Evaluating treatment to a target of transmural healing in patients with moderately to severely active Crohn’s disease: rationale, design and protocol for the randomised controlled VECTORS trial

Abstract

Introduction

The optimal treatment target for Crohn’s disease (CD) is unknown. Targeting transmural healing (TMH) may be associated with a lower risk of complications than clinical and endoscopic outcomes. The Study to Evaluate Transmural Healing as a Treatment Target in Crohn’s Disease (VECTORS) aims to investigate TMH as a potential treatment target and its long-term benefits in patients with CD.

Methods and analysis

VECTORS is a phase 4, interventional, parallel-group, multicentre, randomised controlled trial. Approximately 304 adult patients with moderately to severely active CD from multiple international sites will be enrolled and randomly assigned in a 1:1 ratio to treatment target group 1 (corticosteroid-free intestinal ultrasound-based response or TMH plus clinical and biomarker remission) or group 2 (corticosteroid-free clinical and biomarker remission). All patients receive vedolizumab according to the standard dosing regimen, with an additional dose at week 10, followed by a treatment escalation algorithm to reach the assigned targets. Randomisation will be stratified by prior advanced therapy exposure, disease location and disease duration. The primary objective is to determine if treatment target group 1 is superior to group 2 for the primary efficacy outcome of corticosteroid-free endoscopic remission at week 48. CD-related complications (key secondary outcome) are assessed at week 96.

Ethics and dissemination

The trial is conducted in compliance with the protocol and applicable regulatory requirements and is approved by institutional review boards/independent ethics committees at the country or site level. Patients’ written informed consents are obtained and documented prior to trial participation. Findings will be disseminated in peer-reviewed journals and at scientific congresses.

Trial registration numbers

NCT06257706; EUCT, 2023-509096-16-00.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Transmural healing (TMH) has been associated with improved long-term outcomes. Transabdominal intestinal ultrasound (IUS) is a cost-effective, patient-friendly, repeatable and non-invasive method for assessing transmural disease activity in Crohn’s disease (CD).

WHAT THIS STUDY ADDS

• The Study to Evaluate Transmural Healing as a Treatment Target in Crohn’s Disease will help determine whether a treatment target of corticosteroid-free TMH (assessed by serial IUS) plus clinical and biomarker remission is superior to a target of only corticosteroid-free clinical and biomarker remission. The superior treatment target group will have a higher proportion of patients with corticosteroid-free endoscopic remission.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• This trial will provide data on the utility of TMH as a formal treatment target that can be achieved and efficiently monitored with IUS. These results will help to inform clinical practice and future evidence-based recommendations aiming to improve long-term outcomes in patients with CD.

Introduction

Crohn’s disease (CD) is a chronic immune-mediated disease characterised by transmural inflammation that can affect any part of the gastrointestinal tract. Inadequate control of disease activity and ongoing inflammation can lead to fibrotic and penetrating complications requiring surgical intervention, such as strictures, fistulae or abscesses. Prompt and effective management of inflammation is crucial to prevent such long-term complications of CD. Several methods are available to evaluate disease activity and treatment response in patients with CD, including clinical, endoscopic and histologic assessments, cross-sectional imaging and biomarker analysis. Treatment targets in CD have evolved over time with the advent of advanced therapies, the availability of diagnostic tools and scientific progress in understanding disease mechanisms. This advancement involves moving beyond symptom relief to objectively address ongoing inflammation, prevent long-term complications and improve patients’ health-related quality of life.¹,³

Nonetheless, the optimal treatment target in CD has yet to be determined. Various treatment targets for CD have been investigated, including symptomatic remission, symptomatic plus biomarker remission and endoscopic remission.⁴,⁷ Traditionally, the treatment target of mucosal healing by ileocolonoscopy is considered the gold standard and has been recommended by international expert consensus guidelines.¹ However, ileocolonoscopy examines only the innermost mucosal layer and not the deeper layers of the intestinal wall or the ileum proximal to terminal ileum, thereby limiting the assessment of transmural inflammation in CD. Transmural healing (TMH) is an increasingly recognised treatment target that reflects healing of all layers of the intestinal wall but has not yet been formally accepted in CD.¹ While preliminary studies suggest that TMH may be associated with better long-term outcomes,⁸,¹² definitions for TMH, assessment techniques and trial designs have not been standardised. Most studies define TMH as a bowel wall thickness (BWT) of ≤3 mm on CT enterography (CTE), magnetic resonance enterography (MRE) or intestinal ultrasound (IUS).¹¹,¹³ Although CTE and MRE are non-invasive cross-sectional imaging modalities that can assess transmural inflammation in CD, these modalities are associated with radiation exposure and are cost-intensive and not readily accessible. Transabdominal IUS is a promising assessment tool that is cost-effective, non-invasive, patient-friendly and readily available at the point of care for evaluating and monitoring transmural disease activity in patients with CD.¹⁴ While IUS is increasingly used in routine clinical care to assess disease activity and response to treatment, well-designed prospective studies evaluating IUS-defined TMH are lacking.

