Clinical trial NCT03496545
Conditions: Subarachnoid Hemorrhage Subdural Hematoma Traumatic Brain Injury Ischemic Stroke Fever Intracerebral Hemorrhage
Keywords: fever central fever neurogenic fever hyperthermia bromocriptine subarachnoid hemorrhage SAH subdural hematoma SDH intracerebral hemorrhage ICH traumatic brain injury TBI ischemic stroke
Sponsor: University of California, San Francisco
Start date: 2018-11-30; Completion date: 2019-11-02
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the antipyretic effect of bromocriptine in critically-ill patients with acute neurologic injury and fever from infectious and non-infectious etiologies.

Detailed description:
In patients with acute neurologic injury such as subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), traumatic brain injury (TBI), subdural hematoma (SDH), and ischemic stroke, fever has been found to be an independent predictor of poor outcome including increased mortality rates, longer hospital stays, depressed level of consciousness, and worse functional outcomes. Our current antipyretic therapy of acetaminophen and sometimes nonsteroidal anti-inflammatory drugs are not very effective and external cooling requires sedatives and other medications to prevent shivering and pain. Bromocriptine is a dopamine D2 receptor agonist which acts at the hypothalamus, a specific area of the brain that regulates body temperature. Fevers of both central and infectious etiologies must be regulated through the hypothalamus and we have evidence that bromocriptine has an antipyretic effect at the hypothalamus; thus, we hypothesize that bromocriptine could be used safely and more broadly to treat all fevers in the acute setting and not just refractory central fevers in this patient population.

Here, we propose to evaluate the acute antipyretic effects of bromocriptine in this critically-ill population through a pilot, open label, blinded endpoint, randomized controlled trial. In both enrolling centers, University of California, San Francisco Medical Center Parnassus (UCSF) and Zuckerberg San Francisco General Hospital, every patient who is admitted to the neurointensive care unit for an anticipated stay of greater than 48 hours with a diagnosis of subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), traumatic brain injury (TBI), subdural hematoma (SDH), and ischemic stroke will be screened and consented. If they have a temperature reading ≥ 38.3 ºC, the investigational pharmacy will randomize them to the control arm of acetaminophen or the intervention arm of acetaminophen and bromocriptine for 48 hours. We will continuously measure their temperature and other vitals data. Retrospectively, we will review imaging and labs ordered to work up infectious etiologies of fever. The ICU nurse will do a 5 minute assessment every shift during the 48 hour study period for side effects. The temperature data will be analyzed between the two study arms.

Arms: arm 1: Standard of care - acetaminophen 650mg every 4 hours PO/NG/FT (per oral, nasogastric tube, feeding tube) for 48 hours, initiated within 1 hour after temperature reading ≥ 38.3ºC. arm 2: Bromocriptine 5mg every 4 hours PO/NG/FT for 48 hours and acetaminophen 650mg every 4 hours PO/NG/FT for 48 hours, initiated within 1 hour after temperature reading ≥ 38.3ºC.
Interventions: intervention 1: Bromocriptine 5 MG intervention 2: Acetaminophen 650 MG
Intervention descriptions: intervention 1: Bromocriptine 5 mg every 4 hours PO/NG/FT intervention 2: Acetaminophen 650 mg every 4 hours PO/NG/FT for 48 hours

Protocol documents:
Prot_SAP_001.pdf: 
Efficacy of Bromocriptine to Reduce Body Temperature in 
Febrile Critically-ill Adults With Acute Neurologic Disease: an 
Open-label, Blinded Endpoint, Randomized Controlled Trial 
 
NCT03496545 
 
Document Date: 02/17/2021 
 


    Study Application (Version 1.12)
1.0
General Information
*Enter the full title of your study:
Efficacy of bromocriptine to reduce body temperature in febrile critically-ill adults with
acute neurologic disease: an open-label, blinded endpoint, randomized controlled trial
*Enter the study number or study alias
Bromocriptine for Fever Trial or The BFF trial
* This field allows you to enter an abbreviated version of the Study Title to quickly identify
this study.
2.0
Add Department(s)
2.1 List the departments associated with this study. The Principal Investigator's department
should be Primary.:
Primary
Dept?
Department Name
p
UCSF - 140020 - M_Neurology
3.0
List the key study personnel: (Note: external and affiliated collaborators
who are not in the UCSF directory can be identified later in the
Qualifications of Key Study Personnel section at the end of the form)
3.1 *Please add a Principal Investigator for the study:
Kim, Anthony S
Select if applicable
Department Chair
Resident
Fellow
If the Principal Investigator is a Fellow, the name of the Faculty Advisor must be supplied
below.
3.2 If applicable, please select the Research Staff personnel:
A) Additional Investigators
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
1 of 45
4/8/21, 11:36 AM


Ch'ang, Judy 
Co-Principal Investigator
Schell-Chaple, Hildegarde M 
Other Investigator
B) Research Support Staff
Chyall, Lawrence 
Study Recruiter
Mcguire, Daniel W 
Study Recruiter
Nguyen, Melissa N 
Study Recruiter
Randazzo, Dominica B 
Study Coordinator
Singhal, Neel MD, PHD, MD PHD 
Study Recruiter
Slown, Kristin 
Study Recruiter
Tran, Nhat 
Biostatistician
Trillanes, Michael R 
Study Recruiter
Villaroman, Andrea L 
Study Coordinator
Vuong, Maximilian N 
Study Coordinator
Winkelman, Amy 
Study Recruiter
3.3 *Please add a Study Contact:
Kim, Anthony S 
Randazzo, Dominica B 
The Study Contact(s) will receive all important system notifications along with the Principal
Investigator. (e.g. The project contact(s) are typically either the Study Coordinator or the
Principal Investigator themselves).
3.4 If applicable, please add a Faculty Advisor/Mentor:
Kim, Anthony S
3.5 If applicable, please select the Designated Department Approval(s):
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
2 of 45
4/8/21, 11:36 AM


Josephson, Scott MD 
Department Chair
Add the name of the individual authorized to approve and sign off on this protocol from your
Department (e.g. the Department Chair or Dean).
4.0
Initial Screening Questions
Updated June 2017
4.1  * PROJECT SUMMARY: (REQUIRED) Give a brief overview of this project (250 words or less). Tell
us what this study is about, who is being studied, and what it aims to achieve. If you have an NIH
Abstract, paste it here:
Click on the orange question mark to the right for more detailed
instructions.
Up to 70% of patients with acute neurologic injury such as subarachnoid hemorrhage (SAH),
intracerebral hemorrhage (ICH), traumatic brain injury (TBI), subdural hematomas (SDH) and
ischemic stroke have fevers during their intensive care stay. Several studies have demonstrated that
with acute neurologic injury, fever is associated with increased mortality, worse functional outcomes,
and a longer ICU and hospital course. Thus, it has become standard of care to immediately and
aggressively treat fever in this population. In addition to treating the etiology of fever, patients will
receive continuous acetaminophen, ice packs, and external cooling to decrease their temperature.
However, current antipyretic therapy is not effective and patients are subjected to the pain of physical
cooling, sedatives, and anti-shivering medications. Acetaminophen only decreases the daily average
temperature by 0.28°C and the peak effect is in the first two hours. Furthermore, external cooling
devices for SAH are associated with increased frequency of tracheostomy, sedative use, and ICU
length of stay. Thus, we must find a better way to establish normothermia.
Bromocriptine, a dopamine receptor agonist, acts at the hypothalamus. Already FDA approved
in several diseases, bromocriptine is known for its antipyretic effect in neuroleptic malignant syndrome
and paroxysmal sympathetic hyperactivity. In recent case reports, bromocriptine successfully treated
refractory central fever. There is one published prospective study of giving bromocriptine to severe TBI
patients to prevent central fever. Here, we propose to evaluate the acute antipyretic effects of
bromocriptine in any etiology of fever in this critically-ill population. Despite its antipyretic activity in
specific febrile syndromes, bromocriptine has never been prospectively studied as a more general
antipyretic in the acute setting. If shown to be effective, this medication could prevent the detrimental
outcomes associated with fever and improve antipyretic management in the ICU. 
4.2  * HUD DEVICE: (REQUIRED) Does this application involve a Humanitarian Use Device (HUD):
No 
Yes, and it includes a research component 
Yes, and it involves clinical care ONLY 
4.3  * TYPE OF RESEARCH: (Click the Help link for definitions and guidance): (REQUIRED)
Biomedical research 
Social, behavioral, educational, and/or public policy research 
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
3 of 45
4/8/21, 11:36 AM


Hybrid - includes aspects of BOTH types of research (check this option if your research is mainly
social/behavioral but also involves specimen collection or blood draws to look at biological
measures) 
4.4  * SUBJECT CONTACT: (REQUIRED) Does this study involve ANY contact or interactions with
participants:
Yes (including phone, email or web contact) 
No (limited to medical records review, biological specimen analysis, and/or data analysis) 
4.5  * RADIATION EXPOSURE: Does your protocol involve any radiation exposure to
patients/subjects EITHER from standard care OR for research purposes (e.g., x-rays, CT-scans,
DEXA, CT-guided biopsy, radiation therapy, or nuclear medicine including PET, MUGA or bone
scans): (REQUIRED)
  Yes   
  No
4.6  * RISK LEVEL: (REQUIRED) What is your estimation of the risk level, including all screening
procedures and study activities (Help Text updated 9/13):
Minimal risk 
Greater than minimal risk 
4.7  * REVIEW LEVEL: (REQUIRED) Requested review level (Click on the orange question mark to the
right for definitions and guidance):
Full Committee 
Expedited 
Exempt 
4.11  * CLINICAL TRIAL: (REQUIRED) Is this a clinical trial? According to The World Health
Organization (WHO) and the International Committee of Medical Journal Editors (ICMJE) a
clinical trial is:
Any research study that prospectively assigns human participants or groups of humans to
one or more health-related interventions to evaluate the effects on health outcomes.
ICMJE requires registration of a clinical trial in a public database (such as ClinicalTrials.gov)
prior to enrollment, for eventual publication of results in member biomedical journals.
Guidance: Public Law 110-85 requires that all investigators who perform an applicable clinical
trial must ensure that the trial is registered on a government web site called ClinicalTrials.gov.
The FDA requires registration for “applicable clinical trials,” defined as follows:
For any trials of drugs and biologics: controlled clinical investigations, other than Phase 1
investigations, of a product subject to FDA regulation.
For trials of biomedical devices: controlled trials with health outcomes of devices subject
to FDA regulation, other than small feasibility studies, and pediatric post-market
surveillance.
For additional information on the ClinicalTrials.gov registration process at UCSF and the
definition of a clinical trial for purposes of registration, visit the ClinicalTrials.gov section of the
UCSF Clinical Research Resource HUB.
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
4 of 45
4/8/21, 11:36 AM


 Yes   
 No
Clinical Trial Registration
"NCT" number for this trial:
NCT03496545
If you don't yet have the NCT#, type 'Pending.' 
4.12  * CLINICAL TRIAL PHASE (REQUIRED) Check the applicable phase(s) (Help Text updated 9/13):
Phase I
Phase II
Phase III
Phase IV
4.13  * INVESTIGATOR-INITIATED: (REQUIRED) Is this an investigator-initiated study:
 Yes   
 No
4.14  * CANCER: (REQUIRED) Does this study involve cancer (e.g., the study involves patients with
cancer or at risk for cancer, including behavioral research, epidemiological research, public
policy research, specimen analysis, and chart reviews):
  Yes   
  No
If you don't know if you should answer 'Yes' or 'No,' please email the Cancer
Center's Protocol Review Committee for help.
4.15  SCIENTIFIC REVIEW: If this study has undergone scientific or scholarly review, please indicate
which entity performed the review (check all that apply):
Cancer Center Protocol Review Committee (PRC) (Full approval is required prior to final CHR
approval for cancer-related protocols.)
CTSI Clinical Research Services (CRS) Advisory Committee
CTSI Consultation Services
Departmental scientific review
Other:
4.16  * STEM CELLS: (REQUIRED) Does this study involve human stem cells (including iPS cells and
adult stem cells), gametes or embryos:
No 
Yes, and requires IRB and GESCR review 
Yes, and requires GESCR review, but NOT IRB review 
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
5 of 45
4/8/21, 11:36 AM


4.17  * FINANCIAL INTERESTS: (REQUIRED) Do you or any other responsible personnel (or the
spouse, registered domestic partner and/or dependent children thereof) have financial interests
related to this study:
  Yes   
  No
5.0
Funding
5.1  * FEDERAL FUNDING: (REQUIRED) Is this study currently supported in whole or in part by Federal
funding, even by a subcontract, OR has it received ANY Federal funding in the past:
  Yes   
  No
5.2  * DoD INVOLVEMENT: Is this project linked in any way to the Department of Defense (DoD):
(REQUIRED)
  Yes   
  No
5.3  SPONSORS: Identify all sponsors and provide the funding details. If funding comes from a
Subcontract, please list only the Prime Sponsor:
External Sponsors:
View
Details
Sponsor Name
Sponsor Type
Awardee
Institution
Contract
Type:
UCSF RAS
"P
number"
or
eProposal
number 
UCSF
RAS
System
Award
Number
("A" +
6
digits) 
No Sponsor has been added to this IRB Study
If the funding is coming through UCSF and you don't know the
A or P number,  you can search the eProposal side for the
contract or grant (this does NOT replace adding the sponsor
by name above AND entering the A or P number):
Project Status
Proposal Number
Project Title
Principal
Investigator
No Projects are Linked to this IRB Study
Other Funding Sources and Unfunded Research - Gift,
Program, or Internal Funding (check all that apply):
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
6 of 45
4/8/21, 11:36 AM


