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    Summary
    EudraCT Number:2021-003913-21
    Sponsor's Protocol Code Number:NL78575.018.21
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-05-11
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2021-003913-21
    A.3Full title of the trial
    A Prospective, Open-label Pilot Study to Evaluate Effector mechanisms of Hyperbaric Oxygen Therapy in Patients with Moderate-to-Severe Ulcerative Colitis: The PARADOX study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study on the mechanisms of hyperbaric oxygen therapy in patients with ulcerative colitis
    A.3.2Name or abbreviated title of the trial where available
    PARADOX study
    A.4.1Sponsor's protocol code numberNL78575.018.21
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAmsterdam UMC
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportECCO
    B.4.2CountryAustria
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmsterdam UMC
    B.5.2Functional name of contact pointprof. dr. G.R.A.M. D'Haens
    B.5.3 Address:
    B.5.3.1Street AddressMeibergdreef 9
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1105AZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+310205664301
    B.5.6E-mailg.dhaens@amsterdamumc.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Compressed oxygen
    D.2.1.1.2Name of the Marketing Authorisation holderSOL SpA
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameOxygen Medicinal Gas SOL 100% v/v medicinal gas, compressed
    D.3.4Pharmaceutical form Inhalation solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeMedicinal gas
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Ulcerative colitis
    E.1.1.1Medical condition in easily understood language
    Chronic inflammatory bowel disease affecting the large bowel
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10045365
    E.1.2Term Ulcerative colitis
    E.1.2System Organ Class 100000004856
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10066678
    E.1.2Term Acute ulcerative colitis
    E.1.2System Organ Class 100000004856
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.0
    E.1.2Level LLT
    E.1.2Classification code 10082448
    E.1.2Term Ulcerative colitis relapse
    E.1.2System Organ Class 100000004856
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10057480
    E.1.2Term Hyperbaric oxygen therapy
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective of this study is to evaluate molecular effects in patients with moderate-to-severe ulcerative colitis refractory to medical therapy, more specifically:
    - 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
    E.2.2Secondary objectives of the trial
    The secondary aim of this study is to evaluate dose-response relationship and feasibility of hyperbaric oxygen therapy in moderate-to-severe ulcerative colitis refractory to medical therapy.
    E.2.3Trial contains a sub-study No
    E.3Principal 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]).
    E.4Principal 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
    E.5 End points
    E.5.1Primary end point(s)
    Co-primary endpoints include: methylome of peripheral blood and mucosal monocytes, mucosal single transcriptomics, cytokine profiles, microbiome, drug concentrations and blood flow
    E.5.1.1Timepoint(s) of evaluation of this end point
    Co-primary endpoints will be evaluated at week 12 after the last session of HBOT compared to baseline.
    E.5.2Secondary end point(s)
    - 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be evaluated trough the treatment phase up until 26 weeks after the last session of HBOT.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the trial is the last visit of the last subject undergoing the trial, unless following criteria are met that require temporary suspension or early termination:
    - New information on the safety of efficacy of HBO that indicates a change in the known risk/benefit profile for HBO, such that it is no longer acceptable for participating subjects.
    - Significant violation of GCP that compromises the ability to achieve the primary study objectives or compromises subject safety.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 24
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After the trial patients continue their treatment as they did before the trial, during the trial the dose should remain unchanged unless their treating physician decides differently. If a patients deteriorates or does not improve during the trial, the treating physician (and the multi-disciplinary team) may decide to stop the treatment, which consequently would imply a proctocolectomy.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-05-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-07-20
    P. End of Trial
    P.End of Trial StatusOngoing
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