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    Summary
    EudraCT Number:2021-005694-87
    Sponsor's Protocol Code Number:UCDCRC/21/01
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-10-22
    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 ConcernedIreland - HPRA
    A.2EudraCT number2021-005694-87
    A.3Full title of the trial
    A Randomised Pilot Study of the Safety and Efficacy of Tofacitinib (Xeljanz) in Improving Endoscopic Outcomes in Subjects with Ulcerative Colitis with Active, Chronic, Antibiotic Dependent or Refractory Idiopathic Pouchitis
    (Healing of Antibiotic Refractory Pouchitis with Xeljanz): HARP-X
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of healing of pouchitis with tofacitinib.
    A.3.2Name or abbreviated title of the trial where available
    HARP-X
    A.4.1Sponsor's protocol code numberUCDCRC/21/01
    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 SponsorUniversity College Dublin
    B.1.3.4CountryIreland
    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 supportPfizer
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUCD
    B.5.2Functional name of contact pointCRC Monitoring
    B.5.3 Address:
    B.5.3.1Street AddressCatherine McAuley, MMUH, Nelson Street
    B.5.3.2Town/ cityDublin
    B.5.3.3Post codeD07 R2WY
    B.5.3.4CountryIreland
    B.5.6E-mailcrc@ucd.ie
    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 XELJANZ
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameTofacitinib
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTofacitinib
    D.3.9.1CAS number 477600-75-2
    D.3.9.4EV Substance CodeSUB33104
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number5 to 10
    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 No
    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
    Subjects with Ulcerative Colitis with Active, Chronic, Antibiotic Dependent or Refractory Idiopathic Pouchitis
    E.1.1.1Medical condition in easily understood language
    Antibiotic Refractory Pouchitis
    E.1.1.2Therapeutic area Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10036463
    E.1.2Term Pouchitis
    E.1.2System Organ Class 10017947 - Gastrointestinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the effect of tofacitinib maintenance therapy on endoscopic response in subjects with active, chronic, antibiotic dependent or refractory pouchitis
    E.2.2Secondary objectives of the trial
    • To determine the ability of tofacitinib to improve the clinical symptoms associated with antibiotic dependent or refractory pouchitis
    • To determine the ability of tofacitinib to induce remission of pouchitis
    • To determine the effect of tofacitinib on health-related quality of life
    • To determine the effect of tofacitinib on reducing pouchitis “rescue” intervention
    • To determine the effect of tofacitinib on changes in biological markers including C-reactive protein, fecal calprotectin and histology
    • To evaluate the duration of effect following cessation of therapy
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Subjects who are willing and able to provide written informed consent
    • Male or female subjects, >/=18 years of age who have undergone an ileo-anal pouch anastomosis (IPAA) for UC
    • Documented evidence of active pouchitis – must have a PAS >/= 13
    • Pouchoscopy at screening, or within the previous 3 months, documenting endoscopic activity by photography and confirmed by histology; to be considered active, there must be a Mayo endoscopic sub score >/= 1
    • Symptomatic activity: subjects must demonstrate increased stool frequency compared to what is considered “normal” after their IPAA operation (“baseline”); stool frequency must be an absolute value of > 6 stools per day, and > 3 stools per day above the post-IPAA “baseline”
    • Must have chronic antibiotic dependent or refractory pouchitis
    E.4Principal exclusion criteria
    1. Subjects who are unwilling or unable to give informed consent
    2. Lack of effective contraception
    3. Women who are pregnant or breastfeeding
    4. History of allergy to tofacitinib or any of its components
    5. History of regular NSAID use
    6. Oral 5-aminosalicylate (5-ASA) compounds; exclude subjects who have discontinued or changed doses of oral 5-ASA within 2 weeks of the screening visit. Subjects on stable doses of oral 5-ASAs may be included.
    7. Oral budesonide >6mg/day is not permitted (doses </= 6mg must be stable for 2 weeks prior to screening visit)
    8. Oral steroids other than budesonide; exclude subjects who exceed a daily dose of 20mg prednisolone or equivalent (doses </= 20mg must be stable for 2 weeks prior to the screening visit)
    9. Use of rectal compounds is not permitted; these agents must be discontinued at the screening visit
    10. Immunosuppressant therapy (azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, tacrolimus) is not permitted within 4 weeks of the screening visit
    11. Biologic agents (anti-TNF therapy, anti-CD20 monoclonal antibodies and anti-integrins (ie: Vedolizumab)) are not permitted within 8 weeks of the baseline visit. Ustekinumab (and all interleukin (IL)-1R antagonists, IL-6R antagonists, IL-17 antagonists, IL-12/IL-23 antagonists) are not permitted within 12 weeks of the baseline visit. Sites are allowed to assay drug levels to shorten the washout periods. The washout period can be reduced if serum levels of the biologic in question are undetectable.
