Clinical trial NCT02730793
Conditions: Cystic Fibrosis
Keywords: Cystic Fibrosis P. aeruginosa (PA)
Sponsor: Virginia Commonwealth University
Start date: 2017-01-01; Completion date: 2019-09-19
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed as a masked, two center, randomized, placebo-controlled pilot study to evaluate the safety and efficacy of nasal and oral inhalation of 75 mg aztreonam in subjects with CF and lung infection due to PA. The study will involve two sites: Virginia Commonwealth University Medical Center (VCU) and Eastern Virginia Medical School (EVMS). Potential subjects will be identified in each site's CF clinic.

Detailed description:
This study is designed to explore the efficacy and safety of nasal aztreonam administered using the Pari Sinus Nebulizer combined with oral Cayston aerosol therapy compared to placebo on clinical and laboratory endpoints such as risk of antibiotic-resistant Pseudomonas aeruginosa (PA), time to pulmonary infection exacerbation, nasal quality of life, pulmonary function, nasal and lower airway cultures, and properties of mucus.

P. aeruginosa (PA) is a primary cause of lung infections in persons with cystic fibrosis (CF) (1). Over the past decade, studies have shown that aerosolized antibiotics can reduce lower respiratory bacterial load, decrease exacerbations of pulmonary disease, and in many patients improve pulmonary function. Cayston (aztreonam) oral aerosol using the PARI Altera Nebulizer System was approved by the FDA in February 2010 for CF patients 7 years of age or older with PA (2). In 2011, 35.8% or patients in the National CF Patient Registry used Cayston for treatment (3). Bacterial cultures suggest that the upper airways and lower airways of CF patients are cross-infected by PA and that the paranasal sinuses can act as a bacterial reservoir (4). There is improved post-transplanation patient survival for recipients that undergo sinus surgery and daily nasal washes to reduce bacterial load (2).

Routine CF care does not generally include upper airway assessment. There are no published studies evaluating the effect of aerosol antibiotics to treat nasal and sinus infections in CF in combination with oral inhaled aerosol therapy to treat the lower airway disease. However Mainz and colleagues published a case report that suggested that sinonasal administration of tobramycin using the Pari Sinus nebulizer (Pari Corp, Starnberg, Germany) delayed PA lower respiratory infection in a 12 year-old with CF who had chronic mucopurulent rhinosinusitis (5) and studies in chronic obstructive pulmonary disease suggest that treating upper airways can also improve coexistent lower airway disease.

Arms: arm 1: Oral Inhalation via PARI Altera Device: Standard Therapy Comparator (Oral Aztreonam 75mg three times a day) AND Nasal Inhalation via PARI PAS Device: Nasal Placebo-Normal Saline twice per day arm 2: Oral Inhalation via PARI Altera Device: Standard Therapy Comparator (Oral Aztreonam 75mg three times a day) AND Nasal Inhalation via PARI PAS Device: Experimental- Nasal Aztreonam 75 mg twice per day
Interventions: intervention 1: Oral Aztreonam intervention 2: Nasal Aztreonam intervention 3: Nasal Placebo
Intervention descriptions: intervention 1: Standard Therapy Comparator (Oral Cayston 75mg three times a day) intervention 2: Study Therapy (nasal Aztreonam 75mg twice per day) intervention 3: Placebo (nasal saline twice per day)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Title: Aztreonam Aerosol to Treat Cystic Fibrosis Nasal Disease 
 
NCT #: NCT02730793 
 
Document approval date: March 3, 2017 
 
Document Type: Protocol and Statistical Analysis Plan 
 
 
 


Nasal Aztreonam – Protocol V2.1 – March 2017 
 
Page 1 
 
Aztreonam aerosol to treat cystic fibrosis nasal disease. 
 
