Randomized Placebo Controlled Trial of High Dose Intravenous Thiamine for the Prevention of Delirium in Allogeneic Hematopoietic Stem Cell Transplantation
Phase: PHASE2
Conditions: Hematopoietic Stem Cell Transplantation, Delirium, Thiamine Deficiency
Sponsor: UNC Lineberger Comprehensive Cancer Center

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
April 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #__8__ 
 
 
LCCC 1726: Randomized Placebo Controlled Trial of High Dose Intravenous 
Thiamine for the Prevention of Delirium in Allogeneic Hematopoietic Stem Cell 
Transplantation 
 
NCT03263442 
 
Date Reviewed: 12/30/2020 
 
Last Modified: 3/26/2020 
 
AMENDMENT INCORPORATES (check all that apply): 
_X_ Editorial, administrative changes 
___ Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
 
 
Editorial, administrative changes 
(1) The version date was updated throughout the protocol 
(2) In Sections 5.8 and 7.5 we have broadened allowable methods of follow-up 
assessment to include email and online, in addition to in-person assessment, mail, 
video conferencing, and over the phone. This enhances our ability to complete 
study assessments and questionnaires whenever possible in cases that in-person 
assessments (preferred method) are restricted or prohibited. 
(3) In Section 7.5 we have modified the follow-up assessment schedule to allow for 
the three-month follow-up to be completed within four weeks of the specified 
time point and the six-month follow-up to be completed within 2 months of the 
specified time point. While we will make every attempt to schedule assessments 
on their ideal dates, this will allow us more flexibility in scheduling in light of 
COVID-19 policy. 
 
Per the PRC Coordinator, this amendment is exempt from PRC review.  
 
 
 
 
THE ATTACHED VERSION LAST MODIFIED __3/16/20__ INCORPORATES THE 
ABOVE REVISIONS 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
April 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
 
PROTOCOL AMENDMENT #__7__ 
 
 
 
LCCC 1726: Randomized Placebo Controlled Trial of High Dose Intravenous 
Thiamine for the Prevention of Delirium in Allogeneic Hematopoietic Stem Cell 
Transplantation 
 
AMENDMENT INCORPORATES (check all that apply): 
_X_ Editorial, administrative changes 
___ Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
 
 
Editorial, administrative changes 
(1) The version date was updated throughout the protocol 
(2) We have removed Thomas Shea, MD as a co-investigator given his retirement 
from UNC. 
 
Per the PRC Coordinator, this amendment is exempt from PRC review.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED __1/14/20__ INCORPORATES THE ABOVE 
REVISIONS 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
April 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
PROTOCOL AMENDMENT #__6__ 
 
 
LCCC 1726: Randomized Placebo Controlled Trial of High Dose Intravenous 
Thiamine for the Prevention of Delirium in Allogeneic Hematopoietic Stem Cell 
Transplantation 
 
AMENDMENT INCORPORATES (check all that apply): 
_X_ Editorial, administrative changes 
___ Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
 
 
Editorial, administrative changes 
(1) The version date was updated throughout the protocol 
(2) In Sections 1.1, 4.1, 5.1, 7.2, and 9.1 we have modified language to expand 
recruitment to the outpatient setting prior to planned allogeneic bone marrow 
transplant, in addition to after patients are admitted. This allows us to have 
additional time to secure formal insurance authorization prior to randomizing 
participants to our study drug. 
 
Per the PRC Coordinator, this amendment is exempt from PRC review.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED __8/13/19__ INCORPORATES THE ABOVE 
REVISIONS 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
April 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
 
PROTOCOL AMENDMENT #__5__ 
 
 
LCCC 1726: Randomized Placebo Controlled Trial of High Dose Intravenous 
Thiamine for the Prevention of Delirium in Allogeneic Hematopoietic Stem Cell 
Transplantation 
 
AMENDMENT INCORPORATES (check all that apply): 
_X_ Editorial, administrative changes 
___ Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
 
 
 
Editorial, administrative changes 
(1) The version date was updated throughout the protocol 
(2) In Sections 5.8 and 7.5 we have broadened allowable methods of follow-up 
assessment to include video conferencing, in addition to in-person assessment, 
mail, and over the phone. 
(3) In Section 7.5 we have modified the follow-up assessment schedule to allow for 
the six-month follow-up to be completed within 1 month of the specified time 
point. This enhances our ability to complete assessments in-person (preferred 
method). 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED __1/10/19__ INCORPORATES THE ABOVE 
REVISIONS 
 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
April 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT #__4__ 
 
 
LCCC 1726: Randomized Placebo Controlled Trial of High Dose Intravenous 
Thiamine for the Prevention of Delirium in Allogeneic Hematopoietic Stem Cell 
Transplantation 
 
AMENDMENT INCORPORATES (check all that apply): 
_X_ Editorial, administrative changes 
_X_ Scientific changes (IRB approval) 
_X_ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
 
Editorial, administrative changes 
(1) The version date was updated throughout the protocol 
(2) In Sections 5.8 and 7.5 we have broadened allowable methods of follow-up 
assessment to include mail, in addition to in person assessment and over the 
phone. 
(3) All personnel, except for the Principal Investigator, Co-Investigators, and 
Biostatistician have been removed from the cover sheet to limit future protocol 
amendments related only to staff changes, as recommended by the Protocol 
Review Committee Compliance Coordinator 
(4) A minor error in Table 7.1 was corrected.  Specifically, in the legend “c.” was 
previously incorrectly attributed to the DRS and “d.” to the longitudinal measures. 
(5) Throughout the protocol, we have modified the delirium assessment schedule to 
specify that delirium assessments will be performed at one, three, and six months 
after transplant for patients who develop delirium in the inpatient phase. This 
modification was made to ensure that delirium has resolved before completion of 
longitudinal follow-up measures.  
(6) Throughout the protocol, we have modified plan to continue recruitment until we 
have 60 evaluable participants to account for subjects who do not meet criteria for 
efficacy analysis (as described in Section 7.11) and will subsequently be replaced. 
 
Scientific changes 
(1) In Section 7.11 we have modified the requirements for efficacy assessment to 
stipulate that patients must have delirium assessed at least weekly during 
hospitalization, until any of the following have occurred: 1.) they develop 
delirium (primary endpoint); 2.) they are discharged; or 3.) they reach 30 days 
post-transplant.  
 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
April 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
Therapy changes 
(1) Throughout the protocol, the preparation of our intervention was changed 
from Thiamine 200 mg diluted in 25 mL 0.9% normal saline to Thiamine 200 
mg diluted in 100 mL 0.9% normal saline.  Our placebo was changed from 25 
mL 0.9% normal saline to 100 mL 0.9% normal saline to maintain blinding.  
The intervention will be administered over 30 minutes.  No changes were 
made to strength, route (intravenous), frequency (TID), or duration (seven 
days).  This modification was made in response to the nation-wide IV bag 
shortage following the hurricane in Puerto Rico.  This modification in no way 
increases risk to subjects. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED __9/4/18__ INCORPORATES THE ABOVE 
REVISIONS 
 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
April 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT #__3__ 
 
 
LCCC 1726: Randomized Placebo Controlled Trial of High Dose Intravenous 
Thiamine for the Prevention of Delirium in Allogeneic Hematopoietic Stem Cell 
Transplantation 
 
AMENDMENT INCORPORATES (check all that apply): 
_X_ Editorial, administrative changes 
_X_ Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
 
Editorial, administrative changes 
(1) The version date was updated throughout the protocol 
 
Scientific changes 
(1) Throughout the protocol, we have modified the delirium assessment schedule 
to acknowledge that there are certain situations, due to an acute medical 
concern (e.g. intubation, sedation, etc.), in which patients are not evaluable for 
the purposes of this study and the DRS will not be performed. 
(2) In Section 7.11 Assessment of Efficacy we have added the phrase “in 
evaluable patients” to account for acute medical concerns that prevent 
participants from being evaluated, as described above. 
(3) Throughout the protocol, we have modified the delirium assessment schedule 
to specify that when patients develop delirium, delirium assessments will be 
performed daily “when scheduling permits”.  This allows for greater 
flexibility for this non-primary outcome (duration of delirium). 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED __1/10/18__ INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
April 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT #__2__ 
 
 
LCCC 1726: Randomized Placebo Controlled Trial of High Dose Intravenous 
Thiamine for the Prevention of Delirium in Allogeneic Hematopoietic Stem Cell 
Transplantation 
 
AMENDMENT INCORPORATES (check all that apply): 
_X_ Editorial, administrative changes 
_X_ Scientific changes (IRB approval) 
_X_ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
 
Editorial, administrative changes 
(1) The version date was updated throughout the protocol 
 
Scientific changes 
(1)  Throughout the protocol, modified schedule of thiamine levels from days 1, 
8, 15, 22, and 29 post-transplant to allow for levels to be drawn up to one day 
earlier or later of this specified schedule.  This allows capture of thiamine 
levels currently missed in patients who are discharged the day before their 
anticipated next thiamine level lab draw. 
 
Therapy changes 
(2) Throughout the protocol, the preparation of our intervention was changed 
from Thiamine 200 mg diluted in 100 mL 0.9% normal saline to Thiamine 
200 mg diluted in 25 mL 0.9% normal saline.  Our placebo was changed from 
100 mL 0.9% normal saline to 25 mL 0.9% normal saline to maintain 
blinding.  The intervention will be administered over 30 minutes.  No changes 
were made to strength, route (intravenous), frequency (TID), or duration 
(seven days).  This modification was made in response to a severe national 
shortage of 100 mL bags related to the hurricane in Puerto Rico.  This 
modification in no way increases risk to subjects. 
 
