Hyperbaric Oxygen Therapy to Prevent Complications After Lower Limb Amputation
Phase: PHASE1
Conditions: Amputation; Postoperative, Sequelae
Sponsor: Duke University

Study Protocol with Statistical Analysis Plan 
Protocol: Hyperbaric Oxygen Therapy to Prevent Complications after Lower Limb 
Amputation 
NCT #: NCT04717557 
Date: February 16th, 2024 

DUHS IRB Application (Version 1.17)
General Information
*Please enter the full title of your protocol:
Hyperbaric Oxygen Therapy to Prevent Complications after Lower Limb Amputation
 
 
*Please enter the Short Title you would like to use to reference the study:
Hyperbaric Oxygen and Amputations
* This field allows you to enter an abbreviated version of the Study Title to quickly identify this 
study.
 
 
Add Study Organization(s):
List Study Organizations associated with this protocol:
Primary 
Dept?
Department Name
DUHS - Anesthesia
DUHS - Duke Default Department
 
Assign key study personnel (KSP) access to the protocol
* Please add a Principal Investigator for the study:
(Note: Before this study application can be submitted, the PI MUST have completed CITI training)
 
Moon, Richard
 
3.1 If applicable, please select the Key Study personnel: (Note: Before this study application can be submitted, all Key 
Personnel MUST have completed CITI training)
* Denotes roles that are not recognized in OnCore. Please select an appropriate role that is recognized in all clinical 
research applications (iRIS, OnCore, eREG, etc.)
 
A) Additional Investigators, Primary Study Coordinator (CRC), and the Primary Regulatory 
Coordinator (PRC):
Allen, Justin 
 Co-PI
B) All Other Key Personnel
Allen, Justin 
 Sub-Investigator
Cooter Wright, Mary 
 Analyst*
N

Covington, Derek 
 Study Coordinator (CRC/CRNC/RPL)
Cox, Mitchell 
 Sub-Investigator
Derrick, Bruce 
 Sub-Investigator
Ellis, Mary 
 Sub-Investigator
Gregory, Thomas 
 Sub-Investigator
Lauer, Laura 
 Sub-Investigator
Long, Chandler 
 Sub-Investigator
Makowski, Matthew 
 Sub-Investigator
Natoli, Michael 
 Regulatory Coordinator
Pack, Neena 
 Research/Physician Assistant
Pack, Neena 
 Clinical Research Specialist/Study Assistant
Southerland, Kevin 
 Sub-Investigator
Stolp, Bryant 
 Collaborator
Vallee, Isabelle 
 Sub-Investigator
*Please add a Study Contact:
 
Allen, Justin 
Moon, Richard 
Natoli, Michael 
Pack, Neena 
The Study Contact(s) will receive all important system notifications along with the Principal 
Investigator. (e.g., The study contact(s) are typically the Principal Investigator, Study Coordinator, 
and Regulatory Coordinator.) 
 
Oncore
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This field is used in OnCore and determines the Reference Lists, Forms, Protocol Annotations, Notifications, 
and Signoffs available for the protocol. Protocols that require reporting to the NCI (National Cancer Institute), 
must select the Oncology library.
Oncology 
Non-Oncology 
 
Protocol Application Type
Select the type of protocol you are creating:

Please see additional criteria and information in the policy titled, “Reliance on the IRB of Another Institution, 
Organization, or an Independent IRB", on the 
.
IRB web site
Regular Study Application - Most common. The IRB will determine if the study is eligible for expedited 
review or requires full board review upon submission. 
Application for Exemption from IRB Review - Includes Exempt, Not Human Subject Research, & Not 
Research. 
External IRB Application - Any study using an external IRB as the IRB-of-Record. 
Trainee Research While Away from Duke - Research conducted by medical students overseen by the 
Office of Curriculum & other student/trainee research away from Duke. 
Individual Patient Expanded Access, Including Emergency Use - Use of an investigational product 
under expanded access, including emergency use of an investigational drug or biologic or emergency 
use of an unapproved device. 
 
Conflict of Interest
Are any key personnel an inventor of any of the drugs, devices or technologies used in this research?
  Yes   
  No
Do any key personnel have a conflict of interest management plan issued by DOSI-COI related to this 
research?
  Yes   
  No
 
Oversight Organization Selection
CRU (Clinical Research Unit) or Oversight Organization Selection:
Please select the CRU.
Anesthesiology
The Clinical Research Unit that takes responsibility for this study.
Please select 
as the CRU 
if the PI is in one of these Divisions or Institutes: 
Medicine 
only 
Endocrinology, Gastroenterology, General Internal Medicine, Geriatrics, Hematology, Infectious 
Diseases, Nephrology, Pulmonary, Rheumatology & Immunology, Center for Applied Genomics and 
Precision Medicine, Center for the Study of Aging and Human Development, Duke Molecular Physiology 
Institute.
More information on CRUs can be found on the Duke Office of Clinical Research (DOCR) website, 
http://docr.som.duke.edu
Questions concerning CRU selection should be directed to docr.help@dm.duke.edu.
For questions about the Campus Oversight Organization, please visit Campus Oversight 
.
Organization
List all Key Personnel on the study who are outside Duke:
In the panel below, “PHI” is Protected Health Information. 
Note: If outside key personnel will have access to Duke PHI, you will need the following: 
Attach the documentation of Human Subjects Certification for each individual, if they have 
completed the certification somewhere other than Duke. 
A data transfer agreement AND external site IRB approval (or IRB authorization agreement). 
See HRPP policy Use of Research Data by Former Duke Students or Former Duke 
Faculty and Employees

