The Effects of Hyperbaric Oxygen on Rheumatoid Arthritis: A Pilot Study
Phase: NA
Conditions: RheumatoId Arthritis
Sponsor: David Grant U.S. Air Force Medical Center

For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
PROPOSAL FOR HUMAN RESEARCH 
CLINICAL INVESTIGATION FACILITY 
60th Medical Group (AMC) 
David Grant USAF Medical Center 
101 Bodin Circle 
Travis AFB, CA 94535-1800 
FW A00003321,.DoD 50004; IRBOOOllll 7 
APPROVED 
/tl.P . f-VW 
MAR 1 2· 2019 
60MDGIRB 
TRAVIS AFB CA 
For assistance, call the Chief, Research Oversight and Compliance at (707) 423-7206 
1. Title of Investigation
The Effects of Hyperbaric Oxygen on Rheumatoid Arthritis: a Pilot Study.
2 I 
. nves ti 2ator an di nvestiii ation s ff
ta 
Name 
Rank 
Study Role 
Lt 
PI 
Col 
CTR 
AI 
Lt 
AI 
Col 
Maj 
AI 
Consultant 
Maj 
RM 
CTR 
CRC 
CTR 
CRN 
CTR 
RA 
Form Revised as of 14 Apr 14 
Date of 
Staff/ 
Dept/ 
DoD 
Investigator 
Resident/ Office 
Phone 
Assurance 
E-mail
Training 
Fellow 
Symbol 
Number 
12/8/17 
Staff 
SGOM 
50004 
1/22/18 
Staff 
SGPH 
50004 
9/28/17 
Staff 
SGPH 
1/5/18 
Staff 
SGQX 
50004 
12/4/17 
Volunte 
er 
7/19/17 
Staff 
SGSE 
50004 
4/10/18 
Staff 
SGSE 
50004 
6/19/17 
Staff 
SGSE 
50004 
8/5/17 
Staff 
SGSE 
50004 
contact info redacted 28 Jan 20
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names 
redacted 
28 Jan 20

For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMDl 3  
CTR 
CRC 
2/4/19 
Staff 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
SGSE 
50004 
Research Monitor (RM): name redacted 28 Jan 20, 60 MDG/SGSE 
3. Facility and/or Contractor: NI A
4. Purpose of Investigation
This is a pilot study. The purpose of this investigation is to determine the effects and feasibility
of using hyperbaric oxygen therapy (HB02) for the treatment of rheumatoid arthritis joint pain
and prevention of disease progression. In this study it is our intention to not only evaluate effects
and feasibility but time, cost, adverse events and effect size in an attempt to predict an
appropriate sample size and improve on the study design prior to a more extensive study.
5. Category of Study and Risk Assessment
5.1. Category of Study 
Pilot Study. Hyperbaric oxygen is not an established treatment for rheumatoid arthritis. 
D Medical Utilization D Prevention D Medical Readiness 4 Diagnosisffreatment/Other 
5.2. Proposed Risk: 
D Minimal Risk 
T Greater Than Minimal Risk 
6. Proposed Research
6.1. Background and Review of Literature: 
Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disorder of unknown 
etiology that primarily involves synovial joints, typically symmetrically. If untreated and/or 
uncontrolled, joint destruction due to erosion of cartilage and bone can cause joint 
destruction, joint deformities, loss of physical function, severe disability, and difficulties 
maintaining employment. 1 ACR/EULAR 2010 classification criteria2 is a score-based 
algorithm which adds scores of four categories including, joint involvement, serology, 
acute-phase reactants and duration of symptoms. A score of >6/ 10 is needed for 
classification of a patient as having definite RA. 
Non-pharmacologic and supplementary therapies include patient education, rest, 
exercise, nutrition counseling, cardiovascular disease risk reduction, and immunizations to 
decrease risk of infectious complications of immunosuppression. These are important in the 
comprehensive management of RA in all stages of disease and are used in addition to drug 
therapy. Pharmacologic therapies typically start with a disease-modifying antirheumatic 
drug (DMARD), preferably as soon as possible after diagnosis. DMARDs are commonly 
used in combination with anti-inflammatory drugs such as nonsteroidal anti-inflammatory 
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contact info redacted 28 Jan 20
name 
redacted 28 
Jan 20

For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
drugs (NSAIDs) and glucocorticoids which are often used as bridging therapies until the 
DMARDs become effective. The goal is disease remission. To assess response, disease 
activity scores are used along with inflammatory markers3
David Grant USAF Medical Center Case Experience 
Three patients with active RA treated in the multi-place hyperbaric facility at DGMC, 
Travis Air Force Base, CA, for non RA-related indications, all noted significant 
improvement in arthralgia's, sleep patterns and overall well-being during the course of 
therapy. Two were treated at two atmospheres absolute (ATA) oxygen for 90 minutes daily 
Monday through Friday. One patient received two ATA air on the same treatment protocol 
as a participant in a research study, and a subsequent course of hyperbaric oxygen (HB02) 
at two ATA. 
Sixty-two year old female with diabetes, hypertension (HTN), RA, status post double 
mastectomy referred for HB02 for healing enhancement of infected and poorly healing 
bilateral surgical sites. Immuno-suppressive medications were discontinued due to negative 
·effect on healing. The patient had significant improvement of joint pain early in her course
of HB02 ( < 10 sessions). She received a total of 5 5 treatments, last 17 Dec 2014. She had
no RA pain recurrence for 13 months after the last HB02 session. After complete healing
of the mastectomy sites was assured, RA meds were restarted.
Seventy-one year old male with diabetes mellitus (DM), RA, treated with 50 HB02 
sessions ending in May 2013 for chronic, non-healing foot ulcers. A second course of 
therapy for the same diagnosis ended in May 2015 (31 sessions). Arthralgias slowly 
returned after about six months following the first course of HB02, and still has significant 
clinical benefit six months after the last course of HB02. Both times, the patient 
experienced not only complete relief of his arthralgias within the first seven daily (five 
days/week) HB02 sessions, but also had significant clinical improvement in his chronic, 
bilateral Dupuytren' s contractures. 