 
 
 
 
 
THE ATTACHED VERSION DATED __11/16/17__ INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
April 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT #__1__ 
 
 
LCCC 1726: Randomized Placebo Controlled Trial of High Dose Intravenous 
Thiamine for the Prevention of Delirium in Allogeneic Hematopoietic Stem Cell 
Transplantation 
 
AMENDMENT INCORPORATES (check all that apply): 
_X_ Editorial, administrative changes 
_X_ Scientific changes (IRB approval) 
_X_ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
 
Editorial, administrative changes 
(1) The version date was updated throughout the protocol 
(2) Stephanie Chien added as the study coordinator 
(3) Section 7.9.  Samples will be drawn by nurses rather than phlebotomists and 
stored in McLendon laboratory.  This modification in no way increases risk to 
subjects, but only reflects the actual workflow on the Bone Marrow 
Transplant Unit. 
 
Scientific changes 
(1) Throughout the protocol, Medical/Surgical Tracking Form is omitted, as it 
was overly inclusive and not necessary to accomplish the study’s aims.  In its 
place, a Delirium Risk Factor Form has been added, which will document 
previous history of delirium, alcohol and substance use, and neurological 
conditions (stroke, traumatic brain injury, seizures, abnormal brain imaging 
findings) from chart abstraction. 
(2) Throughout the protocol, revised baseline labs to no longer include folate and 
vitamin B12.  These are also not necessary to accomplish the study’s aims and 
not typically drawn on patients undergoing hematopoietic stem cell 
transplantation (HSCT). 
(3) Throughout the protocol, revised schedule of baseline labs (CBC, CMP, Mg, 
Phos) to within 2 days of transplant, rather than specifically on post-transplant 
day 1.  These labs are routinely drawn on Mondays and Thursdays, so this 
modification prevents additional blood draws, thereby improving nursing 
workflow and minimizing patient burden. 
(4) Class of concurrent CNS active medications will continue to be documented, 
but throughout the protocol revised to indicate that details regarding dose, 
route, frequency, and indication will no longer be captured, as this data will 
not be necessary to accomplish the study’s aims. 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
April 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
(5) The four yes/no questions of the PTSS-14 have been removed, as the results 
from these four questions are not used in calculating the total score, not 
typically reported in the literature, and are more appropriate for ICU settings, 
which the scale was originally designed for.  This modification is reflected in 
Appendix E and does not necessitate modification in other areas of the 
protocol. 
(6) Section 5.2.  Language added to explicitly reflect that the PI, primary medical 
providers, or other emergency personnel may request unblinding of a subject’s 
randomized treatment from the IDS pharmacy.  
 
 
 
Therapy changes 
(1) Throughout the protocol, the preparation of our intervention was changed 
from Thiamine 200 mg in a 2 mL syringe to Thiamine 200 mg diluted in 100 
mL 0.9% normal saline.  Our placebo was changed from 2 mL of 0.9% 
normal saline to 100 mL 0.9% normal saline to maintain blinding.  The 
intervention will be administered over 30 minutes, rather than the four 
minutes described in the previous version of this protocol.  No changes were 
made to strength, route (intravenous), frequency (TID), or duration (seven 
days).  This modification was made to improve nursing workflow, as it is not 
practical for them to administer the syringe by hand at 50 mg/min as outlined 
in the previous version of the protocol.  This modification in no way increases 
risk to subjects. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED __9/14/17__ INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
April 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC  1726: 
Randomized Placebo Controlled Trial of High Dose Intravenous Thiamine for the 
Prevention of Delirium in Allogeneic Hematopoietic Stem Cell Transplantation 
 
Short Title: High Dose Intravenous Thiamine for the Prevention of Delirium in Allogeneic 
Hematopoietic Stem Cell Transplantation 
 
Principal Investigator 
Zev Nakamura, MD 
101 Manning Drive 
Campus Box 7160 
Chapel Hill, NC 27599 
984-974-3829 (PHONE) 
984-974-9646 (FAX) 
Email: zev_nakamura@med.unc.edu 
 
Medical Monitor 
Zev Nakamura, MD 
984-974-3829 (PHONE) 
919-216-3157 (PAGER) 
Email: zev_nakamura@med.unc.edu 
 
Co-Investigator(s) 
Donald Rosenstein, MD 
3134 Physician’s Office Building 
170 Manning Drive 
Campus Box 7305 
Chapel Hill, NC 27599-7305 
919-843-8895 (PHONE)  
919-966-6735 (FAX) 
Email: donald_rosenstein@med.unc.edu 
 
William Wood, MD, MPH 
3147 Physician’s Office Building 
170 Manning Drive 
Campus Box 7305 
Chapel Hill, NC 27599-7305 
919-966-4431 (PHONE) 
919-843-5945 (FAX) 
Email: william_wood@med.unc.edu 
 
Eliza Park, MD 
3135 Physician’s Office Building 
170 Manning Drive 
Campus Box 7305 
Chapel Hill, NC 27599-7305 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
April 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
919-966-4772 (PHONE)  
919-966-6735 (FAX) 
Email: leeza_park@med.unc.edu 
 
Biostatistician  
Allison Deal, MS 
Biostatistics and Data Management, Rm 20-024 
Lineberger Comprehensive Cancer Center 
Campus Box 7295 
Chapel Hill, NC 27599-7295 
919-966-1387 (PHONE)  
919-966-4244 (FAX) 
Email: allison_deal@med.unc.edu 
 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
 
Funding Source: Rising Tide Foundation for Clinical Cancer Research 
 
Version 1 Date: 6/21/2017 
Version 2 Date: 9/14/2017 
Version 3 Date: 11/16/2017 
Version 4 Date: 1/10/2018 
Version 5 Date: 9/4/2018 
Version 6 Date: 1/10/2019 
Version 7 Date: 8/13/2019 
Version 8 Date: 1/14/2020 
Version 9 Date: 3/16/2020 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
April 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC 1726: 
Randomized Placebo Controlled Trial of High Dose Intravenous Thiamine for the 
Prevention of Delirium in Allogeneic Hematopoietic Stem Cell Transplantation 
 
Principal Investigator 
Zev Nakamura, MD 
101 Manning Drive 
Campus Box 7160 
Chapel Hill, NC 27599 
984-974-3829 (PHONE) 
984-974-9646 (FAX) 
Email: zev_nakamura@med.unc.edu 
 
 
 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal regulations 
and ICH guidelines.  
 
Principal Investigator (PI) Name:____Zev Nakamura M.D._______ 
 
PI Signature: ___
_______________ 
 
Date:_____3/16/2020________ 
 
Version date: 3/16/2020 
 
 
 

LCCC XXXX 
 
CONFIDENTIAL 
PI: Zev Nakamura 
 
UNIVERSITY OF NORTH CAROLINA 
 
 
 
April 2017 
 
i 
TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ..................................................................4 
1.1 
Study Synopsis ......................................................................................................4 
1.2 
Disease Background ..............................................................................................4 
1.3 
Current Standard of Care.......................................................................................6 
1.4 
High Dose Intravenous Thiamine .........................................................................6 
1.5 
Rationale for Clinical Study ..................................................................................7 
2.0 
STUDY OBJECTIVES ...........................................................................................7 
2.1 
Primary Objectives ................................................................................................7 
2.2 
Secondary Objectives ............................................................................................7 
3.0 
Criteria for Evaluation / Study Endpoints ...........................................................8 
3.1 
Primary Endpoint ..................................................................................................8 
3.2 
Secondary Endpoints .............................................................................................8 
4.0 
PATIENT ELIGIBILITY ......................................................................................8 
4.1 
Inclusion Criteria ...................................................................................................8 
4.2 
Exclusion Criteria ..................................................................................................8 
5.0 
TREATMENT PLAN .............................................................................................9 
5.1 
Schema ..................................................................................................................9 
5.2 
Treatment Dosage and Administration .................................................................9 
5.3 
Toxicities and Dosing Delays .............................................................................10 
5.4 
Usual Care ...........................................................................................................10 
5.5 
Prohibited Medications/Treatments ....................................................................11 
5.6 
Duration of Therapy ............................................................................................11 

LCCC XXXX 
 
CONFIDENTIAL 
PI: Zev Nakamura 
 
UNIVERSITY OF NORTH CAROLINA 
 
 
 
April 2017 
 
ii 
5.7 
Duration of Follow Up ........................................................................................11 
5.8 
Study Withdrawal ................................................................................................11 
5.9 
Study Questionnaires...........................................................................................12 
6.0 
DRUG INFORMATION ......................................................................................13 
6.1 
Thiamine Description and Management .............................................................13 
7.0 
EVALUATIONS AND ASSESSMENTS ............................................................14 
7.1 
Time and Events Table ........................................................................................14 
7.3 
Randomization ....................................................................................................15 
7.4 
Post-Transplant Days 1 – 30 Assessments ..........................................................15 
7.5 
Long-term Follow-Up Assessments ....................................................................16 
7.6 
Concurrent CNS Active Medications ..................................................................16 
7.7 
Demographics......................................................................................................16 
7.8 
Delirium Risk Factors .........................................................................................16 
7.9 
Handling of Biospecimens Collected for Correlative Research..........................16 
7.10 
Assessment of Safety ..........................................................................................17 
7.11 
Assessment of Efficacy .......................................................................................17 
8.0 
ADVERSE EVENTS ............................................................................................18 
8.1 
Definitions ...........................................................................................................18 
8.2 
Documentation of non-serious AEs or SARs ......................................................19 
8.3 
SAEs or Serious SARs ........................................................................................20 
8.4 
Adverse Event Reporting ....................................................................................20 
8.5 
Data and Safety Monitoring Plan ........................................................................20 
9.0 
STATISTICAL CONSIDERATIONS ................................................................21 
9.1 
Study Design/Study Endpoints ...........................................................................21 

