Determination of the Optimal Treatment Target in Ulcerative Colitis
- Conditions
- Colitis, Ulcerative
- Interventions
- Biological: Treatment Algorithm ABiological: Treatment Algorithm BBiological: Treatment Algorithm C
- Registration Number
- NCT04259138
- Lead Sponsor
- Alimentiv Inc.
- Brief Summary
Disease activity and response to therapy in ulcerative colitis (UC) can be assessed by a range of endpoints including symptoms, endoscopic mucosal activity, histological disease activity, and biomarkers. This study aims to determine the optimal treatment target, which is a research priority for the management of UC both to inform clinical practice and to help inform regulatory endpoints and targets for drug development.
Participants with active UC will be randomized in a 5:4:1 (initially 2:3:5) ratio to 1 of 3 groups, each with a different treatment target. Treatment targets will be defined as:
* Group 1: corticosteroid-free symptomatic remission
* Group 2: corticosteroid-free endoscopic + symptomatic remission
* Group 3: corticosteroid-free histological + endoscopic + symptomatic remission
An interim analysis was performed to assess the proportion of subjects that reached their assigned treatment target after 50 subjects in each group had reached the first 32-week assessment. The interim analysis and projections made based on target achievement rates for all subjects included in the interim analysis resulted in a recommendation to adjust the randomization ratio from 2:3:5 to 5:4:1 for Groups 1, 2 and 3 respectively as of May 5th, 2023. This change was necessary in order to complete the study with approximately 100 subjects achieving treatment target within each group.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 672
- Age ≥ 18 years.
- Diagnosis of UC confirmed by clinical, endoscopic, and histological evidence prior to screening as per standard criteria.
- Moderately to severely active UC with a Mayo rectal bleeding subscore ≥ 1 and a MES ≥ 2, with minimum disease extent of 15 cm and objective evidence of inflammation that can be visualized using central endoscopic imaging system.
- Ability of participant to participate fully in all aspects of this clinical trial.
- Written informed consent must be obtained and documented.
- Agree not to participate in an investigational trial for the duration of the trial (observation or other noninterventional trials may be permitted at the discretion of the investigator).
- Negative standard of care tuberculosis (TB) test and hepatitis B and C test prior to randomization unless negative results available from within 12 months prior.
- A male participant who is nonsterilized* and sexually active with a female partner of childbearing potential* agrees to use adequate contraception* from signing of informed consent throughout the duration of the study and for 18 weeks after last dose.
- A female participant of childbearing potential* who is sexually active with a nonsterilized* male partner agrees to use routinely adequate contraception* from signing of informed consent throughout the duration of the study and for 18 weeks after last dose.
- Up to date with colorectal carcinoma surveillance according to local standards and guidelines. If a subject is not up to date at screening, a standard of care surveillance assessment may be performed during the screening period.
- Participants who are not responding to their existing treatment for UC (Netherlands-specific criterion).
- Participants who have historically failed (i.e., had an inadequate response with, lost response to, or were intolerant to) 2 or more compounds or classes of advanced therapeutic options (biologics or small molecules; e.g., anti-TNFs, ustekinumab, or tofacitinib) for the treatment of their UC.
- Current or previous treatment with vedolizumab, etrolizumab, or natalizumab.
- Topical therapy (corticosteroid or 5-aminosalicylate [5-ASA]) use within 2 weeks prior to screening endoscopy.
- Change to oral corticosteroid dosing within 2 weeks prior to randomization or a corticosteroid dose of > 30 mg of prednisone or equivalent at randomization.
- Known diagnosis of CD, indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, or microscopic colitis.
- Short gut syndrome.
- Positive stool culture for or active Clostridioides difficile infection (as demonstrated by positive toxin and/or antigen).
- Known hepatitis B or C infection. If a negative test result is available in the 12 months prior to randomization, retesting is not required.