The Study to Evaluate Transmural Healing as a Treatment Target in Crohn’s Disease (VECTORS) aims to compare outcomes of two different treatment targets in patients with CD: (1) TMH (defined as BWT ≤3.0 mm without colour Doppler signal in all segments assessed by IUS) plus clinical and biomarker remission and (2) clinical and biomarker remission only. The comparator arm in this trial follows the treatment strategy used in the phase 3 randomised controlled CALM trial, which resulted in better clinical and endoscopic outcomes than treatment guided by clinical symptoms alone.⁶ Here, we report on the design and protocol of the VECTORS trial.

Methods and analysis

Trial design

This is an interventional, parallel-group, multicentre, randomised controlled trial. The trial consists of a screening period (up to 35 days), a 48-week treatment optimisation and target achievement assessment period, and a 48-week follow-up period (figure 1). Approximately 304 patients will be enrolled from 66 international sites (including academic institutions and hospitals) across 13 countries (including Australia, Belgium, Canada, Czech Republic, Denmark, France, Germany, Italy, The Netherlands, Poland, Portugal, the UK and the USA).

Figure 1. Study design schematic. ^aStratified by prior advanced therapy (yes or no), disease location (ileal only/ileocolonic or colonic) and disease duration (≤2 or >2 years). CD, Crohn’s disease; CDAI, CD Activity Index; CSF, corticosteroid-free; IUS, intestinal ultrasound; SES-CD, Simple Endoscopic Score for CD; W, week.

The study protocol was developed and reported in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline. A completed SPIRIT checklist is provided in online supplemental appendix 1.

Patient eligibility

Eligible patients are adults (aged 18–80 years) with moderately to severely active CD (as defined in table 1) and a BWT of >4.0 mm in the terminal ileum or any colonic segment (excluding the rectum) averaged across two cross-sectional and two longitudinal IUS measurements of the same segment. Patients who are biologic naïve or previously exposed to no more than one advanced therapy (biologic or small molecule) approved for the treatment of CD within the last 5 years of the screening date are considered for inclusion. Full inclusion and exclusion criteria are provided in table 1.

Table 1. Inclusion and exclusion criteria.

Inclusion criteria

Adults aged 18–80 years, inclusive, at the time of consent. Moderately to severely active CD with a CDAI score of 220–450 (inclusive) and SES-CD ≥6 (excluding the presence of a narrowing component) or ≥4 for isolated ileal disease. BWT on IUS of >4.0 mm in the terminal ileum or any colonic segment (excluding the rectum) as assessed by a central reader using the mean of 2 longitudinal and 2 cross-sectional measurements of the same segment. Biologic naïve or previously exposed to no more than 1 advanced therapy (biologic or small molecule) approved for the treatment of CD, within the last 5 years of the screening date (note: only approximately 15%–30% of the enrolled population will have had prior exposure to an advanced therapeutic compound). Receiving a stable dose (initiated at least 4 weeks prior to screening) of 5-ASA for CD. Females of childbearing potential must have a negative serum pregnancy test prior to randomisation and must use a highly effective method of contraception throughout the trial. Females unable to bear children must have documentation of such in the source records. Ability to participate fully in all aspects of the trial and provide written informed consent.

Exclusion criteria

Current or previous treatment with vedolizumab, etrolizumab or natalizumab. Previously exposed to two or more compounds of advanced therapies (biologics or small molecules) approved for the treatment of CD. Change to oral corticosteroid therapy dosing within 2 weeks prior to randomisation or receiving a corticosteroid dose of >40 mg of prednisone or equivalent at randomisation. Only have inflammation proximal to the terminal ileum that cannot be reached by ileocolonoscopy. Have a CD complication, such as symptomatic strictures in the small bowel with >3 cm prestenotic dilatation on any imaging modality, requiring procedural intervention. Previous extensive colonic resection or missing >2 segments out of 5 (terminal ileum, right colon, transverse colon, sigmoid and left colon and rectum), ileorectal anastomosis, or a proctocolectomy. Ostomy or ileoanal pouch. Short bowel syndrome. Fibrotic-only stricture in the ileum or colon without evidence of active inflammation (in the investigator’s judgement), including any impassable stenosis. Abscess >2 cm, detected by IUS or endoscopy, but patients with draining fistulas are not excluded. Serious underlying disease other than CD that, in the opinion of the investigator, may interfere with the patient’s ability to participate fully in the trial or would compromise patient safety. Positive stool test for Clostridioides difficile infection (as demonstrated by positive toxin). Known HIV or hepatitis B or C infection. If a negative test result is available in the 12 months prior to randomisation, retesting is not required. Known active or latent tuberculosis; if a negative test result is available in the 12 months prior to randomisation, confirmatory testing (per standard of care) is not required before randomisation. Other systemic or opportunistic infection (including cytomegalovirus), any other clinically significant extraintestinal infection, or recurring infection within 6 months of randomisation. Active cerebral/meningeal disease, signs, symptoms or any history of progressive multifocal leukoencephalopathy prior to randomisation. Hypersensitivity, allergy or intolerance to any excipient of vedolizumab or any other contraindication to vedolizumab. Active severe infection such as sepsis, cytomegalovirus, listeriosis or opportunistic infection. Unwillingness to withhold protocol-prohibited medications during the trial. Concurrent or previous participation in another clinical trial and received any investigational therapy within 30 days prior to randomisation. History of alcohol or drug abuse that, in the opinion of the investigator, may interfere with the patient’s ability to comply with the trial procedures. Prior enrolment in the current trial and had received study treatment. Pregnant, lactating or intending to become pregnant/impregnate a partner before, during or within 18 weeks after the last dose; or intending to donate ova or sperm during such time period. Vaccination with a live or live-attenuated vaccine within 4 weeks prior to randomisation, or planned vaccination with a live or live-attenuated vaccine during participation in the trial. Performing mandatory military service, deprived of liberty, in a residential care setting, or cannot take part in clinical studies due to a judicial decision. Immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this trial (eg, spouse, parent, child, sibling).