LCCC XXXX 
 
CONFIDENTIAL 
PI: Zev Nakamura 
 
UNIVERSITY OF NORTH CAROLINA 
 
 
 
April 2017 
 
iii 
9.2 
Sample Size, Accrual and Duration of Accrual ..................................................22 
9.3 
Data Analysis Plans .............................................................................................22 
10.0 STUDY MANAGEMENT ....................................................................................23 
10.1 
Institutional Review Board (IRB) Approval and Consent ..................................23 
10.2 
Required Documentation.....................................................................................24 
10.3 
Registration Procedures.......................................................................................24 
10.4 
Data Management and Monitoring/Auditing ......................................................24 
10.5 
Adherence to the Protocol ...................................................................................25 
10.6 
Amendments to the Protocol ...............................................................................26 
10.7 
Record Retention .................................................................................................26 
10.8 
Obligations of Investigators ................................................................................26 
11.0 REFERENCES ......................................................................................................28 
12.0 APPENDICES .......................................................................................................36 

LCCC XXXX 
 
CONFIDENTIAL 
PI: Zev Nakamura 
 
UNIVERSITY OF NORTH CAROLINA 
 
 
 
April 2017 
 
4 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
This is a randomized double-blind controlled trial in participants undergoing 
allogeneic hematopoietic stem cell transplantation (HSCT) to determine if high 
dose intravenous (IV) thiamine can prevent delirium and minimize the deleterious 
impact of delirium on health-related quality of life (HRQOL), functional status, 
and other neuropsychiatric outcomes.  We will recruit 60 evaluable patients 
scheduled for allogeneic HSCT at UNC, randomize them to treatment with high 
dose IV thiamine (n = 30) versus placebo (n = 30), and systematically evaluate all 
participants for delirium and related comorbidities.  We will use the Delirium 
Rating Scale (DRS) to measure the severity and duration of delirium immediately 
prior to transplant and after HSCT until 30 days post-transplant or discharge.  We 
will obtain thiamine levels and other laboratory parameters associated with 
delirium the day after transplant, and continue to monitor thiamine levels weekly 
thereafter.  We will also monitor HRQOL (FACT-BMT), functional status 
(ECOG-PS), depression (PROMIS-D), post-traumatic stress symptoms (PTSS-
14), and cognitive function (MOCA) prior to transplant and at one, three, and six 
months after transplant to elucidate the persistent impact of delirium in this 
population and the potential for thiamine to mitigate these negative outcomes. 
1.2 
Disease Background 
Delirium is a highly prevalent and potentially preventable neuropsychiatric 
condition with major health consequences in cancer patients.  Delirium is seen in 
25 – 40% of cancer patients,1,2 and in those with late-stage and terminal cancers 
the prevalence may be as high as 85%.3  Delirium is associated with increased 
length of stay,4 elevated mortality,5 impaired activities of daily living,6 and has 
profound immediate and long-term impact on mental health with studies 
demonstrating persistent symptoms of depression,7 post-traumatic stress,8 and 
impaired cognition.9  Cancer patients undergoing HSCT are at even higher risk 
given that they typically present with advanced disease and have already received 
one or more courses of systemic chemotherapy.  In the only two studies to 
evaluate the epidemiology of delirium in HSCT patients, delirium was described 
in at least 40%, and possibly as many as 73%, of patients during post-transplant 
hospitalization.10,11  Delirium in HSCT patients confers worse HRQOL, more 
severe distress, poor cognitive outcomes, and a 14-fold greater mortality rate.9,11  
In sum, delirium in cancer patients, particularly those receiving HSCT, is 
extremely common, has major medical and neuropsychiatric consequences that 
persist even after the delirium has resolved, and, therefore, demands efforts to 
prevent its occurrence. 
 
Thiamine deficiency is an underappreciated cause of delirium.  Wernicke’s 
encephalopathy (WE) is a condition, most commonly but not exclusively 
associated with alcoholism, in which thiamine deficiency leads to a triad of 

LCCC XXXX 
 
CONFIDENTIAL 
PI: Zev Nakamura 
 
UNIVERSITY OF NORTH CAROLINA 
 
 
 
April 2017 
 
5 
clinical signs (ophthalmoplegia, ataxia, and mental status changes).  Because its 
diagnosis requires a high index of suspicion and reliance on complex clinical 
findings, more than 80% of cases of the closely related Wernicke-Korsakoff 
Syndrome (WKS) go undiagnosed during patients’ lifetimes.12-14   Of note, WKS 
refers to the spectrum of neuropsychiatric conditions that result from thiamine 
deficiency, which includes WE as well as Korsakoff’s syndrome, an irreversible 
dementia with marked anterograde amnesia.  Only in the past 20 years have 
clinicians and researchers become aware of the potential for thiamine deficiency 
to impact mental status and lead to delirium without the other physical signs of 
WE.15  Accordingly, the precise incidence of delirium due to thiamine deficiency 
is not known.   However, this connection, specifically in cancer patients, is 
rapidly evolving.  A recent retrospective study, for example, reported that 
thiamine deficiency occurred in 55% of cancer patients, 80% of whom 
demonstrated some mental status abnormality.16    
 
HSCT patients are particularly vulnerable to thiamine deficiency.  In the only 
study to systematically monitor thiamine levels in cancer patients undergoing 
HSCT, 100% of patients developed thiamine deficiency during post-transplant 
hospitalization.17   There are several pathways by which HSCT patients become 
thiamine deficient.  First, less thiamine is absorbed from the diet due to anorexia 
and vomiting common with many cancers and their treatments.18  Second, there is 
increased metabolism of thiamine secondary to rapid cell turnover inherent in 
hematologic malignancies and complications after transplant, such as graft versus 
host disease (GvHD) and infection.  Finally, chemotherapies and calcineurin 
inhibitors, commonly administered during hospitalization for HSCT, impair 
conversion of thiamine to its biologically active form.18,19  There is insufficient 
data regarding relative incidences of thiamine deficiency or delirium in allogeneic 
vs. autologous transplants.  However, allogeneic transplant recipients do display 
increased mortality and morbidity, including outcomes such as infection and 
GvHD, known to increase risk of thiamine deficiency, potentially making them an 
even greater risk group.11,20,21  Therefore, while thiamine deficiency is unlikely to 
be the sole source of delirium in HSCT patients, it appears to be a universal and 
treatable one. 
 
High dose IV thiamine is a promising intervention for delirium in cancer patients 
undergoing HSCT.  Currently, there is no established way to treat or prevent 
delirium in this patient population.  Standard approaches for delirium 
management, including use of antipsychotics, are limited by potentially life-
threatening side effects in the medically ill.  Treatment of suspected thiamine-
related mental status changes with high dose IV thiamine, defined as at least 200 
mg three times daily, has preliminary evidence for improving a variety of 
cognitive symptoms.22-25  Unfortunately, delirium due to thiamine deficiency is 
often missed entirely or diagnosed late in the course of delirium, leading to 
treatment delays, after patients have been put at risk for immediate and long-term 
consequences of delirium.  This highlights the need for prophylaxis strategies, but 
surprisingly, the use of high dose IV thiamine has never been studied for the 

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prevention of delirium in any condition, including in this highly vulnerable HSCT 
population. 
1.3 
Current Standard of Care 
Currently, there is no standard of care for the prevention or treatment of delirium 
in HSCT patients.  There is also no consensus regarding dose for treatment or 
prophylaxis of delirium specifically due to thiamine deficiency, but it is generally 
dosed at ≥ 50 mg IV or intramuscularly (IM) daily.26  An unpublished electronic 
medical record review from our group, investigating thiamine prescribing 
practices at UNC Hospitals between 4/4/2014 and 11/1/2015, described over 
5,000 prescriptions for thiamine.  Of these, 29% (N = 1531) were given IV with 
41% (N = 633) of IV prescriptions for doses 200 mg or greater.  This same study 
described 432 subjects who had delirium and received IV thiamine.  Only 15 
subjects with delirium received at least 200 mg IV three times daily (tid).  
1.4 
High Dose Intravenous Thiamine 
For this trial we have chosen to study the effects of high dose IV thiamine.  
Parenteral thiamine administration has been well studied in large population 
samples and shown to be safe with the most common adverse effects being 
immediate, transient burning at the injection site (1.02%) and pruritis (<0.1%).27-
29  Other side effects are sufficiently rare that rates of occurrence are not 
available. 
 
Thiamine (vitamin B1) is a water soluble vitamin.  It is an important cofactor in 
the Kreb’s Cycle and Pentose Phosphate Pathway, thus critical for metabolism of 
lipids, glucose, amino acids, and neurotransmitters.   It is absorbed by an energy-
dependent active transport system in the gut, which limits absorption such that no 
more than 4.5 mg thiamine is absorbed for oral doses 50 mg or greater.28  It 
reaches the brain across the blood brain barrier through facilitated diffusion, 
active transport across the choroid plexus, and simple diffusion mechanisms.  
Thiamine has FDA indications for Wernicke’s encephalopathy and the related 
Wernicke-Korsakoff syndrome, thiamine deficiency, administration of dextrose-
containing fluids, berberi, and peripheral neuritis in pregnancy.30  It is 
metabolized in the liver (exact mechanism not known) and excreted in the kidney.   
 