       Entry 1       
Name
Study Role
Email Address
Institution / Organization
Will he/she have access to 
Duke P.H.I.?
  Yes   
  No
Is he/she an unpaid 
volunteer at Duke on the 
study?
  Yes   
  No
Describe Role of External Personnel:
Patients will receive care from their treatment team as they otherwise would were they not enrolled in the 
study. Patients will receive treatment from hyperbaric chamber personnel as they otherwise might were 
they not in this study. 
Indicate the Protocol source below:
The protocol source is the author of the protocol. If the protocol is a joint authorship between multiple 
sources, select the primary author. 
An IRB fee may be assessed for all research that is supported by for-profit entities and requires full board 
review. For additional information, see the 
.
IRB fees section of the IRB web site
Duke PI initiated 
Commercial / Industry (for-profit entity) initiated 
Federal Government initiated 
Cooperative Group Initiated 
Foundation (non-profit group) initiated 
Other 
 
Sponsor and Funding Source
Add all funding sources for this study: (Select 'Duke University' if you do not have funding or a sponsor for 
your study).
View 
Details
Sponsor Name
Sponsor Type
Contract 
Type:
Project 
Number 
Award 
Number 
Duke University 
Institutional 
Unfunded 
Research 
Collaboration 
 
 
Sponsor Name:
Duke University 
Sponsor Type:
Institutional 
Sponsor Role:
Project Period:
From:09/06/2018   to:09/06/2020 
Is Institution the Primary Grant 
Holder:
Yes 
Contract Type:
Unfunded Research Collaboration 
Project Number:
 
Award Number:
 

Grant Title:
 
PI Name:
(If PI is not the same as identified 
on the study.)
 
Explain Any Significant 
Discrepancy:
 
Is this a federally funded study?
  Yes   
  No
Does this study have any of the following?
Industry sponsored protocol
Industry funded Duke protocol
Industry funded sub-contract from another institution
Industry provided drug/device/biologic
SBIR/STTR funded protocol
 
  Yes   
  No
As part of this study, will any samples or PHI be transferred to/from Duke to/from anyone other than the 
Sponsor, a Sponsor subcontractor, or a Funding Source?
  Yes   
  No
Is the Department of Defense (DOD) a funding source?
  Yes   
  No
 
Mobile Devices and Software
Does this study involve the use of a software or a mobile application?
  Yes   
  No
List all software, including third party (non-Duke) and mobile apps, that will be utilized for ascertainment, 
recruitment, or conduct of the research/project: (eg, MaestroCare, DEDUCE):
This project will use Maestrocare, redcap, and the Duke research sites such as iris, oncore for compliance 
purposes. 
 
Multi-site Research
Is this a multi-site study?
  Yes   
  No

Complete for each site if Duke is the Primary grant awardee or coordinating center:
       Entry 1       
Site Name:
City:
State/Province:
Country:
Site Contact Information
Primary Contact Name:
Primary Contact Phone:
Primary Contact Email:
Site Details
Does the site have an IRB?
  Yes   
  No
Site IRB approval expiration 
date:
If date not provided, 
explanation of why:
Has the site granted 
permission for the research 
to be conducted?
  Yes   
  No
Does the site plan to rely on 
the DUHS IRB for review?
  Yes   
  No
What is the status of the 
study at this site?
Open 
Closed 
Site approval letters or site 
personnel lists:
Attach site approval letters, site closure letters (if applicable), or site 
personnel lists in the Initial Submission Packet.
 
Research Abstract
Please type your Research Abstract here:
The Research Abstract should summarize the main points of your study in one paragraph. The following 
guidelines may help you:
 
1. Purpose and objective (1-2 sentences)
2. Study activities and population group (2-4 sentences)
3. Data analysis and risk/safety issues (1-2 sentences)

We are proposing a clinical study to test the hypothesis that Hyperbaric Oxygen (HBO ) given in the 
2
immediate postoperative period for a total of 10 treatments after Below-the-Knee Amputation (BKA) will 
reduce postoperative complications. Patients scheduled for BKA at Duke University Medical Center will be 
reviewed for contraindications to HBO . Patients for whom HBO  is not contraindicated may choose to be 
2
2
enrolled in the study. Patients enrolled will be randomly assigned to receive treatment or standard 
postoperative care. Each patient receiving treatment will receive twice daily HBO  for 2 hours at 2 ATA. 
2
Patients receiving HBO  will breathe 100% oxygen via head tent while inside a hyperbaric chamber at 
2
Duke University Hospital. The statistical plan for this study will test non-directional hypotheses (two-sided 
tests). Bonferroni correction will be used to adjust for multiple tests. SAS 9.4 (SAS Institute, Inc.) will be 
used to analyze the data. The main analysis of the primary efficacy hypotheses will include data from all 
randomized patients in the group to which random assignment is made.  Hence, the analysis will be 
intention to treat.
 
Research Summary
State your primary study objectives
This study will primarily aim to assess whether patients receving treatment suffered fewer complications, 
as defined by the Vascular Quality Initiative, vs. patients who receive standard care.   
State your secondary study objectives
This study will secondarily collect data pertaining to hospital length of stay, 90-day mortality, failure to 
heal at 4 and 8 week follow-up visits and ability to ambulate with a prosthesis at 6 months post 
amputation. 
Please select your research summary form:
Standard Research Summary Template
This is the regular (generic) research summary template which is required  for all regular applications (unless 
your protocol fits under the other research summary templates in this category).  Use of these instructions is 
helpful for ensuring that the research summary contains all necessary elements.
 
Standard Research Summary
Purpose of the Study
 
Objectives & hypotheses to be tested
This study is being conducted to assess the utility of hyperbaric oxygen as an adjunctive treatment to 
reduce postoperative complications. It is hypothesized that HBO  given in the immediate postoperative 
2
period will reduce postoperative complications in patients undegoing below-the-knee amputations. The 
objective of this study will be to compare treatment and standard care groups, randomly created of eligible 
patients, to compare their postoperative complications and to assess their postoperative hospital length of 
stay, 90-day mortality, failure to heal at 4 and 8 week follow-up visits and ability to ambulate with a 
prosthesis at 6 months post amputation.  
Background & Significance
Should support the scientific aims of the research

Lower limb amputations (LLA) are commonly performed at Duke University Hospital and are associated 
with major morbidity, mortality, hospital length of stay and costs. We are proposing a clinical study to test 
whether hyperbaric oxygen therapy (HBO ) administered immediately after surgery for ten 2 hour 
2
treatments following below knee amputation (BKA) in diabetic patients will reduce surgical site infections 
(SSIs), reoperations and hospital length of stay (LOS).
 
