Diabetic Foot Ulcer Clinical Trial
Official title:
Adjunctive Hyperbaric Oxygen Therapy (HBOT) for Lower Extermity Diabetic Ulcer: A Prospective Double-Blind, Randomized Control Clinical Trail
Diabetic foot ulcers are associated with high risk of amputation. About 50% of patients
undergoing non-traumatic lower limb amputations are diabetics5. The 5-year amputation rate is
estimated to be 19% with a mean time to amputation 58 months since the onset of an diabetic
foot ulcer6.Because infection and tissue hypoxia are the major contributing factors for
non-healing diabetic foot ulcers, hyperbaric oxygen therapy (HBO) carries a potential benefit
for treating these problematic wounds that do not respond to standard therapy.
The role of oxygen in the wound healing cascade and subsequent combatting action against
bacterial invasion, especially anaerobes, is well documented.14 Delayed or arrested healing
and the development of infection is a direct result from decreased perfusion and poor
oxygenation of tissue.15 The presence of wound hypoxia is an major etiological pathway in the
development of chronic non-healing diabetic foot ulcers
1 KHUH Research Center
The Premise of the study:
Hyperbaric Oxygen as adjunctive therapy is effective towards the healing of diabetic lower
extremity ulcers and has a role to play in major amputation prevention for persons with
Diabetes Mellitus.
Title of the project:
Adjunctive Hyperbaric Oxygen Therapy (HBOT) for Lower Extremity Diabetic Ulcers: A
Prospective, Double-Blind, Randomized, Controlled Clinical Trial Background Diabetes Mellitus
is a major health problem with significant morbidity and mortality. The number of people with
diabetes mellitus worldwide is estimated at 285 million in 2010; and expected to increase to
438 million by 20301. In western countries, like the United Kingdom, diabetic foot ulcers are
the most commonly found chronic wound2. A diabetic foot ulcer is defined as a 'full
thickness' lesion of the skin, that is, a wound penetrating through the dermis below the
ankle joint3. The lifetime risk of developing foot ulcers in diabetics is estimated to be
15%4. These ulcers may heal with proper wound care, but some may become chronic and others
may lead to amputation. These different outcomes are influenced by several risk factors
including, among others, peripheral arterial disease (ischemia), peripheral neuropathy,
mechanical foot deformity, poor foot care and inappropriate shoe wear.
Diabetic foot ulcers are associated with high risk of amputation. About 50% of patients
undergoing non-traumatic lower limb amputations are diabetics5. The 5-year amputation rate is
estimated to be 19% with a mean time to amputation 58 months since the onset of an diabetic
foot ulcer6.Because infection and tissue hypoxia are the major contributing factors for
non-healing diabetic foot ulcers, hyperbaric oxygen therapy (HBO) carries a potential benefit
for treating these problematic wounds that do not respond to standard therapy7.
Vascular: Approximately 35% of diabetic foot ulcers result from peripheral vasculopathy with
an additional 15-20% caused by mixed neuropathic-vasculopathic pathology8. There is an
accelerated development of atherosclerosis in the distal arteries (tibial and peroneal
arteries) of diabetic patients with the dorsalis pedis artery often spared. Abnormal smooth
muscle tone and decreased perfusion exacerbate these changes. On a macrovascular level,
thickening of the basement membrane and abnormal endothelial function is often found. Tissue
ischemia may be worsened by capillary thrombosis and by impaired neurogenic control.9 The
microcirculation of diabetic patients exhibits characteristic structural changes such as the
reduction in the size of capillaries and thickening in basement membrane that impairs the
normal hyperemic or vasodilatory response to injury10, 11 and interferes with transportation
of nutrients and oxygen. Arterial thrombosis commonly develops in the presence of
pre-existing atherosclerotic 2 changes in the vascular endothelium, as a result of low blood
flow and increased blood viscosity or a pro-coagulative state. All of these changes are
exacerbated by a smoking habit (cigarettes, cigars or water pipes) by inducing peripheral
vasoconstriction that reduces available oxygen to tissue by 20-30% per cigarette for one
hour.12 It induces alterations in lipid metabolism, increases platelet aggregation, and
increase blood viscosity.12 Pressure: Peripheral neuropathy is the most common cause of foot
ulcers and is present in 78% of the ulcer formation pathway.8 Foot deformity is the most
common underlying cause and that is leading to unequal pressure redistribution and subsequent
ulceration. Poor glycemic control and poor glycemic control increase the risk of neuropathy
and is directly linked to the duration of living with diabetes (>15 years carrying a higher
risk for developing neuropathy13), manifesting in all three components of the nervous system
(autonomic, motor and sensory).