Funded by gift (specify source below)
Funded by UCSF or UC-wide program (specify source below)
Specific departmental funding (specify source below)
Unfunded (miscellaneous departmental funding)
Unfunded student project
6.0
Sites, Programs, Resources, and External IRB Review
6.1  UCSF AND AFFILIATED SITES (check all that apply):
UCSF (including Laurel Heights and all the other sites outside the main hospitals)
Parnassus
Mission Bay
China Basin
Mount Zion
Helen Diller Family Comprehensive Cancer Center
Langley Porter Psychiatric Institute
San Francisco General Hospital (SFGH)
SF VA Medical Center (SF VAMC)
Blood Centers of the Pacific (BCP)
Blood Systems Research Institute (BSRI)
Fresno Community Medical Center
Gallo
Gladstone
Jewish Home
Institute on Aging (IOA)
SF Dept of Public Health (DPH)
Research involving SFGH: You are required to obtain additional
approvals from the SFGH Dean's Office. Download the SFGH Protocol
Application Form and submit the completed form to the SFGH Dean's
Office.
6.2  LOCATIONS: At what locations will study visits and activities occur:
UCSF Parnassus - Neuro ICU 8 and Neuro ICU 11 
Zuckerberg San Francisco General Hospital - Neuro ICU
6.3  OFF-SITE PROCEDURES: Will any study procedures or tests be conducted off-site by non-UCSF
personnel:
  Yes   
  No
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
7 of 45
4/8/21, 11:36 AM


6.4  RESEARCH PROGRAMS: Check any UCSF research programs this study is associated with:
Cancer Center
Center for AIDS Prevention Sciences (CAPS)
Global Health Sciences
Immune Tolerance Network (ITN)
Neurosciences Clinical Research Unit (NCRU)
Osher Center
Positive Health Program
6.5  * CTSI CRS SERVICES: (REQUIRED) Will this study be carried out at one of the UCSF Clinical
Research Services (CRS) units or utilize CRS services:
  Yes   
  No
6.6  * MULTI-CENTER TRIAL: (REQUIRED) Is this a multicenter research trial? By multi-center trial, we
mean a study where the protocol is developed by an industry sponsor, consortium, a disease-
group, etc., who then selects sites across the nation or in different countries to participate in the
trial. The local sites do not have any control over the design of the protocol. 
  Yes   
  No
6.7  OTHER SITE TYPES: Check all the other types of sites not affiliated with UCSF with which you are
cooperating or collaborating on this project:
Do NOT check any boxes below if this is
a multi-center clinical trial, UCSF is just one of the sites, and neither UCSF
nor its affiliates are the coordinating center.
Other UC Campus
Other institution
Other community-based site
Foreign Country
Sovereign Native American nation (e.g. Navajo Nation, Oglala Sioux Tribe, Havasupai, etc.)
6.10  * RELYING ON AN EXTERNAL IRB: Does this application include a request to rely on an
external IRB other than the NCI IRB (e.g. UC reliance, private/commercial IRB, or institutional
IRB): (REQUIRED)
Check out the orange question mark to the right to find out
if your study is eligible for external IRB review.
  Yes   
  No
7.0
Outside Site Information
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
8 of 45
4/8/21, 11:36 AM


7.1  Outside Site Information
Click "Add a new row" to enter information for a site. Click it again to add a second site again to add a
third site, a fourth site, etc.
Click here to view this form.
Outside Site Information
Non-UCSF affiliated site information:
Site name:
Weill Cornell
Contact name:
Judy Ch'ang
Email:
jhc9010@med.cornell.edu
Phone:
419-324-5828
For Federally-funded studies only, corresponding FWA#:
NA
* The research at this site will be reviewed by:
The non-affiliated site's IRB or a private IRB 
The non-affiliated site is requesting UCSF to be the IRB of record for this
study 
The non-affiliated site is not engaged in the human subjects research and
has provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the
application.  If the IRB approval letter is not yet available, submit it once you
receive it. 
Or, if the other site is not engaged in human subjects research, attach the
letter of support to your application.
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
9 of 45
4/8/21, 11:36 AM


8.0
Research Plan and Procedures
8.1  This new consolidated section requests information about:
Hypothesis
Aims
Study Design
Background and Significance
Preliminary Studies
Procedures
Statistical Methods
References
Later sections include:
Drugs and Devices
Sample Size, Eligibility, and Subjects
Recruitment and Consent
Risks and Benefits
Data and Safety Monitoring Plan
Confidentiality, Privacy and Security
Financial Considerations
Qualifications of Personnel
Other Approval and Registrations
8.2  HYPOTHESIS: Describe the hypothesis or what the study hopes to prove (Help Text updated
9/13):
There is a significant reduction in body temperature over 48 hours after administration of
bromocriptine and acetaminophen compared to acetaminophen alone in febrile critically ill patients in
the neuro intensive care unit. 
8.3  AIMS: List the specific aims:
Aim 1. To evaluate the effect of bromocriptine in addition to standard acetaminophen therapy
compared to acetaminophen alone on total body temperature burden above 37°C over 48 hours when
administered within 1 hour of fever >38.3oC in patients with subarachnoid hemorrhage, intracerebral
hemorrhage, traumatic brain injury, subdural hematomas and ischemic stroke in the neurologic
intensive care unit.
Aim 2. To evaluate the safety of bromocriptine in febrile patients with subarachnoid hemorrhage,
intracerebral hemorrhage, traumatic brain injury, subdural hematomas and ischemic stroke in the
neurocritical care intensive care unit. 
8.4  DESIGN: Briefly describe the study design (e.g., observational, interventional, randomized,
placebo-controlled, blinded, cross-over, cross-sectional, longitudinal, pharmacokinetic, etc.):
Two-center, open-label, blinded end-point, interventional, randomized, controlled trial.
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
10 of 45
4/8/21, 11:36 AM


8.5  BACKGROUND AND SIGNIFICANCE: Briefly provide the background and significance of this study
(e.g. why is this study needed) (space limit: one half page):
If this is a first in humans study, please summarize the safety data from the
animal studies. For pediatric drug or device studies, please identify if this is the
first study in pediatric populations.  
Up to 70% of patients with acute neurologic injury have fevers during their intensive care
hospital course. Preclinical animal models demonstrate that hyperthermia, through various
mechanisms, causes worsening brain injury. In human studies, fever is an independent predictor of
poor outcome including increased mortality rates, longer hospital stays, depressed level of
consciousness, and worse functional outcomes. Thus, it has become standard of care to
aggressively control fever in this population but current antipyretic therapy is not very
effective and external cooling subjects patients to the pain of physical cooling, sedatives,
and other medications to prevent shivering. Acetaminophen decreases the daily average
temperature by only ~0.28°C and its peak effect is within the first two hours then quickly declines.
Furthermore, external cooling devices for SAH are associated with increased sedative use, longer ICU
stays, and a higher frequency of tracheostomy. Bromocriptine is a dopamine D2 receptor agonist which
acts at the hypothalamus. Since it is already FDA-approved for several other indications, there is
extensive clinical experience on its safety and tolerability with maximum dosing of 100mg/day. Its
potential use as a more general antipyretic for all etiologies of fever is suggested by the clear
antipyretic effect seen in neuroleptic malignant syndrome (NMS), paroxysmal sympathetic
hyperactivity (PSH) and several case reports which demonstrate bromocriptine’s effectiveness in
treating refractory central fever. In a prospective study evaluating bromocriptine’s acute antipyretic
effect in 50 severe TBI patients, the findings suggested that early administration of bromocriptine
could safely prevent center fever.
The dosing for this proposed study, bromocriptine 5mg every 4 hours (30mg daily total), is
modified off of the dosing recommendations for NMS, PSH, and the aforementioned study in TBI.
Examining the literature regarding the dosing for NMS, various doses were trialed and uptitrated to
effect. There were various starting doses from 2mg every 12 hours to 5mg every 4 hours uptitrated to
15mg every 8 hours. The purpose of starting at a higher dose of 5mg every 4 hours is to establish
efficacy of the antipyretic effect given that there is currently no established dosing for this indication. 
While dizziness, fatigue, headache, constipation, nausea, skeletal muscle weakness, rhinitis,
orthostatic hypotension and sleepiness have been reported across different dosages and disease states
from clinical trials, all of these studies in critically-ill patients reported no serious adverse events. In
Parkinson's Disease patients, there seemed to be a cumulative dosing effect on increasing the risk of
valvular heart disease. In a retrospective study evaluating 72 bromocriptine patients and 47 control,
the mean cumlative dose was 20053.7mg +/-17660.9 mg and patients were treated for a mean
duration of 43 months. The patients in this study will only be exposed to 30mg daily for 48
hours. Given that the pathogenesis of both infectious and noninfectious fever revolves around the
hypothalamus, and we have evidence that bromocriptine has an antipyretic effect at the
hypothalamus, we deduce that bromocriptine could be used more broadly to treat all fevers in the
acute setting and not just refractory central fevers. Here, we propose to evaluate the acute antipyretic
effects of bromocriptine in this critically-ill population through a pilot, open label, blinded endpoint,
randomized controlled trial. It is imperative that in this population already stricken with significant
mortality and morbidity, we develop better methods of achieving normothermia to prevent the
detrimental outcomes that fever has on the already injured brain. Data from this pilot study would
form the basis for a definitive study on the impact of bromocriptine on outcomes in neuro
ICU patients.
8.6  PRELIMINARY STUDIES: Briefly summarize any preliminary studies relevant to your proposed
research (space limit: one half page):
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
11 of 45
4/8/21, 11:36 AM


Although there are several case reports, a retrospective study in SAH, and a prospective RCT
in TBI, significant limitations exist and many questions regarding the use of bromocriptine still remain.
These case reports describe patients with mostly ICH and one with mixed autonomic hyperactivity
disorder who all underwent extensive infectious and noninfectious work ups. Patients were treated with
current antipyretic management; but, they were only responsive to bromocriptine, suggesting an
antipyretic effect in refractory fevers in acute neurologic illnesses. However, bromocriptine was not
administered immediately upon fever diagnosis and not all of the specific dosing regimens were
reported. Then in 2017, an Egyptian group published a prospective randomized control trial (N=50) in
severe TBI patients where bromocriptine was administered upon admission. This trial did not state the
duration of treatment, nor did they define what medications/interventions were in the control therapy
group. They demonstrated that bromocriptine could be safely administered in the acute setting of TBI.
Recently, an abstract was published which retrospectively evaluated eight aneurysmal subarachnoid
hemorrhage patients who received bromocriptine and found no significant difference in median time to
fever cessation and length of ICU or hospital stay. The abstract does not provide how the comparison
group was chosen, the dosing of bromocriptine, the difference of antibiotic use, and if all patients were
exposed to the same cooling practices amongst many other confounding factors. They do admit that
prospective studies are warranted. With all of this initial data on bromocriptine’s antipyretic effect, still
no study exists which prospectively evaluates this drug’s efficacy in the acute setting for all etiologies
of fever in a heterogeneous population of acute neurologic illness. These cases and studies have
suggested bromocriptine’s efficacy and safety in refractory fevers and in the acute setting. However,
we need a prospective randomized trial which evaluates a standard antipyretic dosing of bromocriptine
and its use not as fever prophylaxis but as immediate fever treatment in SAH, TBI, ICH, SDH and
ischemic stroke. Prior data hints at bromocriptine’s potential to change antipyretic management and
this study is protocoled and powered to investigate just that. 
8.7  * TREATMENT PROTOCOL: Is this a treatment study, i.e. does this study intend to provide
treatment to individuals with a medical or psychological condition: (REQUIRED)
 Yes   
 No
8.8  * BILLABLE PROCEDURES: Does this study involve any services or procedures (e.g. physical
exams, surgeries, lab tests, imaging studies, or drugs) that could be billable to patients, their
insurance, Sponsor, or any other entity (answer 'Yes' even if the study is going to pay for all the
procedures): (REQUIRED)
 Yes   
 No
If you are not sure if your study involves billable procedures, send an email to
the UCSF Office of Clinical Research (OCR) for help answering this question.
8.9  * COMMON RESEARCH ACTIVITIES: Types of research activities that will be carried out. Check all
that apply and describe in more detail in the 'Procedures / Methods' section: (REQUIRED)
Interviews, questionnaires, surveys
Educational or cognitive tests
Focus groups
Observation
Non-invasive imaging or testing (MRI, EEG, pulse oximetry, etc.)
Administration of contrast agent
Imaging procedures or treatment procedures that involve radiation (x-rays, CT scans, CT-guided
biopsies, DEXA scans, MUGA or PET scan)
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
12 of 45
4/8/21, 11:36 AM


Biopsy conducted solely for research purposes
Use of placebo
Sham surgical procedure
Collection of data from wearable tech such as Fitbit, Apple Watch, Garmin, motion actigraphs, etc.)
Fitness tests or other exertion activities
Use of mobile health apps or other apps
Social media-based research activities
None of the above
8.10  * PROCEDURES / METHODS: (REQUIRED)
For clinical research, list all study procedures, tests and treatments
required for this study, including when and how often they will be
performed. If there are no clinical procedures, describe the research
activities.
If some of the activities would occur even if the person were not in the
study, as in the case of treatment or tests performed for diagnostic
purposes, clearly differentiate between those activities that will be
done solely for research purposes and those that are happening as part
of routine care.
Examples may include:
additional scans outside standard clinical diagnosis or monitoring
additional biopsies to collect tissue for research
extra clinic visits
extra lab tests not required for clinical care
If you have a procedure table, attach it to the submission with your
other study documents.
1. Communicate with primary team physician about patient's eligibility to participate in study.
2. Screen and consent all patients/surrogates upon arrival to the ICU: signed consent in patient
chart. Copy to send to pharmacy. 
3. Screen body temperature from routine thermometry methods used in ICUs for temperatures ≥
38.3°C for routine care through esophageal, bladder, or rectal means. Patients at SFGH must
be attached to a Moberg monitor. All apart of routine care. 
4. Enroll patient when body temperature ≥ 38.3°C: Activate study protocol.
5. If for any reason, the patient or surrogate decides they initially do not want to participate in the
study but then later would like to participate after the patient becomes febrile, the research
team will re-screen the patient to make sure the patient is still eligible. If the patient is eligible,
they can be enrolled; medical intervention administration will be based off of 1) the washout
period of any antipyretics given prior to enrollment and 2) body temperature of the patient ≥
38.3 ºC within 1 hour of study drug administration. 
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
13 of 45
4/8/21, 11:36 AM


