Hyperbaric Oxygen Therapy for Ulcerative Colitis Flares (HBO-UC)

Hyperbaric Oxygen Therapy for Moderate to Severe Ulcerative Colitis Flares: A Multi-Center Randomized Trial

Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with recurrent mucosal inflammation. Clinically, the disease is characterized by bloody diarrhea, abdominal pain, and constitutional symptoms such as fever and weight loss. Treatment strategies vary based on disease activity and target various aspects of the inflammatory cascade. Options include: anti-inflammatory drugs (mesalamine), immunosuppressive or modulatory medications (corticosteroids, thiopurines, cyclosporine) and biologic agents (Anti-TNF). Disease severity can be wide ranging, and nearly 25% of UC patients are hospitalized for acute severe disease. Of these patients, 30% will undergo colectomy after the acute episode, a quarter of which will experience post-operative complications. Although there has been great progress in treatment of UC over the past decade, even with the anti-TNF agent infliximab, the one-year remission rate for patients not responding to conservative management is barely 20%. Furthermore, corticosteroids have significant long-term consequences and immune suppressive drugs such as 6-mercaptopurine, azathioprine and infliximab have been associated with serious adverse events including life-threatening infections and lymphomas. With growing evidence that the pathogenesis of UC is multi-factorial and involves a complex interaction of genetic and environmental factors, newer treatment modalities are being evaluated to target the mucosal immune response and mucosal inflammatory regulatory system.

Hyperbaric oxygen offers a promising new treatment option since it targets both tissue hypoxia and inflammation. Recent small scales studies evaluating the impact of hyperbaric oxygen treatment in acute ulcerative colitis flares demonstrated improved outcomes. The mechanisms underlying the improvement are not known. In this study, we will treat ulcerative colitis flares with hyperbaric oxygen and measure changes in both markers of tissue hypoxia and inflammation. We hypothesize that hyperbaric oxygen will (a) improve outcomes, and (b) show reductions in markers of both tissue hypoxia and inflammation.

Study Overview

• Status: Completed
• Conditions: Colitis, Ulcerative
• Intervention / Treatment: Other: Hyperbaric Oxygen Therapy

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093
      • UC San Diego Health Systems
    • San Diego, California, United States, 92103
      • University of California San Diego
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03766
      • Dartmouth-Hitchcock Medical Center
  • New York
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
  • Washington
    • Yakima, Washington, United States, 98902
      • Virginia Mason Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Hospitalized patients with known or newly diagnosed moderate to severe ulcerative colitis (as defined by the Mayo score ≥6)
• Consented within the first 48 hours of initiating IV steroids

• Risk score of >3 points (pts)

  • Mean stool frequency/24 hrs (<4 = 0 pts, 4-6 = 1 pt, 7-9 = 2 pts, >9 = 4 pts)
  • Colonic Dilation = 4pts
  • Hypoalbuminemia (< 3mg/dL) = 1 pts
• Mayo endoscopic sub-score >2 (moderate to severe)
• Age >18 and able to make their own medical decisions

Exclusion Criteria:

• Complication requiring urgent surgical intervention (in the opinion of the investigators)

• Clinically significant cardiac, renal, neurological, endocrine, respiratory or hepatic impairment in the opinion of the investigator, including but not limited to:

  • Pulmonary (COPD with CO2 retention; Previous/current imaging showing hyperinflation/air trapping/bullous disease/blebs (opinion of investigators), Current pneumothorax or previous spontaneous pneumothorax, Bronchogenic cyst(s))
  • Cardiac (Uncontrolled HTN (systolic >160 or diastolic >100), Unstable angina or myocardial infarction within the previous 3 months, Ejection fraction < 35%, Current or previous amiodarone use, ICD in place, Pacemaker in place not approved for chamber use)
  • Hematological/Oncological (Current chemotherapeutic drug use, and past history of bleomycin use,Hereditary Spherocytosis, Sickle cell anemia)
  • Gastrointestinal and Infectious Disease (Known or suspected Crohn's disease, Previous infection with mycobacterium, fungus, HIV, Hepatitis B or C, Severe gastrointestinal or systemic infection (opinion of investigator), Current capsule endoscopy or previously non-retrieved capsule
  • Endocrinology (Uncontrolled hyperthyroidism)
  • Neurological and Psychological (Vagal or other nerve stimulators, Uncontrolled seizure disorder, Medications or medical conditions that lower seizure threshold (opinion of the investigator), Drug or alcohol abuse/dependence,Current treatment for alcohol cessation with disulfiram, Current or recent (within past week) use of baclofen)
  • Head and Neck (Previous middle ear damage, surgery or infection(s) which may increase the risk for needing ear tubes (opinion of the investigator),Current or previous retinal detachment or optic neuritis, Retinal or vitreous surgery within the past 3 months)
• Implanted devices not on the approved list for use with HBOT
• Women who are pregnant or nursing. Women with childbearing potential were required to use effective birth control if not surgically sterile or postmenopausal for >2 years.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 5 Days Hyperbaric Therapy; Patients will be enrolled and follow an identical medical treatment algorithm. At day 3 responders (based on partial Mayo score) will be re-randomized in a 1:1 fashion to complete 5 total days of HBOT (1 session per day) or to stop after 3 days of HBOT. Non-responders will be entered into an open label arm to complete 5 total days of HBOT.	Other: Hyperbaric Oxygen Therapy; Hyperbaric oxygen (HBO) provides 100% oxygen at a pressure above atmospheric pressure (typically twice to three times standard sea level pressure (2.0-3.0 ATA)). This dramatically increases the amount of oxygen dissolved in blood plasma, which in turn increases oxygen delivery to tissues. This effect of hyperbaric oxygen is used clinically to treat acute hypoxia in crush injuries, severed limbs, and failing skin grafts
Active Comparator: 3 Days Hyperbaric Therapy; Patients will be enrolled and follow an identical medical treatment algorithm. At day 3 responders (based on partial Mayo score) will be re-randomized in a 1:1 fashion to complete 5 total days of HBOT (1 session per day) or to stop after 3 days of HBOT. Non-responders will be entered into an open label arm to complete 5 total days of HBOT.	Other: Hyperbaric Oxygen Therapy; Hyperbaric oxygen (HBO) provides 100% oxygen at a pressure above atmospheric pressure (typically twice to three times standard sea level pressure (2.0-3.0 ATA)). This dramatically increases the amount of oxygen dissolved in blood plasma, which in turn increases oxygen delivery to tissues. This effect of hyperbaric oxygen is used clinically to treat acute hypoxia in crush injuries, severed limbs, and failing skin grafts

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of HBOT on clinical response/remission	Impact of HBOT on clinical response/remission to medical therapy as measured by the partial Mayo score at study day 5.	5 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
relative and absolute reduction in the Mayo score	Relative and absolute reduction in the Mayo score	Day 5, 10
Flair duration	time to reduction in mayo score	day 5, 10
Hospitalization duration	time in the hospital	day5, 10
proportion of patients requiring other therapy	Proportion who require cyclosporine, infliximab or colectomy during index flare	Day 5, 10
Relative and absolute change in inflammatory markers	Relative absolute change in inflammatory markers: ESR	day 10
Relative and absolute change in inflammatory markers	Relative absolute change in inflammatory markers: CRP	day 10
Relative and absolute change in inflammatory markers	Relative absolute change in inflammatory markers: fecal calprotectin	day 10
Relative and absolute change in inflammatory markers	Relative absolute change in inflammatory markers: interleukins	day 10
Relative and absolute change in gene expression	Relative absolute change in gene expression: VEGF	day 10
Relative and absolute change in gene expression	Relative absolute change in gene expression: HIF-1	day 10
Relative and absolute change in gene expression	Relative absolute change in gene expression: HO-1	day 10
microbiome composition	Describe the HBOT specific changes in the microbiome composition	day 10

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Collaborators: Mayo Clinic; University of California, San Diego; NYU Langone Health; University of Texas Southwestern Medical Center; University of Pittsburgh Medical Center; University of Maryland, College Park; Foundation for Clinical Research in IBD; The Eli and Edythe Broad Foundation; Virginia Mason Memorial Hospital
• Investigators: Principal Investigator: Parambir Dulai, MD, University of California, San Diego

Study record dates

Study Major Dates

• Study Start (Actual): September 7, 2017
• Primary Completion (Actual): March 31, 2020
• Study Completion (Actual): March 31, 2020

Study Registration Dates

• First Submitted: April 4, 2018
• First Submitted That Met QC Criteria: April 4, 2018
• First Posted (Actual): April 11, 2018

Study Record Updates

• Last Update Posted (Actual): February 8, 2021
• Last Update Submitted That Met QC Criteria: February 4, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Hyperbaric Oxygen Therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative
• Other Study ID Numbers: Broad-IBD-HBO-UC D12161

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No