Autonomic neuropathy of the foot results in loss of sweat and oil gland function leading to
dry cracked skin prone to bacterial infections; the loss of sympathetic vascular tone that
leads to vasodilatation and the development of edema8.
Motor neuropathy causes loss of nerve supply to the intrinsic foot muscles with subsequent
imbalance of the long flexor and extensor tendons. This produces an anatomic foot deformity
with hyperextension of the toes, dropdown of the metatarsal heads and distal movement of the
protective fat pad leading to pressure imbalance, callus formation and underlying skin
breakdown.
In sensory neuropathy the loss of the protective components of the foot is rendering patients
unaware of repeated traumas and small injury as a pain response is absent. A wound remain
undetected, worsen, becomes secondarily infected with the patient usually late in presenting
to formal health care, adding to the severity of the foot condition on assessment.
The role of oxygen in the wound healing cascade and subsequent combatting action against
bacterial invasion, especially anaerobes, is well documented.14 Delayed or arrested healing
and the development of infection is a direct result from decreased perfusion and poor
oxygenation of tissue.15 The presence of wound hypoxia is an major etiological pathway in the
development of chronic non-healing diabetic foot ulcers.16
Measurement of tissue oxygenation is done with transcutaneous oximetry (TcPO2) and provides a
simple, noninvasive diagnostic technique for an objective assessment of local tissue
perfusion and oxygenation.17 TcPO2 measurements are frequently used in the assessment of
diabetic ulcers to:
1. Assess the severity of tissue hypoxia;
2. Determine a saturation response to 100% oxygen;
3. Serve as a predictor for response to HBO therapy;
4. Provide a guideline on when to stop therapy; and
5. Define healable levels for lower limb amputation18. Studies have shown that an achieved
value below 40 mmHg on breathing normal air, is associated with poor healing of diabetic
foot ulcers adding to amputation risk, while values higher than 40 mmHg is likely to
yield spontaneous resolution of foot ulcers.19 Saturated TcPO2 values (breathing 100%
oxygen via a non-rebreather mask for 15 minutes) that exceeds a cutoff value of 200
mmHg, is associated with a positive predictive value to the extent of 74% for wound
healing improvement, or limb salvage following a therapeutic course of hyperbaric oxygen
therapy.20 Level 1A evidence of the beneficial effect of HBO therapy on diabetic foot
outcomes was initially scant with only two prospective RCT studies available before
2000.21, 22 One study was added in 200323 and 3 then a gap existed that was only filled
in 201324 due to the difficulties associated with a trial using HBO as adjunctive
modality. All of these studies have shown efficacy of HBO with the systematic review
from Liu et al in 201325 showing a reduction of major limb amputations (minor
amputations though present) and establishing a foundation for wound healing to progress
(neovascularization and granulation stimulation). The retrospective cohort study of
Margolis et al26 though, has disproved the effectiveness of HBO as modality in
management of diabetic foot ulcers. Major limitations were identified on doing a
systematic critique27 of that study with design, sample selection with inappropriate
inclusions, unequal study arms, statistical usage of a propensity score to adjust for
wound severity and unclear expected endpoints the most prevalent. This study has
highlighted the difference between effectiveness (if something has been beneficially
employed in the day to day setting) and efficacy (does it work) and that is the answer
would like to provide with an effectiveness study in a prospective, rather than
retrospective design.
Objectives of the study:
Study aim and objectives The aim of this study is to determine the effectiveness of 30
sessions of adjunctive hyperbaric oxygen therapy on the healing rate of diabetic lower
extremity ulcers.
Primary objectives:
To compare between the treatment and control group:
The reduction of wound size at 4 weeks (granulation formation) as measured by the Silhouette
three dimensional photography Time to achieve 80% wound surface reduction as measured by the
Silhouette trajectory Time to achieve bipedal ambulation on an offloading device crossing the
ankle joint The level of neovascularization achieved as measured by transcutaneous oximetry
The proportion of patients ending up with a below knee amputation.
Secondary objectives:
Determine the TCpO2 criteria by which treatment response could be measured.Determine the
TCpO2 criteria by which optimal treatment is assessed (to indicate completion of therapy).
Evaluate the role of minor amputations (one or more toes up to the mid foot) in saving the
major limb (integrity of the knee and ankle joint) Evaluate the role of HBO in resolution of
infection/osteomyelitis in conjunction with appropriate systemic antibiotics.
To determine and describe the side-effects of HBO therapy. 4 Improvement of quality of life
with particular attention to pain. Setting: The hyperbaric and wound care unit of King Hamad
University hospital, Kingdom of Bahrain
Design: A parallel prospective double-blind randomized placebo-controlled trial.
