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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 Methods: In a multicenter randomized clinical trial, including 30 hospitals
work. and all 10 HBOT centers in the Netherlands, we plan to enroll 275 patients
Trial registration: Dutch Clinical Trials
with Types 1 or 2 diabetes, a Wagner 2, 3 or 4 ulcer of the leg present for at
Register NTR3944
least 4 weeks, and concomitant leg ischemia, defined as an ankle systolic blood
Received 21 February 2014; accepted 20 pressure of <70 mmHg, a toe systolic blood pressure of <50 mmHg or a
March 2014. forefoot transcutaneous oxygen tension (TcpO2) of <40 mmHg. Eligible
patients may be candidates for revascularization. Patients will be randomly
doi: 10.1111/1753-0407.12155 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 R.M. STOEKENBROEK et al.

Previous randomized clinical trials (RCTs) on the


Introduction
effectiveness of HBOT in the treatment of diabetic ulcers
Ulcers of the lower extremities can be a debilitating com- have consistently shown an increase in the rates of
plication of longstanding diabetes. Currently, 371 wound healing when HBOT was added to conventional
million people worldwide have diabetes, and this number care, while the effect on major amputation rates was less
has been estimated to reach 552 million by 2030.1 Dia- consistent.20 Yet, clinical heterogeneity with regard to
betic patients have a 311% annual risk of developing a vascular status, wound characteristics, and HBOT regi-
foot ulcer.2 Diabetic ulcers often take a long time to heal, mens was substantial. The beneficial effect seems most
and are a leading cause of non-traumatic lower limb prominent in patients with concomitant leg ischemia, but
amputations, particularly in patients with concomitant no definite conclusions can be drawn at this point.
limb ischemia.3,4 The presence of an ulcer adversely The objective of the DAMOCLES trial is to investi-
affects the patients quality of life (QoL).5,6 In addition, gate in patients with ischemic diabetic ulcers whether
the management of diabetic foot lesions has been esti- HBOT, as an addition to standard care, is cost-effective
mated to account for 20% of the total health-care expen- in improving ulcer healing and decreasing major ampu-
diture on diabetes.3 Thus, diabetic ulcers pose a major tation rates.
health care problem.
Diabetic ulcers usually result from a combination of
(microcirculatory) ischemia, neuropathy, trauma and Methods
infection.7 This multifactorial etiology necessitates a
Protocol and registration
complex, multimodal treatment regimen consisting of
extensive local wound care, off-loading, infection The methods applied in the DAMOCLES (Does
control, glycemic control and endovascular or surgical Applying More Oxygen Cure Lower Extremity Sores)
interventions to improve peripheral circulation.2,8 Dia- trial were specified and registered in advance (http://
betic ulcers in patients with leg ischemia are especially www.trialregister.nl; NTR 3944). The methods used are
refractory to healing, and healing rates have been summarized here based on the SPIRIT 2013 statement
reported at 60% after one year despite optimal care.9,10 and the reporting standards for trials in wound care.21,22
Hyperbaric oxygen therapy (HBOT) has been sug- The full study protocol can be obtained through the trial
gested as a valuable addition to conventional treatment website (http://www.damocles-trial.nl/).
to achieve healing of acute and chronic wounds, particu-
larly in patients with diabetes, due to its ability to Design and setting
improve the oxygenation of hypoxic tissues.8,1114
The DAMOCLES trial was designed as a randomized,
A typical treatment regimen for chronic ulcers
clinical, observer-blinded, multicenter superiority trial
involves intermittent administration of 100% oxygen at
with two parallel groups and a 1:1 allocation ratio. All 10
pressures of 1.53.0 atmospheres absolute (ATA) in a
HBOT centers in the Netherlands agreed to participate
hyperbaric chamber, usually in daily sessions of approxi-
in the trial. Approximately 30 hospitals in the Nether-
mately 90 min.15 When breathing air at ambient pressure,
lands will contribute to patient inclusion and follow-up.
hemoglobin is the major carrier of blood oxygen and is
The vascular surgeons of these hospitals will refer
nearly completely saturated. A minor proportion of
patients allocated to the adjuvant HBOT study arm to
carried oxygen is freely dissolved under normal circum-
the nearest participating HBOT center. A complete list
stances. In contrast, when inhaling 100% oxygen at
of all study sites can be obtained from the trial website.
increased atmospheric pressure, the amount of oxygen
freely dissolved in the blood increases multifold. HBOT
Eligibility criteria
thereby creates an increased diffusion gradient for
oxygen into tissues, ameliorating hypoxia in chronic Patients are eligible for inclusion if they meet the follow-
wounds. The enhanced oxygen supply may have benefi- ing criteria: (i) type 1 or 2 diabetes; (ii) an ulcer of the
cial effects on the process of wound healing through a lower extremities graded as Wagner 24, present for at
number of mechanisms. By increasing the expression of least 4 weeks;23 (iii) leg ischemia, defined by an ankle
several growth factors, HBOT may stimulate angiogen- systolic blood pressure of <70 mmHg, a toe systolic
esis and fibroblast proliferation.16 In addition, HBOT blood pressure of <50 mmHg or a forefoot transcutane-
may exert anti-inflammatory effects, decrease tissue ous oxygen pressure (TcpO2) of <40 mmHg;24,25 (iv) indi-
edema through vasoconstriction and may have antimi- cation for revascularization has been assessed through a
crobial effects, all of which may benefit wound complete examination with duplex ultrasonography,
healing.1719 magnetic resonance angiography, or digital subtraction

