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Journal of Diabetes (2014)

O R I G I N A L A RT I C L E

Is additional hyperbaric oxygen therapy cost-effective

for treating ischemic diabetic ulcers? Study protocol
for the Dutch DAMOCLES multicenter randomized
clinical trial
Robert M STOEKENBROEK,1, Trientje B SANTEMA,1, Mark JW KOELEMAY,1 Rob A van HULST,2
Dink A LEGEMATE,1 Jim A REEKERS3 and Dirk T UBBINK1
Departments of 1Surgery, 2Hyperbaric Medicine, and 3Radiology, Academic Medical Center, Amsterdam, the Netherlands

Correspondence Abstract
Dirk T. Ubbink, Department of Surgery,
Room G4-184, Academic Medical Center, Background: The value of hyperbaric oxygen therapy (HBOT) in the treat-
P.O. Box 22660, 1100 DD Amsterdam, ment of diabetic ulcers is still under debate. Available evidence suggests that
the Netherlands. HBOT may improve the healing of diabetic ulcers, but it comes from small
Tel: +31 20 566 9111
Fax: +31 20 566 4440
trials with heterogeneous populations and interventions. The DAMOCLES-
Email: d.ubbink@amc.uva.nl trial will assess the (cost-)effectiveness of HBOT for ischemic diabetic ulcers in
addition to standard of care.

These authors contributed equally to this
work.
Trial registration: Dutch Clinical Trials
Register NTR3944
Received 21 February 2014; accepted 20
March 2014.
doi: 10.1111/1753-0407.12155
Methods: In a multicenter randomized clinical trial, including 30 hospitals
and all 10 HBOT centers in the Netherlands, we plan to enroll 275 patients
with Types 1 or 2 diabetes, a Wagner 2, 3 or 4 ulcer of the leg present for at
least 4 weeks, and concomitant leg ischemia, defined as an ankle systolic blood
pressure of <70 mmHg, a toe systolic blood pressure of <50 mmHg or a
forefoot transcutaneous oxygen tension (TcpO2) of <40 mmHg. Eligible
patients may be candidates for revascularization. Patients will be randomly
assigned to standard care with or without 40 HBOT-sessions.
Results: Primary outcome measures are freedom from major amputation
after 12 months and achievement of, and time to, complete wound healing.
Secondary endpoints include freedom from minor amputations, ulcer recur-
rence, TcpO2, quality of life, and safety. In addition, we will assess the cost-
effectiveness of HBOT for this indication.
Conclusion: The DAMOCLES trial will be the largest trial ever performed
in the realm of HBOT for chronic ulcers, and it is unique for addressing
patients with ischemic diabetic foot ulcers who may also receive vascular
reconstructions. This matches the treatment dilemma in current clinical
practice.
Keywords: diabetes, hyperbaric oxygen therapy, ulcer, wound.

Significant findings of the study: The DAMOCLES trial will elucidate the ability of hyperbaric oxygen therapy to
increase wound healing and prevent amputations in patients with diabetic ulcers, and its cost-effectiveness.
What this study adds: Current evidence is insufficient to justify the routine use of hyperbaric oxygen therapy
(HBOT) for the treatment of diabetic ulcers. The aim of the DAMOCLES trial is to definitely answer the question
on the (cost-)effectiveness of HBOT for this indication.