There have not been any studies investigating its use specifically in HSCT 
patients.   The longstanding recommendation for treatment of WE in the United 
States is 100 mg IV daily.  This is based on estimates from experts, developed 
over 50 years ago, of what might constitute high doses.  There have been no 
clinical studies validating the efficacy of this dosing strategy.22,23,31 Though the 
most recent Cochrane review on the subject stated that there was insufficient 
evidence regarding dose, frequency, route, or duration of thiamine for treatment 
or prophylaxis of WE and related syndromes,26 there are currently two sets of 
guidelines recommending at least 200 mg IV tid from the European Federation of 
Neurologic Society (EFNS) and Royal College of Physicians (RCP).28,32  This 

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dosing strategy has demonstrated efficacy in several case reports.22-25  The only 
existing randomized controlled trial investigating the dose response of thiamine 
on improving mental status abnormalities, revealed that subjects treated with the 
highest dose studied, 200 mg IM, performed best on one measure of working 
memory.33    
 
1.5 
Rationale for Clinical Study 
Delirium occurs in at least 40%, and up to 73%, of patients undergoing HSCT.10,11  
Delirium is associated with longer length of stay,4 increased mortality,5 impaired 
activities of daily living,6 and can have profound immediate and long-term effects  
on mental health with studies demonstrating lasting symptoms of depression,7 
post-traumatic stress,8 and impaired cognition.9   
 
Thiamine deficiency is an underappreciated cause of delirium.  Thiamine 
deficiency has been reported in 100% of patients undergoing HSCT.17  The co-
occurrence of delirium and thiamine deficiency in HSCT is not known, but in 
cancer patients more broadly thiamine deficiency occurred in 55% of patients, 
80% of whom demonstrated some mental status abnormality.16  There are not 
sufficient data to support a specific dosing strategy for thiamine repletion to target 
delirium due to thiamine deficiency in any patient population,26 and no published 
studies investigating treatment or prophylaxis of delirium due to thiamine 
deficiency in HSCT patients. 
 
In this double-blind, randomized controlled trial, we examine the use of high dose 
IV thiamine to prevent occurrence and decrease severity and duration of delirium.  
Our study design also allows for additional novel data on the temporal 
relationship between thiamine deficiency and delirium in HSCT patients.    
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 To compare delirium incidence between recipients of high dose IV 
thiamine and placebo during hospitalization for allogeneic HSCT.   
2.2 
Secondary Objectives  
2.2.1  To compare delirium severity between recipients of high dose IV thiamine 
and placebo during hospitalization for allogeneic HSCT.   
 
2.2.2 To compare delirium duration between recipients of high dose IV thiamine 
and placebo during hospitalization for allogeneic HSCT.   
 
2.2.3 To determine if thiamine status is predictive of subsequent delirium onset.   
 

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2.2.4 To investigate the effects of high dose IV thiamine on long-term health-
related quality of life (HRQOL), functional status, depression, post-traumatic 
stress symptoms, and cognitive functioning in patients who undergo HSCT.   
 
3.0 
Criteria for Evaluation / Study Endpoints  
3.1 
Primary Endpoint 
Delirium incidence will be defined as:  DRS > 12.  Delirium rating scales will be 
performed at baseline (prior to transplant) and then three times weekly from day 
after transplant to 30 days after transplant or discharge, whichever comes first.  
3.2 
Secondary Endpoints 
3.2.1 Delirium duration will be measured in days and delirium severity will be 
defined as the highest DRS score recorded.  If delirium occurs, frequency of 
assessment will increase to daily, Monday through Friday, as scheduling permits, 
until delirium resolves.   
 
3.2.2 We will examine the relationship between thiamine levels at the end of the 
seven day intervention period and the development of delirium at any point during 
the post-transplant hospitalization. 
 
 
3.2.3  Scores on FACT-BMT, PROMIS-D, PTSS-14, ECOG-PS, and MOCA 
will be measured at one, three, and six months after transplant. 
 
4.0 
PATIENT ELIGIBILITY 
In order to participate in this study a subject must meet ALL of the eligibility 
criteria outlined below.   
4.1 
Inclusion Criteria 
Eligible subjects must meet all of the following criteria to be enrolled in the study: 
4.1.1 Admission or planned admission to the UNC Hospital Bone Marrow 
Transplant Unit for allogeneic stem cell transplant. 
4.1.2 At least 18 years of age. 
4.1.3  Able to speak English. 
4.1.4  Able to provide informed consent. 
 
4.2 
Exclusion Criteria 
Eligible subjects must not have any of the following to be enrolled in the study: 
4.2.1 A history of adverse reaction to IV thiamine 
4.2.2 Pregnancy, confirmed by a negative pregnancy test within 30 days of 
study enrollment 

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5.0 
TREATMENT PLAN 
5.1 
Schema 
 
 
5.2 
Treatment Dosage and Administration 
Subjects in the intervention group will receive thiamine 200 mg IV tid for seven 
days beginning on the day after of transplant.  Subjects in the control group will 
receive 100 mL (equivalent volume to intervention) normal saline IV tid for seven 
days beginning on the day after transplant.  All investigators will be blinded to 
which patients are assigned to which arm of the study.  Only the Investigational 
Drug Service (IDS) will be aware of which patients will be assigned to which 
arms.  At any time, the PI, primary medical providers, or other emergency 
personnel may request unblinding of a subject’s randomized treatment from IDS.  
If there is an adverse reaction, subjects will be treated symptomatically and 
consideration will be given to stopping the medication, as outlined in Section 5.3.   
 
REGIMEN DESCRIPTION 
 
Group 
 
Agent 
 
Dose 
 
Route 
 
Schedule 
Intervention 
Thiamine 
200 mg Thiamine 
HCL solution in  100 
mL infusion bag of 
0.9% Sodium 
Chloride 
IV over 30 
minutes (50 
ml/hr) 
Post-transplant 
Days 1 – 7  
three times daily 

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Control 
Normal Saline 
 100 mL of 0.9% 
IV over 30 
minutes (50 
ml/hr) 
Post-transplant 
Days 1 – 7 three 
times daily 
 
Prescribing Information 
Full prescribing information for thiamine can be found at the following web 
address: http://editor.fresenius-kabi.us/PIs/Thiamine_Inj_45819E_May_08.pdf 
5.3 
Toxicities and Dosing Delays 
Any patient who receives treatment on this protocol will be evaluable for toxicity.  
Each patient will be assessed periodically for the development of any toxicity 
according to the Time and Events table (Section 7.1).  Toxicity will be assessed 
according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), 
version 4.0.  All severe adverse effects will be evaluated immediately by Drs. 
Nakamura or Rosenstein and a decision will be made about stopping the study 
medication. 
 
Toxicity and Dosing Delays 
Event 
Action 
Anaphylaxis 
Grade 1-2 
N/A 
Grades 3 – 4 
Stop medication and consider removing subject 
from trial 
Infusion site extravasation 
Grade 1-2 
Hold until AE are tolerable and then restart 
medication. 
Grade 3-4 
Withhold until ≤ Grade 2 
Pruritis 
Grade 1 
Will provide topical intervention 
Grade 2 
Will provide oral intervention (e.g. 
diphenhydramine) and withhold until < Grade 2 
Grade 3 
Will administer oral corticosteroid or 
immunosuppressive therapy and withhold until < 
Grade 2 
Any other unanticipated toxicity 
 
Grade 1-4 
Management as per CTCAE version 4.0 
 
 
5.4 
Usual Care 
All participants in both study arms will receive usual care for treatment and 
prevention of delirium, including but not limited to behavioral interventions, 
psychiatric consultation, and psychotropic medications at the recommendation of 
psychiatric consultants and discretion of the bone marrow transplant team.  This 
proposed standardized management of delirium is detailed in the attached 
protocol (Appendix A), which provides a framework to minimize variability in 
the treatment of delirium among study participants.  

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5.5 
Prohibited Medications/Treatments 
There are no medications/treatments that would prohibit subjects from inclusion 
and continued assessment in this study. 
5.6 
Duration of Therapy 
 
Treatment will continue for seven days or until: 
• Unacceptable adverse event(s) 
• Inter-current illness that prevents further administration of treatment 
• Subject decides to withdraw from the study, OR 
 
Decisions to remove a subject from the trial or discontinuation of treatment before 
planned study completion will be undertaken in conjunction with consultation 
from the study PI or Co-PI. 
5.7 
Duration of Follow Up 
For determination of study endpoints, subjects will be followed for six months 
after receiving HSCT or until death.  Patients removed from study treatment for 
unacceptable AEs will be followed for resolution or stabilization of the adverse 
event(s). All patients (including those withdrawn for AEs) will be followed after 
removal from study treatment as stipulated in the protocol.   
5.8 
Study Withdrawal 
Patients will be removed from protocol therapy and the PI notified when any of 
the criteria listed in section 5.6 apply.  The reason for discontinuation of the 
protocol therapy will be documented on the eCRF.   
 
If a patient decides to withdraw from the study (and not just from protocol 
therapy) an effort will be made to complete and report study assessments as 
thoroughly as possible.  At the time of withdrawal, Drs. Nakamura or Rosenstein 
will attempt to establish as completely as possible the reason for the study 
withdrawal.  
• 
The patient will be asked if they are willing to allow for the abstraction of 
relevant information from their medical record in order to meet the long-
term follow up objectives outlined in the protocol.   
• 
A complete final evaluation at the time of the patient’s study withdrawal 
will be obtained with an explanation of why the patient is withdrawing 
from the study.   
• 
If they are unwilling to come in for a final visit, then we will attempt to 
complete all assessments over the phone, through video conferencing, 
online, by email, or by mail that can be completed in this manner  
• 
If the patient does not return for an end of study follow-up assessment, this 
will be documented in the eCRF.  
• 
If the reason for removal of a patient from the study is an adverse event, 
the principal specific event will be recorded on the eCRF.  

