Determination of the Optimal Treatment Target in Ulcerative Colitis

Colitis, Ulcerative Clinical Trial

— VERDICT  

Official title:

VERDICT: In actiVE Ulcerative Colitis, a RanDomIzed Controlled Trial for Determination of the Optimal Treatment Target

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04259138
• Other study ID #: RP1706
• Secondary ID: 2019-002485-12
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: February 18, 2020
• Est. completion date: March 31, 2026

Study information

• Verified date: June 2024
• Source: Alimentiv Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 672
• Est. completion date: March 31, 2026
• Est. primary completion date: March 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer

Intervention

Biological:
• Treatment Algorithm A
Participants who are not on UC treatment at screening (or who have only used topical therapy) will require standard first-line therapy. Either oral 5-ASA and/or immunosuppressive (azathioprine, 6-mercaptopurine, or methotrexate), with optional oral corticosteroid up to a maximum of 30 mg or prednisone or equivalent, will be initiated.
• Treatment Algorithm B
Participants who are taking oral 5-ASA, immunosuppressive (azathioprine, 6-mercaptopurine, methotrexate), and/or oral corticosteroid at screening will follow the treatment algorithm. Participants will change to intravenous vedolizumab therapy. 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.
• Treatment Algorithm C
Participants who are taking a TNFa antagonist (infliximab, golimumab, or adalimumab), tofacitinib, or ustekinumab therapy at screening will follow the treatment algorithm. Participants will change to intravenous vedolizumab therapy. 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.

Locations

Country	Name	City	State
Belarus	Gomel Regional Clinical Hospital	Gomel	Homiel
Belarus	Vitebsk Regional Clinical Hospital	Vitebsk	Viciebsk
Belgium	Imelda Ziekenhuis Bonheiden	Bonheiden	Antwerp
Belgium	University Hospital Ghent	Ghent	East Flanders
Belgium	UZ Leuven - University Hospital Gasthuisberg	Leuven	Flemish Brabant
Canada	Barrie GI Associates Inc.	Barrie	Ontario
Canada	University of Calgary	Calgary	Alberta
Canada	McMaster University Medical Centre	Hamilton	Ontario
Canada	LHSC - Victoria Hospital	London	Ontario
Canada	London Health Sciences Centre - University Campus	London	Ontario
Canada	McGill University Health Centre (MUHC) Montreal General Hospital	Montreal	Quebec
Canada	ABP Research Services Corp.	Oakville	Ontario
Canada	Taunton Surgical Centre	Oshawa	Ontario
Canada	Toronto Immune and Digestive Health Institute (TIDHI)	Toronto	Ontario
Canada	GIRI (GI Research Institute)	Vancouver	British Columbia
France	CHU Besançon - Hôpital Jean Minjoz	Besançon	Bourgogne-Franche-Comte
France	CHRU de Lille - Hopital Claude Huriez	Lille Cedex	Hauts-de-France
France	CHRU Montpellier - Hopital Saint Eloi	MONTPELLIER cedex 05	Occitanie
France	CHU de Bordeaux - Hopital Haut Leveque - Groupe Hospitalier Sud	PESSAC cedex	Nouvelle-Aquitaine
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
Italy	Azienda Ospedaliera - Polyclinico Sant'Orsola-Malpighi	Bologna	Emilia-Romagna
Italy	Ospedale San Raffaele S.r.I.	Milano	Milan
Italy	Azienda Ospedaliera di Padova	Padova	Padua
Italy	Policlinico Universitario Agostino Gemelli	Roma	Rome
Italy	Istituto Clinico Humanitas	Rozzano	Milan
Netherlands	Amsterdam UMC - Academisch Medisch Centrum	Amsterdam	North Holland
Netherlands	Catharina Hospital	Eindhoven	North Brabant
Netherlands	Radboud University Nijmegen Medical Centre	Nijmegen	Gelderland
Netherlands	ETZ Hospital Tilburg	Tilburg	North Brabant
Poland	Szpital Uniwersytecki nr 2 im. dr Jana Biziela w Bydgoszcz	Bydgoszcz	Kuyavian-Pomeranian
Poland	Szpital Miejski Sw. Jana Pawla II w Elblagu	Elblag
Poland	Gabinet Endoskopii Przewodu Pokarmowego	Krakow	Lesser Poland
Poland	Oddzial Gastroenterologiczny SP ZOZ w Lecznej	Leczna
Poland	Endoskopia Sp. z.o.o.	Sopot	Pomorskie
Poland	Sonomed Sp. z o.o. - Centrum Medyczne	Szczecin	West Pomeranian
Poland	GASTROMED - Kopon, Zmudzinski I Wspolnicy Sp.j.	Torun	Kuyavian-Pomeranian
Poland	WIP Warsaw IBD Point Profesor Kierkus	Warszawa	Mazowieckie
Ukraine	Dniepropetrovsk State Medical Academy	Dnipro
Ukraine	Odesa Regional Clinical Hospital	Odesa
Ukraine	Ternopil City Communal Emergency Medical Care Hosp	Ternopil
Ukraine	Uzhhorod National University	Úzhgorod
Ukraine	Vinnytsia City Clinical Hospital #1, Dept of Gastroenterology	Vinnytsia
Ukraine	Vinnytsia M.I. Pyrohov Regional Clinical Hospital	Vinnytsia
Ukraine	City Clinical Hospital #9 Dept of Gastrosurgery SI Zaporizhzhia MA of PGE of MoHU	Zaporizhzhia
United Kingdom	University Hospitals Birmingham NHS Foundation Trust (UHB) - Queen Elizabeth Hospital Birmingham	Birmingham	West Midlands
United Kingdom	Russells Hall Hospital	Dudley	West Midlands
United Kingdom	Oxford University Hospitals NHS Foundation - John Radcliffe Hospital	Headington	Oxford
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	Hampshire Hospitals NHS Foundation Trust - The Royal Hampshire County Hospital	Winchester	Hampshire
United States	Digestive Health Partners - Asheville Gastroenterology Associate	Asheville	North Carolina
United States	Atrium Health (Carolinas HealthCare)	Charlotte	North Carolina
United States	Icahn School of Medicine at Mt Sinai Hospital	New York	New York
United States	New York-Presbyterian/Weill Cornell Medical Center	New York	New York
United States	St. Joseph Mercy Hospital/Huron Gastroenterology Associates	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Alimentiv Inc.	Takeda Development Center Americas, Inc.