    12. Antibiotic therapy is not permitted during screening or any time during the duration of the study; antibiotics must be stopped prior to the screening visit
    13. All other agents targeted to pouchitis, including experimental agents, must be discontinued at least 8 weeks prior to the screening visit, or for a period equivalent to 5 half-lives of the agent (whichever is longer)
    14. Anastomotic stricture
    15. Those unable to undertake endoscopic evaluation
    16. Fecal incontinence due to anal sphincter dysfunction
    17. Infections with cytomegalovirus or Clostridium Difficile
    18. Intestinal malabsorption
    19. Pancreatic insufficiency
    20. Moderate or severe hepatic impairment (those with mild hepatic impairment may be included
    21. Severe renal impairment (defined as a creatinine clearance < 30mL/min)
    22. Suspected irritable pouch syndrome
    23. Subjects with only cuffitis (inflammation of the rectal cuff of the pouch); subjects with active antibiotic dependent or refractory pouchitis as the predominant condition, but who also have cuffitis, may be enrolled
    24. Crohn’s disease of the pouch
    25 Subjects with a history of neoplastic disease, except for basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin
    26. Subjects with latent or untreated tuberculosis, chronic viral hepatitis, recurrent herpes zoster infection, or other chronic infection likely to be exacerbated by tofacitinib therapy
    27. Subjects with a history of clinically significant and/or persistent illness, which in the investigator’s opinion, would exclude entry into the trial
    28. Subjects with any laboratory tests considered clinically significant at screening
    29. Subjects who may be unavailable for the duration of the trial, likely to be non-compliant with the protocol, or who are felt to be unsuitable by the investigator for any other reason
    30. Subjects who have insufficient protection against the varicella zoster virus as 1) evidenced by undetectable serum VZV antibodies and 2) who have not received varicella vaccination; subjects who have detectable varicella immunity on blood testing or who have received varicella vaccination will be considered eligible.
    31. Subjects in recent receipt of live vaccinations within 4 weeks prior to enrolment
    E.5 End points
    E.5.1Primary end point(s)
    Endoscopic response: The proportion of randomised subjects with endoscopic response/improvement, defined as a reduction in the endoscopy component of the Mayo score of at least 1 point, at week 24 compared to the screening period.
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 24
    E.5.2Secondary end point(s)
    • Clinical response at week 8 or week 16 (all subjects) - defined as a >/= 3-point reduction in the clinical component of the PAS from baseline, OR a >/= 3-point reduction in the endoscopy component of the PAS from screening/baseline.
    • Maintenance of response at week 16 (subjects randomized at week 8)
    • Maintenance of response at week 24 (all randomized subjects)
    • Overall PAS </= 12 at week 8 (all subjects) and week 24 (all randomized subjects)
    • Change from baseline to week 8 and 16 in health-related quality of life, as measured by Inflammatory Bowel Disease Questionnaire (IBDQ) (all subjects)
    • Change from baseline to week 24 in health-related quality of life as measured by Inflammatory Bowel Disease Questionnaire (IBDQ) (in those randomized at week 8 or week 16)
    • Change from baseline to week 8 and 16 in health-related quality of life as measured by Cleveland Global Quality of Life Index (CGQL) (all subjects)
    • Change from baseline to week 24 in health-related quality of life as measured by Cleveland Global Quality of Life Index (CGQL) (in those randomized at week 8 or week 16)
    •Requirement for “rescue” treatment for pouchitis flares during the study (all study subjects)
    • Time to first “rescue intervention” (all subjects)
    • Changes from baseline to week 8, week 16 (all subjects) and week 24 (randomized subjects only) in inflammatory markers including CRP, calprotectin and the histology component of the PAS
    E.5.2.1Timepoint(s) of evaluation of this end point
    Either at Week 8, week 16 or week 24 as specified in E.5.2
    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 Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    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 Yes
    E.8.2.3.1Comparator description
    Control Group will discontinue therapy (no maintenance)
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months18
    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: 23
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 25
    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)
    As this product is licensed for ulcerative colitis, subjects will be able to continue on the medication (or re-initiate treatment if in the no maintenance arm)
    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 Decision2021-12-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-10-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2024-03-19
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