HBOT for Perianal Crohn's Disease (PC-HBOT)

Hyperbaric Oxygen Therapy for Refractory Perianal Crohn's Disease: A Pilot Feasibility Study Background

Perianal fistulising Crohn's disease (pfCD) affects up to one-third of patients with Crohn's disease and is associated with chronic pain, discharge, recurrent abscess formation, repeated surgery, and impaired quality of life. Despite advances in biologic therapies, long-term fistula healing remains difficult to achieve, particularly in patients with refractory disease.

Hyperbaric oxygen therapy (HBOT) delivers 100% oxygen under increased atmospheric pressure and has demonstrated anti-inflammatory and wound-healing effects through enhanced tissue oxygenation, angiogenesis, and modulation of inflammatory pathways. Previous studies have reported clinical response rates of 75-87% and remission rates of approximately 50-60% in refractory perianal Crohn's disease. The HOT-TOPIC trial demonstrated sustained clinical, biochemical, and radiological improvements at one year, while the AMFIBIO study suggested HBOT may reduce fistula inflammation sufficiently to enable definitive surgical closure.

Despite encouraging results, evidence is limited by small sample sizes, heterogeneous treatment pathways, and lack of UK prospective data. This pilot study aims to evaluate the feasibility, safety, and preliminary efficacy of HBOT in adults with refractory perianal Crohn's disease.

Study Objectives Primary Objective

To evaluate the overall clinical response to HBOT in adults with refractory perianal Crohn's disease.

Overall clinical response is defined as:

Clinical remission (closure of all treated fistula openings with complete absence of drainage), or Partial clinical response (reduction in fistula drainage and improvement in perianal symptoms).

Secondary Objectives Evaluate changes in inflammatory biomarkers (C-reactive protein and faecal calprotectin).

Assess changes in quality of life using the Crohn's Anal Fistula Quality of Life (CAF-QoL) questionnaire.

Assess radiological healing using pelvic MRI and/or transrectal ultrasound. Assess treatment safety and tolerability. Evaluate recruitment, retention, adherence, and feasibility outcomes to inform a future larger trial.

Study Design

This is a prospective, single-centre, open-label pilot interventional study conducted at Barts Health NHS Trust.

Ten adults with refractory perianal Crohn's disease will receive HBOT in addition to standard medical and surgical care.

There is no randomisation or control group owing to the feasibility nature of the study.

Total study duration for each participant will be approximately 34 weeks from enrolment.

Study Population Inclusion Criteria

Participants must:

Be aged 18 years or older. Have a confirmed diagnosis of Crohn's disease. Have active draining perianal fistulae classified as TOpClass 2b or 2c, or a non-healing perineal wound following proctectomy (TOpClass 4).

Have persistent disease despite, intolerance to, or loss of response to optimised medical and/or surgical treatment for at least 3-6 months.

Have a loose draining seton in situ for at least 4 weeks prior to treatment. Have stable medical therapy for at least 6 weeks prior to enrolment. Be willing and able to comply with study procedures. Exclusion Criteria

Participants will be excluded if they have:

Undrained perianal abscesses or collections requiring surgical intervention. Rectovaginal fistulae. Fistulae secondary to malignancy, tuberculosis, or non-Crohn's causes. Anal strictures. Severe active proctitis with deep ulceration. Diverting stoma or ileal pouch-anal anastomosis. Untreated pneumothorax. Severe claustrophobia preventing HBOT. Severe chronic obstructive pulmonary disease with carbon dioxide retention. Uncontrolled seizure disorders. Implanted devices incompatible with hyperbaric treatment. Current pregnancy or planned pregnancy during treatment. Intervention

Participants will receive HBOT in a clinically approved multi-place hyperbaric chamber.

Treatment parameters:

100% medical oxygen. 2.4 atmospheres absolute (ATA). Approximately 90 minutes per session. 40 treatment sessions. Five sessions per week over 8 weeks. Scheduled air breaks during treatment to minimise oxygen toxicity.

Participants will continue standard Crohn's disease treatments during the study.

At approximately week 4, and where clinically appropriate, setons may be removed and definitive closure of the external fistula opening performed according to multidisciplinary team recommendations.

Study Assessments Baseline

Participants will undergo:

Medical history and physical examination. Perianal Disease Activity Index (PDAI). Pelvic MRI and/or transrectal ultrasound. Laboratory testing including CRP and faecal calprotectin. CAF-QoL questionnaire. HBOT medical assessment. Follow-Up Schedule

Week 8

End of HBOT treatment assessment.

Week 16

Primary efficacy assessment. PDAI. Clinical drainage assessment. Evaluation of overall clinical response.

Week 24

Durability assessment. PDAI. MRI pelvis and/or transrectal ultrasound. CRP. Faecal calprotectin. CAF-QoL. Safety review.

Outcome Measures Primary Endpoint

Overall clinical response at Week 16.

Clinical remission is defined as complete closure of all treated fistula openings with absence of drainage.

Radiological remission is defined by:

Absence of fluid signal within the fistula tract. Fibrotic replacement of the tract. Absence of contrast enhancement indicating no active inflammation.

Partial response is defined as improvement in fistula drainage and symptoms without complete remission.

Secondary Endpoints Clinical remission rate. Change in PDAI score. MRI evidence of fistula healing. Change in modified Van Assche score and/or PEACE score where applicable. Change in CRP. Change in faecal calprotectin. Change in CAF-QoL score. Treatment completion rate. Participant retention rate. Recruitment rate. Safety and adverse events. Feasibility Outcomes

Pre-specified success criteria include:

Recruitment of at least 8 of 10 planned participants. Completion of at least 75% of scheduled HBOT sessions. Retention at Week 34 of at least 80%. No unexpected serious HBOT-related adverse events.

These outcomes will inform the design of a future larger prospective trial.

Statistical Analysis

As a pilot study, analyses will be exploratory and descriptive.

Baseline characteristics will be summarised using means and standard deviations, or medians and interquartile ranges where appropriate.

Clinical response and remission rates will be reported as proportions with 95% confidence intervals.

Changes in continuous outcomes, including PDAI, CRP, faecal calprotectin, MRI scores, and quality-of-life measures, will be analysed using paired statistical tests according to data distribution.

Effect size estimates and variability measures will be generated to support sample-size calculations for future studies.

Missing data will not be imputed and will be reported descriptively.

Safety Monitoring

HBOT has an established safety profile and is widely used in approved clinical indications.

Potential adverse events include:

Middle-ear barotrauma. Sinus discomfort. Transient myopia. Claustrophobia. Oxygen toxicity (rare). Hypoglycaemia in susceptible individuals.

Participants will undergo standard hyperbaric medicine screening before enrolment and will be monitored throughout treatment by experienced hyperbaric medicine clinicians.

Adverse events will be recorded and reported in accordance with Good Clinical Practice, sponsor requirements, and Health Research Authority guidance.

No independent Data Monitoring Committee has been established for this pilot study. Safety oversight will be provided through the study investigators, sponsor processes, and routine adverse event reporting procedures.

Expected Outcomes

This study aims to provide preliminary estimates of treatment effect, feasibility, and safety for HBOT in refractory perianal Crohn's disease within UK clinical practice.

Findings will support:

Development of a future multicentre prospective trial. Improved understanding of clinical and radiological healing following HBOT. Generation of UK feasibility and safety data. Future peer-reviewed publications and conference presentations.

This pilot study will contribute important evidence regarding the role of HBOT as an adjunctive treatment for refractory perianal Crohn's disease.