This study has been transitioned to CTIS with ID 2024-515278-28-00 check the CTIS register for the current data. To analyze the molecular effects and dose-response relationship of HBOT in patients with moderate-to-severe UC refractory to medical…
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Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Co-primary outcomes will be assessed within 3 days after the last HBOT session
and at week 12 post-treatment in the cohort that reaches predefined response.
Changes between baseline and last day of HBOT will be analyzed to assess the
mechanistic effects of HBOT. The co-primary outcomes include mucosal immune
cell populations, RNA transcription profiles regarding pro- and
anti-inflammatory, HIF-dependent and mucosal barrier function cascades,
cytokine profiles, changes in microbiome and blood flow assessed by
ultrasonography.
Secondary outcome
- Response after completion of HBOT and at week 12 post-treatment defined as a
reduction in complete MAYO score of 3 points AND at least 1 point reduction in
the MAYO ES WITHOUT escalating therapy such as dose escalations, switching to
another drug, adding corticosteroids or colectomy,
- Clinical disease activity assessed by the PRO-2 score during treatment at day
2, 4, 6 and the last day of treatment, for the group with 20 and 30 sessions:
day 10 and 14 and the group with 30 sessions: day 20, and after treatment at
week 2, 4, 6, 9, 12 and 26
- Endoscopic disease activity assessed by Mayo endoscopic score within 3 days
of last HBOT session and at week 12 post-treatment,
- Histologic disease activity assessed by Robarts* histopathology index within
3 days of last HBOT session and at week 12 post-treatment,
- Biochemical disease activity assessed by CRP, albumin and fecal calprotectin
at day 0 and 6, for the group with 20 and 30 sessions: day 10 and for the group
with 30 sessions: day 20, and for all groups: within 3 days of last HBOT
session, week 6, 12 and 26.
- Ultrasonographic disease activity assessed by intestinal ultrasound
parameters (Bowel wall thickness (mm), color Doppler Signal, presence of
inflammatory fat, loss of haustrations, loss of stratification, presence of
lymph nodes) at baseline, after HBOT and at week 12.
- Quality of life assessed by EQ-5D-5L during treatment at day 0, 6 and the
last day of treatment, for the group with 20 and 30 sessions: day 10 and the
group with 30 sessions: day 20, and after treatment at week 2, 6, 12 and 26
- Dose-response relationships for 10, 15 or 20 days of HBOT on the co-primary
and secondary outcomes above.
- Adverse events. All adverse events related or not to study procedures or
hyperbaric oxygen therapy will be registered. Side-effects and complications of
HBO will be scored by a hyperbaric physician, for the example of barotrauma by
the modified TEED score.
Background summary
Ulcerative colitis (UC) is characterized by relapsing and remitting symptoms of
urgency, diarrhoea, fatigue and abdominal pain, which significantly impact
patient*s quality of life. Despite the increase in treatment options, a group
of patients remain refractory to sequential drug treatment, ultimately
requiring proctocolectomy. Recently, hyperbaric oxygen therapy (HBOT) was shown
effective in a difficult to treat population of patients with acute severe
ulcerative colitis (ASUC) as an add-on treatment, showing benefit already after
a few days of treatment. However, the molecular effects and dose-response
relationships remain unclear.
Study objective
This study has been transitioned to CTIS with ID 2024-515278-28-00 check the CTIS register for the current data.
To analyze the molecular effects and dose-response relationship of HBOT in
patients with moderate-to-severe UC refractory to medical therapy, more
specifically to evaluate:
- Clinical, endoscopic, histological and ultrasonographic disease activity
- Mucosal blood flow, oedema and oxygen delivery
- Mucosal immune cell populations
- Mucosal transcriptional profiles, mainly hypoxia inducible factor (HIF)
dependent cascades
- Mucosal cytokine profiles
- Drug penetration
- Mucosal stem cell populations important to mucosal healing
- Dose-response relationship of HBOT
- Feasibility of HBOT in treatment-refractory UC
Study design
This study is a prospective, open-label, single-center pilot study. Patients
older than 16 y/o, visiting the IBD clinic at the Amsterdam UMC, with
moderate-to-severe UC refractory to (anti-TNF and vedolizumab) therapy and on a
stable dose of ustekinumab or tofacitinib will undergo daily sessions of HBOT.
Initially 8 patients undergoing 10 sessions will be recruited. If predefined
criteria (Total MAYO score -3 and endoscopic MAYO score -1 without therapy
escalation in at least 50% of the patients) for response are not met, a second
cohort of 8 patients undergoing 20 sessions will be recruited. If this cohort
still does not meet response, a third cohort undergoing 30 sessions will be
recruited. Molecular effects will be analyzed in the first cohort fulfilling
the response criteria on colonic mucosal biopsies obtained during
sigmoidoscopy. Responders will be compared to non-responders. Total follow-up
will be 26 weeks or until colectomy.
