Clinical trial NCT03680911
Conditions: Anosmia Head Trauma
Sponsor: University of Miami
Start date: 2018-10-12; Completion date: 2020-01-07
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will compare administration of N-Acetyl Cysteine (NAC) versus placebo for the treatment of olfactory loss due to head injury. The hypothesis is that treatment with NAC acutely after head injury will result in improved olfactory function

Detailed description:

Arms: arm 1: NAC group will be administered orally as a 4 gram loading dose, followed by 2 g PO BID for 4 days, then 1.5 g PO BID for 2 days arm 2: Placebo group will be administered orally as a 4 gram loading dose, followed by 2 g PO BID for 4 days, then 1.5 g PO BID for 2 days
Interventions: intervention 1: N Acetyl Cysteine intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: 2 g PO BID for 4 days, then 1.5 g PO BID for 2 days intervention 2: 2 g PO BID for 4 days, then 1.5 g PO BID for 2 days

Protocol documents:
Prot_SAP_000.pdf: 
Early N-Acetyl Cysteine treatment for head trauma-
induced anosmia 
Protocol Number: 20170856 
National Clinical Trial (NCT) Identified Number:  NCT03680911 
Principal Investigator: Bradley J. Goldstein, M.D. P.h.D. 
UM Site Principal Investigator: Roy R. Casiano, M.D. 
Sponsor: Investigator initiated study 
Funded by: Internal UM funded 
Version Number:  v.2.0 
August 19, 2019 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.2, 1.3, 1.11, 
1.26.8 
Add the Brief Smell test to be use at the 
screening visit in Emergency Room. 
- Option to mail the subjects the full smell 
test and the questionnaire for follow ups 
visits. 
 
 
 
 
 


 
Table of Contents 
STATEMENT OF COMPLIANCE ......................................................................................................................... 1 
1 
PROTOCOL SUMMARY .......................................................................................................................... 1 
1.1 
Synopsis ........................................................................................................................................... 1 
1.2 
Schema ............................................................................................................................................ 1 
1.3 
Schedule of Activities (SoA) ........................................................................................................... 3 
2 
INTRODUCTION ....................................................................................................................................... 3 
2.1 
Study Rationale ............................................................................................................................... 4 
2.2 
Background ...................................................................................................................................... 4 
2.3 
Risk/Benefit Assessment ................................................................................................................ 5 
2.3.1 
Known Potential Risks ................................................................................................. 5 
2.3.2 
Known Potential Benefits............................................................................................. 6 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................. 6 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................................ 6 
4 
STUDY DESIGN ........................................................................................................................................ 7 
4.1 
Overall Design ................................................................................................................................. 7 
4.2 
Scientific Rationale for Study Design ............................................................................................ 7 
4.3 
Justification for Dose ....................................................................................................................... 7 
4.4 
End of Study Definition ................................................................................................................... 7 
5 
STUDY POPULATION .............................................................................................................................. 7 
5.1 
Inclusion Criteria .............................................................................................................................. 8 
5.2 
Exclusion Criteria ............................................................................................................................ 8 
5.3 
Lifestyle Considerations ................................................................................................................. 8 
5.4 
Screen Failures ............................................................................................................................... 8 
5.5 
Strategies for Recruitment and Retention ..................................................................................... 9 
6 
STUDY INTERVENTION .......................................................................................................................... 9 
6.1 
Study Intervention(s) Administration ............................................................................................. 9 
6.1.1 
Study Intervention Description .................................................................................... 9 
6.1.2 
Dosing and Administration ........................................................................................ 10 
6.2 
Preparation/Handling/Storage/Accountability ............................................................................. 10 
6.2.1 
Acquisition and accountability ................................................................................... 10 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .............................................. 10 
6.2.3 
Product Storage and Stability ................................................................................... 10 
6.2.4 
Preparation ................................................................................................................. 10 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................ 10 
6.4 
Study Intervention Compliance .................................................................................................... 11 
6.5 
Concomitant Therapy.................................................................................................................... 11 
6.5.1 
Rescue Medicine ........................................................................................................ 11 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................................................ 11 
7.1 
Discontinuation of Study Intervention .......................................................................................... 11 
7.2 
Participant Discontinuation/Withdrawal from the Study............................................................. 12 
7.3 
Lost to Follow-Up .......................................................................................................................... 12 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................................................. 13 
8.1 
Efficacy Assessments ................................................................................................................... 13 
8.2 
Safety and Other Assessments ................................................................................................... 13 
8.3 
Adverse Events and Serious Adverse Events ............................................................................ 14 