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5.9 
Study Questionnaires 
5.9.1 Delirium Rating Scale (DRS)  
The DRS is a is a 10-item, clinician-rated scale that rates the severity of delirium 
symptoms over a 24-hour period using all available information from the patient 
interview, mental status examination, medical history and tests, nursing 
observations, and family reports.34 The maximum possible score is 32. A cut-off 
score of > 12 has been suggested to distinguish patients with delirium from 
patients with other neuropsychiatric disorders.34,35  Each assessment will require 
up to 10 minutes of the subject’s time. 
 
5.9.2 Functional Assessment of Cancer Therapy – Bone Marrow 
Transplant (FACT-BMT) 
The FACT-BMT is a 47-item self-administered assessment which has been well 
validated in the literature and permits the measurement of HRQOL in bone 
marrow transplant patients.36  It asks individuals to rate questions related to 
physical, social/family, emotional, and functional well-being on a 5-point Likert 
Scale (0, not at all to 4, very much).  All participants who are enrolled in the trial 
will be evaluated pre-transplant and will have repeat assessment at one, three, and 
six month follow-up visits after transplant.  If the subject exhibits difficulty in 
completing the assessment due to its length, the CRA will help the subject 
complete it by reading items and answer choices aloud.  The FACT-BMT will 
take no greater than 15 minutes to complete. 
 
5.9.3 Patient Reported Outcomes Measurement Information System – 
Depression (PROMIS-D) 
The National Institute of Health’s Patient-Reported Outcomes Measurement 
Information System (PROMIS) contains a depression bank.37 We will use the 
PROMIS Depression 8a short form.  Scores for all PROMIS measures are 
reported on the T-score metric in which the mean=50 and standard deviation (SD) 
= 10 are centered on the general population means. Higher scores represent 
greater degrees of mood symptoms.  All participants who are enrolled in the trial 
will complete the self-administered assessment pre-transplant and will have repeat 
assessment at one, three, and six month follow-up visits after transplant.  The 
PROMIS-D will take no greater than 5 minutes to complete. 
 
5.9.4 Post Traumatic Stress Syndrome Scale 14 (PTSS-14) 
The PTSS-14 is a 14-item self-administered assessment which has been well 
validated in the literature and permits the measurement of post-traumatic stress 
disorder (PTSD) symptoms.38  It has been used in a variety of populations, 
including assessment following a period of delirium.39  Questions are on a 7-point 
Likert-type Scale (1, never to 7, always) resulting in a total score between 14 and 
98.  Higher scores represent a more likely diagnosis of PTSD.  All participants 
who are enrolled in the trial will be evaluated pre-transplant and will have repeat 
assessment at one, three, and six month follow-up visits after transplant.  The 
PTSS-14 will take no greater than 10 minutes to complete. 

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5.9.5 Montreal Cognitive Assessment (MOCA) 
The MOCA is a clinician administered tool which has been well validated in the 
literature, studied in a wide variety of patient populations, and permits assessment 
of cognitive impairment.  It is measured on a 30-point scale with lower scores 
indicating greater impairment.  Scores ≤ 25 are considered clinically significant.  
All participants who are enrolled in the trial will be evaluated at baseline and will 
have repeat assessment at one, three, and six month follow-up visits after 
transplant.  The MOCA will take no greater than 10 minutes to complete. 
 
5.9.6 Eastern Cooperative Oncology Group Performance Status (ECOG-
PS) 
The ECOG performance scale is one of the most widely used measures of 
functional status.40  It has high reliability and validity and is frequently used to 
estimate prognosis and treatment eligibility in oncology clinical trials.41  ECOG 
performance status is scored on a 6-point scale with higher scores representing 
greater physical restriction due to illness.  The ECOG-PS will take no greater than 
2 minutes to complete. 
 
6.0 
DRUG INFORMATION 
6.1 
Thiamine Description and Management 
 
6.1.1 Mechanism of Action 
Thiamine combines with adenosine triphosphate (ATP) to form thiamine 
pyrophosphate, also known as cocarboxylase, a coenzyme.  Its role in 
carbohydrate metabolism is the decarboxylation of pyruvic acid in the blood and 
α-ketoacids to acetaldehyde and carbon dioxide.   
 
6.1.2 Indications 
Thiamine hydrochloride injection is indicated for the treatment of Wernicke’s 
encephalopathy, Wernicke-Korsakoff syndrome, thiamine deficiency, beriberi 
(wet or dry), peripheral neuritis in pregnancy, and with dextrose-containing IV 
fluids. 
 
6.1.3 How Supplied 
The drug will be obtained from commercial supply through UNC Pharmacy and 
UNC Investigational Drug Service (IDS).  
 
Full prescribing information for (Thiamine) is available at: 
(http://editor.fresenius-kabi.us/PIs/Thiamine_Inj_45819E_May_08.pdf) 
 
6.1.4  Dosage and Administration: 
Subjects in the intervention group will receive Thiamine 200 mg IV tid.   

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6.1.5 Storage and Stability: 
Thiamine should be stored at room temperature (between 68° to 77° F). 
 
6.1.6  Handling and Disposal: Local requirements for disposal of hazardous 
drugs will be followed. 
 
Please see UNC policy on hazardous drugs:  
http://news.unchealthcare.org/empnews/att/2011/nov/admin0188/.  
6.1.7 Adverse Events Associated with Commercial Drug 
In a study of 989 patients given a rapid IV push of 100 mg IV thiamine, the only 
identified side effects were immediate, transient burning (1.02%) and generalized 
pruritis (0.093%).27  Anaphylaxis has been reported at a rate of one reaction per 
every 5 million ampules used.28  The following have also been reported with 
unknown frequency: a feeling of warmth, weakness, sweating, nausea, 
restlessness, tightness of the throat, angioneurotic edema, cyanosis, pulmonary 
edema, and hemorrhage into the gastrointestinal tract.  Parenteral doses of 100 to 
500 mg singly have been administered without adverse effect.29   A 
comprehensive list of adverse effects can be found at the following web address: 
http://editor.fresenius-kabi.us/PIs/Thiamine_Inj_45819E_May_08.pdf 
 
7.0 
EVALUATIONS AND ASSESSMENTS 
7.1 
Time and Events Table 
 
 
Baseline 
(Pre-
Transplant) 
Post-Transplant 
Day 1 
Post-Transplant 
Days 2 – 30 
F1c 
F2 
F3 
Informed Consent 
• 
 
 
 
 
 
Group Assignment 
• 
 
 
 
 
 
Demographic Data Form 
• 
 
 
 
 
 
Cancer History Form 
• 
 
 
 
 
 
Delirium Risk Factor Form 
• 
• 
• 
 
 
 
Concurrent CNS Active 
Medication Tracking Form 
• 
• 
• 
 
 
 
Baseline Labsa 
 
• 
 
 
 
 
Thiamine Levelsb 
 
• 
• 
 
 
 
FACT-BMTc 
• 
 
 
• 
• 
• 
PROMIS-Dc 
• 
 
 
• 
• 
• 
PTSS-14c 
• 
 
 
• 
• 
• 
MOCAc 
• 
 
 
• 
• 
• 
ECOG-PSc 
• 
 
 
• 
• 
• 
DRSd 
• 
• 
• 
 
 
 
Adverse Events Form 
 
• 
• 
 
 
 

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a. Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP), Magnesium (Mg), 
Phosphorus (Phos) 
b. Thiamine levels will be drawn on post-transplant day 1, 8 days post-transplant, 15 days post-
transplant, 22 days post-transplant, and 29 days post-transplant. 
c. FACT-BMT, PROMIS-D, PTSS-14, MOCA, and ECOG-PS will be performed at baseline (pre-
transplant) and at one (F1), three (F2), and six months (F3) after transplant. 
d. DRS will be performed at baseline, on post-transplant day 1, and three times weekly thereafter.  
If a participant is identified as having delirium, assessments will increase to daily until delirium 
resolves at which point frequency will resume at three times weekly. For participants who develop 
delirium during the inpatient phase, DRS will be performed at one (F1), three (F2), and six months 
(F3) after transplant. 
 
7.2  
Pre-Study (Baseline) Assessments 
Patients scheduled for admission to the UNC Bone Marrow Transplant unit will 
be considered for enrollment in this trial.  Prior to transplant, the clinical research 
assistant (CRA) will review the trial with the subject, obtain informed consent, 
and the subject will complete self-report assessments for depression (PROMIS-
D), post-traumatic stress symptoms (PTSS-14), and HRQOL (FACT-BMT), as 
well as clinician-rated assessments of cognition (MOCA), functional status 
(ECOG-PS), and for delirium (DRS).  See Appendices A – F.  The CRA or 
investigators will also conduct a review of electronic medical records to obtain 
baseline information regarding delirium risk factors, the subject’s cancer and 
cancer treatment, and demographic information.   
7.3 
Randomization 
If the patient meets all inclusion/exclusion criteria, provides informed consent, 
and is not delirious (DRS≤12), the subjects will then be randomized in a 1:1 ratio 
to the intervention or control arms in a double-blind fashion such that the 
investigators, biostatistician, CRA(s), nursing staff, and subjects will not know 
which agent is being administered.  The statistician of record will design a block 
randomization scheme, stratified by age (<65 or ≥65) and baseline cognitive 
function (MOCA >25 or ≤25), both well-known risk factors for delirium.  This 
information will be provided to UNC Investigational Drug Services, who will 
manage the actual assignment of subjects to each arm using the randomization list 
designed by the statistician. 
 