5-ASA, 5-aminosalicylate; BWT, bowel wall thickness; CD, Crohn’s disease; CDAI, CD Activity Index; IUS, intestinal ultrasound; SES-CD, Simple Endoscopic Score for CD.

Randomisation and blinding

This is an algorithmic trial in which eligible patients are randomised in a 1:1 ratio to one of two treat-to-target groups. Group 1 will be treated for 48 weeks with the goal to achieve corticosteroid-free IUS-based targets (IUS response or TMH) plus clinical remission (CD Activity Index <150) plus biomarker remission (C reactive protein (CRP) <5 mg/L and faecal calprotectin (FCal) <250 µg/g). In group 1, the IUS response target (defined as a 25% reduction from baseline in BWT) will be assessed at weeks 22 and 30, and the final treatment target of TMH will be assessed at week 38. Group 2 will be treated for 48 weeks with the goal to achieve a target of corticosteroid-free clinical remission plus biomarker remission (figure 1).

Randomisation will be performed using an interactive web response system and stratified by the following baseline factors: prior exposure to an approved advanced biologic or small-molecule therapy for CD (yes or no), disease location (ileal only/ileocolonic or colonic), and disease duration (≤2 years or >2 years, based on the date of diagnosis). These are considered key factors influencing response to advanced therapies.¹⁵,¹⁷ Patients and investigators will be unblinded to the treatment target group assignment. Central readers who assess the IUS cineloops, endoscopic videos and histologic slides will be blinded to the treatment target group assignment, patient, treatment and time point used to determine treatment escalation. All imaging, clinical assessments, biomarker results and details of corticosteroid use will be provided to an unblinded off-site assessor who will inform the site investigator whether treatment escalation is needed. Investigators and site personnel are not permitted to influence patient-reported symptom scores.

Trial objectives and outcomes

The primary objective of this trial is to determine if treating to a target of corticosteroid-free IUS outcomes plus clinical remission plus biomarker remission is superior to treating to a target of only corticosteroid-free clinical remission plus biomarker remission. The primary outcome is corticosteroid-free endoscopic remission at week 48, with endoscopic remission defined as a total Simple Endoscopic Score for CD (SES-CD) ≤4 for patients with ileocolonic or colonic CD (or SES-CD ≤2 for patients with isolated ileal CD) and at least a 2-point reduction from baseline with no subscore >1 (as scored by a central reader).

Specific secondary and exploratory objectives and outcomes are presented in table 2.

Table 2. Trial objectives and outcomes.

	Objectives	Outcomes	Week(s)
Primary	To determine if treating to a target of CSF IUS outcomes+clinical remission+biomarker remission (group 1) is superior to a target of CSF clinical remission+biomarker remission (group 2)	CSF endoscopic remission*	48
Secondary	To compare composite outcomes between groups 1 and 2	CSF TMH†+endoscopic remission*+clinical remission‡	48
		CSF IUS response§+endoscopic remission*+clinical remission‡
		CSF endoscopic remission*+clinical remission‡
		CSF endoscopic response¶+clinical response**
	To compare clinical outcomes between groups 1 and 2	CSF clinical remission‡	14, 22, 48
		CSF clinical response**
		CDAI total score and corresponding changes from baseline	6, 14, 22, 30, 38, 48
	To compare endoscopic outcomes between groups 1 and 2	CSF endoscopic response¶	48
		SES-CD total score and corresponding change from baseline
	To compare IUS outcomes between groups 1 and 2	TMH†	48
		IUS response§
		BWT, colour Doppler signal and IBUS-SAS (per segment and total) and corresponding change from baseline
	To evaluate kinetics of IUS outcomes in group 1	TMH†	14, 22, 30, 38, 48
		IUS response§
		BWT, colour Doppler signal and IBUS-SAS (per segment and total) and corresponding change from baseline
	To compare histologic outcomes between groups 1 and 2	Histologic remission††	48
		Histologic response‡‡
	To compare biomarker outcomes between groups 1 and 2	Biomarker remission§§	48
		Biomarker response¶¶
		CRP response***	6, 14, 22, 30, 38, 48
		FCal response***
		CRP and FCal and corresponding changes from baseline
	To compare patient-reported outcomes between groups 1 and 2	PRO2, SIQ-CD and Urgency Numerical Rating Scoref and corresponding changes from baseline	6, 14, 22, 30, 38, 48
		IBDQ score and corresponding changes from baseline	30, 48
	To compare longer-term outcomes between groups 1 and 2	Time to CD-related complications†††	Randomisation through week 96
		Switched to an alternate biologic	48, 96
		CDAI, CRP, FCal and patient-reported outcomes (as specified above)	64, 80, 96
	To compare safety outcomes between groups 1 and 2	Exposure-adjusted incidence rates of AEs, SAEs and AESIs	48
Exploratory	To evaluate stool, serum and mucosal tissue levels of drug and other biomarkers associated with clinically important outcomes in groups 1 and 2	Changes from baseline in stool, serum and mucosal tissue levels of drug and other exploratory biomarkers	6, 14, 22, 30, 38, 48, 64, 80, 96
		Correlation between clinical outcomes; stool, serum and mucosal tissue levels of drug; and other exploratory biomarkers
	To compare longer-term IUS outcomes between groups 1 and 2	Time to treatment target achievement	22, 36 and 48
		CD-related complications in patients with or without target achievement at week 48	48–96