2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd 1
HBOT for diabetic ulcers: trial protocol
Introduction
Ulcers of the lower extremities can be a debilitating com-
plication of longstanding diabetes. Currently, 371
million people worldwide have diabetes, and this number
has been estimated to reach 552 million by 2030.1 Dia-
betic patients have a 311% annual risk of developing a
foot ulcer.2 Diabetic ulcers often take a long time to heal,
and are a leading cause of non-traumatic lower limb
amputations, particularly in patients with concomitant
limb ischemia.3,4 The presence of an ulcer adversely
affects the patients quality of life (QoL).5,6 In addition,
the management of diabetic foot lesions has been esti-
mated to account for 20% of the total health-care expen-
diture on diabetes.3 Thus, diabetic ulcers pose a major
health care problem.
Diabetic ulcers usually result from a combination of
(microcirculatory) ischemia, neuropathy, trauma and
infection.7 This multifactorial etiology necessitates a
complex, multimodal treatment regimen consisting of
extensive local wound care, off-loading, infection
control, glycemic control and endovascular or surgical
interventions to improve peripheral circulation.2,8 Dia-
betic ulcers in patients with leg ischemia are especially
refractory to healing, and healing rates have been
reported at 60% after one year despite optimal care.9,10
Hyperbaric oxygen therapy (HBOT) has been sug-
gested as a valuable addition to conventional treatment
to achieve healing of acute and chronic wounds, particu-
larly in patients with diabetes, due to its ability to
improve the oxygenation of hypoxic tissues.8,1114
A typical treatment regimen for chronic ulcers
involves intermittent administration of 100% oxygen at
pressures of 1.53.0 atmospheres absolute (ATA) in a
hyperbaric chamber, usually in daily sessions of approxi-
mately 90 min.15 When breathing air at ambient pressure,
hemoglobin is the major carrier of blood oxygen and is
nearly completely saturated. A minor proportion of
carried oxygen is freely dissolved under normal circum-
stances. In contrast, when inhaling 100% oxygen at
increased atmospheric pressure, the amount of oxygen
freely dissolved in the blood increases multifold. HBOT
thereby creates an increased diffusion gradient for
oxygen into tissues, ameliorating hypoxia in chronic
wounds. The enhanced oxygen supply may have benefi-
cial effects on the process of wound healing through a
number of mechanisms. By increasing the expression of
several growth factors, HBOT may stimulate angiogen-
esis and fibroblast proliferation.16 In addition, HBOT
may exert anti-inflammatory effects, decrease tissue
edema through vasoconstriction and may have antimi-
crobial effects, all of which may benefit wound
healing.1719
2 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
R.M. STOEKENBROEK et al.
Previous randomized clinical trials (RCTs) on the
effectiveness of HBOT in the treatment of diabetic ulcers
have consistently shown an increase in the rates of
wound healing when HBOT was added to conventional
care, while the effect on major amputation rates was less
consistent.20 Yet, clinical heterogeneity with regard to
vascular status, wound characteristics, and HBOT regi-
mens was substantial. The beneficial effect seems most
prominent in patients with concomitant leg ischemia, but
no definite conclusions can be drawn at this point.
The objective of the DAMOCLES trial is to investi-
gate in patients with ischemic diabetic ulcers whether
HBOT, as an addition to standard care, is cost-effective
in improving ulcer healing and decreasing major ampu-
tation rates.
Methods
Protocol and registration
The methods applied in the DAMOCLES (Does
Applying More Oxygen Cure Lower Extremity Sores)
trial were specified and registered in advance (http://
www.trialregister.nl; NTR 3944). The methods used are
summarized here based on the SPIRIT 2013 statement
and the reporting standards for trials in wound care.21,22
The full study protocol can be obtained through the trial
website (http://www.damocles-trial.nl/).
Design and setting
The DAMOCLES trial was designed as a randomized,
clinical, observer-blinded, multicenter superiority trial
with two parallel groups and a 1:1 allocation ratio. All 10
HBOT centers in the Netherlands agreed to participate
in the trial. Approximately 30 hospitals in the Nether-
lands will contribute to patient inclusion and follow-up.
The vascular surgeons of these hospitals will refer
patients allocated to the adjuvant HBOT study arm to
the nearest participating HBOT center. A complete list
of all study sites can be obtained from the trial website.
Eligibility criteria
Patients are eligible for inclusion if they meet the follow-
ing criteria: (i) type 1 or 2 diabetes; (ii) an ulcer of the
lower extremities graded as Wagner 24, present for at
least 4 weeks;23 (iii) leg ischemia, defined by an ankle
systolic blood pressure of <70 mmHg, a toe systolic
blood pressure of <50 mmHg or a forefoot transcutane-
ous oxygen pressure (TcpO2) of <40 mmHg;24,25 (iv) indi-
cation for revascularization has been assessed through a
complete examination with duplex ultrasonography,
magnetic resonance angiography, or digital subtraction
R.M. STOEKENBROEK et al.
