Clinical trial NCT04259138: Determination of the Optimal Treatment Target in Ulcerative Colitis
Official title: VERDICT: In actiVE Ulcerative Colitis, a RanDomIzed Controlled Trial for Determination of the Optimal Treatment Target
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Colitis, Ulcerative
Lead sponsor: Alimentiv Inc.
Sponsor class: OTHER
Collaborators: name: Takeda Development Center Americas, Inc.
First posted: 2020-02-06
Enrollment: 672
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In this study, participants with active UC will be randomized in a 5:4:1 ratio (initially 2:3:5) to 1 of 3 treatment target groups. Participants will be assigned a treatment algorithm based on their existing UC treatment at time of entry. Treatment algorithms may include the use of vedolizumab. A key premise is that vedolizumab has a favorable safety profile and can be used to treat participants who are in symptomatic remission but who have not attained endoscopic or histopathologic remission.

Participants will be assessed to determine it remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm.
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 years.
2. Diagnosis of UC confirmed by clinical, endoscopic, and histological evidence prior to screening as per standard criteria.
3. 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.
4. Ability of participant to participate fully in all aspects of this clinical trial.
5. Written informed consent must be obtained and documented.
6. 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).
7. 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.
8. 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.
9. 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.
10. 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.
11. Participants who are not responding to their existing treatment for UC (Netherlands-specific criterion).

Exclusion Criteria:

1. 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.
2. Current or previous treatment with vedolizumab, etrolizumab, or natalizumab.
3. Topical therapy (corticosteroid or 5-aminosalicylate \[5-ASA\]) use within 2 weeks prior to screening endoscopy.
4. Change to oral corticosteroid dosing within 2 weeks prior to randomization or a corticosteroid dose of \> 30 mg of prednisone or equivalent at randomization.
5. Known diagnosis of CD, indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, or microscopic colitis.
6. Short gut syndrome.
7. Positive stool culture for or active Clostridioides difficile infection (as demonstrated by positive toxin and/or antigen).
8. Known hepatitis B or C infection. If a negative test result is available in the 12 months prior to randomization, retesting is not required.
9. 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.
10. Received any investigational drug within 30 days prior to randomization/target assignment.
11. 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).
12. 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.
13. The participant has active cerebral/meningeal disease, signs, symptoms, or any history of progressive multifocal leukoencephalopathy (PML) prior to randomization.
14. Hypersensitivity to any excipient of vedolizumab.
15. Active severe infection such as sepsis, cytomegalovirus, listeriosis, or opportunistic infection.
16. History of HIV or positive test at screening (Italy-specific criterion).
17. Any other contraindication(s)to vedolizumab (Italy-specific criterion).
18. 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.
19. If male, the participant intends to donate sperm during the course of this study or for 18 weeks after the last dose.
20. 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).

Primary outcomes:
measure: Difference in Time to UC-related Complication Between Treatment Target Groups 1 and 3
timeFrame: From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first
Secondary outcomes:
measure: Difference in Time to UC-related Complication Compared Between Treatment Target Groups 1 and 2.
timeFrame: From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first
measure: Difference in Time to UC-related Complication Compared Between Treatment Target Groups 2 and 3.
timeFrame: From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first
measure: Difference in time to UC-related complication compared between subgroups
timeFrame: From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first
measure: Difference in Time to Achieve Treatment Target
timeFrame: up to 96 weeks
measure: Fecal Calprotectin Levels
timeFrame: Baseline, weeks 8, 16, 32, 48, and 96.
