Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05343754 |
| Other study ID # |
NL 2021-006013-11 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
August 2022 |
| Est. completion date |
December 2026 |
Study information
| Verified date |
July 2022 |
| Source |
Erasmus Medical Center |
| Contact |
Ellen Kop, MD, Phd |
| Phone |
+3170 |
| Email |
e.kop[@]erasmusmc.nl |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Rationale: Pyoderma gangrenosum (PG) is a rare auto-inflammatory neutrophilic dermatosis
characterized by a spectrum of clinical presentations with variable courses. Diagnosis and
management are challenging in PG. Treatment, including systemic prednisone and anti-TNF
therapy, is directed towards reducing pain and associated inflammation that leads to
ulceration. Positive effects of hyperbaric oxygen (HBO) therapy have been reported in small
case series.
Objective: To investigate the therapeutic efficacy of hyperbaric oxygen on top of standard
wound care and regular anti-inflammatory treatment in patients with pyoderma gangrenosum
wounds.
Study design: Prospective cohort study with a follow-up to one year. Study population: 15
adult patients with pyoderma gangrenosum refractory to standard-prednisone or anti-TNF
therapy will be included for hyperbaric oxygen therapy. Patients with pyoderma gangrenosum
that are eligible but reject hyperbaric oxygen treatment will serve as controls. In total the
investigators will include 30 patients.
Intervention (if applicable): 30 sessions of HBO therapy will be applied on top of regular
wound care and systemic anti-inflammatory treatment. Controls will be treated with regular
wound care and anti-inflammatory treatment.
Main study parameters/endpoints: Wound healing time (time to wound closure). PG wounds will
be measured at baseline using a validated, objective 3D photographical wound measurement
tool, and again after 3 and 6 weeks at the end of HBO treatment and after 3 months. Patients
will take weekly photographs at home using a 2D validated measurement tool of the wounds.
Secondary parameters: Alteration in the expression of markers of inflammation by
micro-biopsies of wound edges, non-invasive mitochondrial O2 measurements at wound edges,
blood neutrophil count and patient-reported outcomes like WOUND-Q, pain on NR scale and
treatment satisfaction scores. Assessment concerning laboratory findings will be done at
baseline before starting the trial, at 3 weeks and at week 6 at the end of HBO treatment.
Patient reported outcomes, WOUND-Q will be measured at baseline, 3 weeks, 6 weeks, 3 months,
6 months, and 12 months. Mean NRS scores will be recorded once a week.
Description:
INTRODUCTION AND RATIONALE
Pyoderma gangrenosum (PG)
Background information Pyoderma gangrenosum (PG) is a rare, uncommon auto-inflammatory
neutrophilic dermatosis characterized by a spectrum of clinical presentations including
painful chronic and recurrent cutaneous ulcers with a necrolytic border with variable
courses. PG has an overall prevalence of 5 to 10 per 100,000 individuals and an increased
mortality rate compared with the general population. Its pathophysiology is complex and not
fully understood. PG affects patients of both sexes equally and of any age, although female
predominance has also been reported, with a peak incidence between 20 and 50 years of age.
Legs are most commonly affected but head, trunk and neck involvement are not uncommon in
children, while involvement of the genital and perianal area has been reported in adults as
well in infants. There are multiple subtypes of PG, including ulcerative (A), bullous (B),
pustular (C), vegetative (D) (pyostomatitis vegetans), peristomal, drug-induced and
post-surgical PG (E).
Pathergy, an exaggeration of skin injury occurring after minor trauma, is seen in one-third
of patients with PG and can contribute to peristomal and post-surgical PG (PSPG). PSPG occurs
at the site of surgery, most commonly reported after breast, chest, or cardiothoracic
surgery. PG is considered a "diagnosis of exclusion of clinical features" due to lack of
definitive laboratory or histopathological diagnostic criteria and is thus frequently
misdiagnosed.