angiography of the lower limb arteries depending on
local preference.
Patients will be excluded from participation if they
meet one or more of the following criteria: (i) previous
major amputation (i.e. above the ankle) of the leg with
the index ulcer; (ii) metastasized malignancy; (iii) current
renal replacement therapy; (iv) pregnancy; (v) current
treatment with chemotherapy, immunosuppressive
drugs, or systemic corticosteroids >10 mg per day; and
(vi) inability to complete questionnaires in Dutch. In
addition, patients with contraindications for HBOT
(including chronic obstructive pulmonary disease
(COPD) GOLD IV, external pacemaker, heart failure
with a left ventricular ejection fraction <20%) are not
eligible for participation. The ulcer with the largest diam-
eter at the time of inclusion will be defined as the index
ulcer.
Interventions
All patients will receive standard of care in accordance
with the guideline produced by the International
Working Group on the Diabetic Foot, which involves
wound care, revascularization if possible, foot protec-
tion, treatment of diabetes and comorbidities, and sec-
ondary prevention of complications of systemic arterial
disease.26,27 The indication for revascularization (either
angioplasty with or without stent placement, or surgical
revascularization) is to be assessed in a local multidisci-
plinary meeting prior to randomization of the patient, so
that treatment allocation does not influence the decision
whether or not to revascularize.
Wound care is standardized according to evidence-
based practice guidelines, for example, the use of iodine
rather than silver dressings in case of local wound infec-
tion, and local debridement whenever possible.2732
Chemical debridement is to be done with hydrogels
rather than with Edinburgh University Solution of Lyme
(EUSOL).32 Infection is treated with local antiseptics or
systemic antibiotics depending on the extent of the infec-
tion and according to the results of culture.
Patients in the HBOT group are treated in multiplace
chambers using a uniform treatment regimen, which has
been predefined and adopted by all HBOT centers in the
Netherlands. This regimen consists of forty 90-min treat-
ment sessions at 2.5 ATA. We chose this number of
sessions to make sure the HBOT exerts its effect, if any.
Patients will breathe 100% oxygen during the session,
except for three blocks of 5 min during which ambient
air will be administered to prevent oxygen intoxication.
Patients will be treated five times per week, once daily,
until the ulcer has fully re-epithelialized or until a
maximum of 40 sessions has been reached.
2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
HBOT for diabetic ulcers: trial protocol
Patients requiring temporary discontinuation of the
treatment, for example, because of other illnesses, ampu-
tation or unscheduled revascularization, will continue
treatment as soon as possible after recovery. In case of
adverse events related to the HBOT, the hyperbaric
medicine specialist will decide if the patient may safely
continue the planned treatments. Patients unable to con-
tinue HBOT, for example, unwillingness or inability to
tolerate treatment, will remain in the study and will con-
tinue to receive standard of care. Treatment adherence
will be registered by the HBOT centers.
Primary outcome measures
The primary outcome measures are freedom from major
amputation and occurrence of, and time to, complete
wound healing after 12 months of follow-up. A major
amputation is defined as an amputation above the ankle
joint. The indication for an amputation will be discussed
in a multidisciplinary meeting.
The second primary outcome, complete healing of the
index ulcer, is defined as complete re-epithelialization,
and includes the time to complete wound healing,
assessed by an observer who is unaware of treatment
allocation.
Secondary outcome measures
The following secondary endpoints will be assessed: pro-
portion of patients free from minor amputations (i.e. toe
or transmetatarsal); proportion of patients who require
an additional vascular intervention; proportion of
patients who require debridement in the operating room;
proportion of patients with recurrence of the index ulcer
and new ulcers; forefoot TcpO2, to assess the persistence
of changes in cutaneous ischemia and to assess if baseline
TcpO2 is a predictor of the effectiveness of HBOT; func-
tional status, expressed as change from baseline, as
assessed using the AMC Linear Disability Score (ALDS)
questionnaire;33 quality of life (QoL), expressed as change
from baseline, as assessed using the generic EQ-5D and
Short-Form 36 (SF-36) questionnaires, and the disease-
specific Vascular quality of life (VascuQol) question-
naire;33 pain scores (10-point numeric rating scale [NRS]);
and (serious) adverse events, defined as any untoward
medical occurrence, including complications related to
HBOT, major morbidity and all-cause mortality.
Cost-effectiveness
We will investigate the differences in medical costs and
direct non-medical costs between the two trial arms
during the 12 months of follow-up to assess cost-
effectiveness and cost-utilities per quality adjusted life
3
HBOT for diabetic ulcers: trial protocol R.M. STOEKENBROEK et al.