Fifty-nine year old male with DM and RA, was a subject in a double-blind, randomized 
research study on the use of HB02 in patients with Wagner 2 diabetic wounds in the fall of 
2014. When the study was discontinued, it was determined that the patient had been 
randomized to the control group and received 30 sessions of hyperbaric air at 2 ATA per 
research protocol. D_uring the study participation, the patient had complete relief of his 
chronic joint pain due to rheumatoid arthritis within one to two weeks of the study 
participation period, without a change in his medications. He also noted significant 
improvement in sleeping patterns. About one month after ending the research study 
hyperbaric exposures, the patient had a significant RA flair. He was seen several times in 
the ER for worsening RA pain. He was disenrolled for follow-up in the research trial in Feb 
2015 so that he could be treated with HB02 for the RA flare, and for an infection and 
healing enhancement of a right olecranon surgical site. The patient again had complete 
relief of arthralgias within three to four HB02 sessions, was able to sleep through the night 
and able to significantly increase his activity level. 
It seems intuitively unlikely that the latter. a patient could benefit from both hyperbaric 
air and hyperbaric oxygen. The bioactivity ofhyperbaric oxygen is well known. Although 
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For Protocol Office use only: 
Protocol title: The Effects ofHyperbaric Oxygen on 
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DGMC Human Research Protocol Template 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
lesser known, the bioactivity of increased atmospheric pressure is well documented in basic 
science literature. Independent and overlapping genes are sensitive to increases in pressure, 
oxygen, or both, and could explain the relief of pain from both hyperbaric air and oxygen. 4 
Literature Review 
There is a paucity of information about the effects of HB02 on patients with RA in the 
medical literature. A 1988 letter to the editor in the British Journal of Rheumatology 
reported ten patients with active classic or definite RA. Eight patients received ten HB02 
treatments at 2 AT A X 90 minutes on alternate days over a 21-day period. Two patients 
received 'sham' treatment breathing air at normal atmospheric pressure. Clinical 
assessments were made at -1, 0, 3 (end of treatment period), six and 12 weeks, and included 
duration of morning stiffness, grip strength, articular index and visual analogue pain scale. 
Lab indices included hemoglobin, platelet count and ESR. Rheumatoid factor (RF) was 
measured at times zero, three, and six weeks. The two pre-treatment assessments defined 
the range for each individual, and subsequent assessments were recorded as improved ( + 1 ), 
in range (0), or worse (-1 ). The authors concluded that there was a trend toward 
improvement in HB02-treated patients. They concluded that the improvement was to be 
expected if active RA patients are recruited, and noted a similar trend in the sham-treated 
group. No patients went into remission, and the Rheumatoid Factor did not significantly 
change. The authors felt that their pilot study failed to demonstrate any therapeutic 
advantage of HB02, and further trials were not justified. Weaknesses in this pilot study 
include small numbers of patients, likely sub-optimal course, frequency of HB02 therapy 
and lack of utility of RF to measure disease activity. Larger differences in outcomes 
between the active and sham groups might have been realized if there were more patients 
enrolled for a longer, daily treatment course, and a more robust data analysis.5
In a 1990 abstract authors reported on their experience treating 50 RA patients with 12 
sessions of HB02 at 1. 7 AT A for 40 minutes. All patients had been previously treated with 
prolonged traditional drug therapy with minor success. The authors reported good 
immediate and remote clinical results, the best, in patients with systemic manifestations. 
After HB02, there were no changes reported in humoral immunity (lgA, lgM or lgG), but 
serum immune complexes decreased significantly, absolute and relative quantities ofT- and 
B-lymphocytes approached normal levels, and the ratio oftheophylline-resistant to
theophylline-sensitive lymphocytes deceased significantly. The authors concluded that the
beneficial effects of HB02 on the immune system of the patients was related to
intensification of the suppressive function ofT-lymphocytes, normalization of cell-bound
. immunity and decreasing the serum concentration of immune complexes. 6 
A 2002 Russian article reported on 46 patients with rheumatoid arthritis (RA) and 18 
with osteoarthritis {OA), all treated with 3.6-4 cGy radiotherapy (RT). Twenty-four of the 
RA, and ten of the OA patients were treated with a combination of oxygen barotherapy 
(OBT) consisting of 9-11 sessions at 1.4 bar (1.45 atmospheres absolute) for 40 minutes 
each, and RT to allow for optimal results from this complex therapy while reducing the 
known adverse effects of radiation. In the two years that followed, basic clinical 
assessments included the Ritchie articular index, total pain index, local articular index, pain 
index for knee and hand joints, circumference of knee and wrist joints, and ultrasound 
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For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
measuring the magnitude of exudate, erosive processes, osteophytes, articular fissure 
stenosis, and the thickness of the synovial membrane and cartilage. 
Joints irradiation after the oxygen barotherapy (OBT) session was associated with a more 
pronounced positive effect than RT alone, including significant positive findings in the 
Ritchie articular index, general pain index, and pain index of the knee joints. 
For RA patients, ultrasonic investigations of knee joints revealed negative correlations 
between treatment effectiveness and synovial membrane thickness (r= -0.65, p< 0.01), and 
severity of effusion (r= -0.71, p< 0.01) for RA patients. For group three OA patients, there 
was no evidence of cartilage thinning throughout the observation period; progression was 
found in group 4 (r= -0.83, p< 0.01). Therapies for all groups were more effective in the 
early stages of the disease and the best outcomes were found in QA patients.7
Although this study evaluated the combination of OBT with radiation therapy for RA and 
OA patients, and found statistically significant improvement in indices of pain and disease 
progression, it raises the question of whether there is potential benefit from the use of OBT 
(hyperbaric oxygen) alone. This is especially true since 6BT was at only the equivalent of 
1.45 ATA for a total of 9-11 sessions, considering that most OBT sessions in the US are 
· provided at 2 to 2.5 ATA, typically for more than ten sessions.
6.2. Relevance/Significance: 
If hyperbaric oxygen consistently relieved the joint pain and stiffness associated with RA, 
led to an increase in exercise tolerance, activity level and sleep quality, and modified disease 
progression, there could be a significant role for the use ofHB02 as an adjunct to current 
therapies, and could reduce the amount of DMARD or Biologic therapy. This would be 
especially true for patients targeted as possible study participants: 1) those that prefer not to 
be on the standard rheumatologic medications, 2) those with contraindications to the 
standard rheumatologic medications, and 3) those that have failed or have incomplete 
response to standard rheumatologic medications. 