 
8.3.1 
Definition of Adverse Events (AE) ............................................................................ 14 
8.3.2 
Definition of Serious Adverse Events (SAE)............................................................ 14 
8.3.3 
Classification of an Adverse Event ........................................................................... 14 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up...................... 15 
8.3.5 
Adverse Event Reporting........................................................................................... 15 
8.3.6 
Serious Adverse Event Reporting ............................................................................ 16 
8.3.7 
Reporting Events to Participants .............................................................................. 16 
8.3.8 
Events of Special Interest .......................................................................................... 16 
8.3.9 
Reporting of Pregnancy ............................................................................................. 16 
8.4 
Unanticipated Problems ............................................................................................................... 16 
8.4.1 
Definition of Unanticipated Problems (UP) .............................................................. 16 
8.4.2 
Unanticipated Problem Reporting ............................................................................. 17 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................. 17 
9 
STATISTICAL CONSIDERATIONS ....................................................................................................... 17 
9.1 
Statistical Hypotheses .................................................................................................................. 17 
9.2 
Sample Size Determination .......................................................................................................... 18 
9.3 
Populations for Analyses .............................................................................................................. 19 
9.4 
Statistical Analyses ....................................................................................................................... 19 
9.4.1 
General Approach ...................................................................................................... 19 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ........................................................... 19 
9.4.3 
Analysis of the Secondary Endpoint(s) .................................................................... 20 
9.4.4 
Safety Analyses .......................................................................................................... 20 
9.4.5 
Baseline Descriptive Statistics .................................................................................. 20 
9.4.6 
Planned Interim Analyses .......................................................................................... 20 
9.4.7 
Sub-Group Analyses .................................................................................................. 20 
9.4.8 
Tabulation of Individual participant Data .................................................................. 20 
9.4.9 
Exploratory Analyses ................................................................................................. 20 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................. 20 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................ 20 
10.1.1 
Informed Consent Process ........................................................................................ 20 
10.1.2 
Study Discontinuation and Closure .......................................................................... 21 
10.1.3 
Confidentiality and Privacy ........................................................................................ 22 
10.1.4 
Future Use of Stored Specimens and Data ............................................................. 22 
10.1.5 
Key Roles and Study Governance ........................................................................... 22 
10.1.6 
Safety Oversight .............................................................. Error! Bookmark not defined. 
10.1.7 
Clinical Monitoring ...................................................................................................... 23 
10.1.8 
Quality Assurance and Quality Control .................................................................... 23 
10.1.9 
Data Handling and Record Keeping ......................................................................... 23 
10.1.10 
Protocol Deviations .................................................................................................... 24 
10.1.11 
Publication and Data Sharing Policy ........................................................................ 25 
10.1.12 
Conflict of Interest Policy ........................................................................................... 25 
10.2 
Additional Considerations ............................................................................................................. 25 
10.3 
Abbreviations ................................................................................................................................. 26 
10.4 
Protocol Amendment History ....................................................................................................... 27 
11 
REFERENCES ............................................................................................. Error! Bookmark not defined. 
 


 
 
STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 
CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Early N-Acetyl Cysteine treatment for head trauma-induced anosmia 
 
Study Description: 
This study will compare administration of N-Acetyl Cysteine (NAC) versus 
placebo for the treatment of olfactory loss due to head injury. We 
hypothesize that treatment with NAC acutely after head injury will result 
in improved olfactory function.  
Objectives: 
 
Primary Objective:  To determine if early treatment with NAC after head 
injury results in improved olfactory function, compared to placebo. 
 
Endpoints: 
Primary Endpoint: Olfactory function at 1 and 3 months and post-
enrollment. 
Secondary Endpoints: Olfactory-specific quality of life questionnaire. 
Study Population: 
Adult patients of either gender presenting to Ryder trauma center with 
mild or moderate blunt head trauma who have abnormal score on 
objective olfactory testing. 
Phase: 
2  
Description of 
Sites/Facilities Enrolling 
Participants: 
1.1.1.1.1.1.1 Ryder Trauma Center at Jackson Memorial Hospital, Miami, 
FL. Ryder is a Level 1 trauma center associated with an 
academic medical center, the University of Miami. 
Description of Study 
Intervention: 
Subjects will be randomized to receive either NAC or placebo. NAC will be 
administered orally as a 4 gram loading dose, followed by 2 g PO BID for 4 
days, then 1.5 g PO BID for 2 days.  
Study Duration: 
1.1.1.1.1.1.2 12 months 
Participant Duration: 
1.1.1.1.1.1.3 3 months 
 
 
1.2 
SCHEMA 
 


Prior to  
Enrollment
Visit 1 
Day 0 
Treatment 
(Home) 
Visit 2 
30 ± 7 days  
 
 
 
Visit 3 
4 months 
(± 3 weeks) 
 
 
 
 
 
 
 
Total N: Screen potential participants presenting with blunt head trauma, warranting 
overnight observation, by bedside Smell Identification Test. Subjects with abnormal score 
will be offered participation in the study and informed consent will be obtained. 
Perform baseline assessments: 
History and head and neck exam including nasal endoscopy;
Review B-SIT score, trauma CT scans.
Administer NAC loading dose or placebo prior to discharge from trauma center. 
Outpatient follow-up visit in Otolaryngology clinic; 
Repeat SIT test; Questionnaire for Olfactory Disorders, or optional mail of SIT test and 
QOD. 
Outpatient follow-up visit in Otolaryngology clinic; 
Repeat SIT test; Questionnaire for Olfactory Disorders (QOD), or optional mail of SIT test 
and QOD.
Data analysis 
And Interpretation
Placebo 
N=30 
NAC treatment 
N=30 
Outpatient treatment with NAC or placebo for 6 days 
Randomize 


 
 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
 
 
 
INTRODUCTION 
Procedures 
Screening 
Day -2 to 0 
Enrollment/Baseline 
Day 0 
Home treatment 
Day 1-6 
Study Visit 2  
Day 30  +/-7 days 
Study Visit 3 
Month 4 +/- 3 weeks 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
1.3.1.1.1.1.1 
B-IT 
(Brief 
olfactio
n test) 
X 
 
 
 
 
1.3.1.1.1.1.2 
SIT 
(olfactio
n test)In 
person 
or send 
by mail. 
 
 
 
X 
X 
1.3.1.1.1.1.3 
QOD 
(questio
nnaire) 
X 
 
 
X 
X 
1.3.1.1.1.1.4 
Radiolo
gic/Imag
ing 
assessm
ent 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Physical exam, with nasal 
endoscopy  
X 
 
 
 
 
Vital signs 
X 
X 
 
X 
X 
1.3.1.1.1.1.5 
Concom
itant 
medicati
on 
review 
X 
X 
 
X 
X 
Pregnancy test  
X 
 
 
 
 
1.3.1.1.1.1.6 
Adminis
ter 
study 
interven
tion 
 
X 
X 
 
 
1.3.1.1.1.1.7 
Adverse 
event 
review 
and 
evaluati
on 
 
X 
 
X 
X 


 
 
 
1.4 
STUDY RATIONALE  
 
Head trauma is a common cause of permanent olfactory loss. Studies indicate that objective smell loss 
occurs in 15-35% of traumatic brain injury (TBI) subjects1. In most cases, olfactory problems do not 
receive attention until weeks to months following the injury, and the current standard of care is 
observation, since no specific treatments have been identified2. Recently, neuroprotective agents, such 
as NAC, administered early after TBI have gained attention for the potential to promote recovery or 
prevent long-term neurologic sequelae such as cognitive or vestibular problems3. However, no study has 
tested whether administration of NAC after TBI can promote recovery of olfactory function. Therefore, 
we propose to test this simple pharmacologic intervention in TBI patients with objective olfactory loss, 
identified upon admission to Ryder trauma hospital. 
 