year (QALY). Costs taken into account will be direct and
indirect medical costs such as wound dressing materials
used, hospital admissions, rehabilitation and additional
interventions and therapies. Also direct non-medical
costs such as travelling expenses will be taken into
account.
Cost values will be assigned to healthcare utilization to
determine cost-effectiveness from a societal perspective
and costs per QALY.
Participant timeline
The expected flow through the study is shown in Fig. 1.
Eligible patients will be informed by the treating surgeon
both orally and through information sheets. The patient
will be asked for written informed consent by an inde-
pendent investigator (i.e. not the treating surgeon), after
sufficient time for consideration has been given.
When written informed consent has been obtained,
participants will be randomized using the trial website.
Figure 1 Flow of participants.
Any planned vascular reconstruction is performed after
randomization but prior to the start of the HBOT, to
avoid interruption of the HBOT. The follow-up
moments and measurements are summarized in Table 1.
Patients are to document pain scores and wound mate-
rials used during the first 8 weeks in a diary on a weekly
basis. The treating vascular surgeon will assess a number
of outcome measures at scheduled outpatient visits after
3, 6 and 12 months of follow-up. Questionnaires about
costs, functional status and quality of life will be sent to
the patients at baseline and after 3, 6 and 12 months of
follow-up (Table 1).
Sample size
Sample size calculation is based on the outcomes that are
most likely to influence costs, i.e., limb salvage and com-
plete wound healing 12 months after inclusion. Based on
the data from trials that included patients with ischemic
diabetic ulcers from the Cochrane review by Kranke
et al. we expect a 12% increase in limb salvage after 12
months (91% versus 79%) in favor of additional HBOT.34
A one-sided log-rank test with an overall sample size of
226 patients (113 in either group) will achieve 80% power
at a 0.05 significance level to detect the expected differ-
ence in limb salvage. This corresponds to a hazard ratio
of 2.5, on the assumption that the hazard rates are pro-
portional. Anticipating a 20% drop-out rate due to
death, withdrawal or loss to follow-up, we will include
275 patients in the trial.
Hyperbaric oxygen therapy-trials that included isch-
emic diabetic ulcers included in the Cochrane review
showed a 29.6% difference (53.6% versus 24%) in com-
plete wound healing. A total of 275 patients is amply
sufficient to detect a conservatively estimated 20% differ-