Intervention
Patients take place in a hyperbaric chamber pressurized to 2.4-2.5 atmosphere
absolute (243-253 kPA), while breathing 100% oxygen through a mask for 80
minutes. Including 5-minute air breaks, the total procedure lasts 110 minutes.
Subjects will initially undergo 10 sessions of hyperbaric oxygen, one session
per day. If the predefined proportion of clinical responding patients is not
reached within the first patient cohort, a second cohort will be recruited for
20 sessions. A third cohort receiving 30 sessions will be recruited if the
clinical response outcome is not reached within the second cohort. There will
be an intention to treat for the predefined number of sessions.
Study burden and risks
Burden: hyperbaric oxygen requires daily visits to the hyperbaric oxygen
facility; possible side-effects are barotrauma of the ears and temporary
myopia. Severe side-effects are rare. Besides hyperbaric treatment, all
subjects need to undergo 7 moments of clinical evaluation and investigations
including 3 sigmoidoscopies. In addition to these visits, patients will undergo
10 times of blood sampling and stool collection within 26 weeks, bringing a
total of 14 blood sampling and stool collection moments. Most of these will be
scheduled during clinical necessary hospital visits. The additional blood and
fecal sampling and sigmoidoscopies with biopsies are an extra burden in this
study.
Benefits: patients could benefit of a novel treatment with previous successful
results and thereby reducing the need for proctocolectomy; besides the direct
effect they could benefit from unraveling working mechanisms of hyperbaric
oxygen and its value for the treatment of ulcerative colitis in the long term.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject enrolled in the
treatment groups must meet all of the following criteria: All patients in
treatment groups: 1. Documented diagnosis of UC >= 4 months prior to entry into
the study, confirmed with endoscopy and pathology results available in the
source documents 2. Moderately to severely active UC as defined by a total MAYO
score of >= 5 and a MAYO ES of >= 2 determined within 7 days of starting HBOT
treatment 3. Subjects must have failed or be intolerant (discontinued the
medication due to an adverse event as determined by the investigator) of the
following treatments: a. Oral corticosteroids b. Azathioprine or
6-mercaptopurine c. Anti-TNF therapy: infliximab, adalimumab or golimumab d.
vedolizumab e. Current treatment with ustekinumab (or another p19 inhibitor in
a clinical trial) or small-molecule therapy (e.g., tofacitinib) 4. Current
treatment with a stable dose of ustekinumab or tofacitinib (>12 weeks of stable
dose and interval of ustekinumab and >6 weeks of tofacitinib) 5. Age 16 or
older 6. Approved for compassionate use of hyperbaric oxygen therapy by the
treating physician and the health insurance company 7. In the opinion of the
investigator, the subject is capable of understanding and complying with
protocol requirements. 8. The subject signs and dates a written, informed
consent form and any required privacy authorization prior to the initiation of
any study procedures. 9. Male or non-pregnant, non-lactating females. Females
of child bearing potential must have a negative serum pregnancy test prior to
randomization, and must use a hormonal (oral, implantable or injectable) or
barrier method of birth control throughout week 26. Females unable to bear
children must have documentation of such in the source records (i.e., tubal
ligation, hysterectomy, or post-menopausal [defined as a minimum of one year
since the last menstrual period]).
Exclusion criteria
A subject will not be eligible for participation in this study if any of the
following criteria apply:
1. Presence of indeterminate colitis, microscopic colitis, ischemic colitis,
infectious colitis or clinical findings suggestive of Crohn*s disease
2. Subjects without previous treatment for UC (i.e., treatment-naïve)
3. Subjects at imminent need of surgery as judged by the treating clinician
4. Subjects with evidence of colonic adenomas or dysplasia. However, subjects
with prior history of adenomatous polyps will be eligible if the polyps have
been completely removed and the subjects are free of polyps at baseline
5. Subjects who have positive stool examinations for enteric pathogens
(including Salmonella, Shigella, Yersinia, Campylobacter, C. difficile)
detected by stool analysis within 2 weeks prior to enrollment pathogenic ova or
parasites, at baseline
6. Patients with an ostomy
7. Unfit for hyperbaric oxygen therapy as assessed by the hyperbaric physician.
8. Contra-indication for endoscopy
9. Patients who received any investigational drug in the past 30 days or 5
half-lives, whichever is longer
10. A history of alcohol or illicit drug use that in the opinion of the
principal investigator (PI) would interfere with study procedures
11. Patients with psychiatric problems that in the opinion of the PI would
interfere with study procedures
12. Patients unable to attend all study visits
13. Patients with a history of non-compliance with clinical study protocols
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-515278-28-00 |
| EudraCT | EUCTR2021-003913-21-NL |
| CCMO | NL78575.018.22 |