^*SES-CD ≤4 for ileocolonic or colonic CD (or ≤2 for isolated ileal CD) and at least a 2-point reduction from baseline with no subscore >1, as scored by a central reader.

^†BWT ≤3.0 mm and colour Doppler signal 0 in all evaluable segments assessed by IUS and scored by a central reader.

^‡CDAI <150.

^§Reduction from baseline of 25% in BWT assessed by IUS and scored by a central reader.

^¶Reduction in total SES-CD ≥50% from baseline, as scored by a central reader.

^**CDAI decrease of ≥100 points from baseline.

^††RHI score ≤3 (per segment) and absence of neutrophils and erosions/ulcers, as scored by a central reader; Global Histologic Disease Activity Score ≤8 with subcomponent scores of 0 for epithelial damage, infiltration of polymorphonuclear cells in lamina propria, polymorphonuclear cells in epithelium and erosions/ulcers.

^‡‡≥50% reduction from baseline in RHI, as scored by a central reader.

^§§Normalisation of CRP (<5 mg/L) and FCal (<250 µg/g).

^¶¶≥50% reduction from baseline in either CRP or FCal.

^***≥50% reduction from baseline.

^†††Any of the following: (1) CD-related surgery; (2) CD-related hospitalisation; (3) CD medication-related complication; (4) CD procedure-related complication; (5) rescue therapy for a documented CD-related flare (eg, new initiation of an approved biologic or small-molecule therapy other than vedolizumab, dose escalation of vedolizumab, or dose intensification beyond the dose used at randomisation of a corticosteroid after week 48) or (6) other CD-related complications (eg, bowel obstruction, fistula, abscess or other bowel damage).

AE, adverse event; AESI, AE of special interest; BWT, bowel wall thickness; CD, Crohn’s disease; CDAI, CD Activity Index; CRP, C reactive protein; CSF, corticosteroid-free; FCal, faecal calprotectin; IBDQ, Inflammatory Bowel Disease Questionnaire; IBUS-SAS, International Bowel Ultrasound Segmental Activity Score; IUS, intestinal ultrasound; PRO-2, 2-item patient-reported outcome score; RHI, Robarts Histopathology Index; SAE, serious AE; SES-CD, Simple Endoscopic Score for CD; SIQ-CD, Symptoms and Impacts Questionnaire for CD; TMH, transmural healing.

Treatment

Treatment algorithm

All patients will begin a vedolizumab intravenous induction regimen of 300 mg at weeks 0, 2, 6 and 10, followed by vedolizumab 300 mg intravenous every 8 weeks from week 14 to at least week 22. Vedolizumab may be initiated with or without a corticosteroid, provided that the dose is ≤40 mg/day of prednisone or equivalent. For patients who are receiving other approved CD therapies at screening, investigators will follow their routine clinical practice to determine an appropriate washout period between the prior biologic or small-molecule therapy and initiation of vedolizumab (eg, based on the drug’s half-life or based on the drug levels before initiating vedolizumab coupled with careful patient monitoring). Treatment with immunosuppressive drugs will be discontinued prior to initiation of vedolizumab.

Patients will follow their baseline vedolizumab regimen until at least week 22 and will be evaluated for target achievement at weeks 22, 30 and 38 to determine whether treatment escalation is necessary. If the patient achieves their assigned treatment target and is corticosteroid-free at the time of assessment, no treatment escalation will be required, and the patient will continue therapy without any changes until the next target assessment. Patients who achieve their treatment target but are taking corticosteroids must undergo corticosteroid tapering (see Concomitant and prohibited therapies section for tapering regimen) and continue their other therapies until the next assessment. If the treatment target is not achieved, treatment will be escalated according to a standardised escalation algorithm as outlined in figure 2. Initiation or reintroduction of corticosteroids is optional when indicated by the algorithm. No treatment modifications will be permitted at week 14. Deviations from the baseline treatment regimen or escalation algorithm up to week 48 will not be permitted unless approved by the sponsor.