Table 1 Schedule of outcome assessments

Baseline 3 months 6 months 12 months After vascular

Assessments (T = 0) (T = 1) (T = 2) (T = 3) intervention

Baseline characteristics X
Wound assessment & classification X X X X X
TcpO2 X X X
Adverse events X X X X X
Questionnaires
Pain score X X X X
ALDS X X
SF-36 X X X
EQ-5D X X X X
VascuQol X X X
Costs X X X

ALDS, AMC Linear Disability Score questionnaire; EQ-5D, EuroQol-5D questionnaire; SF-36, Short Form 36 questionnaire; TcpO2, Transcuta-
neous oxygen pressure; VascuQol, Vascular Quality of Life questionnaire.

4 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
R.M. STOEKENBROEK et al.
ence in wound healing. No financial incentives will be
provided to investigators or participants.
Randomization
Participants will be randomly allocated in a 1:1 fashion
to standard of care with or without additional HBOT
group by the treating surgeon via the trial website, which
uses a central, dedicated computer randomization
program (ALEA v. 2.2, NKI, Amsterdam, The Nether-
lands) that releases the result of randomization only after
recruitment and completion of baseline measures to
ensure allocation concealment. Stratification will be per-
formed for wound size (above or below 3 cm in diameter)
and for the indication for a vascular reconstruction.
Blinding
In this trial, we chose not to employ a sham treatment.
As a consequence, participants and their vascular
surgeon are both aware of the treatment allocation.
To limit detection bias, wound healing will be assessed
by an observer who is unaware of treatment allocation,
for example, a wound care nurse or colleague surgeon
who was not involved in the patients treatment. In addi-
tion, the questionnaires and patient diaries will be pro-
cessed by researchers who are unaware of the treatment
allocation.
Data collection and management
Contributing surgeons will enter patient data and treat-
ment characteristics on standard case report forms
(CRFs) using the trial website at baseline and during
follow-up. All local investigators will document any
adverse events (according to good clinical practice rules)
and deviations from the study protocol. The patient will
return the questionnaires by mail after completion.
These data will be entered by two investigators indepen-
dently, and will be compared using the SPSS Data Entry
Builder program (IBM SPSS v. 22, Armonk, NY, USA).
Patient data will be stored anonymously in an elec-
tronic database.
An independent data safety and monitoring board
(DSMB) has been installed to monitor the trial progress
and patient safety. An interim-analysis on the primary
endpoints will be performed and judged by the DSMB to
identify striking treatment effects or threats to patient
safety after inclusion of 80 and 160 participants.
Statistical analysis
Data from all randomized participants will be analyzed
according to the intention-to-treat principle. We will
2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
HBOT for diabetic ulcers: trial protocol
additionally perform a per protocol analysis to assess the
maximum achievable benefit of our HBOT regimen.
Descriptive data will be presented for each trial arm as
means and standard deviations or medians and inter-
quartile ranges where appropriate. Differences in (semi-)
continuous outcome variables between the study groups
will be analyzed with the Students t-test if data are nor-
mally distributed. Otherwise the non-parametric Mann
Whitney U-test will be used. Differences between
dichotomous baseline data will be expressed as risk dif-
ferences and numbers needed to treat, with their 95%
confidence intervals (CI). If needed, correction for base-
line differences will be conducted.
Changes over time of TcpO2 and quality of life scores
will be analyzed using the Wilcoxon signed-ranks test.
Changes and differences in pain scores will be analyzed
using repeated measurements analysis (general linear
mixed model). Time to complete wound healing and limb
salvage will be explored using KaplanMeier survival
analysis and differences between the study groups will be
analyzed using the log-rank test. Possible factors associ-
ated with wound healing and amputation in time will be
analyzed using Cox proportional hazard regression mod-
eling. Missing data will be handled by carrying forward
the last observed outcome. Statistical significance will be
based on P-values of <0.05.
Subgroup analyses will be performed for the random-
ization strata.
Ethics
The study is conducted according to the principles of the
Declaration of Helsinki and in accordance with appli-
cable Dutch laws and regulations.35 The study protocol
was approved by the IRBs and boards of directors of all
