prospective 
Study 
Population 
Mood Disorder 
Major Depressive 
Disorder 
Bipolar Disorder 
76% Major 
Depressive 
Disorder, 22% 
Other 
Bipolar Disorder 
Bipolar and 
Major 
Depression 
Treatment s 
lithium vs. other 
agents 
lithium vs. other 
agents 
lithium vs. divalproex or 
carbamezapine 
lithium vs. placebo 
lithium vs. valproate 
lithium vs. 
placebo 
Sample Size 
2458  
(1389 lithium, 
2069 other 
agents) 
252 lithium, 205 
other,  128 
Crossover 
> 23000  
(16020 li, 10669 valproate, 
2516 carbamazepine)  
167  
(84 lithium, 83 
placebo) 
98  
(49 lithium, 49 
valproate) 
1862 
No. of Years 
followed-up 
Varies across 
studies 
Li, 4.6, Other, 6.7  2.9   
1    
1.35 Li, 1.5 
valproate 
1   
Average Age 
(yrs) 
Varies across 
studies 
Varies across 
studies 
38   
39   
33.5   
~ 44.6 
% male 
Varies across 
studies 
Varies across 
studies 
35%   
42%   
28%   
~ 86%   
Attrition 
Varies across 
studies  
Varies across 
studies  
NA 
Overall: 58% 
lithium, 59% 
placebo 
  
Tx related: 21% 
lithium, 6% 
placebo 
Overall: 50% 
lithium, 53% 
valproate 
 
Tx related: 11% 
lithium, 13% 
valproate 
~ 20% Tx 
related; 40% 
non-Tx related  


 
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Outcomes 
considered 
Suicides, 
Suicides + 
deliberate self-
directed 
violence, all 
cause mortality 
Suicides, Suicidal 
behavior 
Suicide, Attempts w ED visit 
or hospitalization 
Suicide reattempt 
within 1 year after 
index attempt 
Suicide attempt or 
suicide event 
including attempt/ 
hospitalization/ 
change in 
medication in 
response to suicide 
plans. 
Suicide 
attempts, 
interrupted 
attempts, 
hospitalizations 
to prevent 
suicide, and 
deaths from 
suicide 
Observed Event 
Rates 
For suicide, 
2/503 for 
lithium vs. 
11/602 for 
other. For 
suicide 
+deliberate self-
directed 
violence, 2/670 
for lithium vs. 
18/781 for 
other. For all 
cause mortality, 
9/696 for 
lithium vs. 
22/788 for other 
For suicide, 
0.33% for lithium 
vs. 2.22% for 
other. For suicide 
behaviors, 2/252 
for lithium vs. 
19/205 for other 
For suicide 9/13597 for 
lithium, 14/8297 for valproate, 
2/2036 for carbamazepine. For 
attempts. 67/16020 for lithium, 
112/10669 for valproate, 
39/2516 for carbamazepine) 
Lithium: 7/84 
(8.3%), placebo: 
10/83 (12%) 
Lithium: 6/49 
(12.2%), valproate: 
8/49 (16.3%) for 
suicide attempts 
over 2 year period. 
 
At one year, 82% 
survival and 88% 
survival in valproate 
and lithium groups 
respectively. 
~ 15% rate for  
Reattempts, 
interrupted 
attempts, 
hospitalizations 
to prevent 
suicide, and 
deaths from 
suicide 
Observed 
Effects 
74% reduction 
for suicide, 79% 
for suicide + 
deliberate self-
directed 
violence, 58% 
for all cause 
mortality 
85% reduction 
for suicide, 
88.5% for 
suicidal behavior 
60% reduction in suicides, 41-
44% for attempts 
Adjusted reduction 
of 48%. Not 
significant. 
One Year reduction 
estimated as 33%. 
Not significant 
~ 37% reduction 
in repeated 
attempts, 
interrupted 
attempts, 
hospitalizations  
to prevent 
suicide, and 
deaths from 
suicide 
 
 


 
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Table 3: Evaluation of variability in Statistical Power assuming 5% Overall Type I error.  
 
(a) 
Change in statistical power for fixed sample size and a range of effect sizes  
 
 
 
Event Rates 
 
 
 
Evaluable 
N 
N per 
arm 
Placebo 
Active 
#Events 
Effect 
Power 
1490 
745 
15% 
11% 
190 
30% 
73% 
1490 
745 
15% 
10% 
188 
31% 
77% 
1490 
745 
15% 
10% 
187 
33% 
81% 
1490 
745 
15% 
10% 
185 
35% 
85% 
*1490 
745 
15% 
9.5% 
182 
37% 
90% 
1490 
745 
15% 
9% 
179 
40% 
94% 
 
 
(b) 
Change in statistical power for fixed effect size and a range of sample sizes  
 
 
Event Rates 
 
 
 
 
Effect 
Placebo 
Active 
Evaluable 
N 
N  
per arm 
#Events 
Power 
37% 
15% 
9.5% 
1700 
850 
208 
93% 
*37% 
15% 
9.5% 
1490 
745 
182 
90% 
37% 
15% 
9.5% 
1400 
700 
171 
88% 
37% 
15% 
9.5% 
1200 
600 
147 
83% 
37% 
15% 
9.5% 
1100 
550 
134 
79% 
37% 
15% 
9.5% 
1000 
500 
122 
75% 
 
(c) 
Change in statistical power for fixed effect and sample size and a range of event rates  
 
 
 
Event Rates 
 
 
 
Total N 
N per 
arm 
Placebo 
Active 
#Events 
Effect 
Power 
*1490 
745 
15% 
9.5% 
182 
37% 
90% 
1490 
745 
14% 
8.8% 
170 
37% 
88% 
1490 
745 
13% 
8.2% 
158 
37% 
85% 
1490 
745 
12% 
7.6% 
146 
37% 
82% 
1490 
745 
11% 
6.9% 
134 
37% 
78% 
1490 
745 
10% 
6.3% 
121 
37% 
73% 
 
*Highlight indicates parameters proposed in CSP590


 
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Table 4. Potentially eligible subjects for 1-year period by site 
 