2 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
R.M. STOEKENBROEK et al. HBOT for diabetic ulcers: trial protocol

angiography of the lower limb arteries depending on Patients requiring temporary discontinuation of the
local preference. treatment, for example, because of other illnesses, ampu-
Patients will be excluded from participation if they tation or unscheduled revascularization, will continue
meet one or more of the following criteria: (i) previous treatment as soon as possible after recovery. In case of
major amputation (i.e. above the ankle) of the leg with adverse events related to the HBOT, the hyperbaric
the index ulcer; (ii) metastasized malignancy; (iii) current medicine specialist will decide if the patient may safely
renal replacement therapy; (iv) pregnancy; (v) current continue the planned treatments. Patients unable to con-
treatment with chemotherapy, immunosuppressive tinue HBOT, for example, unwillingness or inability to
drugs, or systemic corticosteroids >10 mg per day; and tolerate treatment, will remain in the study and will con-
(vi) inability to complete questionnaires in Dutch. In tinue to receive standard of care. Treatment adherence
addition, patients with contraindications for HBOT will be registered by the HBOT centers.
(including chronic obstructive pulmonary disease
(COPD) GOLD IV, external pacemaker, heart failure Primary outcome measures
with a left ventricular ejection fraction <20%) are not
eligible for participation. The ulcer with the largest diam- The primary outcome measures are freedom from major
eter at the time of inclusion will be defined as the index amputation and occurrence of, and time to, complete
ulcer. 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
Interventions in a multidisciplinary meeting.
All patients will receive standard of care in accordance The second primary outcome, complete healing of the
with the guideline produced by the International index ulcer, is defined as complete re-epithelialization,
Working Group on the Diabetic Foot, which involves and includes the time to complete wound healing,
wound care, revascularization if possible, foot protec- assessed by an observer who is unaware of treatment
tion, treatment of diabetes and comorbidities, and sec- allocation.
ondary prevention of complications of systemic arterial
disease.26,27 The indication for revascularization (either Secondary outcome measures
angioplasty with or without stent placement, or surgical The following secondary endpoints will be assessed: pro-
revascularization) is to be assessed in a local multidisci- portion of patients free from minor amputations (i.e. toe
plinary meeting prior to randomization of the patient, so or transmetatarsal); proportion of patients who require
that treatment allocation does not influence the decision an additional vascular intervention; proportion of
whether or not to revascularize. patients who require debridement in the operating room;
Wound care is standardized according to evidence- proportion of patients with recurrence of the index ulcer
based practice guidelines, for example, the use of iodine and new ulcers; forefoot TcpO2, to assess the persistence
rather than silver dressings in case of local wound infec- of changes in cutaneous ischemia and to assess if baseline
tion, and local debridement whenever possible.2732 TcpO2 is a predictor of the effectiveness of HBOT; func-
Chemical debridement is to be done with hydrogels tional status, expressed as change from baseline, as
rather than with Edinburgh University Solution of Lyme assessed using the AMC Linear Disability Score (ALDS)
(EUSOL).32 Infection is treated with local antiseptics or questionnaire;33 quality of life (QoL), expressed as change
systemic antibiotics depending on the extent of the infec- from baseline, as assessed using the generic EQ-5D and
tion and according to the results of culture. Short-Form 36 (SF-36) questionnaires, and the disease-
Patients in the HBOT group are treated in multiplace specific Vascular quality of life (VascuQol) question-
chambers using a uniform treatment regimen, which has naire;33 pain scores (10-point numeric rating scale [NRS]);
been predefined and adopted by all HBOT centers in the and (serious) adverse events, defined as any untoward
Netherlands. This regimen consists of forty 90-min treat- medical occurrence, including complications related to
ment sessions at 2.5 ATA. We chose this number of HBOT, major morbidity and all-cause mortality.
sessions to make sure the HBOT exerts its effect, if any.
Patients will breathe 100% oxygen during the session,
Cost-effectiveness
except for three blocks of 5 min during which ambient
air will be administered to prevent oxygen intoxication. We will investigate the differences in medical costs and
Patients will be treated five times per week, once daily, direct non-medical costs between the two trial arms
until the ulcer has fully re-epithelialized or until a during the 12 months of follow-up to assess cost-
maximum of 40 sessions has been reached. effectiveness and cost-utilities per quality adjusted life