6. Preprinted provider order for study drug
1. Provider signature (Critical Care Medicine Physician or Primary team)
2. Order in chart and copy sent to pharmacy with copy of signed consent.
3. Pharmacy to randomize and prepare blinded study drug within 30 minutes.
7. Intervention: bromocriptine 5mg every 4 hours PO/NG/FT and acetaminophen 650mg every 4
hours PO/NG/FT for 48 hours, initiated within 1 hour after temperature reading ≥
38.3ºC. Control: acetaminophen 650mg every 4 hours PO/NG/FT for 48 hours, initiated within 1
hour after temperature reading ≥ 38.3ºC.
8. Measure temperature every 3 seconds from initial drug administration if patient has a rectal,
esophageal, or urinary temperature probe. These probes used are in routine care. The patient
must maintain one of these temperature probes for the 48 hour duration of study. 
9. During each nursing shift starting from first medication administration during the 48 hour study
period, the bedside nurse will do a 5-minute assessment, thus a total of 4 assessments. 
10. At the end of every shift from first medication administration for the next 48 hours, please
complete this 5-minute assessment:
1. During your shift, has the patient had episodes of decreases in systolic pressures >20mm Hg
or diastolic pressures >10mm Hg respectively? If no, please go to question 2.   [yes]    [no]    
1a. If you answered yes, how many episodes of decreases in systolic pressures
>20mm Hg or diastolic pressures >10mm Hg respectively occurred?  ___ 
1b. How many episodes of systolic blood pressure < 90mm Hg occurred?  ___
1c. Were any of these episodes associated with dizziness or lightheadedness?    [yes]  
[no]   [not applicable/patient cannot answer] 
1d. Were these episodes associated with position change or movement?  ____
1f. How many episodes received treatment?   ___
1g. Were these episodes within the first 2 hours of receiving the first dose of
bromocriptine? (Only answer if you started bromocriptine on your shift)    [yes]   [no] 
2. During your shift, has the patient had headache?       [yes]    [no]     [patient not able to
report]
If no or patient not able to report, please go to question 3.
2a. Were the headaches (circle all that apply)   [mild]    [moderate]    [severe]
2b. How many headaches received an intervention?   ____
2c. How many headaches self-resolved? ____
2d. Were these headaches within the first 2 hours of receiving the first dose of
bromocriptine? (Only answer if you started bromocriptine on your shift)    [yes]   [no] 
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
14 of 45
4/8/21, 11:36 AM


3. In the last 12 hours, has the patient experienced nausea?    [yes]    [no]     [patient not able
to report]  If no or patient
3a. How many episodes of nausea self-resolved?  ____      
3b. How many episodes of nausea received an intervention?  ____  
3c. Were these episodes of nausea within the first 2 hours of receiving the first dose of
bromocriptine? (Only answer if you started bromocriptine on your shift)    [yes]   [no]   
11. No physical cooling (fans, ice packs, cooling blanket) during study period.
12. No administration of other antipyretics (medications containing acetaminophen, NSAIDs and
Aspirin > 300 mg) during study period.
13. Rescue protocol: If temperature increases to > 40oC during 48 hour study period, the primary
team provider will be notified. Physical cooling or antipyretic medication interventions may be
ordered at the discretion of the provider. All body temperature altering interventions will be
recorded.
14. If heart rate or blood pressure increase or decrease beyond ordered notification parameters,
the nurse will contact the primary team provider per routine standard of care. 
15. After the trial period is over, other clinical data will be extracted from the chart retrospectively
such as laboratory and culture data, antibiotic use, and days spent in ICU. Please see protocol
attachment, schedule of activities. 
16. 30 Day Follow-up
Subjects or surrogates, family members, friends, medical health professionals taking care of the
patient will be contacted by phone at 30 days to complete a modified rankin score. They will be given
the 30 day phone call form which lists the questions they will be asked. This assessment will be
completed by a study team member and will take approximately 15 minutes. The phone script: Hello,
my name is xxxx and I am calling from UCSF Medical Center or Zuckerberg San Francisco General
Hospital. This is a follow up call for [participant name].  Is it possible for me to speak to that person or
[surrogate, family, friend, medical health professional taking care of the patient]? Great. Were you or
[patient name] admitted to [UCSF or ZSFGH] for [SAH, TBI, ICH, or ischemic stroke]? I am calling
about the fever study, bromocriptine for fever, that [you or patient name] took part of.  Is this a
convenient time to talk for about 15 minutes or arrange a time that is better?" 
If the patient remains in an institutional setting at 30 days and is unable to speak on the phone, then
the medical health professionals caring for the patient may be able to answer the quesitons regarding
their functional status as stated in the new consent form. If the patient is in a home setting but is
unable to speak on the phone for any reason, then family, friend or caretaker may also answer
quesitons about their functionality which is stated in the new consent form. Non-English speakers will
be interviewed using the hospital cerfitied language interpreters which can call in on the phone and
interpret the conversation. 
The 30 day phone call document states that 
"A member of the research team will be contacting you or your legally authorized representative,
surrogate, friend, family member, or medical health care professional taking care of you in 30 days to
see how you are doing. This phone call will only take approximately 15 minutes and will ask the
following questions to assess how you are doing." Then the document lists the questions being asked. 
1. Do you have any symtpoms that are bothering you?          yes __     no __
2. Are you able to do the same work as before?          yes __     no __
3. Are you able to keep up with your hobbies?       yes __     no __
4. Have you maintained your ties to friends and family?     yes __     no __
5. Do you need help making a simple meal, doing household chores, or balancing a checkbook?  yes
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
15 of 45
4/8/21, 11:36 AM


__     no __
6. Do you need help with shopping or traveling close to home?     yes __     no __
7. Do you need another person to help you walk?  yes __     no __
8. Do you need help with eating, going to the toilet, or bathing?  yes __     no __
9. Do you stay in bed most of the day and need constant nursing care?  yes __     no __
From these answers, the research team member will then use an online modified rankin calculator to
calculate the MRS. mRS calculator website at: http://www.modifiedrankin.com/ and click on the
blue box “Continue to the Data Entry Page." Enter patient/proxy answers.  Click on the blue box
“Calculate the mRS”. 
For the patients previously enrolled and still admitted in the hospital whose surrogates
signed the consent form without the new modification regarding the 30 day phone follow
up, I will re-consent them with the new consent form and submit to APEX in order to reach
them in 30 days.  
8.11  STANDARD CLINICAL PRACTICE: To what extent, if any, do the planned research procedures
differ from the care that people would otherwise receive at this institution or the study site if not
being done locally:
Currently standard clinical practice at UCSF Parnassus is giving acetaminophen but dosing and
frequency vary per treating team. Then the use of external cooling blankets or intravascular cooling
device is also variable and depends on the treating team or even bedside nurse. 
At the beginning of this year, Zuckerberg San Francisco General Hospital adopted a Fever Management
protocol for Critical Neurological Injury, TBI, and Stroke. To achieve a goal temperature of 37.5°C, the
following will be done: continuous core temperature monitoring with esophageal probe and rectal or
bladder probe. Document temperature q 1 hour and PRN. Acetaminophen will be initiated: 650 mg
PO/FT q 4 hours ATC. Give PR if unable to give PO/FT.  NTE 4 gm in 24 hrs.  Discontinue any prior
acetaminophen orders. Obtain blood cultures x2, urine and tracheal aspirate cultures q 48 hours. For
temperature >38.3°C sustained for 2 or more hours: Initiate surface cooling per Critical Care
Department Policy No. 31.0 “Zoll InnerCool STx—External Temperature System”. Call MD for drop in
temperature of more than 1°C every 15 minutes. Then, for fever not adequately managed by surface
cooling within 8 hours the primary service will consult Neurocritical Care for intravascular cooling
catheter placement.
In this study, if a patient has a temperature ≥ 38.3°C, the patients will be randomized to the control
or intervention arm. Control is currently standard of care as the use of surface cooling is based on
provider preference. No other methods for physical cooling (fans, ice packs, cooling blanket,
external/intravascular cooling) or other antipyretics such as NSAIDS or aspirin >300mg will be
permitted during the 48-hour study period unless the temperature increases to > 40ºC during the
study period or unless required for standard clinical care (e.g. for ischemic stroke patients). 
8.12  INSTRUMENTS: List all questionnaires, surveys, interview, or focus group guides that will be
used for this study:
At the end of every shift from first medication administration for the next 48 hours, please complete
this 5-minute assessment:
1. During your shift, has the patient had episodes of decreases in systolic pressures >20mm Hg or
diastolic pressures >10mm Hg respectively? If no, please go to question 2.   [yes]    [no]    
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
16 of 45
4/8/21, 11:36 AM


1a. If you answered yes, how many episodes of decreases in systolic pressures >20mm Hg or
diastolic pressures >10mm Hg respectively occurred?  ___ 
1b. How many episodes of systolic blood pressure < 90mm Hg occurred?  ___
1c. Were any of these episodes associated with dizziness or lightheadedness?    [yes]   [no]  
[not applicable/patient cannot answer] 
1d. Were these episodes associated with position change or movement?  ____
1f. How many episodes received treatment?   ___
1g. Were these episodes within the first 2 hours of receiving the first dose of bromocriptine?
(Only answer if you started bromocriptine on your shift)    [yes]   [no] 
2. During your shift, has the patient had headache?       [yes]    [no]     [patient not able to report]
If no or patient not able to report, please go to question 3.
2a. Were the headaches (circle all that apply)   [mild]    [moderate]    [severe]
2b. How many headaches received an intervention?   ____
2c. How many headaches self-resolved? ____
2d. Were these headaches within the first 2 hours of receiving the first dose of bromocriptine?
(Only answer if you started bromocriptine on your shift)    [yes]   [no] 
3. In the last 12 hours, has the patient experienced nausea?    [yes]    [no]     [patient not able to
report]  If no or patient
3a. How many episodes of nausea self-resolved?  ____      
3b. How many episodes of nausea received an intervention?  ____  
3c. Were these episodes of nausea within the first 2 hours of receiving the first dose of
bromocriptine? (Only answer if you started bromocriptine on your shift)    [yes]   [no] 
30 Day Phone call FU: Modified Rankin Score (MRS assessment)
The 30 day phone call document states that 
"A member of the research team will be contacting you or your legally authorized representative,
surrogate, friend, family member, or medical health care professional taking care of you in 30 days to
see how you are doing. This phone call will only take approximately 15 minutes and will ask the
following questions to assess how you are doing." Then the document lists the questions being asked. 
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
17 of 45
4/8/21, 11:36 AM


1. Do you have any symtpoms that are bothering you?          yes __     no __
2. Are you able to do the same work as before?          yes __     no __
3. Are you able to keep up with your hobbies?       yes __     no __
4. Have you maintained your ties to friends and family?     yes __     no __
5. Do you need help making a simple meal, doing household chores, or balancing a checkbook?  yes
__     no __
6. Do you need help with shopping or traveling close to home?     yes __     no __
7. Do you need another person to help you walk?  yes __     no __
8. Do you need help with eating, going to the toilet, or bathing?  yes __     no __
9. Do you stay in bed most of the day and need constant nursing care?  yes __     no __
From these answers, the research team member will then use an online modified rankin calculator to
calculate the MRS. 
Attach any unpublished instruments in the 'Other Study Documents'
section of the Initial Review Submission Packet form after completing
the study application. Published instruments should NOT be attached.
8.13  * BIOSPECIMEN COLLECTION: Are you drawing any blood or collecting other biosamples (e.g.
tissue, buccal swabs, urine, saliva, hair, etc.): (REQUIRED)
  Yes   
  No
8.26  STATISTICAL METHODS: Briefly summarize the methods and types of analyses that will be
performed:
Using data from a prior published study of acetaminophen versus ibuprofen to estimate the standard
deviation of the potential treatment effect, which assumes a standard deviation of 0.5ºC, with 20
patients per group, we will have 80% power to detect a 0.46 ºC group difference with a two-tailed a of
0.05. Based on the volume of neuroICU admissions and a prior study evaluating intravenous
acetaminophen that enrolled 2-5 patients a month from just the UCSF Parnassus neuro ICU, we expect
to be able to randomize 40 patients over an 8-month enrollment period at two institutions.
The primary endpoint of this study is the difference in total temperature burden > 37º C over 48 hours
as captured by the area under the temperature—time curve (AUC) between the control and the
intervention groups. We will calculate the AUC for each patient, derive the mean AUC in each group,
and then compare these means using a paired t-test. We will use Fisher's exact test to compare the
side effect profile between the two groups. 
8.27  REFERENCES: List only the 5-10 most relevant references (a separate bibliography can be
attached for reference purposes if this study involves novel approaches, agents, or an emerging
technology that the IRB may not be familiar with):
1. Greer, D.M., et al., Impact of fever on outcome in patients with stroke and neurologic injury: a
comprehensive meta-analysis. Stroke, 2008. 39(11): p. 3029-35.
2. Badjatia, N., et al., Impact of induced normothermia on outcome after subarachnoid hemorrhage: a
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
18 of 45
4/8/21, 11:36 AM