 
Site# 
Facility 
Count 
Cumulative 
 
Site# 
Facility 
Count 
Cumulative 
1 
Orlando 
249 
249 
 
26 
Northern Calif 
101 
3660 
2 
San Diego 
218 
467 
 
27 
Montana 
99 
3759 
3 
Atlanta 
214 
681 
 
28 
Central Texas 
97 
3856 
4 
Las Vegas 
204 
885 
 
29 
Baltimore, includes Perry 
Point 
96 
3952 
5 
Marion, Illinois 
185 
1070 
 
30 
Edward Hines VAMC 
96 
4048 
6 
West Palm Beach 
166 
1236 
 
31 
Palo Alto 
95 
4143 
7 
Denver 
160 
1396 
 
32 
Central Arkansas 
93 
4236 
8 
Milwaukee 
156 
1552 
 
33 
Salt Lake City 
83 
4319 
9 
Central Alabama 
155 
1707 
 
34 
Muskogee 
80 
4399 
10 
Puget Sound HCS 
149 
1856 
 
35 
Philadelphia 
79 
4478 
11 
Madison 
130 
1986 
 
36 
Roseburg 
79 
4557 
12 
Washington DC 
123 
2109 
 
37 
Marion, IN 
78 
4635 
13 
St Louis 
122 
2231 
 
38 
Columbia, SC 
78 
4713 
14 
Tampa 
122 
2353 
 
39 
Pittsburgh 
78 
4791 
15 
Houston 
115 
2468 
 
40 
Reno 
78 
4869 
16 
Gainesville 
115 
2583 
 
41 
Tenn. Valley 
77 
4946 
17 
Phoenix 
114 
2697 
 
42 
Portland 
76 
5022 
18 
Minneapolis 
113 
2810 
 
43 
Mountain Home 
74 
5096 
19 
Jesse Brown VAMC 
111 
2921 
 
44 
West Texas 
71 
5167 
20 
Amarillo 
110 
3031 
 
45 
New Jersey 
71 
5238 
21 
Dallas 
108 
3139 
 
46 
Tomah 
69 
5307 
22 
Tucson 
107 
3246 
 
47 
Battle Creek 
66 
5373 
23 
Indianapolis 
106 
3352 
 
48 
Bay Pines 
66 
5439 
24 
Dublin 
105 
3457 
 
49 
Poplar Bluff 
64 
5503 
25 
Biloxi 
102 
3559 
 
50 
Loma Linda 
64 
5567 


 
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Table 5: Medications with potential interactions with lithium 
 
Increased risk of CNS side effects/toxicity 
Carbamazepine 
Calcium channel blockers  
Haloperidol 
Serotonin Re-uptake Inhibitors 
Serotonin modulators 
Tricyclic antidepressants 
 
Decreased thyroid function 
 
Extended use of iodide preparations 
 
Lower lithium levels 
Acetazolamide 
Aminophylline 
Caffeine 
Theophylline 
Alkalinizing agents such as sodium bicarbonate 
 
Increase lithium levels 
Diuretics 
Angiotensin converting enzyme (ACE) inhibitors 
Angiotensin II Receptor Antagonists 
Calcium channel blockers (non-dihydropyridine) 
Metronidazole 
 
Non-steroidal Anti-inflammatory agents (including COX-2 inhibitors) 
 
MAO Inhibitors 
 
May increase or decrease lithium levels 
 
Fluoxetine  
 
Unstated, Other, or mixed 
Alpha-methyl DOPA (Aldomet) 
Antipsychotic agents (typical and atypical) 
 
 
 
 


 
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Table 6: Study Flowchart for Participants on Study Medication 
Study Activities 
Screening 
Study Entry 
Study Participation with Assigned Treatment 
Termination  
Titration 
Steady State 
 
 
Eligibility 
Evaluation 
(ICF 1) 
Confirming 
Eligibility 
(ICF 2) 
BL  
T 1 
T 2-3 
T 4 
T 5-6 
 
M 6 
M 7-8 
M 9 
M10,11 
Early 
D/C 
End of 
Study 
F/U  (30 
days) 
  M 2-5 
Estimated time per visit 
2 hrs 
2 hrs 
1.25h
rs 
1hr 
45min 
1.25hr 
45min 
1hr 
1.25hr 
1hr 
1hr 
1hr 
1.75hr 
1.75hr 
30min 
Phone contact allowed+ 
  
  
  
  
  
  
  
Yes 
  
Yes 
  
Yes 
  
  
 Yes 
Eligibility Screening 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed Consent++ 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Review Incl/Excl. Criteria (S12) 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Demog. and military history (B02, B03) 
 
X  
 
  
  
  
  
  
  
  
  
  
  
  
  
Medical history reviewed (B04) 
 
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Psychiatric history reviewed (S01) 
X 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Medications and treatments reviewed 
(S03) 
X 
X  
X 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
MH Provider concurrence  
documentation obtained  
X 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Care Provider awareness 
documentation obtained+++ 
X 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical Exam (B01) 
  
X 
  
  
  
  
  
  
  
  
  
  
X 
X 
  
Vital Signs (B01, T04) 
  
X 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
EKG++++ (S09) 
  
X 
  
X (once during titration) 
            X (once during steady state) 
X 
X 
  
Creatinine (S10, T02) 
  
X 
  
X  
X 
X 
 X 
X  
X 
  
X 
  
X 
X 
  
CBC, electrolytes, calcium (S10, T01) 
  
X 
  
  
  
X 
  
  
X 
  
  
  
X 
X 
  
TSH, T4 (S10, T02) 
  
X 
  
  
  
X 
  
  
X 
  
  
  
X 
X 
  
Pregnancy test as appropriate (S10, T01) 
  
X 
X  
 X 
 X 
 X 
 X 
 X 
X  
 X 
 X 
 X 
X  
X  
  
Interim history (B05) 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Enrollment 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


 
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Randomization (S12) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Study Medication 
Eligibility 
Evaluation 
Eligibility 
Confirmation 
BL 
T 1 
T 2-3 
T 4 
T 5-6 
M 
 2-5* 
M 6 
M 7-8 
M 9 
M 
10-11 
Early 
D/C 
End of 
Study 
F/U (30 
days) 
Lithium level (T02) 
  
  
  
X 
X 
X 
X 
X 
X 
  
X 
  
  
  
  
Adherence ( T03, T05) 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Adverse events, (SAEs and AEs) (using 
lithium side effects checklist) (B13, 
T02) 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Planned dose adjustment 
  
  
  
X 
X 
X 
X 
  
  
  
  
  
  
  
  
Dispense study medication+++++ 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
(X) 
  
Current Treatment Info.  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medications (S03) 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
VA record review 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Service use based on the Cornell 
Service Index (B05) 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Psychiatric Measures 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
MINI (S11) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PCL (B12) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID SUD (S05) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
OMC (S06) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
UBACC (S04) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CSSRS-lifetime version suppl with SIS 
for index attempt (S07, S08) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CSSRS-last visit version supple with 
SIS f/u for attempts (B06, S08) 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PHQ-9 (B07) 
  
  
X 
X 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
ISS (B08) 
  
  
X 
X 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
Audit C (B09) 
  
  
X 
X 
  
  
  
Month 3 
X 
  
X 
  
X 
X 
  
Buss-Perry (B10) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  


 
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Barratt (B11) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
+ During months 2-5, if participants have completed titration procedures, participant’s visits may be conducted over the phone at alternating time points (e.g. Months 2 and 4, or 
Months 3 and 5 visits can be over the phone. Visits done by phone will not have VS collected. The same is true of months 7-8 and months 10-11. The exception to this is for 
participants of childbearing potential who will need to be seen in-person for all study visits because a pregnancy test needs to be administered. 
++ Participants will provide informed consent in two stages – consent for screening evaluation (ICF1), followed by consent for main study (ICF2) if eligible (see consent forms) 
+++ The mental health provider must provide concurrence after ICF 1 has been signed and prior to randomization. The primary care provider must be made aware of study 
participation prior to randomization.  
++++ EKG will be performed on all participants at screening, at least once during titration and once when steady state has been achieved and at End of Study/Early Termination 
+++++ Study medication is only dispensed at end of study visits if a warm-hand off has been delayed. 
 