6.3. Hypotheses or Research Questions or Objectives: 
Proposed primary outcomes: 
1. Subjective relief of joint pain, stiffness, and increased activity levels as assessed by the
study rheumatologist as measured by disease activity monitoring score (DAS28)8 and
ACR20 criteria.
2. Improved sleep quality to be tracked separately by a sleep quality questionnaire.
3. Subjective improvement in movement and activities of daily living using the RAPID 3.
4. Visual Analog Scale (VAS)10for pain to assess changes in subjective pain.
5. Altering the progression of joint disease as measured by ultrasound and MRI measured
at baseline, three months, six months.
·6. Changes in inflammatory markers as measured by C-reactive protein (CRP) and
erythrocyte sedimentation rate (ESR) to be performed at baseline, during HB02 
treatments if subject reports pain relief ( defined as improvement of pain of> 40% or 
zero pain) based on pain assessment (numerical pain scale of 1-10 reported verbally) at 
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For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
each hyperbaric treatment visit, at the completion of HB02 treatments, at three months 
and six months. 
A research lab sample for analysis of Microparticles, neutrophil and platelet activation 11
will be collected with each CRP /ESR. Microparticles represent a heterogeneous 
population of vescicles with a diameter of 100 to 1000 nm that are released by budding 
of the plasma membrane and express antigens specific to their parental cells. Although 
microparticle formation represents a physiological phenomenon, a multitude of 
pathologies are associated with a considerable increase in circulating miroparticles, 
including inflammatory and autoimmune diseases; atherosclerosis and malignancies. 
6.4. Research Design and Methods: 
HB02 can be administered either in the multiplace chamber, or the monoplace chamber. The 
multiplace chamber is compressed with air, and the patients breathe oxygen through hoods or 
masks. The monoplace chamber is pressurized with oxygen, so that the patient breathes the 
ambient oxygen. Only the delivery system is different. There is no difference in the oxygen 
delivered, or" in attendant risks. 
This is a pilot study. 
1. Patient eligibility will be determined by the Rheumatologists, specialists in diagnosing
rheumatoid arthritis. Recruitment will take place from their pool of patients.
Additionally, patients that have been seen in the military treatment facility (MTF) within
the past year with a diagnosis of rheumatoid arthritis will be contacted, after obtaining
!RB-approval with a HIPAA waiver. Patients will be recruited if they: diagnosed with
rheumatoid arthritis meeting ACR/EULAR 2010 classification criteria and any one of the
following:
a.
Patient does not want to be on rheumat9logic medications.
b. Patient has contraindications to standard rheumatologic medications.
c.
Patient has failed treatment or an incomplete response with standard
rheumatologic medications.
2. The initial screening visit after the rheumatologist has discussed the trial will be the
consenting and review of the inclusion/exclusion criteria. After the consent is signed the
Hyperbaric physician will do a physical examination, review of inclusion and exclusion
criteria and medication review to determine if it is safe for the subject to receive HB02.
An HCG by point of care testing (POCT) will be completed by the coordinator in women capable
of pregnancy. After this exam is done the subject will be scheduled for a trial hyperbaric
session.
3.
The visit window time line for screening, Baseline, and first HB02 treatment to occur all
within one month (four weeks) before start of HBO Hyperbaric Therapy Session.
4. Baseline The Baseline date is dive #1 date. This visit includes:
•
A visit with the rhematologist to do routine assessments to establish baseline
measurement using the the Disease Activity Scale (DAS28)
•
Labs (CRP and ESR, Basic Metabolic Panel (BMP) and Microparticles) will be
done. A MRI with and without contrast and ultrasound will be done on both hands
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For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
from wrists to proximal phalanges. BMP is done pre-MRI to guarantee adequate 
kidney function. 
•
Subjective patient reporting will be captured using the RAPID 3.
•
Sleep quality will be tracked using the Pain and Sleep Quality Questionnaire
(PSQ-3)12 .
•
Visual Analog Score for Pain (VAS) will be tracked.
•
Surveys will be administered by a study team member.
5. The subject at this time will be scheduled to start HB02 treatments. Screening, baseline ,
first HB02 treatment all in one month.
6. During the period that the HB02 treatments are taking place the hyperbaric
physicians will continue to monitor the subjects and if there is any concern regarding
their physical condition they will consult with one of the rheumatologists. Participants
will complete 30 sessions within 10 weeks.
7. If the subject reports pain relief, as defined as improvement of pain of> 40% or zero
pain, during the HB02 treatments they will be referred to the rheumatologist for
assessment. Pain improvement will be based on a pain assessment (numerical pain scale
of 1-10 reported verbally) at hyperbaric treatment visits. Labs (CPR, ESR and
Microparticles) will be drawn at this time. RAPID 3 and PSQ-3 and VAS will be done at
least six times while undergoing hyperbaric treatments to track subject progress. Labs
(CRP, ESR and Microparticles) will be repeated at the conclusion of the HB02
treatments.
8. At the month three visit ( +/- 2 window) the subject will see the rheumatologist to track
disease activity using the DAS-28. The date of the three month visit will be scheduled
for three months from the Baseline visit. The Rheumatologist will order the MRI
Ultrasound, and lab studies prior to the three month visit. RAPID 3, PSQ-3and VAS for
pain will be administered at this time. Laboratory samples will be collected prior to the
Rheumatology appointment.
9. At the month six visit ( +/- 2 week window) the subject will see the rheumatologist to
track disease activity using the DAS-28. The date of the six month visit will be scheduled
for six months from the baseline visit. The Rheumatologist will order the MRI, Ultrasound,
and lab studies prior to the six month visit. RAPID 3, PSQ-3 and VAS for pain will be
administered at this time. Laboratory samples will be collected prior to the Rheumatology
appointment.
This marks the end of the trial. Patients will continue to be followed in the Rheumatology
Clinic every three months.