case-control study. Neurosurgery, 2010. 66(4): p. 696-700; discussion 700-1.
3. Kang, S.H., et al., Bromocriptine for control of hyperthermia in a patient with mixed autonomic
hyperactivity after neurosurgery: a case report. J Korean Med Sci, 2012. 27(8): p. 965-8.
4. Natteru, P., et al., Central Hyperthermia Treated with Bromocriptine. Case Rep Neurol Med, 2017.
2017: p. 1712083.
5. Samudra, N. and S. Figueroa, Intractable Central Hyperthermia in the Setting of Brainstem
Hemorrhage. Ther Hypothermia Temp Manag, 2016. 6(2): p. 98-101.
6. Yu, K.W., et al., Effectively managing intractable central hyperthermia in a stroke patient by
bromocriptine: a case report. Neuropsychiatr Dis Treat, 2013. 9: p. 605-8.
7. Zakhary, T.S., Ahmed, Bromocriptine in Central Hyperthermia after Severe Traumatic Brain Injury.
Open Journal of Emergency Medicine, 2017. 5: p. 102-109.
8. Reeder, J.C., RS.; Mittal, Manoj, Time to Central Fever Cessation in Aneurysmal Subarachnoid
Hemorrhage Patients with Bromocriptine - Abstract Only. Crit Care Med, 2018. 46(1): p. 376.
9. Mullins, M.E., et al., A prospective randomized study to evaluate the antipyretic effect of the
combination of acetaminophen and ibuprofen in neurological ICU patients. Neurocrit Care,
2011. 15(3): p. 375-8.
10. Tan LC, et al., Bromocriptine use and the risk of valvular heart disease. Mov Disord.
2009;24(3):344-9.
11. Rosenberg, M. R., & Green, M. (1989). Neuroleptic malignant syndrome. Review of response to
therapy. Arch Intern Med, 149(9), 1927-1931. 
9.0
Drugs and Devices
9.1  * DRUGS AND/OR BIOLOGICS: Are you STUDYING any drugs and/or biologics that are either
approved or unapproved: (REQUIRED)
 Yes   
 No
9.2  LIST THE DRUGS OR BIOLOGICS: List the drugs or biologics that will be studied. In the drug
details screen you will be asked questions such as:
Whether the drug or biologic is FDA approved
If the drug or biologic will be provided at no cost
If an IND is necessary, the IND number, and who holds the IND
If the drug or biologic is FDA approved and an IND is not required, the rationale for the
decision
If the Investigational Drug Service (IDS) is dispensing the drug or biologic (required unless
a waiver is obtained from the IDS)
Please see the UCSF IRB website for more details about the use of drugs and biologics in
research, including the IND Decision Worksheet.
Verification of IND numbers: If the sponsor’s
protocol does not list the IND number, you must submit documentation from the sponsor or FDA
identifying the IND number for this study. Attach this documentation in the Other Study
Documents section of the Initial Review Submission Packet.
If you have any
correspondence from the FDA or sponsor regarding this drug or biologic,
please attach it to the application.
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
19 of 45
4/8/21, 11:36 AM


View
Details
Drug Name
FDA Approved
A new drug or a
new use of
approved drug:
IND Number
Trade Drug
Name:
BROMOCRIPTINE
MESYLATE
Generic Drug
Name:
BROMOCRIPTINE
MESYLATE
Investigational
Drug Name:
Yes 
Yes 
Trade Drug Name:
BROMOCRIPTINE MESYLATE 
Generic Drug Name:
BROMOCRIPTINE MESYLATE 
Investigational Drug Name:
Identify the name of the
manufacturer or source of
investigational drug/biologic:
Mylan  
Is the drug supplied at no cost?
No  
Is the Drug FDA Approved:
Yes  
Is this a new drug or a new use
of an already approved drug
Yes  
Is an IND necessary
No  
IND Number
Who holds the IND:
N/A  
IND details:
If FDA Approved and an IND is
not required, Please provide a
rationale for exemption:
An investigator proposes a small pilot study of an approved
drug for a novel use and states that an IND is not needed
because the data will not be submitted to the FDA. The
investigator explains that if the pilot data looks promising a
larger trial will be submitted with an IND. The IRB is likely to
approve the pilot study without an IND because a small pilot
study is an appropriate first step in determining whether a
change in labeling should be sought.  
Are you currently using this IND
in another research project?
No  
If yes, list the IRB Number(s):
Will the investigational pharmacy
be dispensing?
Yes  
If the source is not a FDA
licensed facility, provide details
regarding the purity, quality,
stability and sterility of the
investigational drug/biologic:
Trade Drug
Name: ACETAMINOPHEN
Generic Drug
Name:
ACETAMINOPHEN
Investigational
Drug Name:
Yes 
No 
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
20 of 45
4/8/21, 11:36 AM


Trade Drug Name:
ACETAMINOPHEN 
Generic Drug Name:
ACETAMINOPHEN 
Investigational Drug Name:
Identify the name of the
manufacturer or source of
investigational drug/biologic:
generic manufacturer from the investigational pharmacy  
Is the drug supplied at no cost?
Yes  
Is the Drug FDA Approved:
Yes  
Is this a new drug or a new use
of an already approved drug
No  
Is an IND necessary
No  
IND Number
Who holds the IND:
N/A  
IND details:
If FDA Approved and an IND is
not required, Please provide a
rationale for exemption:
We are using the drug for its approved indication and it is
standard of care.  
Are you currently using this IND
in another research project?
No  
If yes, list the IRB Number(s):
Will the investigational pharmacy
be dispensing?
Yes  
If the source is not a FDA
licensed facility, provide details
regarding the purity, quality,
stability and sterility of the
investigational drug/biologic:
9.3  * MEDICAL DEVICES: Are you STUDYING any medical devices, in vitro diagnostics, or assays that
are either approved or unapproved:(REQUIRED)
  Yes   
  No
9.6  * Is this an expanded access or compassionate use protocol, meaning the primary purpose is to
diagnose, monitor or treat a patient's condition, rather than the collection of safety and efficacy
data of the experimental agent: (REQUIRED)
  Yes   
  No
10.0
Sample Size and Eligibility Criteria
10.1  ENROLLMENT TARGET: How many people will you enroll:
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
21 of 45
4/8/21, 11:36 AM


90
 If there are multiple participant groups, indicate how many people will be in
each group:
acetaminophen 650mg every 4 hours: N = 45
acetamionphen 650mg every 4 hours and bromocriptine 5mg every 4 hours: N = 45 
A targeted enrollment of 30 subjects per group is planned to account for any patients who are
discontinued or excluded due to the potential risk of instability and unplanned procedures related to
their critical illness. 
10.3  SAMPLE SIZE JUSTIFICATION: Explain how and why the number of people was chosen. For
multi-site studies, this is referring to the number that will be enrolled across all sites:
Using data from a prior published study of acetaminophen versus ibuprofen to estimate the standard
deviation of the potential treatment effect, which assumes a standard deviation of 0.5ºC, with 20
patients per group (control arm n = 20, intervention arm n = 20), we will have 80% power to detect a
0.46 ºC group difference with a two-tailed a of 0.05. A targeted enrollment has been increased to 90
because out of the 25 patients enrolled, 3 have been nonfebrile, 2 have received cooling blankets, 2
had missed doses because were away at procedures, 1 died secondary to withdrawal of care, 1 was
withdrawn from the study (patient was doing well and family did not want to give him more
medications). Thus out of enrolling 25 patients, 9 were not able to reach full analysis. Likely with every
25 patients, 9 patients will not fit primary analysis thus, would increase total enrollment to 90 patients
in order to reach 40 that would fit primary analysis. We will enroll 90 patients over both sites. 
10.4  * PARTICIPANT AGE RANGE: Eligible age ranges: (REQUIRED)
0-6 years
7-12 years
13-17 years
18-64 years
65+
10.5  * STUDY POPULATIONS: Data will be collected from or about the following types of people
(check all that apply): (REQUIRED)
Inpatients
Outpatients
Family members or caregivers
Providers
People who have a condition but who are not being seen as patients
Healthy volunteers
Students
Staff of UCSF or affiliated institutions
None of the above
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
22 of 45
4/8/21, 11:36 AM


10.6  * SPECIAL SUBJECT GROUPS: Check the populations that may be enrolled: (REQUIRED)
Children / Minors
Subjects unable to consent for themselves
Subjects unable to consent for themselves (emergency setting)
Subjects with diminished capacity to consent
Subjects unable to read, speak or understand English
Pregnant women
Fetuses
Neonates
Prisoners
Economically or educationally disadvantaged persons
None of the above
If not already addressed in the Background and Significance questions in the
Research Plan section or elsewhere, explain why it is appropriate to include
the types of subjects checked above in this particular study:
It is appropriate to include patients who cannot consent for themselves or have diminished capacity to
consent due to the nature of their critical illness (e.g. neurologically injured) or the therapies they are
receiving (e.g. sedating medications) to achieve the aim of understanding the response and safety of
the study intervention on body temperature. It is common for neuro-critically ill patients with fever to
have a condition or therapy-induced situation that renders them unable to consent for themselves.
We do not want to exlclude non-English speaking patients or surrogates. We do not expect a high
number of non-English speaking patients or surrogates.
Describe the additional safeguards that have been included in the study to
protect the rights and welfare of these subjects and minimize coercion or undue
influence:
Here are some examples:
evaluating capacity to consent for individuals who may be decisionally
impaired (specify how)
calibrating payment amounts to be non-coercive for the financially
disadvantaged
conducting more in-depth evaluations of subjects’ understanding of the
study and the voluntary nature of participation
involving advocates in the consent process
More information and other safeguards are described here: Vulnerable
Subject Populations and Recruiting Staff and Students.
Additional safeguards that will be put in place to protect subjects who are unable to consent for
themselves include the procedure for obtaining consent from a surrogate if the subject is unable to
consent along with informing the subject about their participation in the study when they regain ability
to participate in the consent process. They will be given the option to decline consent at that time.
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
23 of 45
4/8/21, 11:36 AM


10.7  INCLUSION CRITERIA:  Briefly describe the population(s) that will be involved in this study.
Include anyone that data will be collected from or about (e.g. patients, healthy controls,
caregivers, providers, administrators, students, parents, family members, etc.):
1. age ≥18 years old
2. weight ≥ 40 kg
3. at least one reading of body temperature ≥ 38.3 ºC
4. diagnosis of subarachnoid hemorrhage, intracerebral hemorrhage, traumatic brain injury, subdural
hematoma, or ischemic stroke
5. admission to the Intensive Care Unit at UCSF Medical Center or Zuckerberg San Francisco General
Hospital.
10.8  EXCLUSION CRITERIA: List any exclusion criteria (e.g. reasons why someone would not be
included in the study):
1. bromocriptine or acetaminophen hypersensitivity or allergy
2. known contraindication to bromocriptine— known ergot alkaloid hypersensitivity, known history
of syncopal migraine
3. contraindication to nasogastric tube or swallowing pills 
4. contraindication to esophageal, rectal or urinary temperature probe 
5. current diagnosis of acute liver failure, acute liver injury, or prior diagnosis of cirrhosis
1. Acute presentation (< 26 weeks), evidence of coagulation abnormality: international
normalized ratio (INR) ≥ 2; evidence of liver damage: alanine aminotransferase (ALT) of
10 x normal value; and any degree of mental status alteration
5. currently being treated with intra or extravascular therapeutic hypothermia – or where
therapeutic hypothermia treatment is anticipated during study period
6. hyperthermic syndromes: heat stroke, evidence of thyrotoxicosis, malignant hyperthermia,
neuroleptic malignant syndrome, or other drug-induced hyperthermia
7. administration of acetaminophen or acetaminophen containing medications within 9 hours prior
to fever presentation
8. administration of non-steroidal anti-inflammatory drugs (NSAIDs) within 6 hours prior to fever
presentation or aspirin > 300mg less than 1 hour prior to fever presentation.
9. pregnancy or women in the post-partum period (6 months after delivery)
10. extracorporeal blood circuit therapies: replacement therapy, extracorporeal life support
(ventricular assist device, extracorporeal membrane oxygenation) during study period
11. anticipated ICU stay < 48 hours
12. creatinine clearance ≤ 30 mL/min 
13. severe cardiovascular disease (especially unstable angina or severe valvular disease)
14. patients already taking bromocriptine for other indications 
10.9  * RESEARCH CONDUCTED ON PATIENT CARE WARDS: Do any study activities take place on
patient care units at UCSF medical facilities: (REQUIRED)
 Yes   
 No
Attach a letter of acknowledgement for the study from the involved
patient care manager. If you don't know who the patient care manager
is, click here to send an email to the nursing group.
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
24 of 45
4/8/21, 11:36 AM


11.0
Recruitment and Consent
11.1  * RECRUITMENT METHODS: What kinds of methods will be used to identify potential participants
for recruitment (check all that apply): (REQUIRED)
Medical records review
Recruitment registry
Re-contact of participants from the investigators' previous studies
Referrals from colleagues (attach the 'Dear Colleague' letter or other recruitment materials you will
provide to colleagues)
Referrals from the community / word of mouth
Advertisements (flyers, brochures, radio or t.v. ads, posting on clinical research sites or social
media, presentation of the study at community events/media, etc.)
Online recruiting tool such as TrialSpark
CTSI Recruitment Services unit
Other method (describe below)
11.2  * SEARCHING OF MEDICAL RECORDS: (REQUIRED)
Whose patients are they:
Investigators' own patients or patients seen within the same practice
Patients not under the care of the investigators
How and by whom will records be accessed and searched (check all that apply):
Self-search in APeX or other medical records source
Self-search using UCSF's Research Cohort Selection Tool
CTSI Consultation Service Recruitment Services
UCSF Academic Research Services (ARS)
University of California Research Exchange (UC ReX)
Other method (describe below)
11.3  DETERMINATION OF ELIGIBILITY: How, when, and by whom will eligibility for recruitment be
determined:
When patients are admitted to the neuro ICU, a member of the research team will perform initial
screening for eligibility through the EMR, discuss with the primary team and consent the patient or
surrogate if the patient meets inclusion and exclusion criteria. The research team may be contacted by
nurses, primary team members or ICU team members. The research team will be doing all screening
and recruitment.
11.4  * INITIATION OF CONTACT: Who initiates contact (check all that apply): (REQUIRED)
Investigators/study team
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
25 of 45
4/8/21, 11:36 AM