contributing centers.
Discussion
Current evidence on the effectiveness of HBOT in
promoting the healing of diabetic ulcers and pre-
venting amputations appears promising.20,34,3640 The
DAMOCLES trial will be the largest trial ever per-
formed in the realm of HBOT for chronic ulcers, and it
is unique for addressing patients with ischemic diabetic
foot ulcers who may also receive invasive vascular
treatment. This matches the treatment dilemma in
current clinical practice, as wounds often remain refrac-
tory to healing despite revascularization.10
This study specifically includes patients with ischemic
diabetic ulcers, as previous RCTs have hinted towards a
beneficial effect of HBOT, particularly in these ulcers.
Eligible patients have ulcers classified as Wagner 24, in
5
HBOT for diabetic ulcers: trial protocol
accordance with previous trials on HBOT in diabetic
wounds. The Texas wound classification will be addi-
tionally used to classify wounds at inclusion and during
follow-up, as this classification system has gained more
reconnaissance in clinical practice.41,42 Wounds should be
present for >4 weeks. Including both patients with long-
standing and relatively new ulcers will allow us to iden-
tify patients who are most likely to benefit from HBOT.
Patients who are receiving immunosuppressive therapies
will be excluded from participation, as these therapies
may interfere with wound healing. However, patients
receiving relatively low doses of systemic corticosteroids
are eligible because cortisol levels in these patients will
usually not exceed physiologic levels. Patients who are
undergoing renal replacement therapy are not eligible for
participation because of practical difficulties in submit-
ting these patients to daily HBOT sessions, and patients
who are diagnosed with metastasized malignancies are
excluded.
We realize patient inclusion and adherence may be
jeopardized by the effort required from the patients to
adhere to an 8-week treatment regimen with daily trans-
portation to and from the HBOT-centers. However, the
Netherlands seems an ideal, small-scaled country for
such a trial, given the relatively short distances between
hospitals and HBOT-centers. To facilitate sufficient
patient inclusion, we have recruited all Dutch HBOT
centers and as many neighboring hospitals as possible.
A recently completed, but not yet published, RCT
studied the ability of HBOT to decrease amputation
rates within 12 weeks after randomization in 118 patients
with diabetic ulcers in whom vascular reconstruction was
not warranted.43 However, clinically relevant effects of
HBOT may become apparent only after a longer dura-
tion of follow-up.44,45 Hence, we will investigate the effec-
tiveness of HBOT in diabetic patients with an ischemic
ulcer as to wound healing, amputation rates, and costs,
in a 12-month follow-up period. Moreover, it is still
unclear what the cost-effectiveness of HBOT is when
added to current best practice, including vascular inter-
ventions.
Our decision not to use a sham-treatment, for
example, by administering hyperbaric air instead of
oxygen, is based on ethical and practical considerations.
We consider it unethical to submit patients to a large
number of time consuming sham-treatments. Moreover,
adequate blinding of participants would require that the
atmospheric pressure is increased to the extent that the
patient gets the impression of a hyperbaric treatment,
which also significantly increases the partial oxygen
tension, thereby approaching the effect of real HBOT.
Treating the control group as such might obscure a pos-
sible positive effect of HBOT. Alternatively, administer-
6 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
R.M. STOEKENBROEK et al.
ing hyperbaric air with a reduced (e.g. 8%) partial oxygen
tension may increase the risk of decompression sickness,
which is also unethical.
If successful, our study will help define for which
patients HBOT may be indicated. Moreover, it will likely
have inferences for the usage, reimbursement, and pos-
sible extension of the presently available HBOT-
resources.
Acknowledgments
We are grateful for the willingness and enthusiasm of all
Dutch HBOT centers to contribute to this trial, as well as
to the surgeons and wound care nurses of the contribut-
ing hospitals for recruiting the patients and contributing
to the accurate recording of trial data.
Funding
This study received an unrestricted grant from The Neth-
erlands Organisation for Health Research and Develop-
ment, ZonMW (Project Nr: 83700.2005).
Disclosure
The authors declare no conflicts of interest.
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