 
 
 
 
Principal Investigator:                       Bruce K. Rubin, MEngr, MD, MBA, FRCPC 
Virginia Commonwealth University 
 
 
 
Co- Investigators: 
Michael Schechter, MD, MPH 
 
Virginia Commonwealth University  
 
 
Howard Schmidt, MD 
 
Virginia Commonwealth University 
 
 
 
Melissa Yopp, MSHA 
 
Virginia Commonwealth University  
 
 
Kelley Dodson, MD 
 
Virginia Commonwealth University 
 
 
Nauman Chaudary, MD 
 
Virginia Commonwealth University 
 
 
 
Joseph Han, MD 
Eastern Virginia Medical School 
 
 
Correspondence: 
 
Bruce K. Rubin MEngr, MD, MBA, FRCPC 
Jessie Ball duPont Distinguished Professor and Chair, Dept. of Pediatrics  
Professor of Biomedical Engineering 
Virginia Commonwealth University School of Medicine 
Physician-in-Chief, Children's Hospital of Richmond 
1000 East Broad St. PO Box 980270 
Richmond, VA 23298 USA 
Telephone +804 828-9602 
 
Melissa Yopp 
Pediatric Research Director 
Melissa.Yopp@vcuhealth.org 
 
 


Nasal Aztreonam – Protocol V2.1 – March 2017 
 
Page 2 
 
Introduction 
P. aeruginosa (PA) is a primary cause of lung infections in persons with cystic fibrosis (CF) (1). 
Over the past decade, studies have shown that aerosolized antibiotics can reduce lower 
respiratory bacterial load, decrease exacerbations of pulmonary disease, and in many 
patients improve pulmonary function. Cayston (aztreonam) oral aerosol using the PARI Altera 
Nebulizer System was approved by the FDA in February 2010 for CF patients 7 years of age 
or older with PA (2). In 2011, 35.8% of patients in the National CF Patient Registry used 
Cayston for treatment (3). Bacterial cultures suggest that the upper airways and lower 
airways of CF patients are cross-infected by PA and that the paranasal sinuses can act as a 
bacterial reservoir (4). There is improved post-transplantation patient survival for recipients 
that undergo sinus surgery and daily nasal washes to reduce bacterial load (2). 
 
Routine CF care does not generally include upper airway assessment. There are no published 
studies evaluating the effect of aerosol antibiotics to treat nasal and sinus infections in CF in 
combination with oral inhaled aerosol therapy to treat the lower airway disease. However 
Mainz and colleagues published a case report that suggested that sinonasal administration of 
tobramycin using the Pari Sinus nebulizer (Pari Corp, Starnberg, Germany) delayed PA lower 
respiratory infection in a 12 year-old with CF who had chronic mucopurulent rhinosinusitis (5) 
and studies in chronic obstructive pulmonary disease suggest that treating upper airways can 
also improve coexistent lower airway disease (6). 
 
This study is designed to explore the efficacy and safety of nasal aztreonam administered 
using the Pari Sinus Nebulizer combined with oral Cayston aerosol therapy compared to 
placebo on clinical and laboratory endpoints such as risk of antibiotic-resistant 
Pseudomonas aeruginosa (PA), time to pulmonary infection exacerbation, nasal quality of 
life, pulmonary function, nasal and lower airway cultures, and properties of mucus. 
 
 


Nasal Aztreonam – Protocol V2.1 – March 2017 
 
Page 3 
 
Objectives 
This is a pilot study to evaluate the effectiveness of treatment with aztreonam by nasal inhalation 
(Pari Sinus Nebulizer) combined with oral aerosol therapy (PARI Altera Nebulizer System) on 
chronic PA infection in subjects with CF. 
 
Primary Outcome: 
1. 
Number of protocol-defined pulmonary exacerbations treated with IV anti-pseudomonal 
antibiotics on day 140 
Secondary Outcomes: 
1. 
Time to first protocol-defined pulmonary exacerbation treated with IV anti-pseudomonal 
antibiotics 
2. 
Change in Sinus and Nasal QoL questionnaire (SNOT-20) on day 140 and day 168 
3. 
Change in Cystic Fibrosis QoL score (CFQ-R) on day 140 
4. 
Change in Pulmonary function (FVC and FEV1 percent predicted) on day 140 
5. 
Change in paired sputum cultures and nasal swabs for bacteria and antibiotic resistance 
6. 
Number of Safety and adverse events including nasal stuffiness, epistaxis, and 
headache 
7. 
Number of protocol-defined pulmonary exacerbations treated with oral anti-
pseudomonal antibiotics 
 