Stud v· ·t 
IY 
ISi S
Screening Visit Base HBO 
Pain 
Compl 
Mo3 
Mo6 
(maybe split 
into 2 visits) 
*** 
Form Revised as of 14 Apr 14 
line 
TX 
relief 
etion of (+/-2 
(+/- 2 
Visit 
during 
HBOT 
weeks) 
weeks) 
*** 
*** 
HBOT 
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For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
ICD/ 
X 
HIPAA 
Inclusion/ 
X 
Exclusion 
Criteria 
Exam by 
X 
Hyperbaric 
Physican 
Trial HBOT 
X 
Hyperbaric 
treatments 
Rheumatology 
X 
Visit 
Labs 
X 
Ultrasound 
X 
MRI 
X 
DAS28 
X 
RAPID3 
X 
PSQ3 
X 
VAS Pain 
X 
X30 
* 
** 
X 
**** 
X 
**** 
X 
••••••• 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*When subJect reports pain relief during HBOT they will be assessed by Rheumatologist.
** Complete 30 HBO treatments within 10 weeks.
*** Screening, Baseline, First HBOT treatment all within one month (four weeks) 
**** at least 6 times while undergoing hyperbaric treatments 
The optimal dose response of RA patients to HB02 is unknown. Modest benefit has been 
shown in prior studies at 2 AT A and 1.5 bar for 10 and 9-11 sessions, respectively. The subject 
will be compressed with air in the hyperbaric chamber to 2.0 ATA, and then placed on 100% 
oxygen by a head tent or mask, for 90 minutes. After hood removal, the chamber is 
decompressed while the patient breathes chamber air. Treatments are daily, Monday through 
Friday for a planned total of 30 sessions. Time to change in subjective study outcomes (relief of 
joint pain, stiffness, improvement in sleep patterns, and increase in activity level) will be 
documented. Treatments will stop at the end of 30 sessions whether or not there is subjective 
improvement. After the initial assessment, follow-up with the rheumatologist is scheduled at 
three and six months which is standard of care for rheumatology patients. If the participant 
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For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
experiences subjective improvement during the 30 hyperbaric sessions, he/she will be assessed 
by one of the rheumatologists at the time of improvement. The hyperbaric physicians will be 
monitoring the patients daily, five days/week, and provide ongoing clinical assessments during 
the hyperbaric treatments. This is standard of care for HB02 patients. 
If the patient's RA symptoms worsen during the study, the plans are to: 
1. Schedule an appointment with the the Hyperbaric and Rheumatology physicians to
clinically evaluate and· determine the cause. If it is determined that the symptoms could
be due to HB02, the treatment will be stopped and the Research Monitor will be notified.
2. The physicians will institute measures to address the cause.
3. If cause cannot be diagnosed and symptoms persist despite appropriate measures and if
believed the patient may worsen from continued HB02, treatments will be suspended.
4. Any adverse events will be recorded and reported to the IRB according to the AFI 40-402
and SGSE Operating Instructions and the Medical Monitor will be notified ( see Section
6.7)
6.5. Risks/Benefits: 
All diagnostic and therapeutic procedures associated with subject qualification for, or 
participation in this study will be documented in standard patient record format. Copies of 
documentation will be placed in both the patient's medical record and the associated patient 
study record. 
Risks/ Inconveniences: 
Middle ear barotrauma and eustachian tube dysfunction is the most common side effect 
of HBOT with an incidence of at least 2%. Sinus barotrauma is even less common and is 
associated with URI or allergic rhinitis. Symptoms range from mild discomfort equilibrating 
pressure in the ears to actual barotrauma. The majority of patients experiencing these 
symptoms experience relief after the administration of nasal decongestants or nasal steroids 
and can complete the hyperbaric therapy. To mitigate against this known risk, patients 
receive detailed instruction in the proper methods for equilibrating the pressure in the ears 
and sinuses prior to hyperbaric therapy. 
Claustrophobia appears to be present in about 2% of the general patient population, and 
may be higher even in the multiplace and mono-place chamber. True claustrophobia causes 
people to sweat and experience tachycardia in elevators, CT scanners and MRI machines. 
Study participants with true claustrophobia will be excluded from the study. It is far more 
common for people to experience confinement anxiety, rather than true claustrophobia. The 
majority of patients experiencing confinement anxiety are able to complete hyperbaric 
therapy sessions without difficulty. Study participants who are unable to overcome the 
symptoms of confinement anxiety will be allowed to complete the study and occasionally, 
sedation will be used if the participant has people available to drive them to and from the 
DGMC. 
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For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
Vision changes, typically a progressive myopia, can occur in some patients undergoing 
prolonged treatment courses ofHBOT. The exact mechanism is unclear, but is apparently 
lenticular in origin. The incidence documented in the literature ranges from 20% to as high 
as 69%, with complete reversal of the refractive changes occurring in nearly all patients 
except those with pre-existing cataracts. Refractive changes developed in 24 of 25 patients 
studied in Sweden, undergoing prolonged courses of HBOT of 150-850 daily exposures. 
With one possible documented exception, new cataracts do not develop within clinical 
courses of 20-50 sessions. 
Pulmonary barotraumas with or without air embolism may rarely occur during 
decompression, necessitating careful analysis of risk versus benefit. The actual risk is 
indeterminate, but is known to be higher in patients with asthma or pulmonary blebs. To 
protect against these risks, the DGMC hyperbaric chamber does not permit wheezing 
asthmatic patients to enter the hyperbaric chamber. This risk is minimal for controlled 
asthmatics that are compliant with their medication. Similarly, a chest x-ray and pulmonary 
consultation will be required of any patient with known pulmonary disease who wishes to 
enroll in the study. Any participants with known pulmonary disease who wish to enroll in 
the study will be permitted to do so if they are cleared by their pulmonologist. 
Cardiovascular responses and flash pulmonary edema are rare complications of unknown 
risk and unknown incidence due to the rate-dependent reduction in cardiac output with an 
increase in peripheral vascular resistance that hyperbaric oxygen induces. These effects are 
well tolerated by normal individuals, but patients with decreased left ventricular ejection 
fraction must be monitored for the rare complication of acute pulmonary edema. In as little 
as ten minutes, these changes in cardiac output can lead to a collection of fluid in the lungs 
known as flash pulmonary edema. The incidence is unknown. The current inability to 
accurately identify patients susceptible to this rare complication requires careful evaluation 
of known heart failure patients prior to hyperbaric therapy. Potential study participants with 
known heart failure will be required to have an echocardiogram and a cardiology 
consultation prior to enrolling in the study. Study participants with heart failure will be 
allowed to enroll in this study if they are cleared by their cardiologist. 