1.5 
BACKGROUND  
Persistent anosmia (a loss of one’s sense of smell) affects an estimated 14 million people in the 
US4. Many persistent acquired forms of anosmia are thought to be due to neurodegenerative processes 
such as aging (presbyosmia) or damage to the nasal olfactory neuroepithelium (post-viral or post head 
trauma anosmia)5. Of these conditions, patients sustaining head trauma or TBI represent a population of 
particular interest, since the identification of anosmia in this group may afford us an opportunity to 
apply an effective intervention in the acute setting.  Currently, we have no treatments for this problem.  
The pathogenesis of head trauma-induced anosmia is incompletely understood. Evidence 
suggests that blunt trauma causes the brain to move rapidly against the fixed skull base, causing 
shearing or stretch of the delicate olfactory nerve fibers that project from the nasal cavity through the 
cribriform plate of the ethmoid bone to connect to the olfactory bulbs of the brain. Furthermore, the 
trauma can result in bruising or direct injury to the olfactory bulbs, among other intracranial injuries. 
The end result appears to be a rapid degeneration and death of the primary olfactory receptor neurons, 
situated in the olfactory epithelium of the nose. Biopsies of human nasal olfactory tissue from such 
anosmia patients often show neurodegenerative changes, strongly supporting the notion that loss of 
function is related to damage to the nasal neuroepithelium5. Despite an ability of basal cells in the 
olfactory epithelium to produce new neurons6, many TBI patients do not regain olfactory function, 
suggesting that after injury the axons fail to properly reinnervate the olfactory bulbs. It is believed that 
intracranial scarring, or reactive gliosis, develops as a response to the degenerative changes and may 
prevent reinnervation. We hypothesize that an early intervention to prevent degeneration (olfactory 
neuron apoptosis) and the accompanying glial scarring would help promote olfactory recovery 
following TBI. 
In considering possible therapeutic compounds, NAC is an attractive candidate for several 
reasons. It is FDA approved for both systemic and topical respiratory administration and has a long track 
record of safe clinical use. Also, research in other tissue systems has provided strong data supporting its 
neuroprotective effects7. For instance, in animal models of inner ear sensory damage or degeneration, 


 
 
NAC is effective at promoting recovery of neurons8. Finally, a recent human clinical trial tested oral NAC 
administration for neuroprotective effects following traumatic brain injury and found it to be safe and 
effective3. In that study, olfaction was not assessed, but other neurologic outcomes such as cognitive 
and vestibular function were markedly improved. We plan to use the same dosage regimen that was 
used in that study. Since animal modeling of olfactory injury, such as methimazole or methyl bromide 
induced lesion or olfactory bulbectomy results in robust regeneration9,10, testing of medications for 
regenerative efficacy is not feasible. Given the safety and efficacy of NAC therapies in animals and 
humans in other tissue systems, we propose to undertake a human study testing acute NAC therapy for 
treatment of TBI-induced anosmia. Identification of an effective therapy for certain forms of anosmia 
would be a significant advance, as there currently are no treatments available. 
 
 
 
 
 
 
1.6 
RISK/BENEFIT ASSESSMENT   
 
1.6.1 KNOWN POTENTIAL RISKS  
 
Risks from medication: NAC is FDA approved, with a forty-year safety history. It is widely used for 
nebulized delivery to the lower airways for its mucolytic effects (Mucomyst). Otolaryngologists have 
prescribed NAC off-label as a topical nasal medication for years for certain chronic rhinosinusitis patients 
for it mucolytic effects, with no safety concerns reported. It also has a long history of systemic oral 
administration safely. It is used at high dose orally in emergency departments for acetaminophen 
overdose, to prevent hepatotoxicity. Known side effects reported from nebulized pulmonary delivery 
include some patients reporting a noticeable odor. Other possible side effects might include local 
irritation; however it has been used widely in the lower airways and via tracheostomy stoma without 
irritation. There are rare reports of bronchospasm reactions to NAC delivered to the lower airways via 
nebulizer; these typically respond to bronchodilators (albuterol). Loading doses for FDA-approved oral 
administration of NAC are about 55 ml of 20% NAC solution (≈10 g), and our study patients will receive a 
4 g loading dose, much lower. Importantly, a recent published study using the identical oral NAC 
regimen proposed here reported no adverse events or treatment side effects3. NAC can cause headache 
or potentiate effects of nitroglycerine or isosorbide. It may alter levels of homocysteine. It may 
potentiate the effects of certain immunosuppressants, such as cyclophosphamide or azathioprine. It can 
cause GI upset. 
 
Other risks: There is no economic risk, as we will supply the study medication. The pre-study 
work up and care is the trauma standard-of-care, unchanged, and is no different for patients choosing or 
not choosing to participate in this study. Psychologically, there is the risk of disappointment from 
possible lack of improvement or from treatment with placebo. However, the current standard-of-care is 
no treatment, so we will council patients regarding this. 


 
 
 
1.6.2 KNOWN POTENTIAL BENEFITS  
 
The immediate and long-range potential benefit is improvement in olfactory function. As stated, the 
standard of care for TBI induced anosmia is observation, and many patients do not recover olfaction. 
Basic cell culture and animal studies with NAC, as well as a recent human trial of NAC following TBI, 
support the conclusion that NAC can prevent neuronal degeneration or cell death and promote neural 
recovery or regeneration. Thus, there is potential that olfactory neuron damage following TBI, which 
leads to anosmia, will improve with NAC treatment in this study. Secondary potential benefits include 
improvement in other non-olfactory TBI sequelae such as headache, cognitive dysfunction or 
vestibulopathy, as reported in a recent NAC trial for TBI. 
 