Study Design 
 
This study is designed as a masked, two center, randomized, placebo-controlled pilot study to 
evaluate the safety and efficacy of nasal and oral inhalation of 75 mg aztreonam in subjects with 
CF and lung infection due to PA. The study will involve two sites: Virginia Commonwealth 
University Medical Center (VCU) and Eastern Virginia Medical School (EVMS). Informed 
consent will be obtained from the eligible participant’s parent or legal guardian for subjects 7 to 
17 years of age with assent from the child, and consent will be obtained from subjects 18 years 
of age or older. After informed consent is obtained screening and randomization will occur. 
Randomization of medication in a 1:1 manner will be carried out by VCU’s unmasked study 
director who is not involved in the direct care of the patient, or by Gilead Sciences. Patients who 
continue an alternating inhaled antibiotic will be paired 1:1 as the study progresses.  
 
This pilot study is designed to have two arms as shown in Figure 1 with 15 subjects in each arm. 
Nasal delivery will be achieved by using the PARI Sinus Pulsating Aerosol System (PAS) and 
oral aerosol administration will use the PARI Altera device. Oral aerosol treatment will be 3 
times a day for a 28-day course followed by 28 days off aztreonam therapy. The combination 
therapy will be administrated based on study assignment. There will be three cycles of therapy 
over six months. Because of the smaller volume of the nasal and sinus airway and slower 
paranasal clearance rates, published data suggest that less frequent nasal aerosol dosing may 
be as effective as more frequent dosing. 
 
 


Nasal Aztreonam – Protocol V2.1 – March 2017 
 
Page 4 
 
 
Arms 
Assigned Intervention 
Standard therapy 
Comparator 
Oral Inhalation: Cayston 75 mg three times a day (TID)  
Nasal Inhalation: Placebo  treatment per nostril twice per day (BID) 
Experimental 
Oral Inhalation: Cayston 75 mg three times a day (TID)  
Nasal Inhalation: Aztreonam 75 mg per nostril twice per day (BID) 
 
 
Number of Participants: 30 (15 per arm) – If a patient is on an alternating inhaled antibiotic, 
they will be randomized in a 1:1 fashion by the unblinded PI 
 
Target Population: Subjects 7 years or older with CF lung disease and at least 2 sputum 
cultures positive for PA in the previous 24 months. 
Main Eligibility Criteria: 
 
Inclusion Criteria 
 
1. Males or females 7 years of age or older and able to perform pulmonary function testing 
2. Confirmed diagnosis of CF by the 1997 CF Consensus Conference criteria and 
followed by the VCU or EVMS CF clinic 
3. Presence of PA in 2 lower respiratory tract (sputum) or respiratory swab cultures in the 
24 months before baseline (second positive culture can occur at screening)  
4. Subjects and/or parent/guardian must be able to give written informed consent 
prior to any study related procedure 
5. All sexually active female subjects who are of childbearing potential must agree to 
use an effective method of contraception 
6. Clinically stable with no significant new respiratory symptoms  
 
Exclusion Criteria 
 
1. Use of oral or IV antibiotics within 30 days of baseline (V2) other than low dose 
azithromycin 
2. Severe pulmonary disease with FEV1<30% predicted or baseline SpO2<0.90 
3. ENT surgery within 6 months of screening 
4. Allergy or documented adverse reaction to aztreonam 
5. Epistaxis or significant (>30 mL) hemoptysis in the past 6 months 
6. Frequent or severe headaches 
7. Subject is unlikely to comply with the procedures scheduled in the protocol 
8. Subject participates in an interventional clinical trial in  the 30 days prior to baseline 
9. Subjects who have had a lung transplant  


 
Nasal Aztreonam – Protocol V2.1 – March 2017 
 
Page 5 
 
Study Procedures & Frequency 
The study requires 8 study visits over a period of 6 months. The study procedures to be 
performed on/by each subject enrolled in the study are outlined in Appendix 1. Study Flow Chart 
 
Test Product, Dose and Mode of Administration 
 
Study medication 
Medication will be provided by Gilead Sciences supplied in amber glass vials labeled with 
inhalation instructions, storage (keep refrigerated), date dispensed, date of expiration, study ID, 
and a unique barcode for drug tracking. The vials for oral inhalation will be clearly labeled oral 
and contain 75 mg Cayston. The nasal inhalation vials will be masked and contain either 75 mg 
aztreonam or placebo solution.  
 