LLAs have major morbidity and mortality. Overall, more than 60% of patients who require LLA are diabetic1
. Wound complications occur in 12%, and reoperations in 10-16%, often for infection
. Nearly 5% of 
1,2
BKAs require revision to a higher amputation level . Duke University Vascular Quality Initiative (VQI) data 
2
indicates that of the 98 LLAs performed at Duke last year 27 resulted in complications, of which 25 needed 
reoperation. Surgical complications after amputations result in roughly doubling of the cost incurred by 
hospitals , thus less than one third of amputations incur almost half of the total cost of amputations.
3
 
Both wound healing  and infection risk  are related to the partial pressure of oxygen (PO ), in affected 
4
5
2
tissues. Higher peri-wound PO  stimulates wound angiogenesis
 and decreases infection rate . In 
2
6,7
8
patients requiring LLA, decreased blood flow due to diabetic microvascular disease and large vessel disease 
contributes to tissue hypoxia. In this population the combination of hyperglycemia and low tissue PO  is 
2
the major reason for both poor wound healing and surgical site infection (SSI).
 
Hyperbaric oxygen (HBO ) can increase wound PO  to supranormal levels even in the presence of 
2
2
peripheral vascular disease . Evidence suggests that HBO  can facilitate healing in chronic diabetic foot 
9
2
ulcers
. A retrospective analysis suggests that perioperative HBO  may prevent postoperative 
10,11
2
neurosurgical infections
. Regarding postop SSIs and perioperative high inspired O , although there has 
12
2
been some inconsistency in the published data
, well-executed studies have supported the notion that 
13
high-inspired O  during anesthesia may prevent SSIs
. Hyperbaric oxygen specifically has been shown 
2
14,15
to be effective in the treatment of sternal infection, a classic complication of a poorly perfused surgical 
wound, and osteomyelitis after cardiothoracic surgery
. A double blind placebo controlled trial has showed 
16
the efficacy of HBO
as an adjunct to managing crush injuries of the limbs
. 
2 
17
 
Recently concern has been raised about some adverse consequences of perioperative hyperoxia, including 
increased respiratory complications and mortality
. However, a Cochrane systematic review from 2015 
18
reported no statistically significant effect of intraoperative oxygen concentration on all-cause mortality
. H
13
owever, possible beneficial effects of hyperoxia are likely to be minimal when the focus is on the 
intraoperative phase, when an anesthesia provider is continuously providing careful management of blood 
pressure, blood glucose and administering fluid therapy. We feel, and studies cited above have shown, that 
the greatest beneficial impact of hyperoxia is likely to be after surgery, when the processes of healing and 
host response to bacterial infection occur over several days or weeks. Hence, the proposed intervention is 
intended to maximize the demonstrated beneficial physiological effects of hyperoxia by inducing it in the 
postoperative period. 
 
Citations:
1. Curran T, Zhang JQ, Lo RC, Fokkema M, McCallum JC, Buck DB, et al. Risk factors and indications for 
readmission after lower extremity amputation in the American College of Surgeons National Surgical 
Quality Improvement Program. J Vasc Surg. 2014;60(5):1315-24
2. Gabel J, Jabo B, Patel S, Kiang S, Bianchi C, Chiriano J, et al. Analysis of Patients Undergoing Major 
Lower Extremity Amputation in the Vascular Quality Initiative. Ann Vasc Surg. 2018;46:75-82.
3. Healy MA, Mullard AJ, Campbell DA, Jr., Dimick JB. Hospital and Payer Costs Associated With Surgical 
Complications. JAMA Surg. 2016;151(9):823-30.
4. Knighton DR, Silver IA, Hunt TK. Regulation of wound-healing angiogenesis-effect of oxygen gradients 
and inspired oxygen concentration. Surgery. 1981;90(2):262-70.
5. Allen DB, Maguire JJ, Mahdavian M, Wicke C, Marcocci L, Scheuenstuhl H, et al. Wound hypoxia and 
acidosis limit neutrophil bacterial killing mechanisms. Arch Surg. 1997;132(9):991-6.
6. Hopf HW, Gibson JJ, Angeles AP, Constant JS, Feng JJ, Rollins MD, et al. Hyperoxia and angiogenesis. 
Wound Repair Regen. 2005;13(6):558-64.
7. Sheikh AY, Rollins MD, Hopf HW, Hunt TK. Hyperoxia improves microvascular perfusion in a murine 
wound model. Wound Repair Regen. 2005;13(3):303-8.
8. Hopf HW, Hunt TK, West JM, Blomquist P, Goodson WH, 3rd, Jensen JA, et al. Wound tissue oxygen 
tension predicts the risk of wound infection in surgical patients. Arch Surg. 1997;132(9):997-1004; 
discussion 5.
9. Fife CE, Buyukcakir C, Otto GH, Sheffield PJ, Warriner RA, Love TL, et al. The predictive value of 
transcutaneous oxygen tension measurement in diabetic lower extremity ulcers treated with hyperbaric 
oxygen therapy: a retrospective analysis of 1,144 patients. Wound Repair and Regeneration. 2002;10(4):
198-207.