2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd 3
HBOT for diabetic ulcers: trial protocol R.M. STOEKENBROEK et al.

year (QALY). Costs taken into account will be direct and Any planned vascular reconstruction is performed after
indirect medical costs such as wound dressing materials randomization but prior to the start of the HBOT, to
used, hospital admissions, rehabilitation and additional avoid interruption of the HBOT. The follow-up
interventions and therapies. Also direct non-medical moments and measurements are summarized in Table 1.
costs such as travelling expenses will be taken into Patients are to document pain scores and wound mate-
account. rials used during the first 8 weeks in a diary on a weekly
Cost values will be assigned to healthcare utilization to basis. The treating vascular surgeon will assess a number
determine cost-effectiveness from a societal perspective of outcome measures at scheduled outpatient visits after
and costs per QALY. 3, 6 and 12 months of follow-up. Questionnaires about
costs, functional status and quality of life will be sent to
Participant timeline the patients at baseline and after 3, 6 and 12 months of
follow-up (Table 1).
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
Sample size
will be asked for written informed consent by an inde-
pendent investigator (i.e. not the treating surgeon), after Sample size calculation is based on the outcomes that are
sufficient time for consideration has been given. most likely to influence costs, i.e., limb salvage and com-
When written informed consent has been obtained, plete wound healing 12 months after inclusion. Based on
participants will be randomized using the trial website. 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
Figure 1 Flow of participants. 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. HBOT for diabetic ulcers: trial protocol

ence in wound healing. No financial incentives will be additionally perform a per protocol analysis to assess the
provided to investigators or participants. maximum achievable benefit of our HBOT regimen.
Descriptive data will be presented for each trial arm as
Randomization means and standard deviations or medians and inter-
quartile ranges where appropriate. Differences in (semi-)
Participants will be randomly allocated in a 1:1 fashion continuous outcome variables between the study groups
to standard of care with or without additional HBOT will be analyzed with the Students t-test if data are nor-
group by the treating surgeon via the trial website, which mally distributed. Otherwise the non-parametric Mann
uses a central, dedicated computer randomization Whitney U-test will be used. Differences between
program (ALEA v. 2.2, NKI, Amsterdam, The Nether- dichotomous baseline data will be expressed as risk dif-
lands) that releases the result of randomization only after ferences and numbers needed to treat, with their 95%
recruitment and completion of baseline measures to confidence intervals (CI). If needed, correction for base-
ensure allocation concealment. Stratification will be per- line differences will be conducted.
formed for wound size (above or below 3 cm in diameter) Changes over time of TcpO2 and quality of life scores
and for the indication for a vascular reconstruction. will be analyzed using the Wilcoxon signed-ranks test.
Changes and differences in pain scores will be analyzed
Blinding using repeated measurements analysis (general linear
mixed model). Time to complete wound healing and limb
In this trial, we chose not to employ a sham treatment.
salvage will be explored using KaplanMeier survival
As a consequence, participants and their vascular
analysis and differences between the study groups will be
surgeon are both aware of the treatment allocation.
analyzed using the log-rank test. Possible factors associ-
To limit detection bias, wound healing will be assessed
ated with wound healing and amputation in time will be
by an observer who is unaware of treatment allocation,
analyzed using Cox proportional hazard regression mod-
for example, a wound care nurse or colleague surgeon
eling. Missing data will be handled by carrying forward
who was not involved in the patients treatment. In addi-
the last observed outcome. Statistical significance will be
tion, the questionnaires and patient diaries will be pro-
based on P-values of <0.05.
cessed by researchers who are unaware of the treatment
Subgroup analyses will be performed for the random-
allocation.
ization strata.