Figure 2. Treatment algorithm.Initiation or reintroduction of corticosteroids is optional (where noted) when indicated by the algorithm. Only 1 course of corticosteroid (≤40 mg/day prednisone or equivalent) is permitted between weeks 2 and 14 if the patient is not taking corticosteroids at screening. Patients must complete tapering on or before the weeks 22, 30, 38 and 48 assessments to be considered as having achieved their treatment target. CD, Crohn’s disease; IV, intravenous.

Between week 48 and the end of the trial, investigators will direct treatment and will be encouraged to continue the treatment algorithm after week 48 if they believe that treatment escalation is warranted considering their usual practice and if escalation steps remain available for a patient. If all attempts to escalate or optimise treatment with vedolizumab and/or corticosteroids according to the algorithm have been exhausted but the treatment target remains unachieved by week 48, patients may switch to an alternative approved therapy for CD at the discretion of the investigator and in accordance with the local standard of care. Switching from vedolizumab to an alternative approved therapy for CD will not be considered rescue therapy if it is directed by the treatment algorithm prior to week 48. Rescue therapy will be defined as a switch to an alternative approved non-vedolizumab advanced biologic or small-molecule therapy for CD, dose escalation of vedolizumab or initiation of any corticosteroid after week 48.

All patients will remain in the trial and complete the scheduled assessments until week 96 or until a discontinuation criterion is met (see Trial discontinuation section for further details). All postrandomisation medications administered will be documented in the electronic case report form (eCRF), including the name of the medication, indication, date, dosage and route of administration.

Concomitant and prohibited therapies

Concomitant treatment with an oral 5-aminosalicylate (5-ASA) and other non-vedolizumab therapies approved for CD or non-CD indications (with the exception of medications that are prohibited at randomisation) is permitted during the trial. However, treatment decisions are ultimately at the discretion of the investigator, and patients are encouraged to avoid the use of rectal corticosteroids or rectal 5-ASAs and to maintain stable doses of antidiarrhoeal therapy throughout the trial. Prior treatment with two or more advanced biologic or small-molecule therapies approved for CD is not allowed, and any concurrent or previous exposure to an investigational therapy within 30 days prior to randomisation is prohibited.

Patients who are not taking corticosteroids at screening are permitted to receive up to one course of corticosteroids (maximum dose of 40 mg/day prednisone or equivalent) between weeks 2 and 14 and should complete tapering within 8 weeks of initiation. If corticosteroids are initiated between weeks 2 and 14, no additional courses are permitted before week 48. Patients who receive stable oral corticosteroids at randomisation must complete tapering by week 8 of randomisation. A slower taper may be permitted at the discretion of the investigator; however, no additional course of corticosteroids is permitted after the initial tapering through week 48. If a patient initiates oral corticosteroids after the start of the trial, tapering should be completed on or before the week 22, 30, 38 and 48 assessments. However, if complete tapering is not possible without recurrence of clinical symptoms, corticosteroids may be held or increased (up to 40 mg/day prednisone or equivalent) at the discretion of the treating physician. Patients receiving an oral corticosteroid during the assessment phase (ie, up to the first 48 weeks) will not be considered as having achieved their treatment target.

Treatment adherence

Adherence to the treatment algorithm will be assessed using medication records of randomised patients at each study visit, except after week 48 or when the patient switches to an alternative approved therapy for CD. Investigators are asked to document any deviations from the treatment algorithm and the reasons for non-adherence.

Assessments

After initiating baseline treatment, each patient will be evaluated for target achievement at weeks 14, 22, 30 and 38. The primary outcome of corticosteroid-free endoscopic remission will be assessed at week 48. Patients in group 1 will undergo IUS imaging at screening and weeks 14, 22, 30, 38 and 48, whereas patients in group 2 will undergo IUS imaging at screening and week 48 only. Central readers will complete assessments of all IUS cineloops, including assessments of BWT, International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) and disease activity Visual Analogue Scale. Ileocolonoscopy with biopsy collection will be performed for both groups at screening and week 48. Endoscopic disease activity will be assessed by central readers using the SES-CD. Biopsies will be processed by a central laboratory, and histologic disease activity will be centrally assessed using the Robarts Histopathology Index and Global Histologic Disease Activity Score. Patient-reported symptoms, biomarkers (CRP and FCal) and use of corticosteroids will be assessed at baseline and weeks 6, 14, 22, 30, 38 and 48. Stool, serum and mucosal tissue samples will also be collected for assessments of drug concentrations and other exploratory molecular markers that may be associated with clinically important outcomes.