Pathophysiology The pathophysiology of PG represents a complex inflammatory reaction pattern
with involvement of multiple pathways that results in a heterogeneous disease presentation
and course. The course of PG can vary from relatively indolent to aggressive or fulminant to
fatal. Involvement of innate and adaptive immune dysregulation, genetic variants, as well as
neutrophilic abnormalities have been described. PG is associated with other neutrophilic or
inflammatory disorders such as inflammatory bowel disease (both Crohn's disease and Colitis
Ulcerosa), rheumatoid arthritis, suppurative hidradenitis, seronegative arthritis, autoimmune
hepatitis, and hematologic disorders, including paraproteinemia, especially IgA, and
(neutrophilic) malignancies such as acute and chronic myelogenous leukemia. There are also
associations with rare genetic disorders with pyoderma gangrenosum respectively Pyogenic
Arthritis Pyoderma Acne (PAPA), Pyoderma Acne Suppurative Hidradenitis (PASH), Pyogenic
Arthritis Pyoderma Acne Suppurative hidradenitis (PAPASH), and Pyoderma Acne ulcerative
Colitis (PAC).3,7-10 Elevated levels of inflammatory mediators have been found in lesions of
PG, suggesting a pathological inflammatory process. PG lesions show significant
overexpression of cytokines like IL-1α, IL-1β, IL-6, IL-8, IL-12, IL-17, IL-23, IL-36α, TNF,
matrix metalloproteinases, endothelial- and leukocyte-selectins. In the adaptive system the
ratio between T regulatory cells and Th17 cells was found to be reduced in PG lesions. There
are still several unknown factors, including the initiating trigger for immune dysregulation
as well as additional contributory components of the immune system.
Diagnosis Separate diagnostic tools for PG have been published, among others by Su et al in
2004, Maverakis et al in 2018 and by Jockenhöfer in 2019. These tools include major and minor
criteria for the probability of the diagnosis of PG. Biopsy, cultures, blood tests such as
testing for ANCA's and more are necessary to exclude other diagnosis or in particular
underlying not yet diagnosed related diseases. PG is challenging to both diagnosis and
management, and treatment is directed towards reducing the associated inflammation that leads
to ulceration. In this prospective pragmatic trial, both the PARACELSUS as well as the Delphi
criteria will be used to confirm the diagnosis of pyoderma gangrenosum (Appendix 1.
PARACELSUS acronym and criteria
Treatment The choice of treatment depends on numerous factors, including location of
lesion(s), number, size, extra cutaneous involvement, presence of associated diseases,
aggressiveness of the disease, costs or reimbursement possibilities, and side effects of
treatment, as well as patient comorbidities and preferences. Treatment includes general
measures lifestyle changes, advanced wound care, topical therapy such as potent topical
corticosteroids, systemic therapy with corticosteroids and targeted therapy like anti-TNF,
anti-IL-1 or anti-IL-12/23 (Figure 3 and 4).The mean wound healing time in patients treated
with anti-TNF biologics is 86,1 days, compared with a mean wound healing time of 168 days in
47% of patients treated with cyclosporine or prednisolone.
Hyperbaric oxygen therapy Hyperbaric oxygen therapy is a safe treatment procedure that
involves breathing 100% oxygen under higher-than-normal atmospheric pressure, usually 2.0-2.5
atmosphere absolute (ATA). Delivering 100% oxygen to the lungs leads to an increased level of
plasma and tissue oxygen levels and decreases hypoxia. HBOT is commonly used in the treatment
of decompression sickness, carbon monoxide intoxication, arterial gas embolism, necrotizing
soft tissue infections, late radiation injury with or without chronic wounds, diabetic (foot)
ulcers and severe multiple traumata with ischemia. Figure 5 is an example of standard
hyperbaric treatment given in multiplace centers in The Netherlands. After compression for 10
minutes patients will receive 75 minutes (4 times 20 minutes) 100% O2 with 3 airbrakes (21%
O2) of 5 minutes at 2.4-2.5 ATA, and then 10 minutes decompression with the first part of
decompression till 0.3 ATA with 100% oxygen, which will usually take seven minutes. The last
0.3 ATA will be decompressed with air. In total one hyperbaric session will last 110 minutes.
HBOT mechanisms The increased level of plasma and tissue oxygen levels with HBOT is valuable
for the healing of inflammatory and microcirculatory disorders in ischemic circumstances and
the compartment syndrome. HBO has been shown to alter signaling pathways such as Hypoxia
Induced Factor (HIF) and heme-oxygenase (HO), both involved in issue response to hypoxia and
wound repair.21-23 Also, in general, oxidative stress is recognized to play a role in stem
cell mobilization and to promote wound healing. HBOT enhances (neo-)angiogenesis and cell
proliferation, which results in the formation of granulation tissue and subsequent
improvement of wound healing.
The anti-inflammatory effects of HBOT have been reported to play a key role in reducing
tissue damage and infection development. HBOT induces overexpression of growth factors and
down-regulation of pro-inflammatory cytokines to subsequently reduce immune responses. The
increased oxygen levels during HBOT is demonstrated to cause cellular effects such as the
suppression of various cytokines like interferon-gamma, pro-inflammatory cytokines such as
IL-1, IL-6, and TNF, a transient decrease in the CD4:CD8 T cell ratio, the reduction of serum
soluble IL-2 receptor (sIL-2R) levels, enhancement of plasma fibronectin , significant
elevation of IL-10, inhibition of TGFβ-pathway and induction of lymphocyte apoptosis by a
mitochondrial pathway. In short, HBOT induces an anti-inflammatory program across several
pathways.