7.4 
Post-Transplant Days 1 – 30 Assessments 
Within two days of transplant, the subject will have a CBC, CMP, Mg level, Phos 
level, and Thiamine level drawn.  The CRA(s) or investigators will perform the 
delirium assessment (DRS), and a brief history will be obtained to assess for any 
toxicity from therapy. 
 
Over the course of 30 days following transplant (or discharge, whichever comes 
first), the subject will continue to have weekly thiamine levels drawn (at days 8, 
15, 22, and 29 +/- one day).  The CRA(s) or investigators will continue to assess 
for delirium, using the DRS, three times weekly.  If a subject is determined to 

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have delirium, frequency of delirium assessments will increase to daily, Monday 
through Friday, as scheduling permits, until delirium resolves. The DRS 
assessments will not be performed if a patient becomes unevaluable due to an 
acute medical concern (e.g. intubation, sedation, etc.).  The CRA(s) or 
investigators will continue to assess for any toxicity from therapy. 
 
7.5 
Long-term Follow-Up Assessments 
At one, three, and six months post-transplant the CRA(s) or investigators will 
meet with subjects to complete self-report assessments for depression (PROMIS-
D), post-traumatic stress symptoms (PTSS-14), and HRQOL (FACT-BMT), as 
well as clinician-rated assessments of cognition (MOCA) and functional status 
(ECOG-PS). At the time of each follow-up, delirium assessments (DRS) will also 
be performed in participants who became delirious during the inpatient phase.  
Subjects will receive reminders regarding these long-term assessments via 
subjects’ preferred method of contact. Long-term assessments will occur at one 
month (+/- two weeks), three months (+/- four weeks), and six months (+/- two 
months).  The specified window at each of these follow-up time points will allow 
for assessments to coincide with BMT clinic visits. If a face to face assessment is 
not feasible, attempts will be made to perform assessments over the phone, 
through video conferencing, online, by email, or by mail.  When assessments 
cannot be completed, this will be noted in the eCRF. 
 
7.6 
Concurrent CNS Active Medications 
All concurrent CNS active medications, including antidepressants, anxiolytics, 
antipsychotics, antiepileptics, and antihistamines will be documented at 
Baseline/Screening and throughout the study as summarized in the Time and 
Events Table in Section 7.1.   
7.7 
Demographics  
Demographic information (date of birth, gender, race) will be recorded by the 
CRA from review of medical records at baseline. 
7.8 
Delirium Risk Factors 
Relevant risk factors for delirium, including previous history of delirium, alcohol 
and substance use, and neurological conditions (stroke, traumatic brain injury, 
seizures, abnormal findings on imaging) will be abstracted from medical records 
at baseline. 
 
7.9 
Handling of Biospecimens Collected for Correlative Research 
Biospecimens for this study will be collected by a registered nurse and stored in 
the McLendon laboratories.   Blood samples will then be sent Mayo Medical 

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Laboratories for assay of thiamine levels.  Each sample will be assigned a unique 
code number and no identifiable personal health information (PHI) will be on the 
specimen label.  Researchers with IRB-approval for access to PHI for each 
subject in this study will be able to link specimens to relevant medical 
information.   
Storage Time: 
• 
The biospecimen will be used first and foremost for research purposes 
outlined within the confines of this protocol. Samples will be 
discarded/destroyed after relevant data are collected for this study, unless 
consent was obtained from the patient to use his/her blood for other research 
purposes (e.g., consent form was signed by the patient).  In this circumstance, 
there is no time limit on how long biospecimens may be stored. 
 
Compliance Statement 
Biospecimen collection for this study will be conducted in full accordance with all 
applicable University of North Carolina (UNC) Research Policies and Procedures 
and all applicable Federal and state laws and regulations including 45 CFR 46, 
and the Health Insurance Portability and Accountability Act (HIPAA) Privacy 
Rule. Any episode of noncompliance will be documented. 
 
The investigators will perform the study in accordance with this protocol, will 
obtain consent and assent (unless a waiver is granted), and will report unexpected 
problems in accordance with The UNC IRB Policies and Procedures and all 
federal requirements. Collection, recording, and reporting of data will be accurate 
and will ensure the privacy, health, and welfare of research subjects during and 
after the study.  
7.10 
Assessment of Safety  
Any patient who receives at least one dose of study therapy on this protocol will 
be evaluable for toxicity.  Each patient will be assessed periodically for the 
development of any toxicity according to the Time and Events table.  Toxicity 
will be assessed according to the NCI CTCAEv4.0.3. 
7.11 
Assessment of Efficacy 
In order to be considered evaluable for efficacy, patients must: 
- 
receive all 7 days of the treatment; a patient must receive at least 17/21 (80%) 
thiamine doses 
- 
have delirium assessed at least weekly until one of the following is met:  
1.  The participant is found to be delirious (DRS>12)  
2. The participant is at least 30 days post-transplant 
3. The participant is discharged 
 
If a patient is deemed not evaluable, they will be replaced by a new patient.  
However, if a patient develops delirium during the intervention, they will still 

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receive the full 7 day course, not be replaced, and included in the efficacy 
analysis.  
8.0 
ADVERSE EVENTS 
8.1 
Definitions  
8.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a 
drug) in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the 
medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) need not be considered 
AEs and should not be recorded as an AE.  Development or worsening of 
delirium should not be recorded as an AE, unless it is attributable by the 
investigator to the study therapy. 
8.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause.   Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE.  A 
suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration 
of the following factors: temporal relationship of the AE to study drug exposure, 
known mechanism of action or side effect profile of study treatment, other recent 
or concomitant drug exposures, normal clinical course of the disease under 
investigation, and any other underlying or concurrent medical conditions.  Other 
factors to consider in considering drug as the cause of the AE: 
• Single occurrence of an uncommon event known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
• One or more occurrences of an event not commonly associated with drug 
exposure, but otherwise uncommon in the population (e.g., tendon 
rupture); often more than once occurrence from one or multiple studies 
would be needed before the sponsor could determine that there is 
reasonable possibility that the drug caused the event.   

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• An aggregate analysis of specific events observed in a clinical trial that 
indicates the events occur more frequently in the drug treatment group 
than in a concurrent or historical control group 
8.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., package insert/summary 
of product characteristics for an approved product).  Unexpected also refers to 
AEs or SARs that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.   
8.1.4 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• Death; 
• Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of 
existing hospitalization;* 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions; 
• Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in the definition.  For reporting purposes, also consider the occurrences 
of pregnancy as an event which must be reported as an important 
medical event. 
 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered 
serious adverse events. 
 
Pregnancy that occurs during the study must also be reported as an SAE. 
8.2 
Documentation of non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from day 1 of study 
treatment and continue through the 30 day follow-up period after treatment is 
discontinued.   
 

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Collected information should be recorded in the Case Report Forms (CRF) for 
that patient.  Please include a description of the event, its severity or toxicity 
grade, onset and resolved dates (if applicable), and the relationship to the study 
drug. Documentation should occur at least monthly.  
8.3 
SAEs or Serious SARs  
8.3.1 Timing 
After informed consent but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected (e.g. SAEs related to 
invasive procedures such as biopsies, medication washout).  
 
For any other experience or condition that meets the definition of an SAE or a 
serious SAR, recording of the event must begin from day 1 of study treatment and 
continue through the 30 day follow-up period after treatment is discontinued.  
8.3.2 Documentation and Notification 
SAEs or Serious SARs must be recorded in the SAE console within Oncore™ for 
that patient within 24 hours of learning of its occurrence.  Additionally, the 
NCCN Project Manager must also be notified via email of all SAEs within 24 
hours of learning of its occurrence.  
8.4 
Adverse Event Reporting  
8.4.1 IRB Reporting Requirements: 
UNC: 
• The UNC-IRB will be notified of all SAEs that qualify as an 
Unanticipated Problem as per the UNC IRB Policies using the IRB’s web-
based reporting system (see section 10.5.3) within 7 days of the 
Investigator becoming aware of the problem.   
8.4.2 Funding Source (e.g. Manufacturer) Reporting Requirements: 
N/A 
8.5 
Data and Safety Monitoring Plan 
This is a Phase II, single site study of 60 individuals to gather preliminary data on the 
efficacy and safety of high dose IV thiamine for delirium prevention in patients 
undergoing HSCT.  We will follow our standard protocol for monitoring of clinical trials.  
Subjects are screened to ensure that there are no contraindications to their participation. 
 
The study Co-PIs, Drs. Nakamura and Rosenstein, will be responsible for continuous 
monitoring of patient safety during the trial.  For non-serious Adverse Events (AEs), 
documentation will begin from the first day of study treatment and continue through the 
30 day follow-up period after treatment is discontinued. Collected information will be 
recorded in Case Report Forms (CRF) for that patient. A description of the event, its 

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severity or toxicity grade, onset and resolved dates (if applicable), and the relationship to 
the study drug will be included.  For any experience or condition that meets the definition 
of a serious adverse event (SAE), recording of the event will begin after signing of the 
informed consent and continue through the 30 day follow-up period after treatment is 
discontinued.  These events will be recorded in the CRF for that patient within 24 hours 
of learning of its occurrence.  If the event is both serious AND unexpected, it will also be 
recorded on the MedWatch Form 3500A, as per 21 CFR 312.32, and forwarded to the 
FDA in accordance with 21 CFR 314.80 (for marketed drugs).  The UNC IRB will be 
notified of all SAEs that qualify as an Unanticipated Problem (serious, unexpected, and 
related) as per the UNC IRB policies. In accordance with these policies, an aggregated 
list of all SAEs will be submitted to the UNC IRB annually at the time of study renewal. 
 