Oxygen associated risks include central nervous system toxicity manifest by focal and or 
generalized seizures. Recent surveys that include a total of 138,968 patient therapies at three 
different facilities indicate a combined incidence of,..,, 0.03% for three 30-minute oxygen 
breathing periods at 2.4 to 2.5 atm bs. Earlier estimates of the sizure rate during HBO 
exposures at 2.0 to 3.0 atm abs reported a convulsion incidence of 0.01 %. Ha02-induced 
seizures only occur during the exposure to high levels of 02 in the hyperbaric chamber at 
pressure, and there are no residual effects. However, if not diagnosed and managed, seizures 
can recur on re-exposure to HB02. 
Hypoglycemia: In diabetic patients taking hypoglycemic medications, there is a risk of 
hypoglycemia and associated effects. To protect against this complication, the DGMC 
hyperbaric policy requires blood sugar levels of at least 120 in diabetic patients prior to 
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For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
receiving hyperbaric therapy. Diabetics with blood sugar below this level receive juice and 
crackers, and may have blood glucose rechecked prior to therapy. Hyperbaric staff are 
· always present in the hyperbaric chamber, and can monitor for signs or symptoms of
hypoglycemia. At least one member of the hyperbaric team is present in the chamber for
each eight patients in the chamber. If symptoms occur, staff will recheck the blood glucose
immediately, and administer juice and crackers if needed. Following the completion of
hyperbaric therapy, diabetic patients are again tested for blood sugar level. Patients must
have a blood sugar level of at least 100 prior to leaving the hyperbaric medicine department,
or be cleared by the hyperbaric physician.
Fire is always a risk with pressurized oxygen in high concentrations. Hyperbaric chamber 
patients are not allowed to smoke or carry lighters or flammable materials in the hyperbaric 
chamber. Until a recent explosion in a non-certified chamber, there had not been a fire in a 
United States hyperbaric chamber since 1968. 
There is ari inconvenience of the time associated with the study. There are approximately 
40 appointments over a six month period. Thirty of them are two hour appointments for 
hyperbaric treatments. 
Blood draws: there is a risk associated with blood draws. The risks of taking blood include: 
Pain, bruise at the point where the blood is taken, redness and swelling of the vein, infection 
and a rare risk of fainting. 
Ultrasound: There is no risk associated with ultrasound. 
MRI: We will be doing a MRI with and without contrast looking at the wrist from the distal 
radius to the mid diaphysis of the proximal phalanges. Risks include allergy to MRI contrast 
which is extremely rare. There is a risk of nephrogenic systemic fibrosis with poor renal 
function (GFR<30) that is screened for (see Attach 11) if the subject is over 50 years of age 
or has a history of renal insufficiency. 
Benefits: 
The purpose of this study is to determine the effectiveness of HBOT on rheumatoid arthritis. 
The use of HB02 in patients with RA may or may not include decreased joint pain, increased 
activity level, improvement in sleeping patterns. Depending on study outcomes it may benefit 
society, possibly diminished need for use of immunosuppressive rheumatologic medications. 
Risk to Benefit Ratio: 
Risks are well understood, treatable and with few exceptions of low magnitude. The potential 
benefits such as reduction in pain, improved sleep, decreased RA disease activity are 
extremely beneficial. As such, potential direct benefits to the subjects and to future treatments 
outweigh the risks that, as mentioned above, are rare and minor in the well-selected patient. 
6.6. Subject Population 
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For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
Age Range: 
  18 y/o
Sex: 
 Male
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
D Children {S 18) 
IZJ Female 
Vulnerable Population: 
 No
D Yes (explain) 
Number of Subjects: 
•
Total Number of Subjects: 20
•
Number of Subjects Planned for DGMC: 20
A total ofup to 20 subjects will be recruited. We will continue to recruit and treat until 10 
complete data sets have been obtained. In the event that ten total data sets are obtained and 
additional subjects are in the process of the intervention, at the PI's discretion, those additional 
subjects will receive full treatment. 
Inclusion/Exclusion Criteria: 
Inclusion Criteria: 
I. Age 18.
2. Active duty or DoD beneficiary
3. Diagnosed with rheumatoid arthritis meeting ACR/EULAR 2010 classification criteria
and any one of the following:
a.
Patient does not want to be on rheumatologic medications.
b. Patient has contraindications to standard rheumatologic medications.
c. Patient has failed treatment or an incomplete response with standard
rheumatologic medications.
4. Women of childbearing age must have a negative pregnancy test and currently be on a
reliable form of birth control.
Exclusion Criteria: 
1. Severe depression
2. Dementia, mental disability
3. Claustrophobia
4. Uncontrolled seizure disorder
5. Uncontrolled asthma/severe COPD with pC02 > 45 mmHg on arterial blood gas
6. Grade 4 congetive heart failure
7. Unstable angina
8. Chronic/acute otitis media/sinusitis
9. Major tympanic membrane trauma
10. Severe kyphoscoliosis
11. Prior chemotherapy with Bleomycin and evidence of deterioration in diffusion capacity
of the lung for carbon monoxide (DLCO) after a single hyperbaric oxygen exposure.
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For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FD020160004H wAMD13 
12. History of renal insufficiency or GFR< 30
investigator name redacted 28 Jan 20
DGMC Human Research Protocol Template 
13. Women that are currently pregnant or breast feeding or intend on becoming pregnant
while enrolled in the study
Recruitment: 
1. Current or prior patients of the Rheumatology Clinic will be recruited by Rheumatology
Clinic which is located in the Internal Medicine Clinic.
2.
!RB-approved HIP AA waiver to contact patients that have been seen in the military
treatment facility (MTF) within the past year with a diagnosis of rheumatoid arthritis
3. Flyers in the Rheumatology Clinic patient rooms.
4. Investigators may make an announcement at commander's calls after appropriate
approvals have been made.