Rationale Standard advanced wound care in pyoderma gangrenosum consists of topical and
systemic treatments. Aggressive surgical debridement in pyoderma gangrenosum should be
avoided, because of high risk of wound aggravation. The aforementioned combined therapies are
described in case reports with or without adjuvant HBOT. Barr et al. was the first in 1972 to
report the successful treatment of pyoderma gangrenosum with HBOT. In several other case
reports additional HBOT yielded excellent responses in cases of refractory pyoderma
gangrenosum. Mean number of sessions of HBOT needed before remission were respectively 29 and
31 in total, with a range from 11 to 86. Because Pyoderma gangrenosum is an auto-inflammatory
disease and mostly associated with other auto inflammatory disorders like rheumatoid
arthritis and Inflammatory Bowel Disease (both Colitis ulcerosa and M. Crohn), case reports
and series show a good response with adjunctive HBOT with a mean wound healing time of 40,25
days (5,75 weeks with a range of 10 to 90 days).
The anti-inflammatory mechanisms of HBOT at the cellular and cytokine levels in chronic
ulcers are most likely the keystone of success of adjuvant HBO treatment of refractory
pyoderma gangrenosum. Based on the mechanisms of HBOT mentioned above, like suppression of
proinflammatory cytokines like TNF, IL-1, IL-6, reduction in MMPs, neutrophil activation as
well reduction in T cell subsets, the investigators hypothesize that HBOT may have a positive
effect on pyoderma gangrenosum. In addition to the clinical response, our proposed trial will
assess in a prospective cohort the effects and the molecular mode of action of advanced wound
care with and without HBOT on wound healing, pain and PROMs in pyoderma gangrenosum.
Hypothesis Based on several case reports a positive effect of HBOT on wound healing time is
expected.
A significant shorter wound healing time with HBOT can reduce the necessary expensive use of
hospitalization and third line medication like TNF inhibitors.
HBOT exerts an anti-inflammatory effect on local PG inflammation. Does HBOT prevent
recurrence of PG?
OBJECTIVES
Primary objective To compare the clinical efficacy of HBO treatment on top of standard
regular wound care and anti-inflammatory treatment in patients with PG, with time to wound
closure as the primary outcome, using a validated, objective 2D and 3D photographical wound
measurement tools. Controls will be treated with regular wound care and anti-inflammatory
treatment.
Secondary objectives
- Changes in markers of inflammation, mRNA expression in micro-biopsies in wound edges.
- Alterations in mitochondrial O2 levels
- The number of activated neutrophils in peripheral venous blood.
- To assess the effect of HBOT on Pain reduction (NRS score).
- To assess the effect of HBOT on Health Related-Quality of Life (WOUND-Q).
- To assess the prevalence of recurrence of PG in patients treated with and without
adjuvant HBOT.
STUDY POPULATION Population (base) Inclusion of patients with a confirmed diagnosis of a
pyoderma gangrenosum wound, refractory to standard wound care and anti-inflammatory systemic
treatment. These patients will be recruited at the outpatient clinic of the dermatology,
clinical immunology or rheumatology department in the Erasmus Medical Center Rotterdam and
affiliated peripheral general hospitals. The planned number of 15 patients for hyperbaric
treatment and 15 controls can be recruited from external clinics given the referral
population that see 5-10 patients per year per dermatological department and referred to the
ErasmusMC for further follow-up. Patients that wish to participate but turn down hyperbaric
treatment will serve as a control group.
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all of the
following criteria:
- Confirmed consensus on the diagnosis pyoderma gangrenosum by referring specialist,
principal and coordinating investigator (dermatologist, clinical immunologist or
rheumatologist based on PARACELSUS and Delphi score).
- Unsatisfactory response after six weeks of combined standard wound care and systemic
prednisone and/or other anti-inflammatory therapy.
- Fit for hyperbaric oxygen therapy as assessed by the hyperbaric physician.
- Age ≥18 years at baseline
- All genders
- Able and willing to give written informed consent and to comply with the study
requirements.
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded from
participation in this study:
- Language barrier
- Unable to give informed consent or to comply with the trial protocol
- Pregnancy
Sample size calculation The primary outcome is defined as the fraction of patients with
complete wound healing at three months. Assuming that this is 0.2 in the control group and
0.7 in the experimental group. Fixing the test size at 0.05 the investigators need 15
patients in the HBOT group and 15 patients in the control group. In total the investigators
need 30 subjects to achieve a power of 80%.