UCSF recruitment unit (e.g. CTSI Consultation Services)
Potential participant
Other (explain below)
11.5  * HOW IS CONTACT INITIATED: (check all that apply): (REQUIRED)
In person
Phone
Letter / email
Website or app
Other (explain below)
11.6  RECRUITMENT PLAN: Based on the checkboxes you chose above, please provide a narrative
describing your recruitment plan. We want to know:
Who is conducting the search for potential participants, and how?
How are potential subjects being approached for recruitment? By whom, and when?
If there will be more than one participant group (e.g. patients, healthy controls, caregivers,
family members, providers, etc.), provide details about the recruitment plans for each group.
(Recommended length - 100-250 words)
When a patient is admitted to the neuro ICU, the research team will be contacted by the ICU charge
nurse, ICU nurse, ICU team, or primary team or the research team member may find that a new
patient has been admitted through APEX. If the patient is eligible, a member of the research team will
discuss the appropriateness of the patient with the primary team. After determining appropriateness
with the team and eligibility criteria are met, the research team member will approach the patient in
the ICU room for the informed consent process. Potential subjects will be given as much time as they
need to consider whether to enroll in the study. In the situation when a patient clearly agrees to
participate in the study, but is unable to sign the consent form because of a physical impairment, such
as the temporary inability to use a writing instrument due to limited mobility, device interference (e.g.
arterial line, arm board), localized edema, and or extremity injury, a present family member or ICU
nurse can provide witnessed consent for the patient's signature. All procedures will be done in a
manner that protects the human subject from research risks. 
If it is determined that the patient is unable to participate in the consent process, the research team
member will describe the research protocol to the patient and indicate the intent to obtain surrogate
consent. If there are no indications of resistance or dissent, the research team member will approach
the patient’s surrogate in the ICU and go to a private location proximal to the ICU room for the
informed consent process. Patient surrogates will be given as much time as they need to consider
consent for participation in the study. 
If for any reason, the patient or surrogate decides they initially do not want to participate in the study
but then later would like to participate after the patient becomes febrile, the research team will re-
screen the patient to make sure the patient is still eligible. If the patient is eligibile, they can be
enrolled in the study at that time. Timing of medical intervention will be based off of 1) the washout
period of any antipyretics given prior to enrollment and 2) timing of last body temperature of the
patient ≥ 38.3 ºC (must be within 1 hour of study medication administration). 
11.7  * CONSENT METHODS: How will permission to participate (i.e., informed consent) be obtained
from each potential participant. If there will be multiple groups and different plans for
consenting each, check all that apply. See the orange Help bubble to the right for more detailed
guidance.
Participants will (check all that apply): (REQUIRED)
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
26 of 45
4/8/21, 11:36 AM


Sign a consent form at the end of the consent discussion (signed consent)
Provide online 'eConsent' using DocuSign or another E-Signature system
Click through a link in a survey or email after reading about the study and then complete the study
online (electronic consent)
Be told about the study and be given a handout/information sheet and be asked if they agree to
participate (verbal consent)
Complete the study activities and turn in materials, as in the case of a completed survey that is
placed in a drop box or mailed to the study team (implied consent)
Not be able to provide consent and will have a family member consent for them, as in the case of a
critically ill or unconscious patient (surrogate consent)
Not be able to provide consent (emergency waiver of consent - allowed for minimal risk research
or greater than minimal risk research with an approved community consultation plan)
Not know about the study, as in the case of chart reviews or observations of public behavior
(waiver of consent)
Other method (describe below)
Attach your consent form, information sheet, or electronic consent text
in the Informed Consent Documents section of the Initial Review
Submission Packet Form.
11.8  * CONSENT PROCESS: Describe the process for obtaining informed consent, including details
such as who will have the consent discussion and when participants will be asked to sign the
consent form in relation to finding out about the study: (REQUIRED)
We encourage researchers
to review our guidance on obtaining and documenting informed consent.
If there are multiple groups being consented differently, provide details about the consent
process for each group.
If you are relying on verbal or implied consent, provide details about how that will
happen.
For studies using online recruitment and consent or consent via mail, provide details here.
After the research team member identifies an eligible patient and the patient’s primary
service physician determines approval for participation in the study, the eligible patient’s nurse will be
approached and asked if the patient is able to participate in the informed consent process as evidenced
by being alert, able to answer questions and follow commands. The patient will be approached by the
research team member who will complete the informed consent process if the nurse reports the
patient is able to participate appropriately. If the nurse reports that the patient is not able to
participate appropriately, the patient’s surrogate (legally authorized representative) will be identified
and contacted to obtain informed consent.
Patients or surrogates will be informed about the purpose of the study and its potential benefits to
future ICU patients by providing direction for clinical practice of fever management and for future
studies on the management of fever in critically ill patients. They will be informed that there is no
direct benefit from participating in the study. However, information that patients provide may help
critical care professionals learn how to improve patient care related to fever management with
bromocriptine. Informed consent will be documented by the patient’s or surrogate’s signature on the
approved consent form. In situations when a patient clearly agrees to participate in the study, but is
unable to sign the consent form because of physical impairment, such as the temporary inability to
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
27 of 45
4/8/21, 11:36 AM


hold a pen due to localized swelling, extremity injury or limited mobility, the patient’s family member
or ICU nurse may sign the consent as a witness. The patient or surrogate will be informed that they do
not have to participate and that they can refuse continued participation in the study at any time. They
will be told that their decision to not participate or stop participation in this study will have no influence
on the patient’s treatment in ICU. We will ask the patient or surrogate if they have any questions
about the study or about any of its procedures and provide further clarification if necessary. The
patient or surrogate will be asked to answer two questions to evaluate their understanding of
information provided: 1) Do you understand that you will receive 48 hours of a standard of care
medication - acetaminophen or a standard of care medication - acetaminophen and the new
intervention medication - bromocriptine in this study? (answer: yes) and 2) Who do you let know if
you do not want to continue in the study? (answer: ICU nurse or research team member). 
* It is important that the people obtaining consent are qualified to do so. Briefly
describe the training and experience these individuals have in obtaining
informed consent: (REQUIRED)
Judy Ch'ang, MD - current neurocritical care fellow; has obtained informed consent for various
procedures and clinical trials throughout her training as a resident-physician and continued as a
fellow. 
Michael Trillanes, PharmD, BCPS, BCCCP - Neurocritical care pharmacist at UCSF Parnassus. Has
witnessed informed consent being obtained for studies and procedures and will be trained on how to
obtain informed consent.
Kristin Slown, PharmD, BCPS - Critical care pharmacist at ZSFGH. Has witnessed informed consent
being obtained for studies and procedures and will be trained on how to obtain informed consent.
Melissa Nguyen, PharmD, BCPS - Critical care pharmacist at ZSFGH. Has witnessed informed consent
being obtained for studies and procedures and will be trained on how to obtain informed consent.
Jeff Vitt, MD - current neurocritical care fellow; has obtained informed consent for various procedures
throughout training as a resident-physician and continued as a fellow. 
Chung Huan Sun, MD - current neurocritical care fellow; has obtained informed consent for various
procedures and clinical trials throughout training as a resident-physician and continued as a fellow. 
Ivy Nguyen, MD - current neurovascular fellow; has obtained informed consent for various procedures
throughout training as a resident-physician and continued as a fellow. 
Arturo Montano, MD - current neurocritical care fellow; has obtained informed consent for various
procedures throughout training as a resident-physician and continued as a fellow. 
11.9  * CONSENT COMPREHENSION: Indicate how the study team will assess and enhance the
subjects' understanding of study procedures, risks, and benefits prior to signing the consent
form (check all that apply): (REQUIRED)
Tip: Review the Consent Comprehension - Learning
Notes in the Help bubble at the right for specific questions that can be asked to assess
comprehension, consider using the UCSF Decision-Making Capacity Assesment Tool, and review
our guidance on obtaining written or verbal informed consent for more detail on how to conduct
the assessment.
The study team will engage the potential participant in a dialogue, using open-ended questions
about the nature of the study or the experimental treatment, the risks and benefits of
participating, and the voluntary nature of participation
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
28 of 45
4/8/21, 11:36 AM


Potential participants will be asked or shown a series of questions to assess their understanding of
the study purpose, procedures, risks and benefits, as well as the voluntary nature of participation
(especially appropriate when the consent process happens online or through a mobile health app)
Other method (describe below):
Provide details of the other approaches that will be used, if using another
method to assess comprehension:
The patient or surrogate will be asked to answer two questions to evaluate their understanding of
information provided: 1) Do you understand that you will receive 48 hours of a standard of care
medication - acetaminophen or a standard of care medication - acetaminophen and the new
intervention medication - bromocriptine in this study? (answer: yes) and 2) Who do you let know if
you do not want to continue in the study? (answer: ICU nurse or research team member). 
11.11  * NON-ENGLISH CONSENT METHOD: Indicate which method(s) you will use to consent non-
English speaking subjects: (REQUIRED)
Preferred Method—Consent form and other study documents will be available in the subject’s
primary language Personnel able to discuss participation in the patient’s language will be present
for the consent process.
Short-Form—A qualified interpreter will translate the consent form verbally, and subjects will be
given the Experimental Subject’s Bill of Rights in their primary language, following instructions in
Those Who do not Read, Speak or Understand English for required witnessing and signatures
* Explain how you will maintain the ability to communicate with non-English
speakers throughout their participation in the study: (REQUIRED)
We will rely on hospital translators to communicate with the patient as we do in standard practice.  For
patients wishing to speak with the study team or PI, office phone numbers will be provided along with
written explanation of how to obtain interpreter for phone calls.
11.13  TIME: What is the estimated time commitment for participants (per visit and in total):
Time duration for study protocol is approximately 48 hours per patient. 60 patients x 48 hours =
2880 hours. 
30 Day phone call follow-ups will be approximately 15 minutes
IMPORTANT TIP: Ensure this information is consistent with the
information provided in the consent form.
11.14  ALTERNATIVES: Is there a standard of care (SOC) or usual care that would be offered
to prospective participants at UCSF (or the study site) if they did not participate in this
research study:
 Yes   
 No
Describe the care that patients would ordinarily receive at the medical center if
they did not participate in this study (provide details, assuming that some of
the IRB members are not specialists in this field):
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
29 of 45
4/8/21, 11:36 AM


Throughout the different teams on neurology and neurosurgery, the treatment of fever is
different. Patients who would not participate in this study would likely receive acetamionphen at
various doses and dosing intervals and variable use of a cooling blanket versus ice packs. NSAIDs such
as ibuprofen are rarely used in neurosurgery or neurovascular cases given its potential risk of
increasing bleeding. If fevers are correlated with increased intracranial pressures and traumatic brain
injury, very rarely, cooling catheters are placed at ZSFGH. 
11.15  OFF-STUDY TREATMENT: Is the study drug or treatment available off-study:
Yes 
No  
Not applicable 
12.0
Waiver of Consent/Authorization for Recruitment
Purposes
This section is required when medical records may be reviewed to
determine eligibility for recruitment.
12.1  * PRACTICABILITY OF OBTAINING CONSENT PRIOR TO ACCESS: Study personnel need to access
protected health information (PHI) during the recruitment process and it is not practicable to
obtain informed consent until potential subjects have been identified: (REQUIRED)
Yes 
If no, a waiver of consent/authorization is NOT needed.
12.2  * RISK TO PRIVACY: A waiver for screening of health records to identify potential subjects
poses no more than minimal risk to privacy for participants:
Yes 
If no, a waiver of authorization can NOT be granted.
12.3  * RIGHTS/WELFARE: Screening health records prior to obtaining consent will not adversely
affect subjects' rights and welfare:
Yes 
If no, a waiver of authorization can NOT be granted.
12.4  * IDENTIFIERS: Check all the identifiers that will be collected prior to obtaining informed
consent:
Names
Dates
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
30 of 45
4/8/21, 11:36 AM


Postal addresses
Phone numbers
Fax numbers
Email addresses
Social Security Numbers*
Medical record numbers
Health plan numbers
Account numbers
License or certificate numbers
Vehicle ID numbers
Device identifiers or serial numbers
Web URLs
IP address numbers
Biometric identifiers
Facial photos or other identifiable images
Any other unique identifier
None
Note: HIPAA rules require that you collect the minimum necessary.
12.5  * HEALTH INFORMATION: Describe any health information that will be collected prior to
obtaining informed consent:
Patient information that will be collected prior to obtaining consent include the inclusion and exclusion
criteria from the medical record which includes: patient diagnoses, age, weight, laboratory results,
vital signs, antipyretic medications ordered and recorded, allergies, if they are taking pills by mouth or
per nasogastric tube, pregnancy status (if appropriate), presence of extracorporeal blood circuit
therapies and if anticipated ICU stay is < 48 hours. 
Note: HIPAA requires that you collect the minimum necessary.
12.6  * DATA RETENTION/DESTRUCTION PLAN: Describe your plan to destroy any identifiable data
collected to determine eligibility for recruitment. This should be done at the earliest opportunity.
If you plan to retain identifiable recruitment data, provide the justification for doing so:
Data will be coded and the data key will be destroyed at the end of the study or by November 31,
2019.
13.0
Surrogate Consent
13.1  PSYCHIATRIC SCREEN: Are any subjects inpatients on a psychiatric ward or mental health
facility, or on psychiatric hold:
No 
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
31 of 45
4/8/21, 11:36 AM