- Known active or latent TB; if a negative test result is available in the 12 months prior to randomization, confirmatory testing (per standard of care) is not required before randomization.
- Received any investigational drug within 30 days prior to randomization/target assignment.
- Serious underlying disease other than UC that in the opinion of the investigator may interfere with the participant's ability to participate fully in the study or would compromise participant safety (such as history of malignancies, major neurological disorders, or any unstable or uncontrolled medical disorder).
- History of alcohol or drug abuse that in the opinion of the investigator may interfere with the participant's ability to comply with the study procedures.
- The participant has active cerebral/meningeal disease, signs, symptoms, or any history of progressive multifocal leukoencephalopathy (PML) prior to randomization.
- Hypersensitivity to any excipient of vedolizumab.
- Active severe infection such as sepsis, cytomegalovirus, listeriosis, or opportunistic infection.
- History of HIV or positive test at screening (Italy-specific criterion).
- Any other contraindication(s)to vedolizumab (Italy-specific criterion).
- If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 18 weeks after the last dose; or intending to donate ova during such time period.
- If male, the participant intends to donate sperm during the course of this study or for 18 weeks after the last dose.
- Vaccination with a live or live-attenuated vaccine within 4 weeks prior to randomization, or planned vaccination during conduct of the study, except vaccination for coronavirus disease of 2019 (COVID-19).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Symptomatic remission Treatment Algorithm B Treatment target defined as achievement of corticosteroid-free symptomatic remission. Symptomatic and endoscopic remission Treatment Algorithm C Treatment target defined as achievement of corticosteroid-free symptomatic remission plus endoscopic remission. Symptomatic, endoscopic and histological remission Treatment Algorithm A Treatment target defined as achievement of corticosteroid-free symptomatic remission plus endoscopic remission plus histological remission. Symptomatic and endoscopic remission Treatment Algorithm B Treatment target defined as achievement of corticosteroid-free symptomatic remission plus endoscopic remission. Symptomatic remission Treatment Algorithm A Treatment target defined as achievement of corticosteroid-free symptomatic remission. Symptomatic and endoscopic remission Treatment Algorithm A Treatment target defined as achievement of corticosteroid-free symptomatic remission plus endoscopic remission. Symptomatic, endoscopic and histological remission Treatment Algorithm B Treatment target defined as achievement of corticosteroid-free symptomatic remission plus endoscopic remission plus histological remission. Symptomatic, endoscopic and histological remission Treatment Algorithm C Treatment target defined as achievement of corticosteroid-free symptomatic remission plus endoscopic remission plus histological remission. Symptomatic remission Treatment Algorithm C Treatment target defined as achievement of corticosteroid-free symptomatic remission.
- Primary Outcome Measures
Name Time Method Difference in Time to UC-related Complication Between Treatment Target Groups 1 and 3 From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first Time to UC-related complication starting when a participant reaches their assigned treatment target, compared between treatment target groups 1 and 3.
- Secondary Outcome Measures
Name Time Method Fecal Calprotectin Levels Baseline, weeks 8, 16, 32, 48, and 96. Change in fecal calprotectin levels from baseline to Weeks 8, 16, 32, 48, and 96.
C-Reactive Protein Concentration Baseline, weeks 8, 16, 32, 48, 64, 80, and 96 Change in C-Reactive Protein concentration from baseline to Weeks 8, 16, 32, 48, 64, 80, and 96.
Evaluate the change in Mayo Clinic Score (MCS; and subcomponents including the MES) Up to week 96 To evaluate the change in Mayo Clinic Score (MCS; and subcomponents including the MES) from baseline to Week 16,32,48 and 96/end of study (EOS). The Mayo Clinic Score for Ulcerative Colitis is a score that ranges from 0 to 12 with higher scores indicating worse severity. The score has four items (Stool Frequency, Rectal Bleeding, Mucosal appearance at endoscopy, Physician rating of disease activity) each rated from 0 to 3, where 3 means highest severity.