measure: C-Reactive Protein Concentration
timeFrame: Baseline, weeks 8, 16, 32, 48, 64, 80, and 96
measure: Difference in time to UC-related complication (as in the primary outcome and secondary outcomes 2 and 3)
timeFrame: Up to week 96
measure: Evaluate the time to each type of UC-related complication
timeFrame: Up to week 96
measure: Assess the effect of treatment(s) on UC-related complications
timeFrame: Up to week 96
measure: Evaluate change in the UC-100 score from baseline to Weeks 16, 32, 48, and 96
timeFrame: Up to week 96
measure: Evaluate changes in the health-related quality of life (HRQoL) using the Inflammatory Bowel Disease Questionnaire (IBDQ)
timeFrame: Up to week 96
measure: Evaluate changes in the Work Productivity and Activity Impairment-UC (WPAI-UC) questionnaire
timeFrame: Up to week 96
measure: Evaluate the change in Mayo Clinic Score (MCS; and subcomponents including the MES)
timeFrame: Up to week 96
measure: Describe the change in Geboes scores from baseline to baseline to Week 16, 32, 48 and 96/end of study (EOS)
timeFrame: Up to week 96
measure: Describe the change in RHI scores from baseline to all baseline to Week 16, 32, 48 and 96/end of study (EOS)
timeFrame: Up to week 96
measure: Describe the change in Nancy Histological Index scores from baseline to baseline to Week 16, 32, 48 and 96/end of study (EOS)
timeFrame: Up to week 96
measure: Evaluate the numbers of AEs and SAEs among the 3 randomized groups
timeFrame: Up to week 96
measure: Validate the Symptoms and Impacts Questionnaire for UC (SIQ-UC) tool in English-fluent subjects
timeFrame: Up to week 96
Other outcomes:
Locations:
city: Ypsilanti
country: United States
facility: St. Joseph Mercy Hospital/Huron Gastroenterology Associates
state: Michigan
city: New York
country: United States
facility: Icahn School of Medicine at Mt Sinai Hospital
state: New York
city: New York
country: United States
facility: New York-Presbyterian/Weill Cornell Medical Center
state: New York
city: Asheville
country: United States
facility: Digestive Health Partners - Asheville Gastroenterology Associate
state: North Carolina
city: Charlotte
country: United States
facility: Atrium Health (Carolinas HealthCare)
state: North Carolina
city: Gomel
country: Belarus
facility: Gomel Regional Clinical Hospital
state: Homiel
city: Vitebsk
country: Belarus
facility: Vitebsk Regional Clinical Hospital
state: Viciebsk
city: Bonheiden
country: Belgium
facility: Imelda Ziekenhuis Bonheiden
state: Antwerp
city: Ghent
country: Belgium
facility: University Hospital Ghent
state: East Flanders
city: Leuven
country: Belgium
facility: UZ Leuven - University Hospital Gasthuisberg
state: Flemish Brabant
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Vancouver
country: Canada
facility: GIRI (GI Research Institute)
state: British Columbia
city: Barrie
country: Canada
facility: Barrie GI Associates Inc.
state: Ontario
city: Hamilton
country: Canada
facility: McMaster University Medical Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre - University Campus
state: Ontario
city: London
country: Canada
facility: LHSC - Victoria Hospital
state: Ontario
city: Oakville
country: Canada
facility: ABP Research Services Corp.
state: Ontario
city: Oshawa
country: Canada
facility: Taunton Surgical Centre
state: Ontario
city: Toronto
country: Canada
facility: Toronto Immune and Digestive Health Institute (TIDHI)
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre (MUHC) Montreal General Hospital
state: Quebec
city: Saint-Priest-en-Jarez
country: France
facility: CH Saint Etienne Hopital Nord
state: Auvergne-Rhone-Alpes
city: Besançon
country: France
facility: CHU Besançon - Hôpital Jean Minjoz
state: Bourgogne-Franche-Comte
city: Vandœuvre-lès-Nancy
country: France
facility: CHRU De Nancy - Hopital de Brabois
state: Grand Est
city: Lille Cedex
country: France
facility: CHRU de Lille - Hopital Claude Huriez
state: Hauts-de-France
city: PESSAC cedex
country: France
facility: CHU de Bordeaux - Hopital Haut Leveque - Groupe Hospitalier Sud
state: Nouvelle-Aquitaine
city: MONTPELLIER cedex 05
country: France
facility: CHRU Montpellier - Hopital Saint Eloi
state: Occitanie
city: Bologna
country: Italy
facility: Azienda Ospedaliera - Polyclinico Sant'Orsola-Malpighi
state: Emilia-Romagna
city: Milano
country: Italy
facility: Ospedale San Raffaele S.r.I.