If Yes, use of surrogate consent for research is NOT allowed in
California.
13.2  AREAS OF RESEARCH: Is this study related to the cognitive impairment, lack of capacity, or
serious or life-threatening diseases and conditions of the research subjects: 
Yes 
13.3  JUSTIFICATION: Explain why use of surrogates is necessary for completion of this study:
It is important to use surrogates to consent for this study as it can be common for critically ill patients
with fever to have a condition or therapy-induced situation that renders them unable to consent for
themselves. It is appropriate to include patients who cannot consent for themselves due to the nature
of their critical illness (e.g. neurologically injured) or the therapies they are receiving (e.g. sedating
medications) to achieve the aim of understanding the response of the study intervention on body
temperature and its safety. 
13.4  COGNITIVE ASSESSMENT:  Describe the plans for assessing the decision-making capacity of
prospective subjects:
After the research team member identifies an eligible patient and the patient’s primary service
physician determines approval for participation in the study, the eligible patient’s nurse will be
approached and asked if the patient is able to participate in the informed consent process as evidenced
by being alert, able to answer questions and follow commands. If the patient is unable to participate in
the consent process, the patient's legally authorized decision-maker (surrogate) will be contacted and
informed about the purpose of the study and its potential benefits to future ICU patients by providing
direction for clinical practice of fever management and for future studies on the management of fever
in critically ill patients. The surrogate will be informed that there is no direct benefit from participating
in the study. However, information that patients provide may help critical care professionals learn how
to improve patient care related to fever management with the addition of bromocriptine. Informed
consent will be documented by the surrogate’s signature on the approved consent form and the Self-
Certification of Surrogate Decision Makers for Potential Subject's Participation in University of California
Research form will be filled out and signed by the surrogate and a witness as evidence of the
willingness of the person to serve as a surrogate. When the surrogate is not present in the hospital,
the research team member will contact the surrogate via telephone for the informed consent process if
they are in agreement and have access to a facsimile device to receive and transmit the consent form
and the Self-Certification of Surrogate Decision Makers for Potential Subject's Participation in
University of California Research form. 
13.5  POST-ENROLLMENT CONSENT PLANS: Describe the plans for obtaining consent from subjects
who regain ability to consent after a surrogate has given initial consent:
The informed consent process will be applied to patients who regain their capacity for decision making
during their ICU stay. 
13.6  
SURROGATE CONSENT REQUIREMENTS: Check to acknowledge:
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
32 of 45
4/8/21, 11:36 AM


Research takes place in California. All surrogates will complete the “Self-Certification of Surrogate
Decision Makers for Participation in Research” form.
Conscious subjects will be notified of the decision to contact a surrogate. If subjects object to
study participation, they will be excluded even if their surrogate has given consent.
Surrogates will not receive any financial compensation for providing consent.
If a higher-ranking surrogate is identified at any time, the investigators will defer to the higher-
ranking surrogate’s decision regarding the subject’s participation in the research.
For research taking place outside of California, explain how investigators will
confirm that surrogates are legally authorized representatives:
14.0
Risks and Benefits
14.1  RESEARCH-RELATED RISKS: Check if your study involves any of these specific research-related
risks to participants that may need to be disclosed in the consent form:
For interventional studies, risk that the regimen may be more harmful or less effective than other
available interventions
Risks associated with radiation exposure for imaging studies specifically for research purposes
Risks associated with the administration of contrast agent for imaging studies
Risks associated with withholding of treatment or discontinuation of current treatment (e.g.,
washout period is required by the study protocol)
For randomized, placebo-controlled trials, possible temporary or permanent health consequences
from the deprivation of effective therapies during the placebo administration period
For studies involving a sham surgical procedure, the risk that participants may experience
increased morbidity without the possibility of benefit
Risks associated with modification or extension of a surgical procedure primarily for research
purposes (e.g. risks associated with prolonging anesthesia, time in the operating room, etc.)
Risk of pain or physical discomfort caused by the research intervention
Possible personal discomfort due to sensitive topics (stress, embarassment, trauma)
* For any boxes checked above, describe how you will minimize these risks and
discomforts, e.g., adding or increasing the frequency of monitoring, additional
screening to identify and exclude people with diminished kidney or liver
function, or modification of procedures such as changing imaging studies to
avoid giving contrast agent to people who are more likely to suffer side effects
from it, etc.: (REQUIRED)
There are side effects associated with bromocriptine. There is already extensive clinical trial data from
its various other indications and case reports in the literature documenting its side effects and safety
parameters. Already, through the exclusion criteria, patients that are not good candidates for either
medication, acetaminophen and bromocriptine, will not be included in the study such as a past medical
history of cirrhosis or a current diagnosis of acute liver failure or diminished kidney function. From the
package insert, bromocriptine has different side effects in patients with different indications
(hyperprolactinemia, acromegaly, Parkinson's disease). In pregnant patients, it is category B, thus
pregnant women and lactating women will be excluded from the study. 
Per the package insert for hyperprolactinemia, "Therapy was discontinued in approximately 5% of
patients because of adverse effects... nausea (49%), headache (19%), dizziness (17%), fatigue (7%),
lightheadedness (5%), vomiting (5%), abdominal cramps (4%), nasal congestion (3%), constipation
(3%), diarrhea (3%) and drowsiness (3%)."
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
33 of 45
4/8/21, 11:36 AM


Per the package insert for acromegaly, "nausea (18%), constipation (14%), postural/orthostatic
hypotension (6%), anorexia (4%), dry mouth/nasal stuffiness (4%), indigestion/dyspepsia (4%),
digital vasospasm (3%), drowsiness/tiredness (3%) and vomiting (2%). Less frequent adverse
reactions (less than 2%) were: gastrointestinal bleeding, dizziness, exacerbation of Raynaud’s
syndrome, headache and syncope. Rarely (less than 1%) hair loss, alcohol potentiation, faintness,
lightheadedness, arrhythmia, ventricular tachycardia, decreased sleep requirement, visual
hallucinations, lassitude, shortness of breath, bradycardia, vertigo, paresthesia, sluggishness,
vasovagal attack, delusional psychosis, paranoia, insomnia, heavy headedness, reduced tolerance to
cold, tingling of ears, facial pallor and muscle cramps have been reported."
Per the package insert for Parkinson's disease, "In clinical trials in which Parlodel was administered
with concomitant reduction in the dose of levodopa/carbidopa, the most common newly appearing
adverse reactions were: nausea, abnormal involuntary movements, hallucinations, confusion, “on-off’’
phenomenon, dizziness, drowsiness, faintness/fainting, vomiting, asthenia, abdominal discomfort,
visual disturbance, ataxia, insomnia, depression, hypotension, shortness of breath, constipation, and
vertigo."
The effect of liver or renal impairment on the pharmacokinetics of bromocriptine and its metabolites is
not known and has not been specifically evaluated. As only 6% is eliminated via the kidney, renal
impairment may not have significant impact on the pharmacokinetics of bromocriptine and its
metabolites. Since Parlodel is mainly eliminated by hepatic metabolism, liver impairment may increase
the plasma levels of bromocriptine, therefore, any patient with cirrhosis or a new diagnosis of liver
failure or liver injury will be excluded in this study. 
The side effects of acetaminophen are skin rash, pancytopenia, hypersensitivity reaction, and hepatic
injury including liver failure. Thus, any patient with cirrhosis or a new diagnosis of liver failure or liver
injury will be excluded in this study. It is recommended that in cases of severe renal impairment
(creatinine clearance ≤ 30 mL/min), longer dosing intervals and a reduced total daily dose is
warranted. Patients with a creatinine clearance ≤ 30 mL/min will also be excluded from the study. 
In order to capture side effects, bed side nurses will do 4 assessments (once every shift) of the patient
specifically looking at common side effects of bromocriptine. Also, the patients will be monitored
closely in the ICU setting for any other vital sign changes. 
If patients have an esophageal, bladder, or rectal temperature probe for any other indication, they will
continue to have these probes.
14.2  RISKS: Describe any anticipated risks and discomforts not listed above:
Patients must have routine bladder, esophageal, or rectal temperature probes. Because of the
difference in temperature data gathering and the different sensitivities between oral versus bladder,
esophageal, and rectal probes, we are not allowing oral temperature data gathering. These invasive
probes may cause discomfort and carry their own risks, but they are also part of routine care in this
patient population. If the patient refuses placement of any of these invasive probes, then they cannot
be in the study. 
14.3  
MINIMIZING RISKS: Describe the steps you have taken to minimize the risks/discomforts to
subjects. Examples include:
designing the study to make use of procedures involving less risk when appropriate
minimizing study procedures by taking advantage of clinical procedures conducted on the
study participants
mitigating risks by planning special monitoring or conducting supportive interventions for
the study
having a plan for evaluation and possible referral of subjects who report suicidal ideation
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
34 of 45
4/8/21, 11:36 AM


The nursing assessments are designed to be very simple and time efficent for nursing to do which will
not be invasive to patients. Also, patients will be told that they do not have to participate and they can
refuse continued participation in the study at any point during the study period. 
14.4  RESOURCES: Describe the resources in place to conduct this study in a way that assures
protection of the rights and welfare of participants:
These resources typically include
appropriately trained and qualified personnel (in terms availability, number, expertise and
experience), funding, space, equipment, and time to devote to study activities.
Depending on
the nature of the research study, investigators should consider the proximity or availability of
critical resources that may be essential to the safety and welfare of participants, such as
the proximity of an emergency facility for care of participant injury
availability of psychological support after participation
resources for participant communication, such as language translation services
This study protocol will be funded by departamental funds. The research team members are well
versed in HIPAA and informed consent. The data analysts in Dr. Xiao Hu's lab, who will be blinded to
treatment group, are experienced in doing this type of data analysis from ICU 8 and 11 in a private
and confidential manner. If patients have any side effects, they will already be in the ICU and
diagnostic studies and treatments can be initiated immediately. 
14.5  * BENEFITS: (REQUIRED) Note: These are the benefits that the IRB will consider during their
review. They are not necessarily appropriate to include in the consent form.
Possible immediate and/or direct benefits to participants and society at
large (check all that apply):
Positive health outcome (e.g. improvement of condition, relief of pain, increased mobility, etc.)
Closer follow-up than standard care may lead to improved outcomes or patient engagement
Health and lifestyle changes may occur as a result of participation
Knowledge may be gained about their health and health conditions
Feeling of contribution to knowledge in the health or social sciences field
The research presents a reasonable opportunity to further the understanding, prevention, or
alleviation of a serious problem affecting the health or welfare of children
Other benefit (describe below)
None
14.6  RISK TO BENEFIT RATIO: Explain why the risks to subjects are reasonable in relation to
anticipated benefits, if any, to the participant or society:
There is no direct benefit to the patient from participating in this study. However, the information that
patients provide may help guide health professionals in improving care of future neurocritical care
patients with fever and may change the overall management of these patients across the country. The
clinical decision-making for implementing fever management interventions and body temperature
thresholds for administration of antipyretic agents is variable in current practice and medical therapy
for fever control is overall ineffective. Currently, giving patients acetaminophen is the standard of care
and then use of external and intravascular cooling is variable. The risks of bromocriptine with our
current knowledge of the medication's side effects appear to be low. When used in the aforementioned
case reports, prospective TBI study, and retrospective SAH abstract where all patients
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
35 of 45
4/8/21, 11:36 AM


were neurocritically ill patients, no side effects were noted. This study will help us identify in a
prospective manner the safety profile in this critically ill population. Future benefits to neurocritically ill
patients include the potential development of evidence- based recommendations for use of
bromocriptine to treat fever during critical illness based on this study's findings. Future benefits also
include the potential to identify the etiology of fever (central versus infectious) based off of the
difference of fever response to bromocriptine which could possibly be addressed in future studies.
Future benefits also include decreased used of external and intravascular cooling devices which also
means decreased need for anti-shivering medications and sedation. There is potential for the study
findings to guide use of acetaminophen and bromocriptine in neurocritically ill patients which has
potential impact on health care resource utilization. 
15.0
Data and Safety Monitoring Plan
15.2  * DATA AND SAFETY MONITORING PLAN: (REQUIRED)
All greater than minimal risk studies are required to provide a plan.
Lack of an adequate plan is one of the most common reasons why IRB
approval is delayed.
Instructions:
Describe the plan for monitoring data quality and participant safety. Key areas
that should be included in the plan are:
An explanation of the plan to monitor data collection, study progress, and
safety
A description of who will perform the monitoring and at what frequency
(e.g., the PI only, a contract research organization, a Data and Safety
Monitoring Board or Data Monitoring Committee, etc.)
The type of data and events that will be reviewed (e.g., adverse events,
breaches of confidentiality, unanticipated problems involving risk to
participants or others, unblinded efficacy data, etc.)
Procedures and timeline for communicating monitoring results to the
UCSF IRB, the study sponsor, and other appropriate entities
Assurance that the research team will adhere to the UCSF IRB reporting
requirements
As appropriate:
A plan for conducting and reporting interim analysis
Clearly defined stopping rules
Clearly defined rules for withdrawing participants from study interventions
The Principal Investigator (PI), Dr. Judy Ch'ang, has primary responsibility for the overall conduct of
the study and for the safety of the participating human subjects. The PI will ensure that 1) the
informed consent process is conducted appropriately and that informed consent is obtained prior to
proceeding with any study procedures; 2) only eligible subjects, per protocol eligibility criteria, are
enrolled in the study; 3) data are collected per protocol requirements; 4) the control and intervention
drug administration protocol is followed properly and consistently; 5) procedures are implemented to
ensure that the project is consistently monitored for possible adverse events; 6) the privacy and
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
36 of 45
4/8/21, 11:36 AM