Data collection and management Ethics


Contributing surgeons will enter patient data and treat- The study is conducted according to the principles of the
ment characteristics on standard case report forms Declaration of Helsinki and in accordance with appli-
(CRFs) using the trial website at baseline and during cable Dutch laws and regulations.35 The study protocol
follow-up. All local investigators will document any was approved by the IRBs and boards of directors of all
adverse events (according to good clinical practice rules) contributing centers.
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- Discussion
dently, and will be compared using the SPSS Data Entry
Builder program (IBM SPSS v. 22, Armonk, NY, USA). Current evidence on the effectiveness of HBOT in
Patient data will be stored anonymously in an elec- promoting the healing of diabetic ulcers and pre-
tronic database. venting amputations appears promising.20,34,3640 The
An independent data safety and monitoring board DAMOCLES trial will be the largest trial ever per-
(DSMB) has been installed to monitor the trial progress formed in the realm of HBOT for chronic ulcers, and it
and patient safety. An interim-analysis on the primary is unique for addressing patients with ischemic diabetic
endpoints will be performed and judged by the DSMB to foot ulcers who may also receive invasive vascular
identify striking treatment effects or threats to patient treatment. This matches the treatment dilemma in
safety after inclusion of 80 and 160 participants. current clinical practice, as wounds often remain refrac-
tory to healing despite revascularization.10
This study specifically includes patients with ischemic
Statistical analysis
diabetic ulcers, as previous RCTs have hinted towards a
Data from all randomized participants will be analyzed beneficial effect of HBOT, particularly in these ulcers.
according to the intention-to-treat principle. We will Eligible patients have ulcers classified as Wagner 24, in

2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd 5
HBOT for diabetic ulcers: trial protocol R.M. STOEKENBROEK et al.

accordance with previous trials on HBOT in diabetic ing hyperbaric air with a reduced (e.g. 8%) partial oxygen
wounds. The Texas wound classification will be addi- tension may increase the risk of decompression sickness,
tionally used to classify wounds at inclusion and during which is also unethical.
follow-up, as this classification system has gained more If successful, our study will help define for which
reconnaissance in clinical practice.41,42 Wounds should be patients HBOT may be indicated. Moreover, it will likely
present for >4 weeks. Including both patients with long- have inferences for the usage, reimbursement, and pos-
standing and relatively new ulcers will allow us to iden- sible extension of the presently available HBOT-
tify patients who are most likely to benefit from HBOT. resources.
Patients who are receiving immunosuppressive therapies
will be excluded from participation, as these therapies
may interfere with wound healing. However, patients Acknowledgments
receiving relatively low doses of systemic corticosteroids We are grateful for the willingness and enthusiasm of all
are eligible because cortisol levels in these patients will Dutch HBOT centers to contribute to this trial, as well as
usually not exceed physiologic levels. Patients who are to the surgeons and wound care nurses of the contribut-
undergoing renal replacement therapy are not eligible for ing hospitals for recruiting the patients and contributing
participation because of practical difficulties in submit- to the accurate recording of trial data.
ting these patients to daily HBOT sessions, and patients
who are diagnosed with metastasized malignancies are
excluded. Funding
We realize patient inclusion and adherence may be
This study received an unrestricted grant from The Neth-
jeopardized by the effort required from the patients to
erlands Organisation for Health Research and Develop-
adhere to an 8-week treatment regimen with daily trans-
ment, ZonMW (Project Nr: 83700.2005).
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 Disclosure
hospitals and HBOT-centers. To facilitate sufficient
patient inclusion, we have recruited all Dutch HBOT The authors declare no conflicts of interest.
centers and as many neighboring hospitals as possible.
A recently completed, but not yet published, RCT
studied the ability of HBOT to decrease amputation References
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