10. Fife CE, Buyukcakir C, Otto G, Sheffield P, Love T, Warriner R, 3rd. Factors influencing the outcome of 
lower-extremity diabetic ulcers treated with hyperbaric oxygen therapy. Wound Repair Regen. 2007;15(3):
322-31.
11. Kranke P, Bennett MH, Martyn-St James M, Schnabel A, Debus SE, Weibel S. Hyperbaric oxygen 
therapy for chronic wounds. Cochrane Database Syst Rev. 2015
12. Inanmaz ME, Kose KC, Isik C, Atmaca H, Basar H. Can hyperbaric oxygen be used to prevent deep 
infections in neuro-muscular scoliosis surgery? BMC Surg. 2014;14:85.
13. Wetterslev J, Meyhoff CS, Jorgensen LN, Gluud C, Lindschou J, Rasmussen LS. The effects of high 
perioperative inspiratory oxygen fraction for adult surgical patients. Cochrane Database Syst Rev. 2015(6):
CD008884.
14. Greif R, Akca O, Horn EP, Kurz A, Sessler DI. Supplemental perioperative oxygen to reduce the 
incidence of surgical-wound infection. Outcomes Research Group. N Engl J Med. 2000;342(3):161-7.
15. Myles PS, Leslie K, Chan MT, Forbes A, Paech MJ, Peyton P, et al. Avoidance of nitrous oxide for 
patients undergoing major surgery: a randomized controlled trial. Anesthesiology. 2007;107(2):221-31.
16. Yu W-K CY-W, Shie H-G, Lien T-C, Kao H-K, Wang J-H. . Hyperbaric oxygen therapy as an adjunctive 
treatment for sternal infection and osteomyelitis after sternotomy and cardiothoracic surgery. Journal of 
Cardiothoracic Surgery. 2011;6:141.
17. Alquier GBPCJPGJLTATP. Hyperbaric Oxygen Therapy in the Management of Crush Injuries: A 
Randomized Double-Blind Placebo-Controlled Clinical Trial. The Journal of Trauma: Injury, Infection, and 
Critical Care 1996;41(August):333-9.
18. Meyhoff CS, Jorgensen LN, Wetterslev J, Christensen KB, Rasmussen LS, Group PT. Increased long-
term mortality after a high perioperative inspiratory oxygen fraction during abdominal surgery: follow-up 
of a randomized clinical trial. Anesth Analg. 2012;115(4):849-54.
Design & Procedures
Describe the study, providing details regarding the study intervention (drug, device, physical 
procedures, manipulation of the subject or the subject’s environment, etc.). Discuss justifications for 
placebo control, discontinuation or delay of standard therapies, and washout periods if applicable. 
Identify procedures, tests and interventions performed exclusively for research purposes or more 
frequently than standard of care. Include alternative therapies, concurrent therapies discontinued per 
protocol, risk benefit ratio, and use of tissue/specimens. Discuss monitoring during washout periods if 
applicable. Include brief description of follow-up, if any.
Patients will be recruited at Duke University Medical Center and reviewed for contraindications to HBO . 
2
These include bullous lung disease, chronic hypercapnia or hypoxemia, pregnancy, chronic middle ear 
disease that precludes equalization of middle ear pressure, recent therapy with bleomycin or mitomycin C 
and unwillingness to participate in HBO  treatments. Recruitment will consist of in person discussion with 
2
patients by study personnel. 
 
After informed consent is obtained, patients will be assigned to either a treatment group or a standard 
care group. Because of the nature of the treatment blinding is not possible. Patients will be informed of 
their group assignement when they arrive on the floor after surgery. Each patient in the treatment group 
will receive HBO  treatments in the Duke Center for Hyperbaric Medicine and Environmental Physiology 
2
using normal treatment protocols already established and approved by DUHS for the administration of HBO
Treatments will be given twice per day until the patient is discharged or 10 treatments are given. 
2. 
 
Treatments will consist of breathing 100% O  through a head tent while inside a hyperbaric chamber at 2 
2
ATA for 2 hours. Hyperbaric chambers at Duke allow for the presence of nursing staff and emergency 
access into the chamber while treatment is ongoing. Patients will experience a 15 minute compression and 
5 minute decompression phase. 
 
The Vascular Quality Initiative (VQI) is a multicenter voluntary reporting system for outcomes related to 
vascular surgery. The primary outcome of this study, postoperative complications, will be those outcomes 
meeting the definition set out in the VQI data dictionary, the set of definitions for inclusion in the VQI 
databse. This allows for a standard definition of complications recognized by a majority of academic 
medical centers across the country.
 
Secondary outcomes will include: Hospital length of stay, 90-day mortality, failure to heal at 4 and 8 week 
follow-up visits and ability to ambulate with a prosthesis at 6 months post amputation.
Patients will be examined daily during their inpatient stay and then at 4 and 8 week follow-up visits once 
discharged from the hospital. Periwound transcutaneous oxygen presures will be taken prior to 
administration of HBO  and at the completion of 10 treamtents. 
2
 

1.  
2.  
3.  
4.  
5.  
1.  
2.  
3.  
4.  
5.  
6.  
7.  
8.  
9.  
10.  
11.  
The statistical plan for this study will test non-directional hypotheses (two-sided tests). Bonferroni 
correction will be used to adjust for multiple tests. SAS 9.4 (SAS Institute, Inc.) will be used to analyze the 
data. The main analysis of the primary efficacy hypotheses will include data from all randomized patients 
in the group to which random assignment is made.  Hence, the analysis will be intention to treat, and 
regardless of subsequent events and every effort will be made to continue to follow all patients that begin 
the study. 
 
Proportions and differences in proportions in the difference complication rate requiring reoperation in 30 
days will be estimated along with 95% confidence interval. The difference in reoperation rates will be 
examined using Z-test. The analysis is similar for secondary outcomes. Exploratory outcome of 90-day 
mortality in the two treatment groups will be determined using Kaplan-Meier techniques with log-rank test. 
The Cox proportional hazards model will be used to determine the predictors of survival. Model 
assumptions will be examined and goodness of fit of these models will be assessed.
 
Because studies of this type have not been conducted before an effect size is difficult to estimate. 
However, based treatment of diabetic foot ulcers with HBO2  it is hoped that an effect size of 0.62, or 
1
reduction of complications by 60% can be seen. 80% power will be acheived by randomizing 40 subjects 
into each of the treatment and standard care groups. Hence, 80 subjects will be needed for this study. 
Given the high volume of operations conducted at Duke this should be achievable in less than 3 years. 
Midpoint analysis may produce results even sooner than that. 
 