Investigational product/treatment Hyperbaric oxygen therapy: subjects will be placed in the
hyperbaric chamber and breath room air or 100% oxygen through a non-rebreathing mask after
the tank is pressurized to 2.4-2.5 ATA. The duration of this protocol (total of 80 minutes of
breathing 100% oxygen with 5-minute breaks on normal air, total session time: 110 minutes).
This HBOT-regimen is similar to the normal clinical HBO protocol in The Netherlands and thus
remains well within non-decompression and oxygen toxicity limits. Patients allocated to the
intervention group will receive 30 sessions of HBOT excluding the weekend adjunctive to
standard care. In order not to interrupt the induction of anti-inflammatory and wound healing
effects (which take place at the beginning of treatment): if patients for whatever reason
miss more than 2 sessions in the first four weeks, the treatment regimen will be restarted
from the beginning.
The hyperbaric treatment takes place in any of the following hyperbaric facilities if this
will be closer for patients:
- Da Vinci Clinics Netherlands: Rotterdam, Waalwijk, Arnhem, Hoogeveen, Amersfoort or Geldrop
In this trial, oxygen will be used under hyperbaric conditions. In addition, 100% oxygen will
be administered. Both can be either cryogenic preserved oxygen or compressed oxygen.
Summary of findings from non-clinical studies For the scope of this study the finding in
non-clinical studies is not relevant, since HBOT is already widely implemented in humans and
clinical studies are available.
Summary of findings from clinical studies HBOT has a variety of mechanisms of action: it
improves tissue oxygenation; inhibits the pro-inflammatory reaction by reducing cytokines;
improves neo-vascularization; has a bacteriostatic effect on anaerobic bacteria and
stimulates stem cells and growth factors. There are 14 indications of HBOT approved by the
UHMS, including the treatment of air or gas embolism, arterial insufficiencies, carbon
monoxide poisoning and gas gangrene.
A deeper understanding of the role of oxygen was provided by Kaelin, Ratcliffe and Semenza,
who discovered how cells can sense and adapt to changing oxygen availability (for which they
received the Nobel Prize of Physiology or Medicine in 2019). They identified molecular
machinery that regulates the activity of genes in response to varying levels of oxygen.
Summary of known and potential risks and benefits
Risks: HBOT might cause middle ear and sinus barotrauma, myopia, and epileptic seizures; see
the structured risk analysis.
Benefits: patients could potentially benefit from this treatment in terms of faster wound
healing time, pain reduction, improved health and quality of life.
Description and justification of route of administration and dosage Hyperbaric treatment will
consist of 30 daily treatments (6 weeks, excluding the weekends), breathing 100% oxygen at a
pressure of 2.4 - 2.5 atmosphere absolute (ATA). Every 20 minutes an air brake will be
implemented, where patients only breathe room air. The total duration of one treatment is 110
minutes. This reduces risks of oxygen toxicity.
Dosages, dosage modifications and method of administration Depending on local protocols,
patients will breathe 110 minutes of HBOT under 2.4-2.5 ATA. The total number of sessions
will be 30.
6.7 Preparation and labelling of Investigational Medicinal Product All centers have to record
the quality certificates of the oxygen used for patients included in the trial.
Drug accountability The shipment, receipt, disposition, return and destruction of oxygen will
not be affected by this study. All HBOT-centers already have to record the quality
certificates of the oxygen used for patients included in the trial.
STATISTICAL ANALYSIS
All parameters will be assessed for a two-tailed significance of p < 0,05.
Primary study parameter(s) The primary endpoint of this trial is the time to wound closure
which represents a (semi-) continuous variable and will be analyzed with the non-parametric
Wilcoxon signed rank test. Differences in wound healing time between the HBO group and
control group will be analyzed using the unpaired t-test or Mann-Whitney U test.
Secondary study parameter(s) Differences in (semi-)continuous variables before and after
treatment, such as the patient-reported outcomes (NRS scores, WOUND-Q), cytokine-mRNA in
wound biopsies, laboratory venous blood findings (neutrophils, leucocytes and CRP), will be
analyzed with the non-parametric Wilcoxon signed rank test. For differences between the HBO
group and the control group the unpaired t-test or Mann-Whitney U test will be used.
Other study parameters Patient characteristics and demographic data as measured at baseline
will be presented with continuous data as mean ± SD and categorical data as number (%), and
analyzed using descriptive statistics. Differences in baseline characteristics between groups
(intervention and control) will be assessed and included in the interpretation of results.
Interim analysis No interim analysis will be done.