 
Table 7: Study Flowchart for Participants Who Discontinue Study Medication 
Study Activities 
DISCONTINUE STUDY 
MEDICATION  
WITHOUT ACTIVE 
FOLLOW UP 
DISCONTINUE STUDY MEDICATION WITH ACTIVE FOLLOW UP 
At Early 
D/C Visit 
At 30 Days 
F/U Visit 
AT EARLY D/C 
VISIT 
AT 30 DAYS 
F/U VISIT 
DURING ACTIVE 
FOLLOW UP* 
AT END OF STUDY 
VISIT 
AT 30 DAYS F/U 
VISIT 
Physical Exam (B01) 
X 
 
X 
 
 
 
 
Medications and treatments 
reviewed (S03) 
X 
 
X 
 
X 
X 
 
Vital Signs (B01, T04)** 
X 
 
X 
X 
 
 
 
EKG (S09) 
X 
 
X 
 
 
 
 
Creatinine (S10, T02) 
X 
 
X 
 
 
 
 
CBC, electrolytes, calcium 
(S10, T01) 
X 
 
X 
 
 
 
 
TSH, T4 (S10, T02) 
X 
 
X 
 
 
 
 
Pregnancy test as appropriate 
(S10, T01) 
X 
 
X 
 
 
 
 
Service use based on the 
Cornell Service Index (B05) 
X 
X 
X 
X 
X 
X 
X 
Lithium level (T02) 
 
 
 
 
 
 
 
Adherence (T03, T05) 
X 
 
X 
 
 
 
 
Adverse events, (SAEs and 
AEs) (using lithium side 
effects checklist) (B13, T02) 
X 
X 
X 
X 
X 
X 
X 


 
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Medications (S03) 
X 
 
X 
 
X 
X 
 
VA record review 
X 
X 
X 
X 
X 
X 
X 
SIS (S08) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
Columbia Follow up (B06) 
X 
X 
X 
X 
X 
X 
X 
PHG-9 (B07) 
X 
X 
X 
X 
X 
X 
X 
ISS (B08) 
X 
X 
X 
X 
X 
X 
X 
Audit C (B09) 
X 
 
X 
 
 
X 
 
Follow up laboratory 
Information (T01) 
X 
 
X 
 
 
 
 
Participant visit overview 
(T02) 
X 
 
X 
 
 
 
 
Outcome Adjudication (B17) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
Narrative for Outcome 
Adjudication (B18) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
X 
(as needed) 
End of Study (Form E) 
X 
 
X 
 
 
X 
 
*During months 2-5 participant’s visits may be conducted over the phone at alternating time points (e.g. Months 2 and 4, or Months 3 and 5 visits) can be over the phone.  
Visits done by phone will not have VS collected. The same is true of months 7-8 and months 10-11. 
** Vital signs will be collected for all participants at Early D/C.  Additionally, participants that remain in active follow-up will have vitals signs collected 
 at their 30 day follow-up visits. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Figure 1: Eligible Cohort Identification for 24 month period 
 
 
 
 
 
 
 
 


 
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maintenance treatment of bipolar I disorder (Trial 144: a randomized controlled study). The 
Journal of clinical psychiatry 72: 1452, 2011. 
Willson MC, et al. Valproate attenuates dextroamphetamine-induced subjective changes more 
than lithium. European neuropsychopharmacology 15: 633-639, 2005. 


 
Katz, IR: CSP#590 Lithium for the Prevention of Recurrent Suicide Attempts 
CSP#590 Li+ Protocol v 3.2  
Effective:   09/03/2019 
 
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measure of the frequency, intensity, and burden of side effects. Journal of Psychiatric 
Practice 12:71-79, 2006 
Yerevanian  BI, Koek RJ, Mintz J. Bipolar pharmacotherapy and suicidal behavior. Part I: 
Lithium, divalproex and carbamazepine Journal of Affective Disorders 103: 5–11, 2007 
Yerevanian BI, Koek RJ, Feusner JD: Pharmacotherapy and risk of suicidal behaviors among 
patients with bipolar disorder (letter). JAMA 291:939, 2004 
Yerevanian BI, Koek RJ, Mintz J: Lithium, anticonvulsants, and suicidal behavior in bipolar 
disorder. J Affect Disord 73:223–228, 2003. 
 

SAP_001.pdf: 
 
MAVERIC Study 
Specific Documents 
 
DATE OF ISSUE 
 
DOCUMENT DESCRIPTION 
 
4/1/2016 
 
This document describes the statistical analysis 
plan for the CSP590 [Li+] randomized clinical 
trial. 
 
 
AUTHOR:  Soe Soe Thwin, MS, PhD                                                      SUBMITTED BY:   Soe Soe Thwin, MS, PhD 
 
 
DOCUMENT/RECORD HISTORY: 
 
DATE               VERSION               RECORD HISTORY  
 04/01/2016              1.0                         Initial Version 
 
 
 
 
  
 
AUTHORIZATION SIGNATURES 
NAME 
FUNCTION TITLE 
SIGNATURE 
DATE 
Ira Katz MD, PhD 
Study Chairman 
 
 
Matthew Liang, MD 
Study Director 
 
 
Soe Soe Thwin, MS, PhD 
Study Biostatistician 
 
 
Ryan Ferguson , MPH, ScD 
Center Director 
 
 


Page 1 
 
Table of Contents 
 
1. Introduction……………………….…………………………………...page 2 
2. Overview of the study design and study objectives…...……....page 3 
3. Investigational plan…………………………………………………..page 4 
3.1. 
Description of the Study Population 
3.2. 
Description of the Intervention Strategy 
3.3. 
Definition of Intention to Treat Primary Analytic Sample 
3.4. 
Definition of per-Protocol sample 
4. Primary Analysis…………….……………………………….………..page 7 
4.1. 
Primary Objective 
4.2. 
Primary Endpoint 
4.3. 
Statistical Methods for Efficacy Analysis 
4.4. 
Evaluating Covariate Effects and Heterogeneity by site 
4.5. 
Sensitivity Analysis 
4.6. 
Handling of Missing Data in Primary Analysis 
5. Secondary Analysis………………………………………….………page 11 
5.1. 
Secondary Objectives 
5.2. 
Secondary Endpoints 
5.3. 
Statistical Methods for Secondary Analyses 
6. Tertiary Analysis……………..……………………………….………page 14 
6.1. 
Tertiary Objectives 
6.2. 
Tertiary Endpoints 
6.3. 
Statistical Methods for Tertiary Analyses 
7. General Considerations……………………………………………...page 15 
7.1. 
Univariate and Bivariate Distributions 
7.2. 
Description of Baseline Data  
7.3. 
Description of Follow-up Assessment Data 
7.4. 
Safety Data 
8. Data Monitoring Committee (DMC) Report..……………………...page 17 
8.1. 
Analytic Sample for DMC Report 
8.2. 
Algorithm 
8.3. 
Outline of DMC Report 
9. Analytic Tables not included in the DMC Report........................page 19 
10. Sample size and power……………………………………………....page 20 
10.1. Interim Analysis 
10.2. Futility Analysis 
11. Final Statistical Report...................................................................page 24 
12. References……………………………………………………………..page 25 