Oral Administration 
Gilead Sciences will supply the PARI Altera device for oral administration to all subjects. Subject 
instructions will be based on the FDA-approved labeling and reconstitution instructions. Oral 
inhalation will be the recommended dose of a one single-use vial (75 mg of aztreonam) 
reconstituted with 1 mL of sterile diluent administered 3 times a day for a 28-day course followed 
by 28 days off Cayston therapy. 
 
Nasal Administration 
Gilead Sciences will supply the Pari Sinus Nebulizer and training video to be watched by all 
subjects under supervision by the study coordinator. Reconstitution instructions will follow the 
oral reconstitution instructions previously mentioned. Aztreonam or placebo will be aerosolized 
into one nostril, while the contralateral nostril is occluded and the soft palate elevated. Study 
medication will be administered into both nostrils for 4 min each side. Clinical trial material will 
be supplied by the sponsor in sealed, 1 mL vials containing 75 mg of azetreonam or placebo 
and 2 of these vials will be used for each treatment. With a pump residual volume of 1 mL in the 
PARI Sinus it is anticipated that half of the 2 mL loading volume will be delivered. 
 
Drug Adherence 
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate 
accountability of all used and unused study drug. This includes acknowledgment of receipt of 
each shipment of study product (quantity and condition) and patient dispensing records and 
returned or destroyed study product. Dispensing records document quantities received from 
Gilead and quantities dispensed to patients, including kit number, lot numbers if applicable, date 
dispensed, patient identifier number, and the initials of the person dispensing the medication. 
 
Subjects will be asked to complete a Study Medication Dosing Checklist weekly in their diaries to 
indicate the typical day and time of day each dose of aztreonam was administered during study 
participation. Subjects will be required to return empty vials to assess medication adherence. 
Data will be expressed as percent of vials prescribed. 


 
Nasal Aztreonam – Protocol V2.1 – March 2017 
 
Page 6 
 
References 
1. 
Lyczak JB, Cannon CL, Pier GB. Lung infections associated with cystic fibrosis. Clin Microbiol Rev 
2002; 15:194-222. 
 
2. 
Vital D, Hofer M, Benden C, Holzmann D, Boehler A. Impact of sinus surgery on pseudomonal airway 
colonization, bronchiolitis obliterans syndrome and survival in cystic fibrosis lung transplant recipients. 
Respiration 2013; 86:25-31 
 
3. 
Ballmann M, Smyth A, Geller DE. Therapeutic approaches to chronic cystic fibrosis respiratory infections 
with available, emerging aerosolized antibiotics. Resp Med 2011:105:S2-8. 
 
4. 
Bonestroo HJ, de Winter-de Groot KM, van der Ent CK, Arets HG. Upper and lower airway cultures in 
children with cystic fibrosis: Do not neglect the upper airways. J Cystic Fibrosis 2010:9:130-34 
 
5. 
Pynnonen MA, Kim HM, Terrell, JE. Validation of the sino-nasal outcome test 20 (SNOT-20) 
domains in nonsurgical patients. AM J Rhinol Allergy 2009: 23:40-45 
 
6. 
Kim J-S, Rubin BK. Nasal and sinus involvement in chronic obstructive pulmonary disease. Current Opin 
Pulm Med 2008:14:101-04. 
 
7. 
Rudnick, EF, Mitchell RB. Long-term improvements in quality-of-life after surgical therapy for pediatric 
sinonasal disease. Oto Head Neck Surg 2007;137:873-77 
 
8. 
Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, et al. General considerations 
for lung function testing. ERJ 2005;26:153-61 
 
9. 
Nathan RA, Eccles R, Howarth PH, Steinsvag SK, Togias A. Objective monitoring of nasal patency and 
nasal physiology in rhinitis. JACI 2005;115:S442-59 
 
10. Robertson JM, Friedman EM, Rubin BK. Nasal and sinus disease in cystic fibrosis. Paed Resp Rev 
2008; 9:213-19 
 
11. Goss CH, Burns JL. Exacerbations in cystic fibrosis. 1: Epidemiology and pathogenesis. Thorax 2007; 62: 
360- 67 
 
12. Briesacher BA, Quittner AL, Fouayzi H, Zhang J, Swensen A. Nationwide trends in the medical care 
costs of privately insured patients with cystic fibrosis (CF), 2001-2007. Pediatr Pulmon 2011;46:770-76 
 
13. Aitken M, Taylor JA. Prevalence of clinical sinusitis in young children followed up by primary care 
pediatricians. Arch Pedes Adoles Med 1998;152:244-48. 
 