Consent: 
Adequate study staff time will be set aside for each participant to receive information, ask 
questions and consider participation in the study. The consent process will begin with the 
introduction of the study. The Principal Investigator or study staff that have been delegated 
responsibility and have been trained on the protocol and consenting process, will explain the 
nature and scope of the study, potential risks and benefits of participation in lay terms and 
answer any questions the subject may have. At this point the subject will be asked to read 
the Informed Consent Document (ICD) and Health Insurance Portability and Accountability 
Act (HIPAA) authorization. If the subject has any further questions, they will be answered. 
When the subject has had all his/her questions answered, he/she will be offered the 
opportunity to participate in the study. If the participant has further questions, and wants to 
talk to a physician, one of the physicians on the study will be available to meet the 
prospective subject and answer any questions. This information will be discussed in a 
private area of the hospital or doctor's office. 
The subject may elect to discuss the study with others if they so choose, prior to agreeing to 
participate. If the subject agrees to participate, the IRB approved ICD and HIPAA consent 
must be signed and personally dated by the subject and Investigator or study staff who have 
been delegated the responsibility and have been trained on the protocol before any study 
related procedures are done. 
The original signed consent form will be turned into the protocol office and a copy will be 
placed in the subject's study folder and stored with other protected health information in a 
locked filing cabinet in an office that is locked when the office owner is not in the room. A 
copy of the ICD will be placed into their electronic medical record as well. Subjects will be 
assured that they may withdraw from the study at any time and for any reason and their 
medical treatment will not be compromised. Research procedures will not start until the IRB 
approved informed consent document has been signed and dated by the subject and research 
team member who has been delegated responsibility for consenting subjects and has been 
trained on the protocol. 
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For. Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
6. 7. Safeguards for Protecting Subjects:
The Medical Monitor as per 32 CFR 219.109 (e) and IAW DODl3216.02_AFI 40-402 will
serve as the subject advocate and ombudsman. He will have the right to discusses research 
progress with the principal investigator and staff. He will coordinate and review adverse 
event reports with the principal investigator. He may interview and consult on individual 
cases and reports to the IRB/PI any discrepancies or problems. The Medical Monitor may 
stop the research study in progress, remove individual subjects from a study, or take 
whatever steps are necessary to protect the safety and wellbeing of research subjects. The 
Medical Monitor will have the right and duty to review the study progress at varying 
intervals. 
This study involves greater than minimal risk to subjects with the possibility of adverse 
subject reaction to the therapy. Primary monitoring of the study will be performed by the 
study team members, who will review accrual, adverse events (AEs ), and treatment on a real­
time basis. They will ensure that all eligibility criteria and consent requirements are met 
prior to a subject's participation in the study and that all study procedures and adverse event 
reporting occur according to the IRB approved protocol They will follow all study 
participants, while on study treatment, on a real-time basis for development of adverse events 
and study endpoints, utilizing scheduled and as needed physical examinations and laboratory 
studies. Potential adverse events for this study are specifically listed in section 6.5. 
Any event will be graded by severity and outcome. Study staff will make certain that all 
adverse events are recorded and reported according to DODI3216.02_AFI 40-402 and SGSE 
Operating Instruction 40-402-01. Cumulative adverse events and study toxicities will be 
reviewed weekly. The study team will make decisions regarding treatment, cessation of 
accrual, and whether or not to close the study on the basis of frequency or severity of 
UPRISOs, Serious Adverse Events (SAEs ). Any deviation, cessation in accrual or early 
study close will be communicated to the IRB immediately. 
All SAEs, not related to progression of underlying disease, will be reported to the IRB 
immediately and when appropriate, the participant will be dis-enrolled from the study. All 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) related or possibly 
related to the study will be reported by the PI/designee to the IRB according to SGSE 
Operating Instruction 40-402-01. 
All study staff members will be informed by direct personal communication about any 
UPIRSOs or SAEs. If any protocol changes are needed, the PI will submit a modification 
request to the IRB. Protocol changes will not be implemented prior to IRB approval unless 
necessary to eliminate apparent immediate hazards to the research subjects. In such a case, 
the IRB will be promptly informed of the change following implementation (within 5 
working days). 
Serious adverse events can occur inside the hyperbaric chamber that can be either related, or 
unrelated to the exposure. Whenever an adverse event occurs, a stand-by hyperbaric staff 
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For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
member will immediately be compressed in one of the connected chambers, enter the main 
treatment chamber, and accompany the patient to the transport chamber to be decompressed 
to the surface for definitive medical care. If necessary,· an appropriate code can be called, or 
the patient may be immediately transported to the emergency room for further management. 
Standard measures for protection of subject privacy and confidentiality that are currently 
being practiced will continue. All electronic data will be housed on a Common Access Card 
enabled computer accessible only to study personnel within a secured office. All access to 
the subject computer will be logged. All electronic transmissions of data will be encrypted 
over a secured network. All electronic data and hard copy records obtained as a result of the 
HIP AA waiver, will be deleted or shredded after contact has been made or no contact has 
been successful. All hard copy records will be stored in a locked hyperbaric medicine file 
cabinet in a secure room for the duration of the study. Upon the close of the study all records 
will be transferred to the CIF for storage for three years then staged to storage according to 
IA W DODI 3216.02_AFI40-402 and USAF policies. 
Incidental Findings 
All study participants will receive a complete history and physical examination by a 
Rheumatologist at the start of the study and abbreviated history and physical examinations at 
each visit thereafter. Each participant will have a history and physical examination by a 
hyperbaric physician to determine appropriateness for hyperbaric oxygen exposures .. During 
these assessments, patients occasionally complain of symptoms unrelated to the study 
purpose. During the physical examinations, it is possible that a secondary condition will be 
detected. yen unrelated medical conditions are detected or suspected by the hyperbaric 
physicians, the subject will be referred to their provider and may be referred to an appropriate 
physician for further evaluation. A report of all incidental findings will be entered into a 
written report that will be placed in the subject's electronic medical record 
Previously undiagnosed medical conditions that are discovered unintentiozally and are 
unrelated to the current subject of research will, when actionable, be reported to the IRB in a 
timely manner based upon the suspected condition or disease severity. In coordination with 
the IRB, and a qualified specialist the PI will verify the finding. Depending upon the severity 
of the condition or disease the subject or subjects legal representative will be contacted by 
the PI via phone or letter or an in person communication. 