Patients will be followed from weeks 48 to 96 to evaluate the long-term occurrence of CD-related complications. The following events will be defined as a CD-related complication: (1) CD-related surgery; (2) CD-related hospitalisation; (3) CD treatment-related or procedure-related complication; (5) rescue therapy use for a documented CD flare after week 48 (eg, initiation of an approved non-vedolizumab advanced biologic or small-molecule therapy, dose escalation of vedolizumab or dose intensification of a corticosteroid beyond the dose used at randomisation) and (6) other CD-related complication (eg, bowel obstruction, fistula, abscess). Occurrences of CD-related complications will be evaluated through review of medical records and direct questioning of the patient. If the site investigator deems that a patient meets any component of the CD-related complication definition, patient data will be adjudicated by an independent, blinded adjudication panel.

Adverse events (AEs; defined as any untoward medical occurrence), serious AEs (SAEs; defined as any untoward medical occurrence that results in death, a life-threatening condition, hospitalisation, persistent or substantial disability or congenital anomaly), and AEs of special interest (AESIs; defined as any vedolizumab-specific scientific and medical concern such as progressive multifocal leukoencephalopathy) will be assessed at each study visit from the time of informed consent to the end of the trial. All other trial procedures and assessments are shown in online supplemental table 1.

Intestinal ultrasound

IUS acquisition will follow study-specific guidelines across all sites. Mid-range to high-range IUS systems are recommended for cineloop acquisition, and all equipment must meet study-specific technical standards prior to use. All submitted IUS images will undergo centralised quality control review with structured feedback provided to sites to ensure consistency. Central readers are medically qualified (gastroenterologists, radiologists or trainees), have a minimum of 3 years of independent IUS experience, perform at least 300 IUS examinations annually and undergo study-specific training. Cineloops are acquired for all colonic segments, the terminal ileum and proximal small bowel in both longitudinal and cross-sectional planes, including colour Doppler sequences. Together, these measures are intended to minimise inter-site and inter-reader variability and support reliable assessment of transmural disease activity.

Trial discontinuation

Patients may withdraw from the study at any time, either at their own request or at the discretion of the investigator, sponsor, institutional review board (IRB) or independent ethics committee (IEC), for safety, compliance or administrative reasons. Patients will be discontinued from the study if they experience an AE that imposes an unacceptable risk, deviate from the protocol, are lost to follow-up or withdraw consent. All end-of-study procedures will be performed at the time of withdrawal. If a patient is withdrawn due to an SAE, they will be followed until the SAE is resolved or stabilised.

Data collection, monitoring and management

All trial data, including baseline demographics, medical and surgical history, medication history, AEs and reasons for study withdrawal, will be collected through the eCRF by trained investigators and study site personnel. Disease-related symptoms will be collected through patient diaries. Study personnel will train patients on completing the diary and review entries at each visit. The investigator is responsible for the completeness, accuracy and clarity of all data entries in the eCRF and will provide formal approval of the final submitted data. Data validation edit checks will be performed, and any inconsistent or uncertain data will be queried. Data clarification forms will be generated, and any discrepancies will be resolved.

For off-algorithm treatment changes prior to week 48, data will be collected and analysed as if the patient is being treated according to the algorithm. In the event of death, data up to and including the time of death will be evaluated as collected without imputation for efficacy outcomes beyond that timepoint. These data and the relationship to treatment and disease will be included in safety summaries.

The sponsor or its designee will perform onsite monitoring periodically throughout the trial to review eCRF entries against source documents and trial documents to ensure adherence to the trial protocol and regulatory requirements. Any findings from the monitoring visit will be discussed with the investigator. An independent data monitoring committee will ensure the safety of the patients and alert the sponsor of any trial-related safety issues. The sponsor, IRB/IEC or regulatory authorities may conduct an onsite audit, which will require access to all trial records and source documents for inspection.

Statistical analyses

Appropriate summary statistics will be presented. Categorical variables will be summarised using counts and percentages, and continuous variables will be summarised using the number of patients (n), mean, median, SD, 25th percentile, 75th percentile, minimum and maximum.

All efficacy analyses will be performed based on the intention-to-treat (ITT) population, which includes all randomised patients who receive at least one dose of CD treatment from the treatment algorithm. All ITT patients who do not have any major deviations from the protocol will be included in the per-protocol analysis set, which will be used for supplementary analyses. Statistical significance will be declared at the two-sided significance level of 5%.

Primary efficacy analysis

The primary efficacy analysis will compare the proportions of patients in corticosteroid-free endoscopic remission at week 48 between treatment target groups 1 and 2 using the two-sided Cochran-Mantel-Haenszel test adjusted for randomisation stratification factors (prior biologic/small-molecule therapy exposure, disease location and disease duration). In addition to the overall effect measures (ie, difference and ratio in proportions) and the associated 95% CIs, stratum-specific effect measures will be calculated and subject to heterogeneity assessment to examine whether treatment effects vary by stratum.