Page 2 
 
 
1. Introduction 
This document outlines the statistical methods for the analysis of data collected in the 
Department of Veterans Affairs Cooperative Studies Programs (CSP) study #590 entitled “A 
Randomized double-blind placebo-controlled trial of lithium augmentation and enhanced suicide 
prevention management in preventing suicide re-attempts in individuals with depression and 
bipolar disorder.” The purpose of this document is to provide guidelines from which the analysis 
will proceed.  Deviations from these guidelines will be documented and filed electronically in the 
study central file Sharepoint site. 
The following documents were used in preparation of this statistical analysis plan (SAP): 
 
Clinical Study Protocol CSP #590 
 
Case Report Forms (CRF) from above entitled Protocol 
 
Global CSP SOP 2.9: “Developing and Conducting Statistical Analyses 
 
Local Work Instruction WI 201Statistical Analysis Plan and Biostatistical Research Data 
Processing Plan Creation and Amendment 
 
Local Job Aid No. 5: Guide to Writing Statistical Analysis Plans 
 


Page 3 
 
2. Overview of the Study Design and Study Objectives 
This is a double-blind, placebo-controlled randomized clinical trial that will assess the 
effectiveness of lithium augmentation to enhanced usual care for prevention of repeated fatal 
and non-fatal suicide attempts in participants with bipolar disorder or depression who have 
survived a recent episode of suicidal self-directed violence. 
A total of 1862 subjects recruited from 29 Veterans Health Administration (VHA) centers over a 
3 year period are expected to be randomized equally to lithium (Lithium ER) or placebo. 
Participants will be followed actively for 12 months from randomization. Adverse event 
monitoring for safety will be for one additional month beyond active follow up, i.e., up to 13 
months. 
The primary hypothesis is that lithium is superior to placebo for the prevention of episodes of 
suicidal self-directed violence over time. The primary outcome measure is time from 
randomization for treatment allocation to any first episode of suicide attempt, interrupted 
attempt, hospitalization specifically to prevent suicide, or death from suicide.  
As secondary objectives of the study, lithium efficacy will be evaluated for prevention of 
subtypes of suicidal self-directed violence, for all suicidal self-directed violence events (even 
after the first recurrence), for prevention of repeated events in subgroups as well as in the entire 
sample, and to identify potential mediators. 
The tertiary objectives of the study are to extend the follow up period using electronically 
available data to describe patterns of lithium use following active participation in the study 
participants, as well as to evaluate rates and determinants of suicide reattempts and all cause 
mortality over a longer follow up period. 
 
 
 
 


Page 4 
 
3. Investigational Plan 
 
 
3.1. Description of the Study Population 
 
Patients are eligible to enroll if they satistfy all of the 5 inclusion conditions and patients are 
excluded if they satisfy any of the 11 exclusion conditions as outlined in Table 1 below. 
 
Table 1. Inclusion and Exclusion Criteria.  
Inclusion Criteria: 
(1) Survival of an episode of suicidal self-directed violence (including suicide attempts and 
interrupted attempts) that occurred within three months of initial consent to the study, or 
they were admitted to a mental health inpatient unit specifically to prevent suicide within three 
months of initial consent to the study 
(2) Diagnosis of Bipolar I Disorder, Bioplar II Disorder, or current or recurrent Major Depressive 
Disorder. Meeting the diagnosis for a current Major Depressive Disorder requires the presence 
or history of a Major Depressive Epidosde 
(3) Concurrence from the patient’s mental health provider and the provider responsible for the 
pateint’s general medical care about inclusion/exclusion criteria, and confimration of the 
providers’ willingness to work with the research team in managing the patient throughout the 
study 
(4) Able to provide informed consent 
(5) Patient identifies one or more contacts and gives permission for the clinical providers 
and/or the research team to contact them if the patient cannot be reached. 
 
Exclusion Criteria: 
(1) Schizophrenia 
(2) A history of psychotic symptoms in the absence of prominent mood symptoms attributable 
to Major Depressive or Manic Episodes, delirium, or substance use/withdrawal 
(3) Six or more previous lifetime suicide attempts 
(4) Enrollment in another randomized interventional clinical trial 
(5) Lack of decision-making capacity to evaluate the risks versus the benefits of participation 
as determined by UBACC score <14 
(6) Cognitive impairment defined by a score >10 on the OMC 
(7) Current or recurrent (within the past 6 months) use of lithium, or a history of significant 
adverse effects of lithium 
(8) Concurrent medications:  
a.Diuretics 
b.Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors) 
c.Angiotensin II Receptor Antagonists 
d.Haloperidol 
e.Clozapine 
(9) Unstable medical conditions or specific medical comorbidity: 
 
Congestive heart failure by Framingham criteria (See form S12 for worksheet) 
 
Estimated GFR < 60 mL/min/1.73m2 


Page 5 
 
QTc ≥450ms for men and ≥460ms for women 
(10) Active substance abuse: 
 
Active alcohol or opiate dependence requiring medically supervised withdrawal and 
stabilization 
 
Active cocaine, methamphetamine, other stimulant, hallucinogen, or cannabis abuse 
requiring stabilization 
(11)Any possibility of being pregnant, not on appropriate birth control, lactation and 
breastfeeding 
 
 
3.2. Description of the Intervention Strategy 
 
Eligible patients who consent to participate will be randomized to receive Lithium or placebo.  
Initital dosage will be 600 mg /day of lithium (or matching placebo), to be titrated to achieve 
serum lithium level of 0.6 to 0.8 meq/liter. Mock serum lithium level for placebo patients will 
be calculated using Theraputic Drug Monitoring method (Yukawa, 1993) based on age, 
weight, serum creatinine level, adherence, and side-effects. Titration visits will occur at 
intervals of 5-7 days over 3 months, with maximum allowed dosage not to exceed 1500mg.  
 
Once the target serum lithium level has been reached the patient will be on steady state 
maintenance phase for the rest of the study with active participation and intervention 
terminating at 12 months after randomization. 
 
 
3.3. Definition of Intention to Treat Primary Analytic Sample 
 
All consented and randomized subjects will be accounted for and included in the primary 
intention to treat (ITT) analytic cohort. Those who revoked HIPAA authorization will be 
included in the analysis from randomization date to date of HIPAA revocation.   
 
An analytic datafile consisting of only the “ITT” subjects as defined above will be created 
and maintained throughout the study.  This file will be called the “CSP590_ITT” file. 
 
 
3.4. Definition of per-Protocol sample 
 
Adherence to allocated intervention will be ascertained for randomized subjects for 
identification of “per-Protocol” sub-group. Adherence will be determined by pill count for both 
lithium and placebo groups and additionally, by serum lithium level for the lithium group.  
These two methods are described below. Those in the lithium intervention group who are 
adherent to the protocol based on either of the two methods will be considered as adherent. 
All study subjects, who are adherent to the protocol, will be included in the “per-Protocol” 
analytic sub-sample.   
 


Page 6 
 
Method 1: Based on pill count from Form T03 Study Drug Adherence Form data. 
 
Percent adherence for each prescribed dosage will be computed using the following 
algorithm: 
 
% adherence = (Total #tablets taken/Total #tablets prescribed)*100% 
 
These percent adherences for each prescribed dosage will be averaged for each patient 
and those with >=80% overall adherence during the steady state follow up period will be 
considered adherent to the protocol.   
 