Periodic review, at an interval of every six months to annually, by the Lineberger 
Comprehensive Cancer Center Data Safety Committee (LCC DSMC), Protocol Review 
Committee (PRC), and Office of Human Research Ethics (OHRE) Biomedical IRB will 
provide oversight of the Co- PIs’ continuous monitoring.   For each DSMC review, 
summary information regarding toxicity and accrual patterns will be prepared and 
submitted by the Co-PIs.  Specific information submitted for review includes: (1) The 
number of patients enrolled, consented, consented but not treated, currently being treated, 
completed treatment, the number of patients who did not complete treatment and the 
reasons for coming off study; (2) Grade 3 or greater reported Adverse Events to date; (3) 
Serious Adverse Events and Unanticipated Problems since last report, with assurance of 
reporting to internal and external regulating bodies; (4) Exceptions in eligibility or 
treatment and significant protocol deviations/violations; (5) Significant literature 
reporting developments that may affect the safety of participants or the ethics of the 
study; (6) Summaries of team meetings that have occurred since the last report; (7) 
Results of interim analyses required by the protocol.  We will also be submitting a 
preliminary report of response and other endpoints listed in the primary and secondary 
objectives of the protocol for DSMC review. 
 
Though no formal a priori stopping rules are proposed for the study, in the event of a 
serious or unexpected adverse event or frequent occurrence of less serious unexpected or 
expected adverse events we will consult with the OHRE and DSMC as to whether the 
trial should continue. 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design/Study Endpoints 
This is a randomized double-blind controlled trial in participants undergoing 
allogeneic hematopoietic stem cell transplantation (HSCT) to evaluate if high 
dose intravenous (IV) thiamine can prevent delirium and minimize the deleterious 
impact of delirium on health-related quality of life (HRQOL), functional status, 
and other neuropsychiatric outcomes.  We will recruit 60 evaluable patients 
scheduled for allogeneic HSCT at UNC, randomize them to treatment with high 

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dose IV thiamine (n = 30) versus placebo (n = 30), and systematically evaluate all 
participants for delirium and related comorbidities. 
 
Analysis Populations: The Safety Population will be defined as all subjects who 
were enrolled and received at least one dose of study medication.   Efficacy 
Evaluable Population will be defined as all subjects who received at least 80% 
(17/21) of total possible intervention doses and participated in at least one 
delirium assessment weekly. 
 
The primary efficacy endpoint is delirium incidence defined as DRS >12.  
Secondary endpoints include delirium duration and severity, along with FACT-
BMT, PROMIS-D, PTSS-14, ECOG-PS, and MOCA. 
9.2 
Sample Size, Accrual and Duration of Accrual 
For the primary objective of comparing delirium incidence between groups, a two 
group chi-squared test with a 0.050 one-sided significance level will have 80% 
power to detect the difference between a usual care proportion of 0.445 and an 
intervention proportion of 0.155 (odds ratio of 0.229) when the evaluable sample 
size in each group is 30.  The anticipated rate of delirium in the control group is 
based on 43 – 73% incidence of delirium during hospitalization for HSCT 
reported in the literature.  As this is the first study to evaluate the efficacy of 
thiamine as a prevention strategy for delirium, no data is available to generate an 
estimate of delirium incidence in the intervention group.  However, the odds ratio 
(OR) hypothesized for this study is in line with other successful delirium 
prevention trials.42,43  Even if the delirium incidence in the IV thiamine group is 
not this low, the results of this study will provide effect sizes and 95% confidence 
intervals to power a future larger study.    
 
Our sample will include 60 adult participants.  UNC tumor registry records 
demonstrate that between 2015 and 2016 133 patients were admitted for 
allogeneic stem cell transplant.  We estimate that we will enroll at least 50% of 
eligible patients, based on recruitment rates described in previous delirium 
intervention studies,44 allowing us to recruit our target of 60 evaluable participants 
in approximately two years and complete our study in the proposed three year 
grant period.   
9.3 
Data Analysis Plans 
To compare delirium incidence, severity, and duration between recipients of high 
dose IV thiamine and placebo during hospitalization for HSCT.  The primary 
outcome measure is delirium incidence, defined as: DRS > 12.  Secondary 
outcomes are differences in delirium duration (in days) and delirium severity, in 
which higher DRS scores suggest more severe delirium.  A two group chi-squared 
test will be used to compare rates of delirium in the intervention and control 
group.  Maximum severity score will be analyzed using two group t-tests, and 
time to delirium will be compared between groups using the Kaplan-Meier 

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method.  For those with delirium, two group t-tests will compare the duration of 
delirium between intervention groups; Kaplan-Meier methods may also be 
considered for time to delirium resolution.   
 
To determine if thiamine status is predictive of future delirium onset.   We will 
examine the relationship between thiamine levels at the end of the seven day 
administration of thiamine and the development of delirium at any point during 
the thirty days post-transplant or the post-transplant hospitalization, whichever 
comes first.  Patients who develop delirium prior to the end of the thiamine 
treatment will not be included in this analysis.  We will examine the sensitivity 
and specificity of this relationship with ROC curves, and attempt to find a cutoff 
for thiamine levels that is associated with the development of delirium.   
 
To investigate the effects of high dose IV thiamine on long-term health-related 
quality of life (HRQOL), functional status, depression, post-traumatic stress 
symptoms, and cognitive functioning in patients hospitalized for HSCT.  Scores 
on FACT-BMT, PROMIS-D, PTSS-14, ECOG-PS and MOCA will be compared 
between intervention and control groups.  We will summarize scores on the 
FACT-BMT, PROMIS-D, PTSS-14, ECOG-PS, and MOCA between the 
intervention and control groups at one, three, and six months post-transplant.  
Longitudinal modeling will be performed to examine differences/changes over 
time. 
 
Safety Analyses:  We will tabulate AEs and SAEs, by treatment and placebo, 
within strata.  We will include all AEs which occurred at a rate of more than 5% 
in any treatment. 
 
10.0 STUDY MANAGEMENT 
10.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 

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the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
10.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North 
Carolina. 
• A copy of the official IRB approval letter for the protocol and 
informed consent 
• IRB membership list 
• CVs and medical licensure for the principal investigator and any sub-
investigators who will be involved in the study. 
• The Investigator’s signature documenting understanding of the 
protocol and providing commitment that this trial will be conducted 
according to all stipulations of the protocol is sufficient to ensure 
compliance  
• CAP and CLIA Laboratory certification numbers and institution lab 
normal values 
• Executed clinical research contract 
 
10.3 
Registration Procedures 
All patients must be registered with the CPO at the University of North Carolina 
before enrollment to study.  Prior to registration, eligibility criteria must be 
confirmed with the UNC Study Coordinator.  To register a patient call the CPO 
at 919-966-4432 Monday-Friday 9:00 am – 5:00 pm EST or email the UNC 
Project Manager. 
10.4 
Data Management and Monitoring/Auditing 
The CPO of the UNC LCCC will serve as the coordinating center for this trial. 
Data will be collected through a web based clinical research platform, OnCore®. 
All data will be collected and entered into OnCore® by research coordinators from 
UNC LCCC.  
 
The sponsor will provide direct access to source data/documents for trial-related 
monitoring, audits, IRB/IEC review, and regulatory inspection. As an investigator 
initiated study, this trial will also be audited by the LCCC compliance committee 
every six or twelve months. 

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10.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   
10.5.1 Emergency Modifications 
UNC investigators may implement a deviation from, or a change of, the protocol 
to eliminate an immediate hazard(s) to trial subjects without prior UNC IRB 
approval.   
 
For any such emergency modification implemented, a UNC IRB modification 
form must be completed by UNC Research Personnel within five (5) business 
days of making the change.   
10.5.2 Single Patient/Subject Exceptions 
Any request to enroll a single subject who does not meet all the eligibility criteria 
of this study requires the approval of the UNC Principal Investigator and the UNC 
IRB.  
10.5.3 Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria:  
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
 
Protocol Deviations: UNC or Affiliate personnel will record the deviation in 
OnCore®, and report to any sponsor or data and safety monitoring committee in 
accordance with their policies.  Deviations should be summarized and reported to 
the IRB at the time of continuing review. 

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Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems.   
 
Unanticipated Problems:  Any events that meet the criteria for “Unanticipated 
Problems” as defined by UNC’s IRB must be reported by the study personnel 
using the IRB’s web-based reporting system.   
 
10.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at UNC.  It should also 
be noted that when an amendment to the protocol substantially alters the study 
design or the potential risk to the patient, a revised consent form might be 
required.   
 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation.   
10.7 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor correspondence to Investigators, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
10.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 

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staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator will be responsible for assuring that all the required 
data will be collected and entered into the eCRFs. Periodically, monitoring visits 
will be conducted and the Principal Investigator will provide access to his/her 
original records to permit verification of proper entry of data. At the completion 
of the study, all eCRFs will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
 
 

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19. Steinberg A, Gorman E, Tannenbaum J. Thiamine deficiency in stem cell transplant 
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24. Davies SB, Joshua FF, Zagami AS. Wernicke's encephalopathy in a non-alcoholic 
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wernicke's encephalopathy in the accident and emergency department. Alcohol Alcohol. 
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29. APP Pharmaceuticals L. Thiamine hydrochloride injection, USP. . 2008. 
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http://www.micromedexsolutions.com. Updated 2017. Accessed June 13, 2017. 