1. Löndahl M, Katzman, P., Nilsson, A., & Hammarlund, C. . Hyperbaric Oxygen Therapy Facilitates Healing 
of Chronic Foot Ulcers in Patients With Diabetes. . Diabetes Care. 2010;33(5):998-1003.
Selection of Subjects
 
List inclusion/exclusion criteria and how subjects will be identified.
The subject selection will be equitable and all relevant demographic groups will have access to study 
participation (per 45CFR46.111(a)(3), 21CFR56.111(a)(3)).
 
Inclusion Criteria
Patients over the age of 18
Able to Consent
Have been identified as having a non-traumatic indication for amputation surgery of lower limb
Be cleared and scheduled for surgery for below-knee amputation of lower limb at Duke University 
Hospital
Be able to receive HBO
therapy.
2 
 
Exclusion Criteria
Unable to consent
Unable to receive hyperbaric oxygen
No longer need to receive surgery for amputation of lower limb
Patients with End Stage Renal Disease on dialysis
Patients with current renal failure as measured by creatinine levels vs baseline change of more than 
1 mg/dL and for whom dialysis is expected to be required within the next month
Patients with Calciphylaxis
Patients with traumatic injuries that are the cause of the amputation
Patients with cancer being treated by chemotherapy, scheduled to be treated, or being treated or 
scheduled to be treated by radiation.
Patients with limb amputation secondary to ischemic complications from other operations.
Patients undergoing a revision or reoperation on prior below-knee amputation
Patients undergoing above-knee amputation after prior below-knee amputation
 
Subject Recruitment and Compensation
Describe recruitment procedures, including who will introduce the study to potential subjects. Describe 
how you will ensure that subject selection is equitable and all relevant demographic groups have access 

to study participation (per 45 CFR 46.111(a) (3)). Include information about approximately how many 
DUHS subjects will be recruited. If subjects are to be compensated, provide specific prorated amounts 
to be provided for expenses such as travel and/or lost wages, and/or for inducement to participate.
Subjects will be recruited at DUH. Surgeons will identify subjects and refer them to 
the study coordinator for enrollment. All subjects will receive their surgery at Duke 
University Hospital. Any patient meeting the criteria will be accepted for the study. 
All relevant demographic groups have access to study participation (per 45CFR46.
111(a)(3), 21CFR56.111(a)(3)). 
Until this point the number of patients coming through the outpatient clinic for 
primary amputation is very limited. Rather, the majority of patients requiring below-
knee amputation have been going directly to the ED and being admitted. In mid-
November one of the KPs will be transitioning to a new position with the inpatient 
vascular team, which is expected to greatly increase the opportunity to find eligible 
patients and discuss the study with them. She plans to develop a system to have 
the Vascular Surgery census reviewed twice per week to identify patients who may 
be eligible for the study.
Consent Process
 
Complete the consent section in the iRIS Submission Form.
Subject’s Capacity to Give Legally Effective Consent
If subjects who do not have the capacity to give legally effective consent are included, describe how 
diminished capacity will be assessed. Will a periodic reassessment occur? If so, when? Will the subject 
be consented if the decisional capacity improves?
Subjects not competent to give consent themselves will not be allowed to participate in the study. Subjects 
who are incapacitated during the course of their inpatient stay, eg from delirium, will not receive HBO  
2
unless and until they are competent again as determined by the treatment team.
Study Interventions
If not already presented in #4 above, describe study-related treatment or use of an investigational 
drug or biologic (with dosages), or device, or use of another form of intervention (i.e., either physical 
procedures or manipulation of the subject or the subject’s environment) for research purposes.
See above.
Risk/Benefit Assessment
Include a thorough description of how risks and discomforts will be minimized (per 45 CFR 46.111(a) (1 
and 2)). Consider physical, psychological, legal, economic and social risks as applicable. If vulnerable 
populations are to be included (such as children, pregnant women, prisoners or cognitively impaired 
adults), what special precautions will be used to minimize risks to these subjects? Also identify what 
available alternatives the person has if he/she chooses not to participate in the study. Describe the 
possible benefits to the subject. What is the importance of the knowledge expected to result from the 
research?

Only study participants in the treatment group will incur the risks listed below:
 
Risks of High Pressure
Barotrauma: with compression there is occasional difficulty getting the air pressure in the ears, sinuses, 
teeth, lungs and intestines to equal the increasing pressure outside the body. Aural barotrauma, the most 
likely complication, is caused by incomplete pressure equalization between the middle ear and the external 
environment. This is caused by eustachian tube dysfunction and is accompanied by mild pain. Hearing 
loss, inflammation of the ear and sinusitis may occur. In most cases, these problems self-resolve within a 
few days. All subjects will be given standard hyperbaric chamber teaching about ear clearing and when to 
inform the chamber staff of ear pain during compression so that pressure equalization techniques 
(valsalva, sipping water, swallowing, yawning) can be attempted. Patients who have difficulty equalizing 
will be referred for otolaryngology consultation as per the hyperbaric medical service routine.
 
Occasionally individuals have air-filled cysts in their lungs.  If such a person is exposed to increased 
pressure, the cyst could possibly rupture and cause the lung to collapse, requiring medical and/or surgical 
treatment.  This complication is rare, and thus far has not occurred in this laboratory in greater than 20 
years of experience involving thousands of patient exposures. Individuals with a history of bullous lung 
disease will not be excluded from study participation.
 
Risks of High Pressure Oxygen
Only study participants in the treatment group will incur the risks listed below:
 
Oxygen Toxicity: Exposure to higher-than-normal oxygen concentration can cause generalized shaking and 
even seizures. Oxygen induced convulsions are extremely uncommon at two atmospheres of pressure, 
however, if they were to occur they would be treated by removal of the oxygen head-tent by the chamber 
attendant which will cause the convulsion to cease. This is the routine procedure for this complication of 
hyperbaric oxygen. Single oxygen convulsions are not known to have neurological sequelae.
           