Describe the change in RHI scores from baseline to all baseline to Week 16, 32, 48 and 96/end of study (EOS) Up to week 96 To describe the change in RHI scores from baseline to all baseline to Week 16, 32, 48 and 96/end of study (EOS). The Robarts Histopathology Index (RHI) is a validated instrument that measures histological disease activity in ulcerative colitis. The RHI assesses four characteristics of mucosal activity, inflammatory infiltrate, lamina propria neutrophils, neutrophils in epithelium, and erosion or ulceration, all of which are rated on a scale of 0 to 3, with higher scores representing more severe disease activity.
Evaluate the numbers of AEs and SAEs among the 3 randomized groups Up to week 96 To evaluate the numbers of AEs and SAEs among the 3 randomized groups.
Difference in Time to UC-related Complication Compared Between Treatment Target Groups 1 and 2. From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first Time to UC-related complication starting when a participant reaches their assigned treatment target, compared between treatment target groups 1 and 2.
Difference in Time to UC-related Complication Compared Between Treatment Target Groups 2 and 3. From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first Time to UC-related complication starting when a participant reaches their assigned treatment target, compared between treatment target groups 2 and 3.
Evaluate changes in the health-related quality of life (HRQoL) using the Inflammatory Bowel Disease Questionnaire (IBDQ) Up to week 96 To evaluate changes in the health-related quality of life (HRQoL) using the Inflammatory Bowel Disease Questionnaire (IBDQ) from baseline to all follow-up visits.The Inflammatory Bowel Disease Questionnaire (IBDQ) includes 32 questions on 4 domains of health-related quality of life (HRQoL); the total score ranges from 32 and 224, with a higher score signifying a better outcome.
Evaluate changes in the Work Productivity and Activity Impairment-UC (WPAI-UC) questionnaire Up to week 96 To evaluate changes in the Work Productivity and Activity Impairment-UC (WPAI-UC) questionnaire from baseline to all follow-up visits.The WPAI-UC (Work Productivity and Activity Impairment Questionnaire) consists of 6 questions that will grade the productivity while the participant is working on a scale from 0 to 10; a higher score signifies a higher impact on work productivity.
Evaluate the time to each type of UC-related complication Up to week 96 Evaluate, across the 3 target achievement groups, the time to each type of UC-related complication that comprises the primary endpoint.
Validate the Symptoms and Impacts Questionnaire for UC (SIQ-UC) tool in English-fluent subjects Up to week 96 To validate the Symptoms and Impacts Questionnaire for Ulcerative Colitis (SIQ-UC) tool in English-fluent subjects. SIQ-UC consists of a symptom domain, which includes Gastrointestinal, pain and discomfort, nutrition-related, and fatigue-related symptoms; and an impact domain, which includes concepts related to daily activities, nutrition, emotional well-being, and productivity.
Assess the effect of treatment(s) on UC-related complications Up to week 96 Assess the effect of treatment(s) on UC-related complications that is mediated through treatment targets.
Evaluate change in the UC-100 score from baseline to Weeks 16, 32, 48, and 96 Up to week 96 To evaluate change in the UC-100 score from baseline to Weeks 16, 32, 48, and 96 (both in the full and the achieved-target populations). The UC-100 is a composite disease activity index consisting of clinical, endoscopic, and histological findings.The total UC-100 score ranges from 1 to 100, with higher scores representing more severe disease activity.
Describe the change in Nancy Histological Index scores from baseline to baseline to Week 16, 32, 48 and 96/end of study (EOS) Up to week 96 To describe the change in Nancy Histological Index scores from baseline to baseline to Week 16, 32, 48 and 96/end of study (EOS). The Nancy Histological Index is made up of 3 items: acute inflammatory cell infiltrates, chronic inflammatory cell infiltrates, and the presence of ulceration. Histological disease activity is graded on a 5-point scale; from grade 0 (no histologically significant disease) to grade 4 (severely active disease), with this grade being determined by the scoring algorithm.