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31. Donnino MW, Vega J, Miller J, Walsh M. Myths and misconceptions of wernicke's 
encephalopathy: What every emergency physician should know. Ann Emerg Med. 
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33. Ambrose ML, Bowden SC, Whelan G. Thiamin treatment and working memory 
function of alcohol-dependent people: Preliminary findings. Alcohol Clin Exp Res. 
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Psychosomatics. 1999;40(3):193-204. doi: S0033-3182(99)71235-1 [pii]. 
36. McQuellon RP, Russell GB, Cella DF, et al. Quality of life measurement in bone 
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37. Pilkonis PA, Choi SW, Reise SP, et al. Item banks for measuring emotional distress 
from the patient-reported outcomes measurement information system (PROMIS(R)): 

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Depression, anxiety, and anger. Assessment. 2011;18(3):263-283. doi: 
10.1177/1073191111411667 [doi]. 
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questionnaire for post‐traumatic stress disorder (PTSD) on a sample of UK ICU patients. 
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39. Drews T, Franck M, Radtke FM, et al. Postoperative delirium is an independent risk 
factor for posttraumatic stress disorder in the elderly patient: A prospective observational 
study. Eur J Anaesthesiol. 2015;32(3):147-151. doi: 10.1097/EJA.0000000000000107 
[doi]. 
40. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the 
eastern cooperative oncology group. Am J Clin Oncol. 1982;5(6):649-655. 
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in patients with advanced disease. Eur J Cancer. 2008;44(8):1146-1156. doi: 
10.1016/j.ejca.2008.02.030 [doi]. 
42. Mohammadi M, Ahmadi M, Khalili H, Cheraghchi H, Arbabi M. Cyproheptadine for 
the prevention of postoperative delirium: A pilot study. Ann Pharmacother. 
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43. Larsen KA, Kelly SE, Stern TA, et al. Administration of olanzapine to prevent 
postoperative delirium in elderly joint-replacement patients: A randomized, controlled 
trial. Psychosomatics. 2010;51(5):409-418. 

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44. Breitbart W, Marotta R, Platt MM, et al. A double-blind trial of haloperidol, 
chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS 
patients. Am J Psychiatry. 1996;153(2):231-237. doi: 10.1176/ajp.153.2.231 [doi]. 
45. Trzepacz P, Breitbart W, Franklin J, Levenson JD, Martini R, Wang P. Practice 
guideline for the treatment of patients with delirium. . 1999. 
46. Trzepacz PT, Meagher DJ, Leonard M. Delirium. In: Levenson JL, ed. Textbook of 
psychosomatic medicine. Second ed. Washington , DC: American Psychiatric Publishing, 
Inc.; 2011:71. 
  
 

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12.0 APPENDICES 
 
Appendix A: Suggested Management of Delirium 
 
1. Obtain further laboratory work-up45,46  
In all patients with delirium the following should be considered:  
- 
Blood chemistries: electrolytes, glucose, calcium, albumin, blood urea nitrogen 
(BUN), creatinine, AST, ALT, bilirubin, alkaline phosphatase, magnesium, 
phosphorus 
- 
Complete blood count (CBC) 
- 
Electrocardiogram 
- 
Chest X-ray 
- 
Measurement of arterial blood gases or oxygen saturation 
- 
Urinalysis 
 
In patients with delirium the following should be considered if felt to be clinically 
indicated: 
- 
Urine culture and sensitivity 
- 
Urine drug screen 
- 
Blood cultures 
- 
Measurement of serum levels of medications (e.g., tacrolimus, cyclosporine, etc.) 
- 
Lumbar puncture 
- 
Brain computerized tomography (CT) or magnetic resonance imaging (MRI) 
- 
Electroencephalogram (EEG) 
- 
Folate, B12 
 
2. Treat any reversible abnormalities identified in work-up 
3. Initiate environmental and supportive interventions 
- Staff to open blinds every morning. 
- Glasses, hearing aide, and patient’s own shoes to bedside.  Make available to 
patients when possible and encourage use. 
- Encourage po fluids when appropriate, keep fluids within reach. 
- Out of bed to chair with meals. 
- Staff to assess orientation to person, time and place every morning and as 
needed throughout the day. 
- Recommend extended visitation hours with familiar family/friends as feasible. 
- Staff to minimize disturbances at night. Turn off television when patient asleep 
or when not in use. 
 
4. Consult Psychiatry for a.) behavioral disturbance and/or  b.) Delirium Rating 
Score  > 12 

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Note: With the exception of urgent psychiatric consults needed overnight, on 
weekends, or on holidays, consultants will be limited to study investigators Drs. 
Nakamura and Rosenstein.  
 
 

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Appendix B: DELIRIUM RATING SCALE (DRS) 
 
1. Temporal onset of symptoms 
 
0 
No significant change from longstanding behavior, essentially a chronic or 
chronic-recurrent disorder 
 
1 
Gradual onset of symptoms, occurring within a 6-month period 
 
2 
Acute change in behavior or personality occurring over a month 
 
3 
Abrupt change in behavior, usually occurring over a 1- to 3-day period 
 
2. Perceptual disturbances 
 
0 
None evident by history or observation 
 
1 
Feelings of depersonalization or derealization 
 
2 
Visual illusions or misperceptions including macropsia, micropsia; e.g., may 
urinate in wastebasket or mistake bedclothes for something else 
 
3 
Evidence that the patient is markedly confused about external reality; e.g., 
not discriminating between dreams and reality 
 
3. Hallucination type 
 
0 
Hallucinations not present 
 
1 
Auditory hallucinations only 
 
2 
Visual hallucinations present by patient’s history or inferred by observation, 
with or without auditory hallucinations 
 
3 
Tactile, olfactory, or gustatory hallucinations present with or without visual 
or auditory hallucinations 
 
 
4. Delusions 
 
0 
Not present 
 
 
1 
Delusions are systematized, i.e., well-organized and persistent 
 
2 
Delusions are new and not part of a preexisting primary psychiatric disorder 
 
3 
Delusions are not well circumscribed; are transient, poorly organized, and 
mostly in response to misperceived environmental cues; e.g., are paranoid 
and involve persons who are in reality caregivers, loved ones, hospital staff, 
etc. 
 
5. Psychomotor behavior 
 
0 
No significant retardation or agitation 
 

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1 
Mild restlessness, tremulousness, or anxiety evident by observation and a 
change from patient’s usual behavior 
 
 
2 
Moderate agitation with pacing, removing i.v.‘s, etc. 
 
 
3 
 Severe agitation, needs to be restrained, may be combative; or has 
significant withdrawal from the environment, but not due to major 
depression or schizophrenic catatonia 
 
6. Cognitive status during formal testing 
 
 
0 
No cognitive deficits, or deficits which can be alternatively explained by lack 
of education or prior mental retardation 
 
 
1 
Very mild cognitive deficits which might be attributed to inattention due to 
acute pain, fatigue, depression, or anxiety associated with having a medical 
illness 
 
 
2 
Cognitive deficit largely in one major area tested, e.g., memory, but 
otherwise intact 
 
 
3 
Significant cognitive deficits which are diffuse, i.e., affecting many different 
areas tested; must include periods of disorientation to time or place at least 
once each 24-hr period; registration and/or recall are abnormal; 
concentration is reduced 
 
 
4 
 Severe cognitive deficits, including motor or verbal perseverations, 
confabulations, disorientation to person, remote and recent memory 
deficits, and inability to cooperate with formal mental status testing 
 
7. Physical disorder 
 
 
0 
None present or active 
 
1 
Presence of any physical disorder which might affect mental state 
 
2 
Specific drug, infection, metabolic, central nervous system lesion, or other 
medical problem which can be temporally implicated in causing the altered 
behavior or mental status 
 
8. Sleep-wake cycle disturbance 
 
0 
Not present; awake and alert during the day, and sleeps without significant 
disruption at night 
 
1 
Occasional drowsiness during day and mild sleep continuity disturbance at 
night; may have nightmares but can readily distinguish from reality 

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2 
Frequent napping and unable to sleep at night, constituting a significant 
disruption of or a reversal of the usual sleep-wake cycle 
 
3 
Drowsiness prominent, difficulty staying alert during interview, loss of self-
control over alertness and somnolence 
 
4 
Drifts into stuporous or comatose periods 
 
9.  Lability of mood 
 
0 
Not present; mood stable 
 
1 
Affect/mood somewhat altered and changes over the course of hours; 
patient states that mood changes are not under self-control 
 
2 
Significant mood changes which are inappropriate to situation, including 
fear, anger, or tearfulness; rapid shifts of emotion, even over several 
minutes 
 
3 
Severe disinhibition of emotions, including temper outbursts, uncontrolled 
inappropriate laughter, or crying 
 
 
10. Variability of symptoms 
 
 
0 
Symptoms stable and mostly present during daytime 
 
2 
Symptoms worsen at night 
 
4 
Fluctuating intensity of symptoms, such that they wax and wane during a 
24-hr period 
 
 
 
 
 
 
 

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Appendix C: Functional Assessment of Cancer Therapy – Bone Marrow 
Transplant (FACT-BMT) 
 
Below is a list of statements that other people with your illness have said are 
important. Please circle or mark one number per line to indicate your 
response as it applies to the past 7 days. 
 
 
 
 

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Appendix D: Patient Reported Outcomes Measurement 
Information System – Depression (PROMIS-D) 
 
Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days.  Mark only one box per row. 
 
 
 
 

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Appendix E: Post-Traumatic Stress Symptom Scale (PTSS-14) 
 
Please circle or mark one number per line to indicate your response as it applies to 
the past few days.  Mark only one box per row. 
 
Presently I suffer from:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix F: Montreal Cognitive Assessment (MOCA) 
 
 
 

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Appendix G: Eastern Cooperative Oncology Group Performance Status 
(ECOG-PS) 
 
 
 
 
 
a