1.6.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Existing evidence is consistent with a very positive risk to benefit assessment. Prior clinical trial with the 
exact NAC regimen in TBI patients reported no adverse effects. The treatment involves only a 1 week 
course of therapy. There are no existing alternatives. Basic science studies provide a wealth of evidence 
for promoting neuronal recovery using this drug. 
 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To determine if early treatment 
with NAC after head injury results 
in improved olfactory function, 
compared to placebo. 
 
1.6.3.1.1.1.1 Olfactory 
function at 1 and 
3 months post-
enrollment, as 
measured by 
Smell 
Identification 
Test (SIT). 
 
1.6.3.1.1.1.2 SIT is a 
validated test 
for olfaction. 
Time points of 
1 and 3 
months were 
chosen to test 
for early 
recovery of 
olfactory 
neurons 
versus 
evidence for 
successful 
regeneration, 
respectively. 
Secondary 
 
 
1.6.3.1.1.1.3 To assess olfactory-
specific quality of life 
measure in treated 
versus placebo 
groups. 
 
1.6.3.1.1.1.4 Questionnaire on 
olfactory 
dysfunction 
(QOD) scores at 1 
and 3 months.   
 
1.6.3.1.1.1.5 QOD is a 
validated tool 
for measuring 
quality of life 
related to 
olfactory loss. 


 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Tertiary/Exploratory  
 
 
N/A 
 
 
 
 
 
STUDY DESIGN  
 
1.7 
OVERALL DESIGN 
 
• 
Hypothesis: Early treatment with NAC after head injury will result in improved olfactory 
function, compared to placebo. 
• 
Phase 2 trial.  
• 
Design: Randomized, placebo-controlled, double-blind study. 
• 
Study groups: Treatment versus Placebo. 
• 
Number of Sites: Single site. 
• 
Study Intervention: N-Acetyl-Cysteine (NAC) 
 
 
1.8 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
We seek to determine if early treatment with NAC will improve olfaction in TBI patients with olfactory 
loss. To obtain high quality evidence, we chose a prospective randomized placebo control double blind 
approach. There is no standard of care treatment or drug that can be used for comparison; the current 
standard of care is observation. To avoid bias, a double blind approach will be used. Based on the best 
knowledge for mechanism of olfactory loss in TBI patients, we believe that the best chance for efficacy is 
to identify and treat patients as soon as possible following injury. Therefore, the protocol is designed to 
test olfaction in an acute trauma setting and test intervention acutely. 
 
1.9 
JUSTIFICATION FOR DOSE 
 
Dose regimen is based on a prior clinical study of acute TBI patients3. In that study, no adverse effects 
were identified. Although olfaction was not assessed, the dose was found to be efficacious for their 
specific measures, including common TBI sequelae such as dizziness, headache, or memory problems.  
 
1.10 END OF STUDY DEFINITION 
 
The end of the study is defined as completion of the last visit shown in the SoA.  
 
STUDY POPULATION 
 


 
 
1.11 INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Admitted to Ryder Trauma Center for observation acutely following head injury (i.e. concussion), 
with documented hyposmia or anosmia by University of Pennsylvania Brief Smell Identification 
Test (SIT). ( The Brief smell identification test B-SIT is a rapid and effective 5 minute screening test. 
This 12 item version of the Smell Identification Test  is useful for detecting smell loss in situations 
where less than five minutes of time are available) 
2. Male or female, aged 18 years or older 
3. Provision of signed and dated informed consent form 
4. Stated willingness to comply with all study procedures and availability for the duration of the 
study 
5. Ability to take oral medication and be willing to adhere to the NAC regimen 
6. For females of reproductive potential: use of highly effective contraception for at least 1 month 
prior to screening and agreement to use such a method during study participation and for an 
additional 4 weeks after the end of NAC administration  
 
 
1.12 EXCLUSION CRITERIA 
 An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Severe trauma requiring ongoing inpatient treatment beyond 48 hours 
2. Pregnancy (based on urine screening) or lactation 
3. Known allergic reactions to components of NAC, such as Mucomyst 
4. Currently taking nitrates such as nitroglycerine and/or isosorbide regularly 
5. Currently taking azathioprine (Imuran) or cyclophosphamide (Cytoxan) 
6. Known diagnosis of cystinuria (renal condition in which cysteine supplement should be avoided) 
7. Febrile illness within 1 week  
8. Treatment with another investigational drug or other intervention within 3 months 
9. Active sinonasal disease by imaging and/or nasal exam, i.e. rhinosinusitis, nasal polyps 
10. Adults unable to consent 
11. Prisoners, employees or subordinates 
12. Individuals who are not yet adults (infants, children, teenagers). This population is excluded 
because efficacy has not yet been established in adults. 
1.13 LIFESTYLE CONSIDERATIONS 
N/A 
 
 
1.14 SCREEN FAILURES 


 
 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). Re-screening will not be 
performed. 
 
1.15 STRATEGIES FOR RECRUITMENT AND RETENTION 
 
• 
Target study sample size: 30 subjects in each arm, 60 subjects total. No exclusions by gender, 
race and ethnicity.  Anticipated number to be screened in order to reach the target enrollment: 
300 subjects (approximately 33% of trauma subjects may have abnormal SIT scores; of these, 
approximately 40% may have other exclusions or decline). 
• 
Anticipated accrual rate: 60 subjects 
• 
Anticipated number of sites: 1 
• 
Source of participants: inpatient hospital setting, Ryder Trauma unit. The potential study 
subjects will be identified from patients under the care of the Investigators’ team at Ryder 
Trauma. Potential participants will be selected by identifying subjects admitted for observation 
at Ryder Trauma Center following blunt head trauma.  
• 
Types of recruitment strategies planned: N/A, subjects will be identified from inpatient 
population as described, and approached regarding possible participation prior to discharge. 
• 
Incentives for visit attendance: patients will need to follow up in Otolaryngology clinic at 
approximately 1 and 3 months. To improve retention, they will be offered a payment incentive 
of $50 for attending these visits; paid upon completion of the visit, prorated if not complete. 
• 
Specific strategies that will be used to recruit and retain historically under-represented 
populations in order to meet target sample size and conform with the NIH Policy on Inclusion of 
Women and Minorities as Participants In Research Involving Human Subjects: We will not 
exclude any demographic (other than children, as stated); our population in Dade County is 
quite diverse; the study population is anticipated to reflect this diversity, including a majority of 
Hispanic subjects. 
 