Countries where clinical trial is conducted

United States,  Belarus,  Belgium,  Canada,  France,  Italy,  Netherlands,  Poland,  Ukraine,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Difference in Time to UC-related Complication Between Treatment Target Groups 1 and 3	Time to UC-related complication starting when a participant reaches their assigned treatment target, compared 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
Secondary	Difference in Time to UC-related Complication Compared Between Treatment Target Groups 1 and 2.	Time to UC-related complication starting when a participant reaches their assigned treatment target, 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
Secondary	Difference in Time to UC-related Complication Compared Between Treatment Target Groups 2 and 3.	Time to UC-related complication starting when a participant reaches their assigned treatment target, 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
Secondary	Difference in time to UC-related complication compared between subgroups	Time to UC-related complication compared between subgroups on and off corticosteroids at the time of achieving other relevant components of the treatment target.	From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first
Secondary	Difference in Time to Achieve Treatment Target	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.	up to 96 weeks
Secondary	Fecal Calprotectin Levels	Change in fecal calprotectin levels from baseline to Weeks 8, 16, 32, 48, and 96.	Baseline, weeks 8, 16, 32, 48, and 96.
Secondary	C-Reactive Protein Concentration	Change in C-Reactive Protein concentration from baseline to Weeks 8, 16, 32, 48, 64, 80, and 96.	Baseline, weeks 8, 16, 32, 48, 64, 80, and 96
Secondary	Difference in time to UC-related complication (as in the primary outcome and secondary outcomes 2 and 3)	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.	Up to week 96
Secondary	Evaluate the time to each type of UC-related complication	Evaluate, across the 3 target achievement groups, the time to each type of UC-related complication that comprises the primary endpoint.	Up to week 96
Secondary	Assess the effect of treatment(s) on UC-related complications	Assess the effect of treatment(s) on UC-related complications that is mediated through treatment targets.	Up to week 96
Secondary	Evaluate change in the UC-100 score from baseline to Weeks 16, 32, 48, and 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.	Up to week 96
Secondary	Evaluate changes in the health-related quality of life (HRQoL) using the Inflammatory Bowel Disease Questionnaire (IBDQ)	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.	Up to week 96
Secondary	Evaluate changes in the Work Productivity and Activity Impairment-UC (WPAI-UC) questionnaire	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.	Up to week 96
Secondary	Evaluate the change in Mayo Clinic Score (MCS; and subcomponents including the MES)	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.	Up to week 96
Secondary	Describe the change in Geboes scores from baseline to baseline to Week 16, 32, 48 and 96/end of study (EOS)	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].	Up to week 96
Secondary	Describe the change in RHI scores from baseline to all baseline to Week 16, 32, 48 and 96/end of study (EOS)	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.	Up to week 96
Secondary	Describe the change in Nancy Histological Index scores from baseline to baseline to Week 16, 32, 48 and 96/end of study (EOS)	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.	Up to week 96
Secondary	Evaluate the numbers of AEs and SAEs among the 3 randomized groups	To evaluate the numbers of AEs and SAEs among the 3 randomized groups.	Up to week 96
Secondary	Validate the Symptoms and Impacts Questionnaire for UC (SIQ-UC) tool in English-fluent subjects	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.	Up to week 96

External Links

•   Determining the optimal treatment target in patients with ulcerative colitis: rationale, design, protocol and interim analysis for the randomised controlled VERDICT trial