Data Entry: Data will be entered by authorized study personnel only. Upon completion of data 
entry all hard copy documents will be stored as per the hard copy records policy outlined below. 
All electronic Protected Health Information (PHI) data will be housed on the DGMC EPHI drive 
and will only be accessible via a Common Access Card enabled computer accessible only to study 
personnel within a secured office. All electronic transmissions of data will be encrypted over a 
secured network. 
Data security and transfer: Study documents will reside in the Clinical Investigation Facility 
within the 60MDG SGSE Directory in a limited access password protected directory designated 
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For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
exclusively to ·the study. Access will be granted only to study personnel. 
To be in compliance with Government regulations study personnel will utilize 128 bit AES 
encryption. AES is widely used across the government healthcare sector to secure data-at-rest, 
data-in-motion and data-in-transit. All data transfers will be made via (password protected CD, 
encrypted Electronic Mail, Secured FTP server, other). All data files will utilize the Advanced 
Encryption Standard approved cryptographic algorithm used to protect electronic data. 
Hard Copy Records: A copy of the IRB approved informed consent signed and dated by the 
volunteer and designee will be provided to the study volunteer. The original signed and dated 
IRB approved informed consent form will be placed with other study records, in a locked cabinet 
and secured area within the IRB·Protocol Office at the Clinical Investigation Facility. A copy of 
the signed ICD will be in the coordinator offices located in the Internal Medicine Clinic. These 
records will be accessible only to study personnel, the IRB, and employees of authorized Federal 
departments and regulatory agencies. Duplicates will be provided to the volunteer upon written 
request. 
All subjects will be·treated in compliance with DODI3216.02_AFI 40-402 and applicable FDA 
and DHHS guidelines. 
All biologic specimen will be maintained at David Grant Medical Center and will be handled 
and disposed of in accordance with federal regulations. 
6.8. Data Collection/ Analysis: 
This is a pilot study with 10 participants with complete data sets 
Demographic information will be collected including sex, age and ethnic background in 
accordance with HIPP A compliance. 
Data collected during this study will be analyzed at various points in time to include physician 
exams, labs (CRP, ESR, Basic Metabolic Panel, analysis ofMicroparticles, neutrophil and 
platelet activation, radiologic studies, joint inspection. 
Changes in joint pain will be determined by self-reporting and results of the standard outcome 
measures questionnaires (the RAPID 3, PSQ-3 and Visual Analog Scale for pain). 
A separate sleep survey will be administered. 
Source of Research Material per Participant: 
Source of Research Material per Participant 
Standard Care 
Research Driven 
Blood Sample - ESR . 
0 
5 
Blood Sample CRP 
0 
5 
Metabolic Panel 
0 
3 
Microparticles 
0 
5 
Ultrasound/ MRI 
0 
3 
Questionnaires 
0 
9 
Form Revised as of 14 Apr 14 
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For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
Lab sample for analysis of Microparticles, neutrophil and platelet activation will be sent 
to: 
name/contact information redacted 28 Jan 2020
7. Conflict of Interest
NONE.
81 
ti ti 
S h d l 
. nves 12a on c e u e
Recruitment 
Enrollment 
Baseline Data 
Treatment 
Data Collection 
Statistical Analysis 
Publications/Reports 
9. Use of Investigational Drug(s)
Yl 
Qt 
X 
X 
10. Use of Investigational Device(s)
11. Support Required
Yl 
Yl 
Ql 
Q3 
X 
X 
X 
X 
X 
X 
X 
No 
No 
Yl 
Yl 
Q4 
Qt 
X 
X 
X 
X 
X .
X 
0Yes 
0Yes 
Pharmacy Support: Non applicable, no medications will be given.
Yl 
Yl 
Yl 
Ql 
Q3 
Q4 
X 
X 
X 
X 
X 
X 
X 
Contact the pharmacy early in protocol development phase of your study if drugs are involved. 
Drug or Placebo 
Investigational? 
Which pharmacy will 
Support letter 
prepare? 
attached? 
NIA 
NIA 
NIA 
No 
Lab Support: 
R 
t CLIA 
rt·fi t fr 
all l b 
t . 
ti 
fil 
eques 
ce 11ca es om 
a ora ones or your 1 es.
Test Name 
CRP 
ESR 
Metabolic Panel 
Microparticles 
Form Revised as of 14 Apr 14 
Standard 
Which lab will perform each 
Support letter 
Care? 
test? 
attached? 
No 
DGMC 
Yes 
No 
DGMC 
Yes 
No 
DGMC 
Yes 
No 
University of Maryland 
NIA 
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For Protocol Office use only: 
Protocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Rese=ch Protocol Template 
Radiology Support Required: 
If 
d" . t 
d" ti 
d . 
ra 101so opes or ra Ia on-pro ucmi. equipment w1 
dd 
e use , escr1 e ere. 
Procedure 
Standard 
Which facility will perform 
Support letter 
Care?* 
proc.? 
attached? 
Ultrasound 
No 
DGMC 
Yes 
MRI 
No 
DGMC 
Yes 
* Any Radiation exposure that is not standard care requires Radiation Safety Committee
review.
Nursing Support: N/ A 
CIF Support: Consultation, biostatistics, research coordination and administrative support. 
Other Support: Hyperbaric Clinic participation for the administration of 30 HB02 sessions 
with accompanying monitoring. 
12. Budget, Equipment, and Supplies
Requesting Funds: DYes DNo
DR&D DO&M ¥HMJ 
DOTHER (explain source): 
Study Year 
Item 
Unit of Issue 
Cost/UOI 
Description 
(UOI) 
2016 
NIA 
2017 
Labs for 
55 
Microparticles 
2017 
FedEx 
28.90 
2018 
Labs for 
55 
Microparticles 
2018 
FedEx 
28.90 
Quantity 
Total Cost 
50 
2750.00 
50 
1445.00 
30 
1650.00 
30 
867.00 
¥ I understand that the funding is the responsibility of the Pl, which includes; management, 
tracking, recording and must be reported to the IRB annually with your continuation report 
13. Manpower
Estimate the number of work hours to be applied to the investigation, categorized by Air Force
s oecialty code (AFSC).