 
STUDY INTERVENTION 
 
1.16 STUDY INTERVENTION(S) ADMINISTRATION 
 
1.16.1 STUDY INTERVENTION DESCRIPTION 
 
Subjects will be randomized to receive either N-Acetyl-Cysteine (NAC) or placebo, to be prepared and 
packaged by our research pharmacy. NAC will be administered orally as a 4 gram loading dose, followed 
by 2 g PO BID for 4 days, then 1.5 g PO BID for 2 days.  


 
 
 
NAC is available as a generic over-the-counter oral supplement. It is not FDA regulated. Since there is 
not an FDA-approved labeling for over-the-counter oral NAC use, our trial does not change any existing 
label. NAC is also the active ingredient in the drug Mucomyst. Mucomyst is used as a pulmonary inhaled 
nebulized drug for its mucolytic properties to help treat chronic bronchitis. NAC is also administered 
orally or by nasogastric tube in Emergency Departments for the treatment of acetaminophin (Tylenol) 
overdose. 
 
1.16.2 DOSING AND ADMINISTRATION 
 
NAC or placebo will be administered orally as a 4 gram loading dose, followed by 2 g PO BID for 4 days, 
then 1.5 g PO BID for 2 days. The loading dose will be given prior to discharge from Ryder Trauma 
center. Remaining doses will begin on the following morning as an outpatient to complete the 1 week 
treatment course. Delayed doses may be taken late if noted before the next dose, and otherwise will be 
skipped. The doses may be taken with or without meals. 
 
1.17 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
1.17.1 ACQUISITION AND ACCOUNTABILITY 
 
Randomization, drug and placebo preparation, and packaging will be done by our Jackson research 
pharmacy following their established protocols for double-blind studies. When ordered, the loading 
dose will be administered by nursing staff prior to discharge. The remaining outpatient supply will be 
delivered by the pharmacy to the Ryder Trauma nursing staff to be provided to the patient, along with 
instructions, upon discharge. If doses are missed, patients will be instructed to return unused product at 
their follow up visit. 
 
1.17.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Research pharmacy will prepare and label study drug or placebo appropriately for double-blind study. 
 
1.17.3 PRODUCT STORAGE AND STABILITY 
 
Patients will receive a 6-day course of medication. This is to be stored at room temperature. Drug will be 
considered expired after 1 month. 
 
 
1.17.4 PREPARATION 
 
No preparation will be required. Drug or placebo will be ready-to-use capsule to be taken orally. 
 
1.18 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
To minimize bias, this will be a randomized double-blind trial. We will use the Jackson Health System 
Research Pharmacy to prepare study drug or placebo, using their randomization procedures and 


 
 
labeling. Trial randomization codes will be maintained until planned enrollment is reached and the final 
patient has completed the 2 planned follow up visits. There are no planned lab studies or measures that 
would be expected to lead to inadvertent unblinding. If there are serious adverse events (SAEs), this will 
be reported to the PI and unblinding for the affected subject would be performed. 
 
 
1.19 STUDY INTERVENTION COMPLIANCE 
 
The loading dose will be given prior to discharge. The remaining study drug will be taken as an 
outpatient over the next 6 days. We will ask participants to complete a study drug log to record timing 
of each dose. We will not plan any labs or assays for verification. Drug log will be collected at the first 
outpatient visit. 
 
1.20 CONCOMITANT THERAPY 
 
Concomitant medications will not be restricted. No change from standard post-head injury care will be 
implemented, other than use of the study drug or placebo. Concomitant medications will be recorded. 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications and supplements. 
 
 
1.20.1 RESCUE MEDICINE 
 
N/A 
 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
Participants may withdraw voluntarily from the study or the PI may discontinue a participant from the 
study.  This section should state which adverse events would result in discontinuation of study 
intervention or participant discontinuation/withdrawal. In addition, participants may discontinue the 
study intervention, but remain in the study for follow-up, especially for safety and efficacy study 
endpoints (if applicable). Consider requiring separate documentation for study intervention 
discontinuation and participant discontinuation/withdrawal from the study. In addition, a dedicated 
Case Report Form (CRF) page should capture the date and the specific underlying reason for 
discontinuation of study intervention or participant discontinuation/withdrawal.  
 
1.21 DISCONTINUATION OF STUDY INTERVENTION 
 
If a patient notes a possible adverse effect, such as allergic reaction to study medication, we will 
discontinue study medication. Any new clinically relevant finding will be reported as an adverse event 
(AE). Because the outpatient course of study medication is only 6 days, we will not restart study 


 
 
medication in that short timeframe and instead will withdraw the patient from this study. Such patients 
will still be offered planned follow up and the planned outcome measures will still be collected. 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Details of possible adverse event, and appropriate care as indicated (for example ER 
assessment). 
 
1.22 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded on the NAC 
Case Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not 
receive the study intervention may be replaced.  Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are withdrawn or 
discontinued from the study, will be replaced. Patients who do not complete the full course of study 
drug/placebo will be noted in the results tables, and they will not be included in the statistical analysis of 
outcome measures, since this is a simple comparison of SIT score between patients receiving a 1 week 
course of NAC versus placebo. 
1.23 LOST TO FOLLOW-UP 
 
 
 A participant will be considered lost to follow-up if he or she fails to return for the 2 scheduled follow 
up Otolaryngology clinic visits and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 2 weeks 
and counsel the participant on the importance of maintaining the assigned visit schedule. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 


 
 
 
In an effort to minimize failure to follow up, we will incentivize subject with a $50 payment, to be 
provided at the follow up visits. 
 