Difference in time to UC-related complication compared between subgroups From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first Time to UC-related complication compared between subgroups on and off corticosteroids at the time of achieving other relevant components of the treatment target.
Difference in Time to Achieve Treatment Target up to 96 weeks Time taken to achieve the respective targets among the randomized groups. Time will be censored for subjects who do not achieve their assigned target by Week 48.
Difference in time to UC-related complication (as in the primary outcome and secondary outcomes 2 and 3) Up to week 96 Time to UC-related complication (as in the primary outcome and secondary outcomes 2 and 3) in the subgroup of subjects who exclusively reach their assigned target and not a higher target by Week 48.
Describe the change in Geboes scores from baseline to baseline to Week 16, 32, 48 and 96/end of study (EOS) Up to week 96 To describe the change in Geboes scores from baseline to baseline to Week 16, 32, 48 and 96/end of study (EOS). Geboes score is the most commonly used histological score in ulcerative colitis \[UC\] and is divided in 6 grades: architectural changes \[grade 0\], chronic inflammatory infiltrate \[grade 1\], lamina propria neutrophils and eosinophils \[grade 2\], neutrophils in epithelium \[grade 3\], crypt destruction \[grade 4\] and erosions or ulcerations \[grade 5\].
Trial Locations
- Locations (58)
LHSC - Victoria Hospital
🇨🇦London, Ontario, Canada
Sonomed Sp. z o.o. - Centrum Medyczne
🇵🇱Szczecin, West Pomeranian, Poland
Ternopil City Communal Emergency Medical Care Hosp
🇺🇦Ternopil, Ukraine
Vitebsk Regional Clinical Hospital
🇧🇾Vitebsk, Viciebsk, Belarus
CHU Besançon - Hôpital Jean Minjoz
🇫🇷Besançon, Bourgogne-Franche-Comte, France
Gomel Regional Clinical Hospital
🇧🇾Gomel, Homiel, Belarus
GIRI (GI Research Institute)
🇨🇦Vancouver, British Columbia, Canada
Imelda Ziekenhuis Bonheiden
🇧🇪Bonheiden, Antwerp, Belgium
London Health Sciences Centre - University Campus
🇨🇦London, Ontario, Canada
Barrie GI Associates Inc.
🇨🇦Barrie, Ontario, Canada
CHU de Bordeaux - Hopital Haut Leveque - Groupe Hospitalier Sud
🇫🇷PESSAC cedex, Nouvelle-Aquitaine, France
UZ Leuven - University Hospital Gasthuisberg
🇧🇪Leuven, Flemish Brabant, Belgium
Azienda Ospedaliera di Padova
🇮🇹Padova, Padua, Italy
City Clinical Hospital #9 Dept of Gastrosurgery SI Zaporizhzhia MA of PGE of MoHU
🇺🇦Zaporizhzhia, Ukraine
St. Joseph Mercy Hospital/Huron Gastroenterology Associates
🇺🇸Ypsilanti, Michigan, United States
CHRU de Lille - Hopital Claude Huriez
🇫🇷Lille Cedex, Hauts-de-France, France
CH Saint Etienne Hopital Nord
🇫🇷Saint-Priest-en-Jarez, Auvergne-Rhone-Alpes, France
CHRU De Nancy - Hopital de Brabois
🇫🇷Vandœuvre-lès-Nancy, Grand Est, France
Istituto Clinico Humanitas
🇮🇹Rozzano, Milan, Italy
McMaster University Medical Centre
🇨🇦Hamilton, Ontario, Canada
Ospedale San Raffaele S.r.I.