14. Cystic Fibrosis Foundation. Patient registry report. 
http://www.cff.org/research/ClinicalResearch/PatientRegistryReport (Accessed November 13, 2012) 
 
15. Schuschnig M, Luber Y, Waehner G, et al. In‐vitro deposition study of a novel antibiotic solution into nasal 
cast cavities by the PARI SINUS aerosol delivery system. 2005 NA CF Conference, Baltimore, USA (Abstract) 
 
16. Mainz JG, Lindig J, Dopfer C, Pfister W, Beck JF. First colonization with P. aeruginosa – only detected 
in the upper airways – eradicated with sinonasal inhalation of tobramycin. J Cystic Fibrosis, 2009;8:S69 


 
Nasal Aztreonam – Protocol V2.1 – March 2017 
 
Page 7 
 
Appendix 1.  Study Flow 
 
 
   
Study Flow Chart – Aztreonam Aerosol for CF Nasal Disease 
 
Screen 
 
Treatment Period 3 Cycles (6 Months) 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
 
Begin on-
month #1 
Begin on-
month #2 
Begin on-
month #3 
Time of Visit 
7-56 days 
before V2 
Day 1 
Day 28 
(±3 Days) 
Day 56 
(±3 Days)  
Day 84 
(±3 Days) 
Day 112 
(±3 Days)  
Day 140 
(±3 Days) 
Day 168 
(±3 Days) 
 
Eligibility Assessments 
Informed Consent 
x 
 
Obtain Assent (if applicable) 
x 
 
In/Exclusion Criteria 
x 
 
Medical History 
x 
x 
 
Procedures 
Physical Exam 
 
x 
 
 
 
 
x 
x 
Vital Signs 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy Test 
x 
x 
 
 
 
 
 
 
Pulmonary Function Test 
x 
x 
x 
 
x 
 
x 
x 
SNOT20- Survey 
 
x 
x 
 
x 
 
x 
x 
CFQ-R 
 
x 
 
 
 
 
x 
x 
Nasal cultures 
x 
x 
x 
x 
x 
x 
x 
x 
Sputum cultures 
x 
x 
x 
x 
x 
x 
x 
x 
Visual scoring of nasal patency 
 
 
x 
 
 
x 
 
 
x 
Sinus Swab (Sub-Study Only) 
x 
X 
 
 
 
 
 
x 
 
General 
Randomize Patient 
 
x 
Handling/Training in 
product/device use 
 
x 
Diary Instructions/Dispensing 
 
x 
 
x 
 
x 
 
Diary Collection 
x 
 
x 
 
x 
 
Dispense Study Medication 
 
x 
x 
x 
Record Concomitant 
Medications 
x 
x 
x 
x 
x 
x 
x 
x 
Record Adverse Events 
 
x 
x 
x 
x 
x 
x 
x 
End of Trial 
x 


 
Nasal Aztreonam – Protocol V2.1 – March 2017 
 
Page 8 
 
Appendix 2: Detailed study procedure methods. 
 
Power Calculation 
No studies have evaluated the effect of upper airway (nasal) and sinus infections in combination 
with lower (oral) inhaled aerosol therapy to further improve Sino pulmonary symptoms in CF. 
Thus, the current study is designed as a pilot study that is likely to be underpowered to reach 
significance. 
 
Protocol-Defined Pulmonary Exacerbation 
Protocol-Defined Pulmonary Exacerbation includes events that are characterized by change or 
worsening pulmonary symptoms (increase cough, increased sputum production, chest 
congestion, decreased appetite, decreased exercise tolerance, loss of weight, and lung 
function decline) that prompt initiation of antibiotic therapy. 
 
Demographic & Physical Data 
Demographic and baseline measurements will be summarized for the FAS and PP analysis 
sets using standard descriptive methods (overall and by treatment group). Demographic 
summaries will include sex, race, ethnicity, and age. Physical Characteristic data will include 
body weight, height, and body mass index. 
 