Sample size: 100-120 patients equally divided between the two treatment arms Sampling
technique: Randomization by sealed envelope method to either Arm A or Arm B, both blinded to
all apart from the primary researcher.
Timeframe of the study: 12-24 months in order to fill the appropriate sample size on an 80%
confidence interval
Data Collection methods, instruments used and measurements:
1. Transcutaneous oxygen measurements on air and saturated values pre-treatment, 10
sessions, 20 sessions and 30 sessions
2. Silhouette 3 dimensional wound surface photography on each dressing change to determine
% wound size reduction and create a healing trajectory in a quantifiable manner
3. Standard battery of HBO investigations pre-HBO: CBC, CXR, Foot x-ray, HbA1c, BMI
4. Daily pre- and post HBO chamber investigations: Vital signs, random blood glucose, Pain
scale 5
Data management and analysis plan:
1. Basic descriptive statistics to describe the sample demographics and randomization
achieved
2. T-test with Chi-square with confidence interval for healing achieved
3. Logistic regression with linear markers for neovascularization achieved
4. Analysis of co-variants for influence of confounding factors.
;
Status | Clinical Trial | Phase | |
---|---|---|---|
Recruiting |
NCT04497805 -
Clinical Study of ALLO-ASC-SHEET in Subjects With Diabetic Wagner Grade II Foot Ulcers
|
Phase 2 | |
Completed |
NCT04624516 -
Effect of Self-foot Exercise on the Incidence of Plantar Foot Diabetic Ulcer Recurrence
|
N/A | |
Not yet recruiting |
NCT06439667 -
VIRTUALLY SUPERVISED TELE-EXERCISE PLATFORM FOR ACCELERATING PLANTAR WOUND HEALING
|
||
Recruiting |
NCT05608187 -
Evaluating Safety and Biological Effect on Wound Healing of ILP100-Topical in Subjects With Diabetic Foot Ulcers
|
Phase 2 | |
Not yet recruiting |
NCT06278935 -
Lifestyle Tailored Offloading for Diabetic Foot Ulcers
|
N/A | |
Not yet recruiting |
NCT06437028 -
Evaluating the Efficacy of Perinatal Membrane Allografts for the Treatment of Diabetic Foot Ulcers.
|
N/A | |
Withdrawn |
NCT05024656 -
AmnioExcel® Plus vs SOC in the Management of Diabetic Foot Ulcers
|
N/A | |
Terminated |
NCT02202668 -
Transcutaneous Raman Spectroscope (TRS) Analyses of Diabetic Foot Ulcers
|
N/A | |
Completed |
NCT01951768 -
Efficacy and Safety of Garamycin® Sponge in Diabetic Patients With a Moderate or Severe Foot Ulcer Infection
|
Phase 4 | |
Terminated |
NCT01966380 -
Proof of Concept (Design Validation) in Patient With Hard to Heal Wounds Such as Pressure Ulcer, Diabetic Foot Ulcer and Leg Ulcer, Leia
|
Phase 2 | |
Completed |
NCT01657474 -
Comparative Study of Two Application Regimens of Amniotic Membrane Wound Graft In the Management of Diabetic Foot Ulcers
|
N/A | |
Active, not recruiting |
NCT00389636 -
TheraGauzeā¢ Alone and Regranex®Gel 0.01% Plus TheraGauzeā¢ in the Treatment of Wagner Stage I Diabetic Foot Ulcers
|
N/A | |
Completed |
NCT01181440 -
Dermagraft(R) for the Treatment of Patients With Diabetic Foot Ulcers
|
Phase 3 | |
Enrolling by invitation |
NCT05888259 -
Plantar Pressure Distribution in Diabetic Foot Ulcer
|
N/A | |
Completed |
NCT04054804 -
Digital Foot Check by Using the D-Foot, a New Software
|
||
Not yet recruiting |
NCT05877378 -
Efficacy of PICO Single-use System in Chronic Ulcers
|
N/A | |
Recruiting |
NCT06037369 -
The Short Message-based Customized Standardized
|
N/A | |
Completed |
NCT03312595 -
Clinical Outcomes After Treatment With RestrataTM Wound Matrix in Diabetic Foot Ulcers (DFU)
|
N/A | |
Recruiting |
NCT04564443 -
A Unique Micro Water Jet Technology Device Versus Standard Debridement in the Treatment of Diabetic Foot
|
N/A | |
Not yet recruiting |
NCT06444906 -
A Two-Part, Randomized Study of Dermacyte® Amniotic Wound Care Matrix
|
N/A |