Secondary efficacy analyses

Secondary analyses for binary response outcomes will be performed using similar methods as the primary efficacy analysis, with continuous covariates adjusted using the modified Poisson regression.¹⁸ Time-to-event secondary outcomes will be analysed using a stratified Mantel log-rank test, with HRs and corresponding two-sided 95% CIs obtained using a Cox proportional hazard model. Event time will be censored for participants who are lost to follow-up, discontinue study treatment, undergo an off-algorithm treatment change, decease or do not experience a CD-related complication before week 96 or the end of the trial. Continuous and ordinal data will be analysed with a rank-based approach for estimating the visit-specific probability that a patient in group 1 has a better change from baseline than (or wins over) a patient in group 2, adjusting for baseline values.^{19 20} Estimates of the win probabilities (WinPs) and 95% CIs as well as p values for WinP=0.5 will be presented. All secondary analyses, p values and CIs will not be controlled for multiplicity and accordingly will be exploratory and generalised with caution.

Safety analyses

Safety analyses will be performed based on the safety analysis set, which includes all randomised patients. All AEs, SAEs, AESIs, vital signs, physical examination and clinical laboratory results will be recorded at each visit for both treatment target groups. AEs will be coded using the Medical Dictionary for Regulatory Activities and summarised by system organ class, high-level term and preferred term, and by severity and relationship to the study drug. The number and percentage of patients experiencing any treatment-emergent AEs, SAEs, treatment-emergent SAEs and AESIs will be reported. For continuous safety measures, values observed at each visit and corresponding changes from baseline to each visit will be summarised by treatment target group using descriptive statistics (including n, mean, median, SD, 25th percentile, 75th percentile, minimum and maximum) and/or frequency distributions. Categorical safety measures will be summarised by frequencies and percentages for each visit. No formal statistical safety analyses will be performed.

Interim analyses

Two unblinded interim analyses are planned, each assessing the proportion of patients achieving their assigned treatment target at one of two timepoints: (1) after 25 patients per group have completed the week 14 assessment and (2) after 50 patients per group have completed the week 22 assessment. Findings from these interim analyses will be used as a guide to determine the feasibility of achieving the IUS-based outcomes (IUS response and TMH) and as a basis for possible modification of the allowed proportion of patients with prior biologic exposure. Interim analyses will be conducted and reviewed by a statistician, epidemiologist and clinician who have no contact with the study patients.

Sample size estimation

The trial is powered to demonstrate the superiority of group 1 over group 2 with respect to the primary outcome of corticosteroid-free endoscopic remission at week 48. Assuming 40% and 25% corticosteroid-free endoscopic remission rates at week 48 hold across strata for treatment target groups 1 and 2, respectively, with a 1:1 randomisation ratio within each stratification factor, approximately equal enrolment, and normal approximation for two proportions, a sample size of approximately 304 patients will have 80% power at the 5% significance level to detect a difference of 15% between the treatment target groups. The assumed endoscopic remission rates are based on prior vedolizumab studies that evaluated endoscopic remission in patients with CD.²¹,²⁴ The sample size is not inflated to account for dropouts as those who discontinue from the trial prior to the week 48 assessment will be considered as having not reached the primary outcome.

Handling of missing data

Available efficacy and safety data collected for this study will be included in the data listings and/or summary tables. Binary efficacy outcomes will be imputed as non-responders/non-remitters when data are missing and subject to such imputation in cases where a patient terminates the study prior to reaching endoscopic remission and/or the week 48 assessment. Participants without endoscopic remission data at week 48 (eg, due to dropout) will be considered as non-remitters. The missing at random assumption will be made for continuous data, while missing time-to-event data will be censored.

Dissemination

Results will be disseminated at scientific congresses and in peer-reviewed journals.

Discussion

A central feature of a treat-to-target approach in inflammatory bowel disease is early introduction of a therapy with the use of an algorithmic approach to guide subsequent treatment choices based on the patient’s response to a specific treatment target. Current expert consensus recommendations (Selecting Therapeutic Targets in Inflammatory Bowel Disease-II) propose immediate (clinical response), intermediate (clinical remission and normalisation of biomarkers), and long-term treatment targets (endoscopic remission, absence of disability and normalised quality of life) to guide therapeutic decisions based on whether these time-based targets are met.¹ Furthermore, incorporating multiple treatment goals into a treat-to-target strategy may be beneficial in improving patient outcomes.¹

Results from prior studies have suggested that early treatment optimisation guided by deeper treatment targets led to a reduced risk of long-term complications in CD. In the cluster-randomised controlled REACT trial of patients with CD who had clinical symptoms (Harvey-Bradshaw Index >4) that persisted after 4 weeks (in Canada) or 12 weeks (in Belgium) of initial corticosteroid therapy, early introduction of immunosuppressive therapy resulted in a lower combined rate of surgeries, hospitalisations and disease-related complications over 24 months compared with conventional therapy.⁴ Similarly, the subsequent REACT-2 trial (NCT01698307) targeted ulcer remission with early introduction of adalimumab/antimetabolite therapy. Results showed a 25%–29% lower risk of CD-related complications among patients with active inflammation (CRP >5 mg/L) and ulcers at baseline.⁵ In the CALM trial, greater rates of mucosal healing at week 48 were observed with an early adalimumab introduction strategy targeting tight control of clinical symptoms and inflammatory biomarkers (normalisation of CRP and FCal) than with a conventional strategy targeting clinical symptoms alone (46% vs 30%).⁶ Similar findings were observed for corticosteroid-free clinical remission (60% vs 39%). Although different treat-to-target strategies have been evaluated in CD, no study has evaluated a treatment target of TMH, which is currently considered only an adjunctive target in patients with CD.