STUDY ASSESSMENTS AND PROCEDURES 
 
1.24 EFFICACY ASSESSMENTS  
The primary outcome measure is olfactory ability at 1 and 3 months, measured via the SIT, in head 
trauma patients. Patients will be identified from the population admitted for observation at Ryder 
trauma following TBI. Co-investigators on this protocol oversee the trauma unit, round on the admitted 
patients on a daily basis, and will therefore identify candidates as those patients sustaining a TBI from 
blunt head injury requiring overnight observation. Relevant standard of care data from the chart will be 
collected in a HIPPA-compliant fashion, to specifically include (1) history describing mechanism of injury, 
(2) results of head CT and (3) physical exam upon presentation, with Glascow Coma Score or other 
standard head trauma assessment details. No additional imaging is required for the study or efficacy 
measure; however imaging obtained as part of standard routine care available in the medical record will 
be reviewed. Those patients with severe poly-trauma and/or ongoing intubation or inability to 
participate in the SIT test will be excluded. The candidate patients will be administered the Brief SIT to 
assess olfaction. Those with abnormal scores will be offered enrollment in the study. There are only 3 
procedures involved in the study to assess efficacy: (1) SIT measures (2) Administration of study 
medication or placebo, (3) the QOD quality of life questionnaire. 
 
• 
The SIT is a self-administered 40-item test involving microencapsulated (scratch-and-sniff) odors 
with a forced-choice design. There are 4 booklets with 10 questions each, asking the subject to 
identify which of 4 answers best described the odor. Total scores are categorized, based on 
normative data, as normal, mild hyposmia, moderate hyposmia, severe hposmia, total anosmia, 
or probable malingering. The test was developed at University of Pennsylvania as part of an NIH-
funded program project and is widely used as a standard assessment of olfactory function. We 
will use the Brief Smell Identification Test that is a rapid and effective 5 minute test during the 
Screening Visit. This item version of the Smell Identification Test is useful for detecting smell loss 
in situations where less than five minutes of time is available.  For the follow up Visit 2 and Visit 
3, we will use the full SIT. 
 
• 
The QOD is a validated olfactory-specific quality of life questionnaire and is attached. 
 
 
1.25 SAFETY AND OTHER ASSESSMENTS 
 
Screening for, or participation in, this study will not alter head trauma standard of care. The potential 
patient safety issue for the study is the possibility of adverse reaction to study medication. The dosage 
regimen we are using has been used in a previous published trial with no adverse events reported. 
Nonetheless, we are giving the initial loading dose prior to discharge, which will enable us to identify any 
immediate events such as acute allergic reaction. Patients will receive instructions and contact 
information to inform the coordinator or PI promptly of any potential problems. At follow up visit, we 
will collect patient drug logs and any comments or notes regarding possible side effects. 


 
 
   
1.26 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
1.26.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
1.26.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
 
1.26.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
1.26.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”.] 
 
 
 
1.26.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 


 
 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
 
 
1.26.3.3 EXPECTEDNESS  
 
PI will be responsible for determining whether an adverse event (AE) is expected or unexpected.  An AE 
will be considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the study intervention. 
 
1.26.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events 
will be followed for outcome information until resolution or stabilization. 
 
1.26.5 ADVERSE EVENT REPORTING  
 


 
 
Adverse Event reporting will adhere to all established guidelines, as described below. 
 
1.26.6 SERIOUS ADVERSE EVENT REPORTING  
 
The study clinician will immediately report to the UM Human Subjects Research Office any serious 
adverse event, whether or not considered study intervention related, including those listed in the 
protocol or investigator brochure and must include an assessment of whether there is a reasonable 
possibility that the study intervention caused the event. Study endpoints that are serious adverse events 
(e.g., all-cause mortality) must be reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the study intervention and the event (e.g., death from 
anaphylaxis). In that case, the investigator must immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable.  
 
 
1.26.7 REPORTING EVENTS TO PARTICIPANTS  
 
Any subjects who have not yet completed their first follow up visit will be contacted by phone to inform 
them of any Serious Adverse Events, if any occur. 
 
1.26.8 EVENTS OF SPECIAL INTEREST  
In an effort to minimize failure to follow up, we will give the subject the option If for any specific reason 
will not be able to attend the Visit 2 and Visit 3 in person we will mail by Certified Mail the full Smell 
identification Test and the QOD questionnaire and request to be send back to us in  the same way ( 
Certified Mail will be cover by the Investigator). 
 
1.26.9 REPORTING OF PREGNANCY  
 
If pregnancy occurs during the study, this will be reported to the HSRO. The study medication course is 
only 1 week, however if pregnancy is identified prior to completion of study medication it will be 
discontinued. 
 
1.27 UNANTICIPATED PROBLEMS 
 
1.27.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 


 
 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
 
1.27.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will 
include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within 5 days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 1 week of the 
investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 1 week of the IRB’s receipt of the report of the 
problem from the investigator. 
 
 
1.27.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
N/A 
 
STATISTICAL CONSIDERATIONS  
 
1.28 STATISTICAL HYPOTHESES 
 
• 
Primary Efficacy Endpoint(s):  
 
To determine if early treatment with NAC after head injury results in improved olfactory function, 
compared to placebo. Type of comparison: superiority. Time period: 1 and 3 months post-enrollment. 
 


 
 
Null hypothesis: There is no difference in SIT score with NAC treatment or placebo. 
Alternative hypothesis: NAC treatment results in improved SIT score. 
 