🇮🇹Milano, Milan, Italy
Hampshire Hospitals NHS Foundation Trust - The Royal Hampshire County Hospital
🇬🇧Winchester, Hampshire, United Kingdom
New York-Presbyterian/Weill Cornell Medical Center
🇺🇸New York, New York, United States
Icahn School of Medicine at Mt Sinai Hospital
🇺🇸New York, New York, United States
Atrium Health (Carolinas HealthCare)
🇺🇸Charlotte, North Carolina, United States
University Hospital Ghent
🇧🇪Ghent, East Flanders, Belgium
University of Calgary
🇨🇦Calgary, Alberta, Canada
McGill University Health Centre (MUHC) Montreal General Hospital
🇨🇦Montreal, Quebec, Canada
ABP Research Services Corp.
🇨🇦Oakville, Ontario, Canada
Azienda Ospedaliera - Polyclinico Sant'Orsola-Malpighi
🇮🇹Bologna, Emilia-Romagna, Italy
CHRU Montpellier - Hopital Saint Eloi
🇫🇷MONTPELLIER cedex 05, Occitanie, France
Policlinico Universitario Agostino Gemelli
🇮🇹Roma, Rome, Italy
Radboud University Nijmegen Medical Centre
🇳🇱Nijmegen, Gelderland, Netherlands
Catharina Hospital
🇳🇱Eindhoven, North Brabant, Netherlands
ETZ Hospital Tilburg
🇳🇱Tilburg, North Brabant, Netherlands
Szpital Uniwersytecki nr 2 im. dr Jana Biziela w Bydgoszcz
🇵🇱Bydgoszcz, Kuyavian-Pomeranian, Poland
Amsterdam UMC - Academisch Medisch Centrum
🇳🇱Amsterdam, North Holland, Netherlands
GASTROMED - Kopon, Zmudzinski I Wspolnicy Sp.j.
🇵🇱Torun, Kuyavian-Pomeranian, Poland
WIP Warsaw IBD Point Profesor Kierkus
🇵🇱Warszawa, Mazowieckie, Poland
Gabinet Endoskopii Przewodu Pokarmowego
🇵🇱Krakow, Lesser Poland, Poland
Endoskopia Sp. z.o.o.
🇵🇱Sopot, Pomorskie, Poland
Szpital Miejski Sw. Jana Pawla II w Elblagu
🇵🇱Elblag, Poland
Oddział Gastroenterologiczny SP ZOZ w Łęcznej
🇵🇱Łęczna, Poland
Dniepropetrovsk State Medical Academy
🇺🇦Dnipro, Ukraine
Odesa Regional Clinical Hospital
🇺🇦Odesa, Ukraine
Vinnytsia City Clinical Hospital #1, Dept of Gastroenterology
🇺🇦Vinnytsia, Ukraine
Vinnytsia M.I. Pyrohov Regional Clinical Hospital
🇺🇦Vinnytsia, Ukraine
Uzhhorod National University
🇺🇦Úzhgorod, Ukraine
Russells Hall Hospital
🇬🇧Dudley, West Midlands, United Kingdom
Oxford University Hospitals NHS Foundation - John Radcliffe Hospital
🇬🇧Headington, Oxford, United Kingdom
University Hospitals Birmingham NHS Foundation Trust (UHB) - Queen Elizabeth Hospital Birmingham
🇬🇧Birmingham, West Midlands, United Kingdom
Hull & East Yorkshire NHS Trust
🇬🇧Hull, Yorkshire, United Kingdom
Barts Health NHS Trust / Whipps Cross University Hospital
🇬🇧Leytonstone, United Kingdom
Barts Health NHS Trust - Royal London Hospital
🇬🇧London, United Kingdom
University of Nottingham NHS Trust
🇬🇧Nottingham, United Kingdom
Digestive Health Partners - Asheville Gastroenterology Associate
🇺🇸Asheville, North Carolina, United States
Taunton Surgical Centre
🇨🇦Oshawa, Ontario, Canada
Toronto Immune and Digestive Health Institute (TIDHI)
🇨🇦Toronto, Ontario, Canada