The Sino-Nasal Outcome Test questionnaire 
The Sino-Nasal Outcome Test 20 (SNOT-20) is a validated health-related QOL questionnaires 
designed to determine the impact of sinonasal dysfunction (7). Patients will assess nasal 
symptoms, emotion, and activity on a scale of worsening symptoms scored 1 through 7 to 
provide a quantifiable score capable of disease severity. It has been shown as a responsive 
measure of health-related quality of life and suitable for use in outcomes studies and routine 
clinical care (7). 
 
Pulmonary function testing 
Routine including spirometry will be performed according to American Thoracic Society (ATS) 
guidelines (8). A minimum of three maneuvers will be performed. The largest FVC and FEV1 
will be reported after examining data from all acceptable curves even if they did not originate 
from the same maneuver. Data will be expressed both in absolute values and as percent (%) 
predicted based upon NHANES predicted values. 
 
Visual scoring of nasal patency 
Nasal patency scores will be based upon direct visualization score of % obstruction by the 
investigator. Mucosal condition and secretion status, the presence of crusts and polyps will 
be assessed. 
 
Paired nasal and sputum cultures. 
Expectorated sputum and nasal swabs will be cultured at each visit using standardized 
procedures to identify CF pathogens as well as susceptibility to a standard panel of antibiotics 


 
Nasal Aztreonam – Protocol V2.1 – March 2017 
 
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Electronic Database Capture 
Study data for each visit will be collected and managed using REDCap (Research Electronic 
Data Capture). REDCap is a secure web application designed to support data capture for 
research studies, providing user- friendly web-based case report forms, real-time data entry 
validation (e.g. for data types and range checks), audit trails and a de-identified data export 
mechanism to common statistical packages (JMP, Stat view, SAS,). REDCap also includes a 
powerful tool for building and managing online surveys. The database is hosted by VCU 
under award number UL1RR031990 from the National Center for Research Resources and 
NIH Roadmap for Medical Research, National Institutes of Health. 
 
OnCore 
OnCore a clinical trial management systems (CTMS) will be used for recording and tracking 
regulatory approvals, staff training, safety management (SAE tracking and IRB reporting) for 
all sites. The CTMS system was developed by Forte Research and widely used across 
academic research universities nationwide. The program is a secure web-based system 
accessible by all affiliate sites. The system is hosted by VCU and MCV health systems. 
 
Data Analysis 
Statistical analysis of data will be performed using the JMP Pro 10 statistics package (SAS 
Institute, Cary, NC). Counts will be compared with Fisher exact tests.  Continuous variables 
will be compared with parametric (t-test) or non-parametric (Wilcoxon Rank-Sum) tests 
depending upon the normality of data distribution.  Time to pulmonary exacerbation will be 
evaluated using Kaplan-Meier plots and compared using the Mantel-Cox (log-rank) test.   A p< 
0.05 will be considered statistically significant. All results will be presented as means + the 
standard error of the mean. Because this is a pilot study, there will be no post hoc adjustments 
made for multiplicity 
 
Concomitant Medications 
At screening (visit 1), all medications, indications for use, dose (amount, frequency and route of 
administration) will be recorded. Concomitant medications are classified as any medication, 
including over the counter, used by subjects during the duration of the study. During each 
subsequent clinical visit, subjects will be questioned about any changes in their concomitant 
medications and current therapy. 
 
Adverse Reporting 
The frequency, severity and duration of all nasal and pulmonary adverse events, regardless of 
cause, will be recorded in Redcap as an electronic case report form. Serious adverse events will 
be captured in OnCore. The frequency and severity of adverse events will be calculated for each 
patient, with each patient counted once using the most severe grade experienced. The duration 
of adverse events will be calculated by the number of days each event persisted. Tables will be 
generated for all adverse events including serious adverse events and withdraws from the 
study. 
 
 


 
Nasal Aztreonam – Protocol V2.1 – March 2017 
 
Page 10 
 
 
Institutional Review Board 
This protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigators to an IRB and approval from the IRB must be 
obtained before starting the study and should be documented in a letter to the investigator 
specifying the protocol number, protocol version, protocol date, documents reviewed, and date 
on which the committee met and granted the approval. 
 
 
Any modifications made to the protocol after receipt of IRB approval must also be submitted to 
the IRB for approval before implementation.