Method 2: Based on target serum lithium level 
 
Study participants in the lithium augmentation group who reach the target serum lithium 
level of 0.6-0.8 meq/liter during the titration period and maintain within target+0.1 meq/liter 
(i.e., 0.5-0.9 meq/liter) during the entire steady state follow up period will be considered 
adherent to the protocol. 
 
 
 


Page 7 
 
 
4. Primary Analysis 
 
 
4.1. Primary Objective 
 
As the primary objective, this trial will test the hypothesis that lithium is superior to placebo 
for the prevention of suicidal self-directed violence. This will be accomplished by comparing 
event-free survival distribution in the two treatment groups. 
 
 
4.2. Primary Endpoint 
 
The primary outcome measure is time from randomization for treatment allocation to the first 
episode of suicidal self-directed violence assessed over one year follow up period.  Episode 
of suicidal self-directed violence include (1) non-fatal suicide attempts, (2) interrupted 
attempts, (3) hospitalizations specifically to prevent suicide, and (4) deaths from suicide.  
All potential primary endpoints identified via CRFform data (mostly through the serious 
adverse event reporting or Columbia Follow Up form), will be evaluated by two independent 
adjudicators.  If the adjudicators do not agree in deciding the event to be (or not to be) the 
primary endpoint event, then a third adjudicator will evaluate the same information and 
serve as a tie-breaker. 
 
 
4.3. Statistical Methods for Primary Efficacy Analysis 
 
Primary efficacy analysis will include the modified intention to treat sample as defined in 
section 3.3 above.  
 
The primary hypothesis can be stated as follows. 
 
Under the null hypothesis: The 1-year event rate is 15% and the two treatment groups do 
not differ in their time to event hazard rates.   
 
Under the alternative hypothesis:  The 1-year event rate is 9.45% for patients treated with 
lithium and 15% for patients in the placebo group, resulting in an absolute reduction from 
15% to 9.45% = 5.55% and a relative reduction of (15 – 9.45)/15 = 37%. The group on 
lithium augmentation has a lower hazard rate than the placebo augmentation group with a 
hazard ratio for lithium therapy compared to control therapy lower than or equal to 0.61. 
 
We will test this hypothesis with a two sided log rank test at 90% power and 4.8% Type I 
error (i.e., 5% overall error allows for one interim test at 0.2%). Null hypothesis will be 
rejected if the hazard ratio exceeds 1/0.61= 1.64 or falls below 0.61.  


Page 8 
 
 
A significant difference showing that the lithium augmentation compared to placebo 
decreases the hazard of suicidal self-violence will be regarded as a positive result, whereas 
a result that shows lithium augmentation does not significantly differ from placebo or 
significantly increases the hazard rate relative to placebo will be regarded as a negative 
result. 
 
Log rank test will be followed by Cox proportional hazards regression modeling to provide 
the hazard rates, their ratio and the 95% confidence interval about the ratio.  
We will test the proportional hazards assumption by including a time*treatment interaction 
term in the model and use graphic methods to study goodness of fit as described  in 
Anderson et. al., 1991.  
 
The SAS code for the primary analysis is as follows, where, tx is coded as {1=lithium, 
0=placebo}, event is coded as {1=adjudicated outcome, 0=otherwise}, and FUdays is 
counting number of days from randomization date to the first occurrence of (adjudicated 
outcome, death, 12 month date, or last study visit/contact date). 
 
Log-Rank Test: 
title "Survival Estimates by Month"; 
proc lifetest data=endpt plots=(s); time FUdays*event(0); strata tx; run; 
quit; 
proc lifetest data=endpt method=life plots=(ls) intervals=30 90 120 150 
180 210 240 270 300 330 365; time FUdays*event(0); strata tx; run; quit; 
   
title "Survival Estimates by Month"; 
proc lifetest data=endpt method=life plots=s intervals=30 90 120 150 180 
210 240 270 300 330 365; time FUdays*event(0); strata tx; run; quit; 
  
title "Hazard Estimates by Month"; 
ods output lifetableestimates=life(keep=stratum lowertime uppertime 
hazard); 
proc lifetest data=endpt method=life intervals=30 90 120 150 180 210 240 
270 300 330 365; time FUdays*event(0); strata tx; run; quit; 
data life; set life; where hazard ne .;  
time=lowertime+(uppertime-lowertime)/2; keep stratum time hazard; run; 
proc export data=life outfile="life.csv" dbms=CSV replace; run; 
  
title "Basic model - Exponential"; 
proc lifereg data=endpt; model FUdays*event(0)=tx5fu / dist=exp; run; 
quit; 
 
 
Cox-Proportional Model: 
*CHECK PROPORTIONAL HAZARDS FOR TREATMENT*; 
title 'Basic model - Cox model with treatment*time interaction'; 
ods select ParameterEstimates; 
proc phreg data=endpt; where FUdays>0; 


Page 9 
 
      model FUdays*event(0)=tx int/ rl; 
      int=tx*log(FUdays); 
      Proportionality: test int; 
run; quit; 
  
proc phreg data=endpt; where FUdays>0; 
      model FUdays*event(0)=tx; 
      output out=propcheck ressch=schres; 
run; quit; 
proc sgplot data=propcheck; loess x=FUdays y=schres / clm; run; 
 
title "Basic model - Cox model"; 
proc phreg data=endpt; model FUdays*event(0)=tx / rl; 
run; quit; 
 
 
4.4. Evaluating Covariate Effects and Heterogeneity by Site 
 
First, we will identify potential confounding factors that are not balanced between the 
intervention groups and evaluate the possibilities of treatment by covariate effects.  This will 
be done by refiting the primary cox proportional hazard model with a vector of covariates 
included in the model. 
 
We will also fit a random effects or frailty model to investigate potential heterogeneity of 
effect due to site variability.  This will be accomplished by refitting the primary cox 
proportional hazard model with additional classification and random statements. 
title "Random Effects – Cox Model"; 
proc phreg data=endpt;  
class site tx;  
 
model FUdays*event(0)=tx / rl;  
random site; 
hazardratio “Frailty Model Analysis’ site; 
run; quit; 
 
 
4.5. Sensitivity Analysis 
 
The primary efficacy analysis will be repeated under 3 different scenarios as follows. 
 
(1) Randomization was stratified on two factors: (1) Bipolar or Major Depressive Disorder 
diagnosis, and (2) prior history of suicide attempt.  Cox Regression Model as described 
in section 4.3 will be refitted with the inclusion of diagnosis variable and suicide history 
variable in the model. 
(2) Primary efficacy analysis will be repeated on the “per-Protocol” sample with adherence 
as defined in section 3.4 to evaluate efficacy among those adherent to the protocol. 
(3) Primary efficacy analysis will be repeated on the modified ITT analytic cohort that 
excludes all randomized subjects who terminated prior to the first titration visit. 


Page 10 
 
 
4.6. Handling of Missing Data in Primary Analysis 
 
Up to 40% of subjects have been estimated to drop out over the course of follow up prior to 
end of study at 12 months after randomization. To account for complete data loss from 
attrition, evaluable sample size has been inflated by 20% accordingly. Distribution of 
subjects lost to follow-up and missing data on key variables across the treatment groups will 
be monitored throughout the study. 
 