confidentiality of the study subjects is maintained; and, 7) patients are aware of their rights as
research subjects and who/how to reach nurses and research team members regarding stopping the
study. Each patient will be provided with a copy of the Experimental Subject’s Bill of Rights. In the
event that a patient would like to withdraw from the study, their temperature and antipyretic data can
be used for research until that point, but from when they chose to leave the study, their temperature
and other vitals data will not be recorded or monitored. 
If adverse events should occur, they will be reviewed promptly and reported as required to the UCSF
Committee on Human Research. The PI will conduct interim analyses of study information and data to
assure the continuing safety of research participants, efficacy of the study intervention, and the
appropriateness of the study. While implementation of aspects of the Data and Safety Monitoring plan
may be delegated to members of the research team, the PI maintains ultimate responsibility for the
project and for safety of study participants. After enrolling 30 patients, the PI will conduct and report
an interim analysis. There will not be an independent Data Safety Monitoring Board Committee for this
study. 
15.3  * DATA AND SAFETY MONITORING BOARD (DSMB): Will a Data and Safety Monitoring Board
(DSMB) be established: (REQUIRED)
Yes 
No 
Guidelines
A Data and Safety Monitoring Board (DSMB) or Data Monitoring Committee
(DMC) is a formal, independent committee that is specifically established to
conduct interim monitoring, oversight and analysis of study information and
data to assure the continuing safety, efficacy, appropriateness, relevance, and
integrity of the study.
The UCSF IRB reserves the right to request a DSMB/DMC for any study.
However, the following are factors that the IRB will consider when making this
determination:
There is a significant likelihood of a serious adverse event to subjects
The study is conducted at multiple sites and the level of risk is greater
than minimal
The study generates data that are blinded or randomized
The study involves a large number of patients randomized to one of two
or more interventions
A study for which the performance of an interim analysis is crucial for the
protection of the subjects
First use in humans
First use in children
The study involves gene transfer, stem cell therapy, or other novel
interventions for which long-term outcome data are not known or
available
16.0
Confidentiality, Privacy, and Data Security
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
37 of 45
4/8/21, 11:36 AM


16.1  PROTECTING PRIVACY: Indicate how subject privacy will be protected:
Conduct conversations about the research in a private room
Ask the subject how they wish to be communicated with – what phone numbers can be called, can
messages be left, can they receive mail about the study at home, etc.
Take special measures to ensure that data collected about sensitive issues do not get added to
their medical records or shared with others without the subject’s permission
Other methods (describe below)
16.2  SENSITIVE DATA: Do any of the instruments ask about illegal or stigmatized behavior:
  Yes   
  No
16.3  CONSEQUENCES OF A LOSS OF PRIVACY OR CONFIDENTIALITY: Could a breach of privacy or
confidentiality  result in any significant consequences to participants, such as criminal or civil
liability, loss of state or federal benefits, or be damaging to the participant's financial standing,
employability, or reputation:
 Yes   
 No
Describe the potential consequences:
Potential consequences related to loss of privacy related to hospitalization may lead to adverse social
and/or employment consequences. 
Embarrassment
Criminal or civil liability
Loss of state or federal benefits
Damaging to the participant's financial standing, employability, or reputation
Potential risks to insurability (health, disability, or life insurance)
16.4  EXTRA CONFIDENTIALITY MEASURES: Explain any extra steps that will be taken to assure
confidentiality and protect identifiable information from improper use and disclosure, if any:
The PI, co-investigators, and research team members have been certified in HIPAA regulations and
data collection procedures and management are in compliance with HIPAA regulations. Electronically
stored data will be de-identified. All identifying information will be kept separately from the data and
secured electronically. We do not plan to share any personal identifying information outside the
research team. We plan to only collect minimal patient identifying data: names, dates, and medical
record numbers. The research team will access only the information pertaining to the inclusion and
exclusion criteria before obtaining consent for the study from the patient or surrogate. Data will be
kept in a locked office. Data will be coded and the data key will be destroyed at the end of study. 
16.5  * REPORTABILITY: Do you anticipate that this study may collect information that State or
Federal law requires to be reported to other officials, such as elder abuse, child abuse, or threat
to self or others: (REQUIRED)
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
38 of 45
4/8/21, 11:36 AM


  Yes   
  No
16.6  CERTIFICATE OF CONFIDENTIALITY: Will this study obain a Certificate of Confidentiality:
  Yes   
  No
16.7  SHARING OF RESEARCH RESULTS: Will there be any sharing of EXPERIMENTAL research test
results with subjects or their care providers:
  Yes   
  No
16.8  * IDENTIFIERS: Will any personal identifiers be collected: (REQUIRED)
 Yes   
 No
Check all the identifiers that may be included:
Names
Dates
Postal addresses
Phone numbers
Fax numbers
Email addresses
Social Security Numbers*
Medical record numbers
Health plan numbers
Account numbers
License or certificate numbers
Vehicle ID numbers
Device identifiers or serial numbers
Web URLs
IP address numbers
Biometric identifiers
Facial photos or other identifiable images
Any other unique identifier
* Could study records include ANY photos or images (even 'unidentifiable'
ones): (REQUIRED)
  Yes   
  No
16.9  DATA DISCLOSURE: Will identifiable information be shared with outside groups:
  Yes   
  No
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
39 of 45
4/8/21, 11:36 AM


16.11  * DATA COLLECTION AND STORAGE: (check all that apply): (REQUIRED)
Collection methods:
Paper-based (surveys, logs, diaries, etc.)
Electronic case report forms (CRFs), such as OnCore or another clinical trial management portal
Web-based online surveys or computer-assisted interview tool
Mobile applications (mobile or tablet-based)
Wearable devices
Audio/video recordings
Other:
* Data will be collected/stored in systems owned by (check all that
apply): (REQUIRED)
UCSF
SF VAMC
Amazon (Amazon Cloud)
Other academic institution
3rd party vendor (business entity)
Other (explain below)
16.12  DATA SECURITY: Indicate how data are kept secure and protected from improper use and
disclosure (check all that apply):
NOTE: Whenever possible, do not store subject identifiers on
laptops, PDAs, or other portable devices. If you collect subject identifiers on portable devices,
you MUST encrypt the devices.
Data are stored securely in My Research
Data are coded; data key is destroyed at end of study
Data are coded; data key is kept separately and securely
Data are kept in a locked file cabinet
Data are kept in a locked office or suite
Electronic data are protected with a password
Data are stored on a secure network
Data are collected/stored using REDCap or REDCap Survey
Data are securely stored in OnCore
16.13  * DATA SECURITY: Confirm below that you will keep data confidential: (REQUIRED)
I will keep
any data sets that include identifiers secure and protected from improper use and disclosure by
using methods such as:
Physical Security – Keeping data in locked file cabinets, locked offices, locked suites, and
physically securing computers and servers.
Electronic Security – Following UCSF minimum security standards for electronic
information resources, which includes (but is not limited to): not storing identifiers on
portable devices like laptops or flash drives if they are unencrypted, encrypting portable
devices, and storing data in password-protected files and on secure networks.
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
40 of 45
4/8/21, 11:36 AM


Yes 
16.15  HIPAA APPLICABILITY: Study data will be:
Derived from the Integrated Data Repository (IDR) or The Health Record Data Service (THREDS)
at SFGH
Derived from a medical record (e.g. APeX, OnCore, etc. Identify source below)
Added to the hospital or clinical medical record
Created or collected as part of health care
Obtained from the subject, including interviews, questionnaires
Obtained ONLY from a foreign country or countries
Obtained ONLY from records open to the public
Obtained from existing research records
None of the above
Unless a waiver of Authorization is granted, in addition to the consent
form, participants will need to sign UCSF Research Subject
Authorization Form (HIPAA Form). NEW REQUIREMENT - This form
should be uploaded in the Other Study Documents section of the Initial
Review Submission Packet Form. Failure to obtain HIPAA Authorization
for research is one of the most common findings from QIU Routine Site
Visits. Your IRB approval letter will include instructions about HIPAA
requirements specific to your study.
If derived from a medical record, identify source:
APEX (UCSF), ICCA (ZSFGH)
16.16  * HIPAA - PERMISSION TO ACCESS SENSITIVE DATA: Does the research require access to any
of the following types of health information from the medical record: (check all that apply)
(REQUIRED)
Drug or alcohol abuse, diagnosis or treatment
HIV/AIDS testing information
Genetic testing information
Mental health diagnosis or treatment
None of the above
17.0
Financial Considerations
17.1  * PAYMENT: Will subjects be paid for participation, reimbursed for time or expenses, or receive
any other kind of compensation: (REQUIRED)
  Yes   
  No
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
41 of 45
4/8/21, 11:36 AM


17.4  COSTS TO SUBJECTS: Will subjects or their insurance be charged for any study activities:
  Yes   
  No
18.0
Qualifications of Key Study Personnel
18.1  
NOTE: This information is required and your application will be considered
incomplete without it. If this study involves invasive or risky procedures, or
procedures requiring special training or certification, please identify who
will be conducting these procedures and provide details about their
qualifications and training. Also identify each person who will be involved in
the consent process. Click the orange question mark for more information
and examples. Under qualifications, please include:
Academic Title
Institutional Affiliation (UCSF, SFGH, VAMC, etc.)
Department
Certifications
November, 2015 - NEW Definition of Key Study Personnel and CITI
Training Requirements:
UCSF Key Study Personnel include the Principal Investigator, other
investigators and research personnel who are directly involved in
conducting research with study participants or who are directly involved in
using study participants’ identifiable private information during the course
of the research. Key Personnel also include faculty mentors/advisors who
provide direct oversight to Postdoctoral Fellows, Residents and Clinical
Fellows serving as PI on the IRB application.
The IRB requires that all Key
Study Personnel complete Human Subjects Protection Training
through CITI prior to approval of a new study, or a modification in which KSP
are being added. More information on the CITI training requirement can be
found on our website.  
KSP Name
Description of Study
Responsibilities - Briefly
describe what will each person
be doing on the study. If there
are procedures requiring
special expertise or
certification, identify who will
be carrying these out. Also
identify who will be obtaining
informed consent.
Qualifications, Licensure, and
Training
Ch'ang, Judy
Co-principal investigator.
Responsible for grant
submission/revisions, study
design, IRB
submission/revision, subject
enrollment, overall protocol
conduct and safety of
participating human subjects,
Physician and early in
research career of critically ill
patients. UCSF, Department
of Neurology
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
42 of 45
4/8/21, 11:36 AM


ongoing review of procedures
and analysis of data.
Kim, Anthony S
Co-principal investigator and
mentor. Dr. Kim is
responsible for study design,
IRB submission/revision,
grant submission and review.
His role is to continue to
review study procedures and
participate in ongoing
analysis and review of
results.
Physician, medical director of
the UCSF Stroke Center. He
is a leader in the field of
cerebrovascular diseases and
an expert in statistics,
serving as the head of Clinical
and Translational Science
Institute’s Consultation
Services including the Study
Design Consultation Unit. He
is an established researcher
in care of neurovascular
patients and has served as a
principal investigator of
numerous clinical trials at
UCSF. UCSF, Department of
Neurology
Schell-Chaple, Hildegarde M
Co-investigator and mentor.
Dr. Schell-Chaple is
responsible for study design,
IRB submission/revision,
grant submission and review,
and subject enrollment. Her
role is to continue to review
study procedures and
participate in ongoing
analysis and review of
results.
PhD, clinical nurse specialist
in adult critical care. Co-
investigator and consultant to
research studies in adult
critical care units at UCSF
over past 15 years. Has
published her own study in
the UCSF Medical Center ICUs
on fever management. UCSF,
Department of COO
Trillanes, Michael R
Study recruiter. He is
responsible for helping with
the study design pertaining to
adverse effects and
monitoring and patient
enrollment. His role is to
continue to participate in
ongoing enrollment and
reviewing results.
PharmD with a specialization
in neurointensive care. UCSF,
Department of Pharmacy
Villaroman, Andrea L
Study coordinator. She is
responsible for patient
enrollment helping obtain and
analyze data. Her role is to
participate in patient
enrollment, ongoing analysis
and review of results.
Study coordinator working for
Dr. Hu's lab with ongoing
experience related to IRB
submission/revision,
obtaining and analyzing
results. UCSF, Department of
Nursing
Slown, Kristin
Study recruiter. She is
responsible for helping with
the study design pertaining to
adverse effects and
monitoring and patient
enrollment. Her role is to
continue to participate in
ongoing enrollment and
PharmD with a specialization
in critical care. ZSFGH,
Department of Pharmacy
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
43 of 45
4/8/21, 11:36 AM


reviewing results.
Nguyen, Melissa N
Study recruiter. She is
responsible for helping with
the study design pertaining to
adverse effects and
monitoring and patient
enrollment. Her role is to
continue to participate in
ongoing enrollment and
reviewing results.
PharmD with a specialization
in critical care. ZSFGH,
Department of Pharmacy
Randazzo, Dominica B
Her role is to continue to
participate in ongoing
enrollment and reviewing
results.
Experienced CRC with CCRP
certification
Dr. Singhal, Neel MD, PHD, MD
PHD
Study recruiter. His role is to
continue to participate in
ongoing enrollment and
reviewing results
MD, Neurocritical care
attending at ZSFGH and UCSF
Chyall, Lawrence
Study recruiter. His role is to
continue to participate in
ongoing enrollment.
Nurse Practitioner,
Neurosurgery SFGH
Mcguire, Daniel W
Study recruiter. His role is to
continue to participate in
ongoing enrollment.
Nurse Practitioner,
Neurosurgery SFGH
Winkelman, Amy
Study recruiter. Her role is to
continue to participate in
ongoing enrollment.
Nurse Practitioner,
Neurosurgery SFGH
Tran, Nhat
Biostatistician. Will blindly
review results and data of
these patients and do
statistics.
PHD candidate, UCSF in Xiao
Hu's lab (one of the
investigators)
Vuong, Maximilian N
Coordinator. His role is to
help with IRB issues.
Experienced Assistant CRC
19.0
Other Approvals and Registrations
19.1  * ADMINISTRATION OF RECOMBINANT DNA: Does this study involve administration of vaccines
produced using recombinant DNA technologies to human subjects (Help Link added Aug '15):
(REQUIRED)
  Yes   
  No
19.2  * HUMAN GENE TRANSFER: Does this study involve human gene transfer (NOTE: Requires NIH
Recombinant DNA Advisory Committee (RAC) review prior to IRB approval): (REQUIRED)
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
44 of 45
4/8/21, 11:36 AM