Rank 
names 
redacted 28 
Jan 2020
Form Revised as of 14 Apr 14 
AFSC 
# hours duty time 
# hours off-duty 
time 
44M 
35 
0 
CTR 
70 
0 
44M 
25 
0 
44R 
40 
0 
44Rl 
40 
0 
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FDG20160004H wAMD13 
Consultant 
CTR 
CTR 
CTR 
CTR 
names redacted 28 
Jan 2020
CTR 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
30 
NA 
55 
0 
5 
0 
40 
0 
5 
0 
5 
0 
14. Institutional Official (IO)
(name/contact info redacted 28 Jan 2020)
15. Bibliography
1. UpToDate: Venables PJW, Maini RN. Diagnosis and differential diagnosis of 
rheumatoid arthritis. UpToDate, Last updated March 03, 2015
2. Aletaha et al. 2010 Rheumatoid arthritis classification criteria: an American College of 
Rheumatology / European League Against Rheumatism collaborative
initiative. Ann Rheum Dis 2010;69:1580-1588.
3. Schur, PH, Moreland L W. General principles of management of rheumatoid arthritis in 
adults. UpToDate, 6 May 2015Davis JC.
4. Harch, P. Hyperbaric oxygen in chronic traumatic brain injury: oxygen, pressure, and 
gene therapy. Medical Gas Research 2015,
5:9{http://www.medicalgasresearch.com/conten/5/l/9).
5. Davis TC, Griffiths ID, Stevens J. Hyperbaric oxygen treatment for rheumatoid arthritis; 
failure to show worthwhile benefit. British J. ofRheumatology 1988; 27:72-81.
6. Lukioh, VL, Polyadova, LV, Sotnikova TI, Belokrinitsky, DA. Hyperbaric Oxygen 
treatment for rheumatoid arthritis: Immunoassay. Abstract of the Undersea and 
Hyperbaric Medical Society, Inc. Joint Annual Scientific Meeting with the International 
Congress for Hyperbaric Medicine and the European Undersea Biomedical Society held
11-18 August 1990. Okura Hotel, Amsterdam, The Netherlands (http://www.uhms.org) 
Form Revised as of 14 Apr 14 
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For Protocol Office use only: 
Pr?tocol title: The Effects of Hyperbaric Oxygen on 
Rheumatoid Arthritis: a Pilot Study. 
FDG20160004H wAMD13 
investigator name redacted 28 Jan 20  
DGMC Human Research Protocol Template 
7. Varga 0, lgnat'ev VK, Vezikova NN, Kheifetz IV. Radiation-modifying effect of
oxygen barotherapy in complex treatment of patients with rheumatoid arthritis and
osteoarthosis. [Article in Russian] Ter. Arkh. 2002: 74(12): 83-36.
8. DAS28; Home of the Disease Activity Score and DAS28; www.das-score.nl
9. "Arthritis and Rheumatism: 2010 Rheumatoid Arthritis Classification." Aletaha, et al.
Journal of the American College ofRheumatology. Vol 62, No 9, Sept 2010, pp 2569-
2581.
10. T Pincus, C Swearingen, F Wolfe; Toward a multidimensional health assessment
questionnaire (MDHAQ); Arthritis Rheum, 1999 - researchgate.net
11. High correlation of VAS pain scores after 2 and 6 weeks of treatment with VAS pain
scores at 12 weeks in randomised controlled trials in rheumatoid arthritis and
osteoarthritis: meta-analysis and implications, Andreas Karabis· et al; Arthritis Research
& Therapy;201618:73
12. Assessment of chronic pain. Aspects of the reliability and validity of the visual analogue
scale. Carlsson, Anna Marie, Pain, Vol 16 Issue 1 May 1983,pp 87-101
13. Lindsay E Ayearst, PhD, 1 Zoltan Harsanyi, MBA PStat,2 and Kenneth J Michalko,
PharrnD MBA2 ;The Pain and Sleep Questionnaire three-item index (PSQ-3): A reliable
and valid measure of the impact of pain on sleep in chronic nonmalignant pain of various
etiologies. Pain Res Manag. 2012 Jul-Aug; 17(4): 281-290.; PMCID: PMC3411378
14. Microparticles: Protagonists of a Novel Communication Network for Intercellular
Information Exchange; Sebastian F. Mause and Christian Weber;
http://dx.doi.org/10.l 161/CIRCRESAHA.110.226456
Circulation Research. 2010; 107:1047-1057
15. Rapi_d 3, an index to Assess and Monitor Patients with Rheumatoid Arthritis, Without
Formal Joint Counts; Similial Results to DAS28 and CDAI in Clinical Trial and Clinical
Care. Theodore Pincus; Yusuf Y azici; Martin Bergman. Rheumatic Disease Clinics of
North America, Volume 35, Issue 4, November 2009, Pages 773-778
16.
Attachments:
1. Informed Consent
2. HIP AA consent
3. Certificate of Compliance
4. Laboratory Support Letter
5. Hyperbaric Clinic Support Letter
6. CIF Support Letter
7. Radiology Support Letter
8. CV s and NIW CITI training
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9. Recruitment flyers
investigator name redacted 28 Jan 20 
DGMC Human Research Protocol Template 
10. Surveys (DAS28, PSQ-3, VAS scale for pain using a grid & numbers)
11. MRI Screening form
12. RAPID 3
13. HIPAA Waiver
14. Patient Letter
17. Commander's Acknowledgment of Review and Approval
Principal Investigator: I am aware that I am not authorized to accept any funds or other form 
of compensation for conducting research. All subjects will be treated in compliance with 
applicable Air Force, DoD and federal regulations, as well as applicable FDA and DHHS 
guidelines. I have read, understand, and signed the attached Certificate of Compliance. I 
understand I must complete a review of this protocol at least every 12 months to prevent 
expiration of the study's approval. I will notify the protocol office prior to relocations, 
separation actions, or closure. 
D Initial Submission 
(ALL signatures required) 
r Amendment Submission 
(Pl signature ONLY) 
. 
d } I (4Jt Cj 
(name/signature redacted 28 Jan 20) Lt Col, USAF, MC 
Rheumatology Staff 
Date 
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