All those who terminated early will be censored at the date of last visit or last contact and 
their time in the study from randomization to termination date will be considered in the 
primary analysis.  
 
The primary analysis assumes that data are missing at random.  This assumption will be 
tested by evaluating the distribution of missing data across the two treatment groups. 
Additionally, a Baysan sensitivity analysis utilizing Pattern Mixture Modelling approach will 
be performed to determine potential bias in inference from all possible non-random patterns 
of missing data. (Rybin et. al., 2015) 
 


Page 11 
 
 
5. Analysis Plan for Secondary Objectives 
 
 
5.1. Secondary Objective 
 
This trial has 5 secondary objects, which are described below.  Analyses for these 
objectives are exploratory in nature and as such, they are not statistically powered for formal 
hypothesis testing.  These objectives are to:   
1) explore the effectiveness of lithium augmentation of enhanced suicide prevention 
management in preventing separately: 
a. all-cause mortality 
b. impulsive suicide reattempts 
c. non-impulsive suicide reattempt 
d. non-suicidal self-directed violence 
2) explore heterogeneity of response to treatment subgroups including: 
a. categories of age, race/ethnicity, and gender 
b. diagnosis of depression vs. bipolar disorder  
c. impulsive index attempt vs. non-impulsive index attempt 
d. substance use vs. absence of substance use  
e. individuals with and without trait impulsivity  
f. individuals with and without trait aggression 
g. subjects who have vs. have not received evidence based psychotherapies 
3) explore the effect of lithium augmentation of enhanced suicide prevention management 
on total occurrence of all event types and cumulative occurrence of individual event type 
as follows: 
a. all suicide attempts 
b. all hospitalizations for prevention of suicide attempts 
c. all self-directed violence 
d. all emergency department visits 


Page 12 
 
4) explore longitudinally the effect of lithium augmentation of enhanced suicide prevention 
management on symptoms of bipolar disorder and depression and suicidal ideation 
5) explore mediators of the effect of lithium augmentation on prevention of suicide 
reattempt, specifically improved control of symptoms and lithium plasma levels 
 
5.2. Secondary Endpoints 
 
There are multiple secondary endpoints being considered for the study where endpoint 
events for  secondary objectives #1, 2, and 5 will be assessed as time to event outcomes, 
endpoint events for secondary objective # 3 will be assessed as count data, and endpoint 
events for Secondary Objective #4 will be evaluated as a binary outcome.  
 
For Secondary Objective #1, Time from randomization to death from any cause will be 
analyzed.  Additionally, self-directed violence as described in section 4.2 will be classified 
further as either impulsive or non-impulsive attempt based on Beck Suicide Intent Scale, 
(Question#15 on CRF-Form S8), and will be analyzed separately. Lastly, non-suicidal self-
directed violence behavior defined as the primary endpoint wihout the death from suicide  
will be considered as a separate outcome.   
 
For Secondary Objective #2 which evaluates efficacy in different subgroups, the primary 
endpoint as described in section 4.2 will be analyzed. 
 
The endpoint for Secondary Objective #3 considers all components of self-directed violence 
as described in section 4.2.  Therefore, a combined total of all episodes of all components of 
the primary outcome will be an endpoint, and total counts of each component, in addition to 
all emergency department visits will be separate endpoints. 
 
For Secondary Objective #4, dependent variables being considered longitudinally include (1) 
presence or absence of symptoms, and (2) presence or absence of suicidal ideation.  
Presence or absence of symptoms will be derived by the Internal State Scale (CRF-Form 
B8), and presence or absence of suicidal ideation will be derived from the Columbia Follow 
Up Questionnaire (CRF-Form B6).  
 
Lastly, for Secondary Objective #5, the endpoint event will be the same as the primary 
endpoint described in section 4.2.  
 
 
5.3. Statistical Methods for Secondary Analyses 
 
Secondary objective#1 will use a time to event, survival analysis to determine whether there 
is a treatment difference in event rates for each of the defined endpoints. The null 
hypothesis for each endpoint is that the two treatment groups do not differ in their hazard 


Page 13 
 
rates.  The alternative hypothesis is that the intervention group on lithium has a lower 
hazard rate than the placebo group.  As with the primary analysis, log-rank test and Cox 
proportional hazards models will be used. 
  
 
For secondary objective#2, the null hypothesis for each of the factors is that treatment effect 
does not differ over levels of the factor.  The alternative hypothesis is that there is differential 
treatment effect over levels of the factor.  Effect modification will be evaluated through 
regression methods.  Cox proportional hazards regression model will include the treatment 
term, a term for the target factor, and the interaction term of the two. If the null hypothesis is 
rejected at p=0.05 level, i.e., the interaction term in the model is statisticially significant, 
separate regression models will be refitted for each level of the factor. A forest plot will be 
used to display the results. 
 
For secondary objective#3,  the null hypothesis is that total event rates do not differ by 
treatment assignment, and the alternative hypothesis is that there is a difference in total 
event rates across treatment groups. We will use Generalize Linear Models (glm), namely 
Poisson regression, to model cumulative total of endpoint events with an offset for follow up 
time. 
 
For secondary objective#4, the null hypothesis is that change in symptoms and suicidal 
ideation in the lithium group is similar to that of the placebo group. The alternative 
hypothesis is that there is a difference in change across treatment groups over time. We will 
use Generalize Linear Models (glm), namely Logistic regression, to model presence or 
absence of symptoms and suicidal ideation at each follow up visit,while allowing for random 
effects of variation in symptoms of bipolar disorder and depression at baseline. 
 
Secondary objective#5 will be evaluated by Cox Proportional Hazard regression analysis 
method comparing regression coefficients for treatment effect in the models with and without 
the mediator (Sobel, 1982). Additionally, we will explore bootstrapping methods to evaluate 
mediators as described in MacKinnon et al.(2002), Preacher & Hayes (2008), and 
MacKinnon (2003). 


Page 14 
 
6. Analysis Plan for Tertiary Objectives 
 
 
6.1. Tertiary Objective 
 
Active follow up period for study subjects is 12 months after randomization. As a tertiary 
objective the study will obtain electronically available data up to the end of study recruitment 
and follow up period, which is 4 years from start of enrollment for the study. Data sources for 
this objective will be the Suicide Prevention and Application Network (SPAN) and VHA 
Corporate Data Warehouse (CDW). 
 
  Analyiss of this passively obtained data will be to:   
1) describe the pattern of Lithium use following active participation in the study participants,  
2) evaluate suicide reattempt and all cause mortality over a longer follow up period, and 
3) evaluate all cause mortality over a longer follow up period. 
 
 
6.2. Tertiary Endpoints 
 
For Teriary Objective #1  continued use (yes/no) of Lithium is the outcome event of interest.  
 
For Tertiary Objectives #2 the endpoint event is the same as the primary endpoint as 
described in section 4.2. 
 
For Tertiary Objective #3, death from any cause is the endpoint event.  
 