state: Milan
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: Milan
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
state: Padua
city: Roma
country: Italy
facility: Policlinico Universitario Agostino Gemelli
state: Rome
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
state: Gelderland
city: Eindhoven
country: Netherlands
facility: Catharina Hospital
state: North Brabant
city: Tilburg
country: Netherlands
facility: ETZ Hospital Tilburg
state: North Brabant
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC - Academisch Medisch Centrum
state: North Holland
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki nr 2 im. dr Jana Biziela w Bydgoszcz
state: Kuyavian-Pomeranian
city: Torun
country: Poland
facility: GASTROMED - Kopon, Zmudzinski I Wspolnicy Sp.j.
state: Kuyavian-Pomeranian
city: Krakow
country: Poland
facility: Gabinet Endoskopii Przewodu Pokarmowego
state: Lesser Poland
city: Warszawa
country: Poland
facility: WIP Warsaw IBD Point Profesor Kierkus
state: Mazowieckie
city: Sopot
country: Poland
facility: Endoskopia Sp. z.o.o.
state: Pomorskie
city: Szczecin
country: Poland
facility: Sonomed Sp. z o.o. - Centrum Medyczne
state: West Pomeranian
city: Elblag
country: Poland
facility: Szpital Miejski Sw. Jana Pawla II w Elblagu
city: Łęczna
country: Poland
facility: Oddział Gastroenterologiczny SP ZOZ w Łęcznej
city: Dnipro
country: Ukraine
facility: Dniepropetrovsk State Medical Academy
city: Odesa
country: Ukraine
facility: Odesa Regional Clinical Hospital
city: Ternopil
country: Ukraine
facility: Ternopil City Communal Emergency Medical Care Hosp
city: Vinnytsia
country: Ukraine
facility: Vinnytsia City Clinical Hospital #1, Dept of Gastroenterology
city: Vinnytsia
country: Ukraine
facility: Vinnytsia M.I. Pyrohov Regional Clinical Hospital
city: Zaporizhzhia
country: Ukraine
facility: City Clinical Hospital #9 Dept of Gastrosurgery SI Zaporizhzhia MA of PGE of MoHU
city: Úzhgorod
country: Ukraine
facility: Uzhhorod National University
city: Winchester
country: United Kingdom
facility: Hampshire Hospitals NHS Foundation Trust - The Royal Hampshire County Hospital
state: Hampshire
city: Headington
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation - John Radcliffe Hospital
state: Oxford
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust (UHB) - Queen Elizabeth Hospital Birmingham
state: West Midlands
city: Dudley
country: United Kingdom
facility: Russells Hall Hospital
state: West Midlands
city: Hull
country: United Kingdom
facility: Hull & East Yorkshire NHS Trust
state: Yorkshire
city: Leytonstone
country: United Kingdom
facility: Barts Health NHS Trust / Whipps Cross University Hospital
city: London
country: United Kingdom
facility: Barts Health NHS Trust - Royal London Hospital
city: Nottingham
country: United Kingdom
facility: University of Nottingham NHS Trust
Study officials:
affiliation: Alimentiv Inc.
name: Vipul Jairath, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jairath V, Zou G, Wang Z, Adsul S, Colombel JF, D'Haens GR, Freire M, Moran GW, Peyrin-Biroulet L, Sandborn WJ, Sebastian S, Travis S, Vermeire S, Radulescu G, Sigler J, Hanzel J, Ma C, Sedano R, McFarlane SC, Arya N, Beaton M, Bossuyt P, Danese S, Green D, Harlan W 3rd, Horynski M, Klopocka M, Petroniene R, Silverberg MS, Wolanski L, Feagan BG. Determining the optimal treatment target in patients with ulcerative colitis: rationale, design, protocol and interim analysis for the randomised controlled VERDICT trial. BMJ Open Gastroenterol. 2024 Feb 8;11(1):e001218. doi: 10.1136/bmjgast-2023-001218.