Visual Changes: Some patients undergoing repeat exposures to elevated oxygen pressure develop blurred 
vision at a distance after 20-30 exposures. This involves a change in the refractive index of the lens, which 
causes mild myopia. Vision usually normalizes in 2-3 months after treatment.
Costs to the Subject
Describe and justify any costs that the subject will incur as a result of participation; ordinarily, subjects 
should not be expected to pay for research without receiving direct benefit.
There will be no medical costs to the subjects directly related to the study. Routine medical costs not 
associated with the study will remain the subject’s responsibility.
Data Analysis & Statistical Considerations
Describe endpoints and power calculations. Provide a detailed description of how study data will be 
analyzed, including statistical methods used, and how ineligible subjects will be handled and which 
subjects will be included for analysis. Include planned sample size justification. Provide estimated time 
to target accrual and accrual rate. Describe interim analysis including plans to stop accrual during 
monitoring. Phase I studies, include dose escalation schema and criteria for dose escalation with 
definition of MTD and DLT.
The statistical plan for this study will test non-directional hypotheses (two-sided tests). Bonferroni 
correction will be used to adjust for multiple tests. SAS 9.4 (SAS Institute, Inc.) will be used to analyze the 
data. The main analysis of the primary efficacy hypotheses will include data from all randomized patients 
in the group to which random assignment is made.  Hence, the analysis will be intention to treat, and 
regardless of subsequent events and every effort will be made to continue to follow all patients that begin 
the study. 
Proportions and differences in proportions in the difference complication rate requiring reoperation in 30 
days will be estimated along with 95% confidence interval. The difference in reoperation rates will be 
examined using Z-test. The analysis is similar for secondary outcomes. Exploratory outcome of 90-day 
mortality in the two treatment groups will be determined using Kaplan-Meier techniques with log-rank test. 
The Cox proportional hazards model will be used to determine the predictors of survival. Model 
assumptions will be examined and goodness of fit of these models will be assessed.
 

Based on randomized control trials of HBO  effects on healing diabetic foot ulcers this study is proposed to 
2
achieve 80% power to detect an effect size of 0.62, or reduction of complications by 60% by randomizing 
40 subjects into each of the treatment and placebo groups. Hence, 80 subjects will be needed for this 
study. Given the high volume of operations conducted at Duke this should be achievable in less than 3 
years. 
Data & Safety Monitoring
Summarize safety concerns, and describe the methods to monitor research subjects and their data to 
ensure their safety, including who will monitor the data, and the frequency of such monitoring. If a 
data monitoring committee will be used, describe its operation, including stopping rules and frequency 
of review, and if it is independent of the sponsor (per 45 CFR 46.111(a) (6)).
Clinical and demographic data will be collected electronically and stored using Duke University’s Redcap 
system. Information pertaining to blinding, patient treatment, or any other study information that may 
arise incidentally will be stored in the Duke hyperbaric treatment facility in a locked cabinet in the nurse 
manager's office. 
Privacy, Data Storage & Confidentiality
 
Complete the Privacy and Confidentiality section of the iRIS submission form.
 
Study Scope
Does this study have a cancer focus?  Cancer focus includes studies that enroll >50% oncology or malignant 
hematology patients; or, preventing, detecting, and diagnosing cancer or understanding the impact of 
cancer on patients and their caretakers.
  Yes   
  No
Does this study involve the use of a drug, biologic, food, or dietary supplement?
 Yes   
 No
Does this study involve the use of a medical device, an algorithm (whether computer based or not), an in 
vitro diagnostic test, or samples to look for biomarkers?
  Yes   
  No
Does this study employ magnetic resonance, including imaging (MRI), spectroscopy (MRS), angiography 
(MRA) or elastography (MRE) beyond the standard of care?
  Yes   
  No
Does this study specify or require the performance of diagnostic procedures using ionizing radiation (x-rays, 
DEXA, CT scans, nuclear medicine scans, etc.) that are beyond the standard of care?
  Yes   
  No
Does this study specify or require the performance of therapeutic procedures using ionizing radiation 

(accelerator, brachytherapy or systemic radionuclide therapy) that are beyond the standard of care?
  Yes   
  No
Does this study specify or require the use of a laser system for diagnosis or therapy that is beyond the 
standard of care (excludes the use of lasers as a standard surgical instrument)?
  Yes   
  No
Will the participant be subjected to increased or decreased ambient pressure?
 Yes   
 No
Please justify the reasons for the exposure and the safety of doing so by describing the safety measures.
The study is to determine specifically whether subjects benefit from hyperbaric oxygen. Administration of 
hyperbaric oxygen requires exposure to higher than ambient pressure. The Duke Center for Hyperbaric 
Medicine and Enviornmental Physiology houses Duke University Hospital's treatment chambers where 
patients will receive their treatments. Safety procedures are strictly followed at Duke and the chamber's 
record of safety is excellent. The chamber's at Duke are the only civilian chambers in the world to be 
certified by the U.S. Navy. 
 
Do you plan to recruit subjects from Duke Regional Hospital (DRH)?
  Yes   
  No
Do you plan to recruit subjects from Duke Raleigh Hospital (DRAH)?
  Yes   
  No
Does this study include using the Duke logo in any advertisements?
  Yes   
  No
Is this study retrospective, prospective, or both?
"Retrospective" means that data or samples already in existence (collected prior to the study submission) will 
be used.
"Prospective" means there will be data or samples collected in this study for research purposes.
Retrospective 
Prospective 
Retrospective and Prospective 
If the study is both retrospective and prospective: Is this a review solely of information collected for non-
research purposes (i.e. a review of medical records)?
  Yes   
  No
Does this protocol include any research using botulinum toxin, including the FDA-approved clinical product 
(Botox)?
  Yes   
  No

Does this protocol involve the administration of any of the following materials to humans?
   •Any viral vector or plasmid
   •Any cells that have been modified by a viral vector
   •Any other genetically-modified cells
   •Any genetically-modified virus, bacterium, or other agent
   •Any other recombinant or synthetic nucleic acid
  Yes   
  No
 
Subject Population Groups and Enrollment
Population Groups (Select 
 population groups only):
targeted
Adults
Minors who are Wards of State
Minors
Duke Patients
Pregnant individuals
Fetuses
Prisoners
Adults incapable of giving consent
Adults with diminished capacity
Disabled subjects
Students
Employees
Healthy Controls
Deceased subjects
Blanket Protocol
Please select any population groups excluded from participation in this study:
Pregnant individuals
Will you administer a pregnancy test to eligible female subjects prior to the start of study activities?
 Yes   
 No
Maximum number of subjects to be consented at Duke:    
Enter a single number. If you anticipate consenting a range of subjects, enter the 
 limit of the range. 
upper
The number should represent the maximum number of subjects for the life of the study.
140
Maximum number of subjects to be consented at all sites:
Enter a single number. If you anticipate consenting a range of subjects, enter the 
 limit of the range. 
upper
The number should represent the maximum number of subjects for the life of the study.
140
 
Subject Procedures and Costs
Biobank - Does this study involve the collection, use, tracking, banking (storage) or distribution of human 
biological specimens?