• 
Secondary Efficacy Endpoint(s): 
 
To assess olfactory-specific quality of life measure in treated versus placebo groups. 
Type of comparison: superiority. Time period: 1 and 3 months post-enrollment. 
 
Null hypothesis: There is no difference in QOD score with NAC treatment or placebo. 
Alternative hypothesis: NAC treatment results in improved QOD score. 
 
1.29 SAMPLE SIZE DETERMINATION 
Number of participants to enroll to have adequate power to test the key hypotheses for the study:  
Placebo group: 30 
Treatment group: 30 
 
• 
Target study sample size: 30 subjects in each arm, 60 subjects total. Anticipated number to be 
screened in order to reach the target enrollment: 300 subjects (approximately 33% of trauma 
subjects may have abnormal SIT scores; of these, approximately 40% may have other exclusions 
or decline). 
 
• 
Outcome measure used for calculations: SIT score  
• 
Test statistic: t-test 
• 
Null and alternative hypotheses: 
Null hypothesis: There is no difference in SIT score with NAC treatment or placebo. 
Alternative hypothesis: NAC treatment results in improved SIT score. 
 
• 
Type I error rate (alpha): 0.05 
• 
Power level: 0.8 
• 
Assumed mean and variance: 
Placebo group, mu1: SIT=17 ± 10 
Treatment group, mu2: SIT=25 ± 10 
 
Reference: “Hypothesis Testing: Two-Sample Inference - Estimation of Sample Size and Power for 
Comparing Two Means” in Rosner, Bernard Fundamentals of Biostatistics, Belmont, Calif. : Duxbury 
Press, [1995]. 
 
 
SIT score of 17 is used for the placebo group because this is at the upper range of a score 
categorized as anosmia (total loss of olfaction). In a recent large review and meta-analysis of TBI-
induced olfactory loss1 a range of SIT scores are reported in the 7-27 score range, for mild-moderate 
TBI. Based on these data, we anticipate identifying and enrolling patients with a mean score of 
approximately 17 and a variance of approximately 10.  
 
In terms of estimated possible improvement in SIT score with NAC treatment, we have chosen an 
increase of 8 ± 10 points, because a jump of more than a few points on a repeat SIT test after one 


 
 
month is considered to be greater than just random chance11; (and Doty, R., personal 
communication). There are no published data available for specifically measuring olfactory change 
following treatment with NAC for head trauma. In a pilot study testing topical intranasal NAC for 
different forms of anosmia (Clinicaltrials.gov), no published results are available. However, in a study 
using the same dosage regimen of oral NAC following blast TBI and assessing non-olfactory outcome 
measures, quantifiable neuropsychiatric measures did show a roughly 25-33% improvement versus 
placebo, providing an additional indirect basis for expecting a similar magnitude effect on our 
measures3.  
 
• 
Anticipated impact of dropout rates, withdrawal, missing data, etc. on study power: to 
compensate for such issues, we have increased our sample size by 5 subjects per group.  
 
• 
Secondary endpoint: We have included a secondary endpoint to measure quality of life via a 
validated questionnaire (QOD). We have no specific guides for mean or variance for the 
questionnaire in terms of possible NAC or placebo treatment, so no calculations are possible. 
Nonetheless, a simple questionnaire poses no cost or risk, such that we see no reason to not 
collect these data. 
 
1.30 POPULATIONS FOR ANALYSES 
 
• 
Intention-to-Treat (ITT) Analysis Dataset (i.e., all randomized participants): 
 
Placebo group (n=30) 
NAC treated group (n=30) 
 
1.31 STATISTICAL ANALYSES 
 
General Approach 
1.31.1  
Data (SIT scores, QOD scores) will be presented as means with standard deviations, as well as range. 
Placebo and NAC-treated groups will be compared statistically, with p<0.05 considered significant, via 
two-tailed t-test. If data are not normally distributed, nonparametric testing or appropriate post-hoc 
corrections will be applied. 
 
1.31.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Primary endpoint is SIT score at 1 month and 3 months. 
Placebo and NAC-treated groups will be compared. SIT (mean ± sd) will be compared via two-tailed t-
test.  
SIT scores may range from 0-40, and normal scores are well-established. An assignment of normosmia, 
mild hyposmia, moderate hyposmia, severe hyposmia, anosmia, or probable malingering can be made 
based on SIT score. 
 


 
 
1.31.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Secondary endpoint is QOD score at 1 month and 3 months. 
Placebo and NAC-treated groups will be compared. QOD (mean ± sd) will be compared via two-tailed t-
test.  
QOD scores may range from 0-75. There are 25 quality of life questions, scored 0-3 each. A lower score 
implies more severe dysfunction. 
 
1.31.4 SAFETY ANALYSES 
 
There is no formal safety endpoint being evaluated. AEs will be counted per event and will be presented 
as number of AEs and severity.  
 
1.31.5 BASELINE DESCRIPTIVE STATISTICS 
 
The baseline characteristics of the placebo group and the NAC-treated groups will be presented. Data 
will include age (mean ± sd) and SIT score (mean ± sd) on enrollment. Also, gender, ethnicity, and details 
of the injury (i.e. punch, fall, motor vehicle accident, blast, etc.) will be captured.  
 
1.31.6 PLANNED INTERIM ANALYSES  
N/A 
 
1.31.7 SUB-GROUP ANALYSES 
 
Although no differences are anticipated based on gender, we will capture this information and present 
mean SIT scores for males or females. The primary endpoint will include both genders. 
 
1.31.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
A Table containing individual patient data will be included. 
 
1.31.9 EXPLORATORY ANALYSES 
 
N/A 
 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
1.32 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
 
1.32.1 INFORMED CONSENT PROCESS 
 


 
 
1.32.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
The consent form that will be used for this study is attached. 
 