TMH is an emerging concept without a universally accepted definition; most studies rely on BWT, the most reliable and reproducible IUS parameter. An international expert consensus defines TMH as a BWT of ≤3 mm in the absence of an abnormal colour Doppler signal. The VECTORS trial adopts this definition and includes complementary IUS metrics, such as the IBUS-SAS, to provide a comprehensive assessment of transmural disease activity. The primary outcome is evaluated at week 48 and targets TMH, which is considered a challenging endpoint, and the optimal time frame to achieve it remains uncertain. Nevertheless, this study is expected to provide important insights into IUS-based TMH as a treatment target. Given the rapidly evolving field of IUS, emerging standardised outcomes and scoring systems will be explored as they become available during the course of the study.

The evidence for TMH as a treatment target in CD is largely based on observational studies and post hoc analyses. In the phase 3b, open-label, single-cohort VERSIFY trial, transmural remission was detected by MRE (based on the Magnetic Resonance Index of Activity score) in 22% and 38% of patients with CD after 26 and 52 weeks of vedolizumab treatment, respectively.²³ In a substudy of the randomised controlled STARDUST trial, the effect of ustekinumab on transmural disease activity was assessed using IUS in 77 adults with moderate to severe CD.²⁵ Rates of IUS response and transmural remission at week 48 were 46% and 24%, respectively, with responses observed as early as week 4 after initiating ustekinumab and gradual increases over time. Given the association between TMH and improved long-term outcomes and the advantages of IUS in evaluating and monitoring transmural inflammation in CD, well-designed randomised controlled trials are needed to assess IUS-defined TMH as a potential therapeutic goal in CD.

The VECTORS trial is the first prospective trial to provide data to support the utility of TMH as a formal treatment target that can be efficiently and closely monitored with IUS. The treatment algorithm defined in this trial is based on current treatment guidelines for CD and includes the use of oral corticosteroids, vedolizumab and other approved biologics or advanced small-molecule therapies. Vedolizumab is considered as part of the treatment algorithm for VECTORS as it is widely available across the world and has shown efficacy in both biologic naïve and biologic experienced populations with CD. Treatment with vedolizumab has been shown to induce TMH (assessed by MRE) in patients with CD, as well as clinical remission and endoscopic remission in those with early disease.^{26 27} The treatment algorithm features the standard vedolizumab dosing regimen, with an additional dose at week 10, and early escalation of treatment for patients who have not achieved their assigned treatment target at the time of assessment. The favourable long-term safety profile of vedolizumab makes it a suitable candidate for evaluation in studies with a proactive escalation strategy. The algorithm in the VECTORS trial was carefully designed to reflect routine practice, allowing early escalation of vedolizumab to maximise patient benefit before considering a premature switch to a different advanced therapy. Furthermore, the algorithm provides an option to switch to an alternative approved therapy for CD if the treatment target remains unmet after vedolizumab optimisation.

We acknowledge several limitations of this study, including its open-label design, which may introduce bias. However, outcome assessment and treatment escalation are based on prespecified objective criteria with independent adjudication to mitigate this risk, and the study incorporates a partially blinded design with central readers, blinded endpoint adjudication and standardised investigator training to ensure consistency across sites. Second, the escalation of vedolizumab maintenance dosing from every 8 weeks to every 4 weeks did not demonstrate clear additional efficacy over dosing the drug every 8 weeks in the GEMINI trials. However, these studies were not powered to compare dosing regimens. Furthermore, post hoc exposure–response analyses and real-world data suggest that higher vedolizumab exposure and dose escalation may be associated with improved or recapture of clinical response in selected patients.^{28 29} Lastly, the treatment algorithm in the VECTORS trial permits physicians to either initiate corticosteroids or escalate vedolizumab dosing if the patient is on the dosing regimen of every 8 weeks and not receiving corticosteroids at the time of target assessment. While this strategy provides flexibility and allows physicians to prescribe corticosteroids early in the treatment course to manage symptoms, confounding effects from transient corticosteroid responses may be introduced. Nonetheless, the VECTORS trial focuses on objective disease control and corticosteroid-free outcomes, which helps mitigate these confounding effects. Furthermore, the use of corticosteroids within the escalation algorithm is optional and at the discretion of the treating physician with tapering schedules implemented prior to target assessments.

As of 7 August 2025, the trial has activated 53 sites in 11 countries, with 50 patients enrolled and randomised. The first participant was randomised on 4 September 2024. Complete enrolment is anticipated by 28 February 2027.

Data availability statement

Data sharing is not applicable as no datasets were generated and/or analysed for this study. Data are available on reasonable request.