Human biological specimens include blood or its components, healthy or diseased tissue, bodily fluids, DNA
/RNA or human stem cells.
  Yes   
  No
Procedures
Check all that apply:
Genetic Testing
Gene Transfer
DNA Banking
Testing for Reportable Infectious Diseases
Human Cell Banking
*Use of Human Embryonic Stem Cells
*Use of Human-induced Pluripotent Stem Cells
*Use of Other Cells Derived from Human Embryos
*Use of Human/Animal Chimeric Cells
*Specialized Cell Populations for Cell Therapy
Use of Human Tissue
Use of Bodily Fluids
Use of Blood (or its components)
Not Applicable
Will blood be drawn in this study for research purposes?
  Yes   
  No
Will the Operating Room be used in this study?
Include only research time, not clinical care time.
  Yes   
  No
Will there be extra costs to subjects or insurance as a result of the research (e.g. tests, hospitalization)?
  Yes   
  No
Will there be Subject Compensation?
  Yes   
  No
 
Subject Recruitment Materials
For each document to be reviewed, use the table below to provide the following information:
Attach a copy of each advertisement to be used with this study in the Initial Submission Packet. 
If any Advertisement will have multiple wording variations, attach a copy of each version of the 
Advertisement.
The IRB must approve all study advertisements used to recruit subjects.

Types of subject recruitment materials include, but are not limited to, the following:
Direct Advertising
Posters
Billboards
Flyers
Brochures
Media Advertising
Newspaper Ads
Magazine Ads
Radio Ads
TV commericals / Video
Internet website
Social Media
Other Types of Advertising
Newsletter
Email
Postcards / Letters
(Note: Doctor-to-Doctor letters do not require IRB approval)
Document name
Material category
Location material 
displayed
Has this material 
previously been 
approved by the IRB?
No records have been added
 
Consent Process
Attach draft consent forms in the Initial Review Submission Packet.
Consent forms must be MS Word documents and follow the specific format outlined by the IRB. 
 to 
Click here
download a copy of the consent form template.
 Please do not edit the section of the footer that contains the Protocol ID, Continuing Review 
Note:
and Reference Date fields. Those fields will be used to stamp the final consent form when it is approved by the 
IRB. If you want to add an internal version date, please put it in the header.
Who will conduct the consent process with prospective participants? 
Provide their role(s) in this study (PI, Study Coordinator, etc.):
The consent process will either be conducted by the PI, any Co-I's, or the study coordinator. 
Who will provide consent or permission?
(Select all that apply):
Participant
Parent(s) or Legal Guardian(s)
Legally Authorized Representative (LAR)

How much time will the prospective participant (or legally authorized representative) have between being 
 
approached about participating in the study and needing to decide whether or not to participate?  
If you are not giving the person overnight to consider whether or not to participate, please justify.
Subjects will have as much time as possible to consider their participation and may withdraw at any time. 
Since they will be approached at pre-surgical appointments and can conset any time up until their date of 
surgery patients should have days to weeks to consider their participation. 
Where will the consent process occur?
Patients will be offer the opportunity to consent in their pre-surgical appointments. They may also consent 
on the day of surgery or any day up until that day by contacting the clinical coordinator. 
What steps will be taken in that location to protect the privacy of the prospective participant?
Consent will be given in clinical care areas of Duke (i.e. in exam rooms) and so privacy should be 
protected along with and at the same level as all other clinical care. 
How much time will be allocated for conducting the initial consent discussion, including presenting the 
information in the consent document and answering questions, with each prospective participant?
Patients will have as long as they desire to discuss their participation and will then be able to follow up in 
writing or by phone with the clinical coordinator. Approximately 20-30 minutes will be allocated in addiion 
to their regular appointments. The clinical coordinator will be available for follow up by phone or email. 
What arrangements will be in place for answering participant questions before and after the consent is 
signed?
The attending surgeon and clinical coordinator will be available during the initial approach of the subjects 
for consent. The clinical coordinator will be available by phone or email to follow up with patients to 
answer questions. The Duke Center for Hyperbaric Medicine and Environmental Physiology is accessable to 
patients by appointment and patients may choose to visit the facility prior to their surgery to see the 
chambers and meet chamber staff. 
Describe the steps taken to minimize the possibility of coercion or undue influence.
No compensation will be given to patients for this study. There is no incentive for patients to enter into the 
study beyond the possibiity that they may receive and benefit from HBO . 
2
 
As much as possible all care is standardized from one patient to the next such that the only difference in 
care received by patients is that which is medically necessary for individual conditions. Hence, there is no 
benefit or loss for patients whether they are in the study or not. 
 
Patients will be consented as early as possible so that patients have the longest time between entering into 
the study and the beginning of treatment to consider their involvement. Since patients may withdraw from 
the study at any time, this should limit any time pressure or other situational influence that may arise 
during the initial consent process. 
What provisions will be in place to obtain consent from participants who do not read, are blind or who do not 
read/understand English?
Patients who are not able to read the consent form themselves will be offered translation services, sign 
interpretation, or other helpful adaptive services to facilitate communication of information about the study 
and the consent process to them. Blind or non-reading patients may choose to have the consent read 
aloud. In no case will study subjects be allowed to have consent given for them. Each participant must be 
able to consent for themselves so every effort will be made to provide all information needed for consent 
to patients directly. 
Do you plan to obtain written consent for the conduct of research?