 
1.32.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. All subjects must provide written 
consent prior to participating in this study. Potential participants will be given an ICF containing 
information in a language understandable to them, which meets all federal, local, ICH and HIPAA 
requirements, and is approved by an Institutional Review Board (IRB). 
Informed consent will be obtained using processes that comply with all federal and local regulations. 
Patients Admitted to Ryder Trauma Center for observation acutely following head injury (i.e. 
concussion), with documented hyposmia or anosmia by University of Pennsylvania Smell Identification 
Test (SIT) will be identified and approached by the treating physician. After gauging the patients’ interest 
in participation in a clinical trial, the patient will be approached by the study investigator or designee. 
The Investigator (or designee) will carefully review the ICF with potential subject, which includes a 
review of the purpose, scope, procedures, and potential consequences to the subject. Patients will be 
informed that participation in the study is completely voluntary, and they may withdraw from the study 
at any time with no penalty or loss of benefits. Likewise, the quality of their medical care will not be 
adversely affected if they decline to participate in this study.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. 
The potential study subject (or healthcare proxy) and Investigator (or designee) must sign and date the 
ICF before the subject can participate in the study. The original will be retained on file at the study site, 
and the subject will receive a copy.  
Should the ICF be amended during the study, the site must use the amended ICF for all new subjects and 
repeat the consent process with the amended ICF for any ongoing subjects. 
Spanish speaking subjects will be provided a translated consent. 
 
1.32.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the PI to study participants and the Institutional Review Board (IRB) and will provide the 
reason(s) for the termination or suspension.  
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    


 
 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, or data quality are addressed and 
satisfy the IRB. 
 
 
1.32.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. Each subject’s name will remain strictly confidential 
and shall be excluded from the database, only subjects’ initials, assigned identifier number, and 
birthdate shall be entered, uploaded, or otherwise documented in the database. The Investigator will 
retain a cross-referencing record of each subject’s name and assigned identifier number. 
All study data and results will be stored in an electronic database. Each study subject will give explicit 
consent for representatives of the IRB/IEC and regulatory authorities to inspect and verify each subject’s 
medical records and collected information. Each study subject will be assured that all their personal 
information will be maintained in the strictest of confidence, and in compliance with HIPAA, and all 
other federal and local laws regulating privacy and data protection. 
All research activities will be conducted in as private a setting as possible. 
The study participants’ contact information will be securely stored at the clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
1.32.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at the PI’s office at University of Miami.  
There are no specimens or biologic samples collected for this study. 
 
 
1.32.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Medical Monitor 
1.32.5.1.1.1.1 Bradley J. 
Goldstein, MD, 
PhD 
Associate Professor, 
Otolaryngology 
To be name 
University of Miami Miller School 
of Medicine 
University of Miami Miller 
School of Medicine 
1120 NW 14th St, 5th Fl, Miami, FL 
33136 
1120 NW 14th St, 5th Fl, Miami, 
FL 33136 


 
 
305-243-1484 
 
b.goldstein4@med.miami.edu 
1.32.5.1.1.1.1.1  
 
 
 
 
1.32.6 CLINICAL MONITORING 
 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
On-site monitoring, by  the research manager of the department from Otolaryngology 
Department will be planned throughout the study. This will included a targeted review of with 
verification of endpoint and safety, and the distribution of monitoring reports will be provided 
to the PI. Study coordinator will help following the regulations in every aspect of the study. 
• 
Independent audits will not be conducted, for this relatively small study. 
 
 
1.32.7 QUALITY ASSURANCE AND QUALITY CONTROL 
 
 
An individualized quality management plan will be developed to describe a site’s quality management. 
No specimens are to be collected for this study, and the data that are to be collected for primary 
endpoint include SIT scores. Thus, we will focus on monitoring that SITs, a self-administered test, are 
being collected and scored properly. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
 
1.32.8 DATA HANDLING AND RECORD KEEPING  
 
1.32.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
This is a Single-Center study, but our Center includes Jackson/Ryder as well as UHealth, which use 
separate electronic medical record (EMR) systems. This is clarified below. Data collection is the 


 
 
responsibility of the clinical trial staff under the supervision of the PI. The PI is responsible for ensuring 
the accuracy, completeness, legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.  Records from the initial Ryder Trauma admission will be kept in the EMR at Jackson, known as 
Cerner. This will include demographics, CT scans, vital signs, and initial admission H&P. Relevant data 
will be summarized on a visit worksheet, including information on initial SIT score, mechanism of injury, 
and key CT scan findings. 
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) will be then entered into UChart , the EMR system at UHealth, since the follow up outpatient visits 
will be conducted at the UHealth Otolaryngology clinic. The data system includes password protection 
and internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. Data will 
include the patient’s drug log, SIT scores and QOD scores. 
 
 
1.32.8.2 STUDY RECORDS RETENTION  
 
Study documents will be retained until at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study intervention. These documents should be retained for a longer period, 
however, if required by local regulations. No records will be destroyed without the written consent of 
the sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. 
 
1.32.9 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 30 working days of identification of the protocol deviation, or within 30 working days 
of the scheduled protocol-required activity.  All deviations must be addressed in study source 
documents.  Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their 


 
 
policies. The site investigator is responsible for knowing and adhering to the reviewing IRB 
requirements.  
 
 
1.32.10 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
This trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted 
to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.  
Data from this study may be requested from other researchers 3 years after the completion of the 
primary endpoint by contacting the PI, Bradley Goldstein, MD, PhD.  
 
 
 
1.32.11 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the University of Miami has established policies and procedures for all 
researchers to disclose all conflicts of interest and, will establish a mechanism for the management of all 
reported dualities of interest. 
 
1.33 ADDITIONAL CONSIDERATIONS 
N/A 
 
 


 
 
1.34 ABBREVIATIONS 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
EMR 
Electronic Medical Record 
FDA 
Food and Drug Administration 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NAC 
N-Acetyl Cysteine 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
QOD 
Questionnaire on Olfactory Disorders 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIT 
Smell Identification Test 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 


 
 
1.35 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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5 
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8 
Kopke, R. D. et al. NAC for noise: from the bench top to the clinic. Hearing research 226, 114-125, 
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