 
6.3. Statistical Methods for Tertiary  Analyses 
 
Tertiary objective#1 will be evaluated by descriptive analysis on duration of lithium use, and 
by regression methods on any lithium use within one month following active study 
participation.  The latter endpoint (continued use yes/no) will be modelled as a binary 
outcome to identify determinants and evaluate their association.   
 
Tertiary objectives #2 and #3 will be evaluated following the same analytic strategy as the 
primary analysis described in section 4.3. 


Page 15 
 
7. General Considerations 
 
 
7.1. Univariate and Bivariate Distributions 
 
In general, the number of observations, mean, median, standard deviation, minimum, and 
maximum will be calculated for continuous variables. The number of decimals places will be 
up to plus two decimal places. Frequencies and percentages will be calculated for 
categorical data. Distribution of continuous variables and proportions of categorical variables 
will be tabulated by treatment group, and t-test and chi-square tests will be performed to 
evaluate if these variables are balanced across the 2 intervention groups. 
Baseline is defined as the randomization visit. 
 
 
7.2. Description of Baseline Data  
 
Demographic details (e.g., age, sex, race, ethnicity, marital status, military service), medical 
history (e.g., co-morbidities), information on index attempt, psychometric measures, and 
baseline labs will be evaluated overall, by intervention group, by diagnosis of Bipolar 
Disorder or Major Depressive Disorder, and by enrollment site. 
 
 
7.3. Description of Follow-up Assessment Data 
 
Details on titration process, concomitant medications, pattern of service use, clinical events 
such as hospital re-admissions, emergency department admissions, suicide reattempts, 
psychometric measures, will be evaluated overall and by intervention group. 
 
 
7.4. Safety Data 
 
Safety information to be collected for this study include description of the event, distinction 
between serious and non-serious adverse event, severity and expectedness of the event, 
relatedness to the study intervention, and outcome of the event. In addition, data on all 
events will be classified using the Medical Dictionary for Regulatory Activities (MedDRA) 
(Version 9.0) coding dictionary. 
 
Safety data will be collected for all consented subjects from the date the first consent was 
signed up to 13 months post randomization for related non-serious adverse events, and all 
serious adverse events.  If the subject terminates from the study prior to 13 months post 
randomization date, collection of safety data will cease on termination date.  
 


Page 16 
 
For reporting to the DMC and inclusion in the final report safety data will be aggregated for 
the ITT analytic sample only as described in 3.3.  Data will be summarized as follows. 
 
 
Frequency and percentages of related non-serious and all serious adverse events 
overall and by intervention group 
 
Frequency and percentages of all unique subjects with non-serious and serious 
adverse events overall and by intervention group 
 
Rates of non-serious and serious adverse events overall, by intervention group, and 
by center, calculated as # events/ person-time in years 
 
Tabulation of event type, MEDRA classification, severity, expectedness, relatedness 
and outcome of all events overall and by intervention group 
 
Overall hospitalization, suicide reattempt, and mortality rates at 1year overall and by 
intervention group 
 
 
 


Page 17 
 
 
8. Data Monitoring Committee Reports 
 
Data and study progress will be monitored by the study executive committee and by the 
Data Monitoring Committee (DMC).  The DMC will review the study progress and safety 
semi-annually with additional meetings and communications as needed. All reports will be 
generated using SQL and SAS. 
 
 
8.1. Analytic Sample for DMC Reports 
 
All subjects randomized more than six weeks prior to the DMC meeting date will be included 
in the analytic cohort for the upcoming DMC report, and all data collected up to four weeks 
prior to the DMC meeting date will be analyzed. This allows for two weeks lag time for 
submission of data from sites. 
 
 
8.2. Algorithm 
 
Shell tables with annotated algorthim for creating the tables to be included in the DMC 
report are kept on the CSP590 Study Central file on Sharepoint in the Statistics and Data 
Management folder. These tables are updated as the study progresses and revisions are 
requested by the DMC members. 
 
 
8.3. Outline of DMC Reports 
   
The report is divided into four sections to cover subject disposition, baseline assessment, 
follow-up assessment, and safety assessment. The “Open Session” report includes 
summary tables that are not aggregated by treatment group (i.e., blinded data), and the 
“Closed Session” report includes summary tables for safety assessment that are aggregated 
by treatment groups (i.e., unblinded data). Following is the list of tables to be included within 
each of these 4 sections.  Revision to this list, if any, will be discussed at the first DMC 
meeting to be held within six months of the initiation of subject enrollment in the VA sites.   
 
 
8.3.1. 
Section A: Subject Disposition (OPEN SESSION ONLY) 
 
Figure A1. CONSORT Diagram for CSP590 
Table A2. Enrollment by site 
Figure A3. Enrollment by site 
Figure A4. Projected Enrollment 
Table A5. Form Completion, by Form Type 


Page 18 
 
Table A6. Form Completion, by Site 
Table A7. Protocol Deviations 
Table A8. Early Study Terminations 
 
 
8.3.2. 
Section B: Baseline Assessment (OPEN SESSION ONLY) 
 
Table B1. Demographics 
Table B10. Study Medication Adherence 
Table B11. Side Effects 
 
8.3.3. 
Section C: Follow-up Assessment (OPEN SESSION ONLY) 
 
Table C1. Study Outcomes 
Table C2. Columbia Follow-up – Repeat Attempts in Detail 
 
8.3.4. 
Section D: Safety Assessment (OPEN SESSION ONLY) 
 
Table D1. Rates of Non-Serious Related Adverse Events (NAEs), by site  
Table D2. Rates of Serious Adverse Events (SAEs), by site  
Table D3. Summary of Related Non-Serious Adverse Events  
Table D4. Summary of Serious Adverse Events (Form B15) 
 
 
8.3.5. 
Section D: Safety Assessment (CLOSED SESSION ONLY) 
 
Table D1. Rates of Non-Serious Related Adverse Events (NAEs), by Site and Treatment 
Table D2. Rates of Serious Adverse Events (SAEs), by Site and Treatment  
Table D3.  **Reported in OPEN SESSION only** 
Table D4. Summary of Serious Adverse Events (Form B15), by Treatment 
Table D5. Related Non-Serious Adverse Events by System Organ Class, by Treatment 
Table D6. Serious Adverse Events by System Organ Class, by Treatment 
Table D7. Deaths Reported, by Treatment  
 
 


Page 19 
 
9. Analytic Tables not included in the Data Monitoring Committee Reports 
 
Following analytic tables will be generated annually and made available to the study team, 
Upon request of the DMC at the intial meeting these tables will not be included in the DMC 
report.   
 
Table X1. Military Service 
Table X2. Medical and Psychiatric History 
Table X3. MINI Module Assessment 
Table X4. Baseline Physical Assessments  
Table X5. Baseline Laboratory Results  
Table X6. Baseline Psychiatric Measures 
Table X7. Baseline Substance Use (SCID-SUD) 
Table X8. Concomitant Medications 


Page 20 
 
10. Sample Size and Power 
 
CSP590 is targeted to enroll a total of 1862 subjects, and approximately 40% of the enrolled 
sample is expected to terminate early (i.e., 20% complete data loss), thereby resulting in an 
analytic sample of 1490 evaluable subjects.  With the evaluable study sample equally 
allocated to the 2 treatment arms, the study is powered to detect at least a 37% reduction in 
the one year outcome event rate. 
 