 Yes   
 No
 
Protected Health Information (PHI)
Indicate how you intend to use potential subjects' Protected Health Information (PHI):
I will review, but not record, PHI prior to consent. 
I will record PHI prior to consent. 
I do not intend to use PHI prior to consent. 
I will record PHI without consent. (decedent research, database repository, chart review) 
 
Review Preparatory to Research (RPR)
Describe the specific PHI that will be reviewed to prepare a research protocol and/or to ascertain and/or 
recruit subjects:
Patient PHI may be reviewed to determine eligibility prior to their consent for the study. This will occur in 
conjunction with their normal preoperative care. 
Principal Investigator's Affirmation:
The PHI is necessary for the purposes of this activity. 
 Yes   
 No
The PHI will be used solely for this activity.
 Yes   
 No
The PHI will not leave DUHS.
 Yes   
 No
The PHI will not be written down or recorded prior to the subject signing a research consent form.
 Yes   
 No
I will not use the information accessed through this RPR procedure for any other purpose, including for 
presentation or publication.
 Yes   
 No
 
Drugs, Biologics, and Other Substances
Select Protocol Phase (for studies with FDA regulated drugs or biologics only). Choose only one:
Phase 0 
Phase I 
Phase I/II 
Phase II 
Phase II/III 
Phase III 
Phase IV 
N/A 
Pilot 

Drugs, biologics, or other substances being evaluated as a part of this research study:
Add all drugs, biologics, or other substances being evaluated as a part of this research study for which an IND 
is provided for the indication used in this study.
Also add any other drugs, biologics or other substances here that are being used as a part of this research 
study, for which an 
.
IND is not provided
 
List every other drug, biologic or other substance for which side effects are described in the consent form.
View 
Details
Drug Name
FDA Approved
A new drug or a 
new use of 
approved drug:
IND Number
Drug/Biologic
/Substance 
Generic Name:
Hyperbaric 
oxygen
Generic Drug 
Name:
Investigational 
Drug Name:
Yes 
No 
 
Drug/Biologic/Substance Generic 
Name:
Hyperbaric oxygen 
Generic Drug Name:
 
Investigational Drug Name:
 
Drug/Biologic/Substance Source:
 
Is the drug/substance being 
provided to the subject free-of-
charge?
Yes  
Is the Drug FDA Approved?:
Yes  
Is this drug/biologic or other 
chemical, metabolite, nutritional 
substance or other substance to 
be used in this research subject to 
the provisions of the Controlled 
Substances Act?
No  
Does this Drug have an IND 
Number?
No  
IND Number
 
IND Holder:
N/A  
IND details:
 
If FDA Approved and an IND is 
not required, Please provide a 
rationale for exemption:
Medical grade oxygen is used for this study.  
Will drug/substance be shipped 
from Duke to external locations
No  
Dose Range:
2 ATA/2 hours  
Frequency:
2x daily  
Will this drug, biologic, chemical, 
metabolite, nutritional substance 
or other substance be 
manufactured or compounded at 
Duke?
No  
Drug Storage Restrictions 
(including temperature, etc.):
N/A  
As indicated in the Investigator's 
Brochure or other available 

documentation, what is the 
highest FDA Use-in-Pregnancy 
Rating for drug used for research 
purposes in this study?:
N/A  
Are you using an investigational pharmacy at Duke?
Please be aware that inpatient administration of an investigational drug requires the use of the Duke IDS or 
Oncology ICS, as per Department of Pharmacy policy.
  Yes   
  No
Who will be responsible for the storage, inventory and control of the drug/biologic or other chemical, 
metabolite, nutritional substance or other substance to be evaluated in this research?
The IDS is available to assist any investigator (upon request) with storage and control of investigational drugs 
in the outpatient setting
The oxygen to be used in this study is standard medical grade oxygen, from the same source as all Duke 
patients receive (see uploaded document).
Where will the drug/biologic or other chemical, metabolite, nutritional substance, or other substance to be 
evaluated in this research be stored?
N/A
From where will the drug/biologic or other chemical, metabolite, nutritional substance or other substance to 
be evaluated in this research be dispensed?
Duke Center for Hyperbaric Medicine & Environmental Physiology
At the completion of this research study, what will be done with the unused or returned investigational drug
/biologic or other chemical, metabolite, nutritional substance or other substance?
N/A
 
Privacy and Confidentiality
Explain how you will ensure that the subject's privacy will be protected:
Consider privacy interests regarding time and place where subjects provide information, the nature of the 
information they provide, and the type of experience they will be asked to participate in during the research.
All information will be protected and PHI will be handled in accordance with all DUke policies and 
procedures. Redcap will be used for data collection and storage and primary documents will be stored in 
the study binder kept in a locked cabinet in the Duke Hyperbaric lab. Patients will be consented and have 
the ability to ask questions in patient care areas where curtains, exam rooms, and other strategieis for 
protecting patient confidentiality will be used to protect patient privacy. 
Describe how research data will be stored and secured to ensure confidentiality:
How will the research records and data be protected against inappropriate use or disclosure, or malicious or 
accidental loss or destruction? Records and data include, for example, informed consent documents, case 
report forms or study flow sheets, survey instruments, database or spreadsheets, screening logs or telephone 
eligibility sheets, web based information gathering tools, audio/video/photo recordings of subjects, labeled 
specimens, data about subjects, and subject identifiers such as social security number.

Data will be stored using the Duke redcap system. Primary data that is in paper form will be stored in the 
study binder kept in a locked cabinet. All correspondence regarding the program will occur through the 
Duke email system. 
 
Application Questions Complete
Please click Save & Continue to proceed to the Initial Submission Packet.
The Initial Submission Packet is a short form filled out after the protocol application has been completed.  This 
is an area to attach protocol-related documents, consent forms, and review the application.