  Yes   
  No
19.4  OTHER APPROVALS: Indicate if this study involves other regulated materials and requires
approval and/or authorization from the following regulatory committees:
Institutional Biological Safety Committee (IBC)
Specify BUA #:
Institutional Animal Care and Use Committee (IACUC)
Specify IACUC #:
Controlled Substances
20.0
End of Study Application
20.1  End of Study Application Form
To continue working on the Study
Application: Click on the section you need to edit in the left-hand menu. Remember to
save through the entire Study Application after making changes.
If you are done
working on the Study Application:
Important: Before proceeding, please go back
to Section 4.0 Initial Screening Questions and Save and Continue through the form to
make sure all the relevant sections and questions have been included. If you've changed
any answers since you started, the branching may have changed. Your application will
be incomplete and it will have to be returned for corrections. 
Once you are sure the
form is complete, click Save and Continue. If this is a new study, you will automatically
enter the Initial Review Submission Packet form, where you can attach consent forms or
other study documents. Review the Initial Review Submission Checklist for a list of
required attachments.
Answer all questions and attach all required documents to speed
up your approval.
The UCSF IRB wants your feedback about this new form. Please
click the link to take a brief survey about the new application form.
iRIS: IRB Study Application
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTM...
45 of 45
4/8/21, 11:36 AM

ICF_002.pdf: 
1
Efficacy of bromocriptine to reduce body temperature in febrile 
critically-ill adults with acute neurologic disease: an open-label, 
blinded endpoint, randomized controlled trial
NCT03496545
03/12/2019
P.I. NAME:
Judy Ch’ang, MD
Title:
Clinical Instructor
Department: 
Neurology
Email:
judy.chang@ucsf.edu

		

	


2
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO CONSENT TO 
PARTICIPATE IN A RESEARCH STUDY
Study Title: Efficacy of bromocriptine to reduce body temperature in febrile critically-ill 
adults with acute neurologic disease: an open-label, blinded endpoint, randomized 
controlled trial
This is a medical research study. Dr. Judy Ch’ang, MD, Kristin Slown, PharmD, Michael 
Trillanes, PharmD, Melissa Nguyen, PharmD, or another member of the research team, will 
explain this study to you. 
Medical research studies include only people who choose to take part. Take your time to make 
your decision about participating. You may discuss your decision with your family and friends 
and with your health care team. If you have any questions, you may ask your study doctor. 
You are being asked to take part in this study because you are currently in one of the adult Neuro 
Intensive Care Units (ICU) as you have had an acute brain injury AND you may develop a body 
temperature or fever (greater than or equal to 38.3°C/ 101°F) due to your brain injury. The 
study’s purpose is to learn if a new approach to lowering your temperature with a drug called 
“bromocriptine” compared to current treatments may reduce the impact of fever in persons with 
acute brain injury. Bromocriptine has not been approved by the Federal Food and Drug 
Administration (FDA) for this use.
If you are the Legally Authorized Representative, the person you are representing is being asked 
to participate in a research study but is unable to consider whether to give consent to participate 
because of their medical condition. You, as the patient’s legally authorized representative, are 
being asked to consider whether to give consent for the patient to participate in this study. 
Why is this study being done? 
The purpose of this study is to see if bromocriptine (Parlodel®) has an effect on you and your 
body temperature when you have a fever. In this study, you will get either acetaminophen 
(Tylenol®) OR acetaminophen and bromocriptine only if your body temperature becomes 
greater than or equal to 38.3 oC (101oF).
How many people will take part in this study? 
About 60 intensive care unit patients will take part in this study. 
What will happen if I take part in this research study? 
If you choose to take part in this study, the following procedures will occur: 
If your body temperature rises to 38.3oC or 101oF, you will be "randomized" into one of the 
study groups described below. Randomization means that you are put into a group by chance. A 
computer program will place you in one of the groups. Neither you nor the research team can 
choose the group you will be in. You will have an equal chance of being placed in any group. 

		

	


3
While being in the neuro intensive care unit, if you maintain a temperature less than 
38.3oC or 101oF, then you will never be randomized to receive these study medications. After the 
trial period is over, other clinical data such as laboratory results, antibiotic use or total days spent 
in the ICU will be obtained through chart review for analysis. 

If you are in Group 1
o
You will receive a tablet of acetaminophen 650mg by mouth (or per nasogastric
or feeding tube if appropriate) every 4 hours for the next 48 hours
o
During the 48-hour study period other measures to reduce body temperature such
as fans, ice packs, and cooling blankets are not permitted unless a study
participant’s body temperature is ≥104°F (40°C).
o
The research team member will gather demographic information from your
hospital medical record such as your age, gender, ethnicity, and clinical
information about your medical diagnosis, acuity, medications, imaging results
and laboratory tests.
o
If your temperature increases to greater than or equal to 40oC (104oF) during the
48-hour study period, your physician will be notified.
o
With a continuous temperature probe, temperature will be recorded every 3
seconds. Heart rate and blood pressure will be recorded every 3 seconds if there is
an arterial line. If there is no temperature probe or arterial line, vital signs will be
recorded at the frequency requested by the treating team.

If you are in Group 2
o
You will receive a tablet of acetaminophen 650mg every 4 hours and
bromocriptine 5mg every 4 hours by mouth (or per nasogastric or feeding tube if
appropriate) for the next 48 hours
o
During the 48-hour study period other measures to reduce body temperature such
as fans, ice packs, and cooling blankets are not permitted unless a study
participant’s body temperature is ≥104°F (40°C).
o
The research team member will gather demographic information from your
hospital medical record such as your age, gender, ethnicity, and clinical
information about your medical diagnosis, acuity, medications, imaging results
and laboratory tests.
o
If your temperature increases to greater than or equal to 40oC (104oF) during the
48-hour study period, your physician will be notified.
o
With a continuous temperature probe, temperature will be recorded every 3
seconds. Heart rate and blood pressure will be recorded every 3 seconds if there is
an arterial line. If there is no temperature probe or arterial line, vital signs will be
recorded at the frequency requested by the treating team.
After 30 days, you will be contacted by a research team member for a follow up phone call 
which should take approximately 15 minutes. If you are unable to complete the phone 
assessment, your surrogate, family member, friend, legally authorized representative, nursing 
staff, physician or medical healthcare professional taking care of you may answer on your behalf.
Study location: All study activities will be done in your room in one of the adult ICUs at UCSF 

		

	


4
Medical Center or Zuckerberg San Francisco General Hospital and Trauma Center
How long will I be in the study? 
Participation in the study will take a total of about 48 hours during your ICU stay. Then 30 days 
later, you or your surrogate will be contacted by a research team member for a follow up phone 
call which should take approximately 15 minutes. 
Can I stop being in the study? 
Yes. You can decide to stop at any time. Tell the research team member if you are thinking about 
stopping or decide to stop. He or she will tell you how to stop your participation safely. The 
research team member may stop you from taking part in this study at any time if he/she believes 
it is in your best interest, if you do not follow the study rules, or if the study is stopped. 
What side effects or risks can I expect from being in the study? 
You may have side effects while in the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don't know all the side effects that may happen. 
Side effects may be mild or very serious. Your health care team may give you medicines to help 
lessen side effects. Many side effects go away soon after you stop taking acetaminophen or 
bromocriptine. In some cases, side effects can be serious, long lasting, or may never go away. 
You should talk to your research team member about any side effects that you experience while 
taking part in the study. 
During each nursing shift throughout the 48-hour study period, from the first time you received a 
study drug, the bedside nurse will do a 5-minute assessment to monitor for any side effects from 
the study medications. 
Risks and side effects related to the drug include those which are: 
Likely 

none
Less Likely 

fatigue

nausea

headache

hypotension

dizziness

abdominal cramps

constipation

drowsiness
Rare but serious 

		

	


5

gastrointestinal bleeding

hypertension

psychosis

seizure, stroke, heart attacks (especially in women in the postpartum period)

arrhythmia or abnormal heart rhythm (seen mostly in patients with history of acromegaly
which is a hormonal disorder that develops when your pituitary gland produces too much
growth hormone during adulthood.)
Randomization risks: You will be assigned to a treatment program by chance, and the treatment 
you receive may prove to be less effective or to have more side effects than the other study 
treatment(s) or other available treatments. 
Unknown Risks: The experimental treatment may have side effects that no one knows about 
yet. The researchers will let you know if they learn anything that might make you change your 
mind about participating in the study. 
For more information about risks and side effects, ask your research team member. 
Are there benefits to taking part in the study? 
Taking part in this study may or may not make your health better. While doctors hope that the 
addition of the drug, bromocriptine, will be more effective than the standard or usual treatment 
(acetaminophen alone), there is no proof of this yet. 
There will be no direct benefit to you from participating in this study. However, this study will 
help doctors and nurses learn more about bromocriptine, and it is hoped that this information will 
help in the treatment of future ICU patients with acute brain injury who have fever. 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 

Getting no treatment

Getting standard treatment for your condition without being in a study

Getting a different experimental treatment/taking part in another study.
Please talk to your doctor about your choices before deciding if you will take part in this study. 
Will my medical information be kept private? 
We will do our best to make sure that the personal information in your medical record is kept 
private. However, we cannot guarantee total privacy. Your personal information may be given 
out if required by law. If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used. 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 

		

	


6

The University of California

Other government agencies, e.g., the Food and Drug Administration (FDA), involved in
keeping research safe for people.
Participation in research may involve a loss of privacy, but information about you will be 
handled as confidentially as possible. A medical record will be created because of your 
participation in this study. Your consent form and some of your research test results will be 
included in this record. Therefore, your other health care providers may see your test results and 
become aware of your participation. Hospital regulations require that all health care providers 
treat information in medical records confidentially. 
What are the costs of taking part in this study?
Two types of procedures will be done during this study. Some are part of your standard medical 
care and others are only for research. You or your insurer will be billed for the standard medical 
care. You will be responsible for your co-pays, deductibles, and any other charges that your 
insurer will not pay. There is a possibility that your insurer may not cover all standard medical 
care costs if you are receiving medical services out of network. Any procedures done only for 
research will not be charged to you or your insurer. The trial itself will provide the drug, 
bromocriptine, and administration of bromocriptine will be at no cost to you.
Will I be paid for taking part in this study? 
You will not be paid for taking part in this study. 
What happens if I am injured because I took part in this study? 
It is important that you tell your research team member, Dr. Judy Ch’ang, MD, Kristin Slown, 
PharmD, Michael Trillanes, PharmD, or Melissa Nguyen, PharmD if you feel that you have been 
injured because of taking part in this study. You can tell the researcher in person or call her/him 
at 415-514-2120 or 415-206-8094.
Treatment and Compensation for Injury: If you are injured as a result of being in this study, 
the University of California will provide necessary medical treatment. The costs of the treatment 
may be billed to you or your insurer just like any other medical costs, or covered by the 
University of California, depending on a number of factors. The University does not normally 
provide any other form of compensation for injury. For further information about this, you may 
call the office of the Institutional Review Board at 415- 476-1814. 
What are my rights if I take part in this study? 
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from our institution. 
We will tell you about new information or changes in the study that may affect your health or 

		

	


7
your willingness to continue in the study. In the case of injury resulting from this 
study, you do not lose any of your legal rights to seek payment by signing this form. 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions, concerns, or complaints you have about 
this study. Contact your research team members(s) Judy Ch’ang, MD, Kristin Slown, PharmD, 
Michael Trillanes, PharmD or Melissa Nguyen, PharmD at 415-514-2120 or 415-206-8094. 
If you wish to ask questions about the study or your rights as a research participant to someone 
other than the researchers or if you wish to voice any problems or concerns you may have about 
the study, please call the Office of the Institutional Review Board at 415-476-1814. A 
description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Website 
will include a summary of the results. You can search this Website at any time. 
CONSENT 
You have been given copies of this consent form and the Experimental Subject's Bill of Rights to 
keep. You will be asked to sign a separate form authorizing access, use, creation, or disclosure of 
health information about you. 
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to which 
you are otherwise entitled. 
If you wish to participate in this study, you should sign below. 
____________
__________________________________________
Date 
Participant's Signature for Consent 
____________
__________________________________________
Date 
Person Obtaining Consent 
AND/OR

		

	


8
____________
__________________________________________
Date 
Legally Authorized Representative  
____________
__________________________________________
Date 
Person Obtaining Consent 
Participant consent after legally authorized representative consent was obtained: 
You were enrolled in this study by a surrogate because your illness rendered you incapable of 
providing informed consent when you were initially enrolled. You have since regained your 
ability to provide consent and now would like to:
_______Continue participation until the study is complete (if applicable)   
_______Terminate your participation in the study but allow the use of data collected to date 
_______Terminate your participation in the study and not allow use of data collected to date 
____________
__________________________________________
Date 
Participant's Signature for Consent 
____________
__________________________________________
Date 
Person Obtaining Consent 

		

	