Expected event rates used in sample size estimation to achieve 90% statistical power for 
hypothesis testing were 15% re-attempt rate in the placebo group and 9.45% re-attempt rate 
in the lithium group. Justification for selecting these rates to estimate sample size and power 
are provided in the protocol. 
 
The results for the primary outcome measure will be analyzed by a two-sided log-rank test to 
detect either a hazards ratio that exceeds 1/0.61=1.64 or is less than 0.61, i.e., the test has 
90% power to detect a hazard ratio of 1.64 or larger or 0.61 or less. 
 
These estimations are adjusted for an O'Brien-Fleming stopping rule with one interim and 
one final test of hypothesis, and allow for an overall two-sided type I error of 5% for the 
hypothesis being tested.  Hence, the interim primary hypothesis will be tested at p=0.002 
level (allowing for 0.2% Type I error), and the final primary hypothesis will be tested at 
p=0.048 level (allowing for 4.8% Type I error). 
 
Tables 2 below consider three scenarios for possible shift in statistical power, specifically (a) 
in the event that an intervention effect different from the projected 37% reduction is 
observed, (b) in the event that the sample size for the study falls either above or below the 
targeted 1490 evaluable subject mark, and (c) in the event that the event rate is below the 
expected 15% in the placebo group. This study will have greater than 80% statistical power 
at 5% overall error if the observed effect is as low as 33% reduction, if the final evaluable 
sample is as low as 1200 subjects, or if we observe an event rate as low as 12% in the 
placebo group. 
 


Page 21 
 
Table 2: Evaluation of variability in Statistical Power assuming 5% Overall Type I error.  
 
 
(a) Change in statistical power for fixed sample size and a range of effect sizes  
 
 
 
Event Rates 
 
 
 
Evaluable 
N 
N 
per 
arm 
Placebo 
Active 
#Events 
Effect 
Power 
1490 
745 
15% 
11% 
190 
30% 
73% 
1490 
745 
15% 
10% 
188 
31% 
77% 
1490 
745 
15% 
10% 
187 
33% 
81% 
1490 
745 
15% 
10% 
185 
35% 
85% 
*1490 
745 
15% 
9.5% 
182 
37% 
90% 
1490 
745 
15% 
9% 
179 
40% 
94% 
 
 
(b) 
Change in statistical power for fixed effect size and a range of sample sizes  
 
 
Event Rates 
 
 
 
 
Effect 
Placebo 
Active 
Evaluable 
N 
N  
per 
arm 
#Events 
Power 
37% 
15% 
9.5% 
1700 
850 
208 
93% 
*37% 
15% 
9.5% 
1490 
745 
182 
90% 
37% 
15% 
9.5% 
1400 
700 
171 
88% 
37% 
15% 
9.5% 
1200 
600 
147 
83% 
37% 
15% 
9.5% 
1100 
550 
134 
79% 
37% 
15% 
9.5% 
1000 
500 
122 
75% 
 
 


Page 22 
 
(c) Change in statistical power for fixed effect and sample size and a range of event rates  
 
 
 
Event Rates 
 
 
 
Total 
N 
N 
per 
arm 
Placebo 
Active 
#Events 
Effect 
Power 
*1490 
745 
15% 
9.5% 
182 
37% 
90% 
1490 
745 
14% 
8.8% 
170 
37% 
88% 
1490 
745 
13% 
8.2% 
158 
37% 
85% 
1490 
745 
12% 
7.6% 
146 
37% 
82% 
1490 
745 
11% 
6.9% 
134 
37% 
78% 
1490 
745 
10% 
6.3% 
121 
37% 
73% 
 
*Highlight indicates parameters proposed in CSP590 
 
 
10.1. 
Interim Analysis 
 
We will conduct one interim analysis after half of the participants have completed their 12 
month follow up. This analysis is projected to take place approximately 2.5 years after 
initiation of enrollment (assuming it will take 1.5 years to enroll half the sample and allow 12 
months of follow-up).  After adjusting for attrition, a sample of 746 evaluable subjects, (373 
in each group), is expected to be included in the analysis. 
 
Projecting the same event rate in this sub-sample we expect to observe a 15%  or 112 
events (56 events in each group) under the interim null hypothesis that event rates are equal 
in the treatment groups.  Under the interim alternative hypothesis, the absolute reduction 
from 15% to 5.3% is (15-5.3) = 9.7%, the relative reduction is (15-5.3)/15 = 65%, and the 
hazard ratio (treatment hazard rate/control hazard rate) is 0.34. The interim log-rank test is 
two-sided, and the interim null hypothesis will be rejected if the hazard ratio exceeds 1/0.34= 
2.94 or falls below 0.34. Using the O'Brien-Fleming procedure, (Turnbull & Jennison, 2000), 
this analysis will have a Type I error of 0.2%. 
 
We will confer with the Data Monitoring Committee members and the program leadership for 
potential stopping guidelines based on results from interim efficacy analysis. 
 
 


Page 23 
 
10.2. 
Futility Analysis 
 
As a part of the interim futility analysis we will estimate the conditional probability (CP) of 
observing a significant final result based on assumptions about the distribution of future 
event rates. Assumptions for  additional data to be collected in the second half of the study 
are:   
 
(1) 
“no-change” scenario where future event rates will occur at the same rate as 
currently observed rates,  
(2) 
“expected” scenario where future event rates occur at the rates expected at the 
beginning of the trial (i.e., as proposed in the protocol),  
(3) 
“extreme” scenario where future event rates occur at the currently observed 
overall event rate, but all new events occur in the placebo group so as to set the 
best scenario for achieving a significant difference. 
 
For conditional probability estimation, we will use the estimation method developed by 
Proschan, Lan, and Wittes,2006 and further described by Jitlal et. al, 2012, where  
CP at a specific time=1–ϕ[(Zα/2–E[B(1)|B(t)])/√1−t], 
E[B(1)|B(t)] is the expected value of B(t) at the end of the trial (when t=1), given 
the data observed until point t.  
The information fraction, t, is the number of observed events so far, expressed as a 
proportion of the planned number of events. 
  


Page 24 
 
 
11. Final Statistical Report 
 
The final statistical report for CSP590 will be the submitted and accepted primary 
manuscript which includes results from the primary ITT analysis as outlined in section 4 and 
any addiitonal analyses to be conducted based on the journal's peer review process.  
At minimum, the final statistical report will include the CONSORT diagram (section 8.3.1), 
descriptive characteristics of the ITT cohort (section 8.3.2), medical and psychiatric history 
of the cohort (sectiion 9), and the primary analysis results (sectiion 4.3). 
 
 


Page 25 
 
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MacKinnon, D. P.; Lockwood, C. M. Hoffman, J.  M., West S. G., Sheets V. A Comparison of 
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Preacher, K. J.; Hayes, A. F. Asymptotic and resampling strategies for assessing and 
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Proschan MA, Lan KKG, Wittes JT (2006) Statistical Monitoring of Clinical Trials: A Unified 
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Shigemasu K, Kano Y, Meulman JJ, editors. New Developments in Psychometrics: 
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