A Study of Guselkumab in Participants With Fistulizing, Perianal Crohn's Disease

Study Overview
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Brief Summary
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The purpose of this study to evaluate the clinical efficacy of guselkumab in fistulizing, perianal Crohn's disease and to assess the overall safety of guselkumab.

Detailed Description
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Crohn's disease is a chronic, progressive, and potentially life-threatening disorder which may affect any part of the gastrointestinal tract. Guselkumab is a fully human immunoglobulin G1 (IgG1) lambda monoclonal antibody (mAb) that binds to the p19 subunit of human interleukin (IL)-23 with high specificity and affinity, without blocking IL-12. The aim is to evaluate the efficacy and safety of guselkumab in the treatment of adult participants with active fistulizing, perianal Crohn's disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or biologic therapy or have medical contraindications to such therapies. This study consists of 3 phases: 6 weeks screening phase, 48 weeks treatment phase, and a 16 weeks follow-up phase. The study will have long term extension (LTE) period for participants who complete the 48-week treatment period and in the opinion of the investigator, will continue to benefit from the study intervention. Comprehensive safety data will be collected and the total duration of the study for participants will be up to 118 weeks (including the LTE period).

Official Title
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A Phase 3, Randomized, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy and Safety of Guselkumab in Participants With Fistulizing, Perianal Crohn's Disease

Conditions
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Fistulizing Crohns Disease, Perianal Crohns Disease

Intervention / Treatment
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* Drug: Guselkumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have a diagnosis of Crohn's disease with a minimum duration of at least 3 months Has at least one active draining perianal fistula as a complication of Crohn's disease, confirmed by screening magnetic resonance imaging (MRI) results Is naïve to biologics, or demonstrated inadequate response or intolerance to conventional therapies or approved biologic therapies for Crohn's Disease (CD) Exclusion Criteria: Has a very severe luminal disease activity History of or concurrent rectovaginal fistulas, rectal and/or anal stenosis or other active complications of perianal disease Has complications of CD, such as symptomatic strictures or stenoses, short gut syndrome, or any other manifestation that might be anticipated to require surgery or preclude fistula evaluation Any medical contraindications preventing study participation Has a history of ongoing, chronic or recurrent enteral or systemic infectious disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Guselkumab<br>Participants will receive guselkumab Dose 1 intravenous (IV) infusion followed by Dose 2 subcutaneously (SC). Participants will receive matching placebo to maintain the blind. Participants who are eligible and willing to continue guselkumab may enter the Long-Term Extension (LTE) period and continue to receive guselkumab. | Drug: Guselkumab<br>* Guselkumab will be administered subcutaneously/IV infusion.<br>* Other names: CNTO1959;Drug: Placebo<br>* Matching placebo will be administered subcutaneously/IV infusion.<br>|
| Experimental: Group 2: Guselkumab<br>Participants will receive guselkumab Dose 1 IV infusion followed by Dose 3 SC. Participants will receive matching placebo to maintain the blind. Participants who are eligible and willing to continue guselkumab may enter the LTE period and continue to receive guselkumab. | Drug: Guselkumab<br>* Guselkumab will be administered subcutaneously/IV infusion.<br>* Other names: CNTO1959;Drug: Placebo<br>* Matching placebo will be administered subcutaneously/IV infusion.<br>|
| Experimental: Group 3: Placebo<br>Participants will receive placebo IV infusion followed by placebo SC. At Week 24, placebo non-responders will continue to receive guselkumab Dose 4 followed by guselkumab Dose 2 SC. Participants will receive matching placebo to maintain the blind. Participants who are eligible and willing to continue guselkumab may enter the LTE period and continue to receive guselkumab. | Drug: Guselkumab<br>* Guselkumab will be administered subcutaneously/IV infusion.<br>* Other names: CNTO1959;Drug: Placebo<br>* Matching placebo will be administered subcutaneously/IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who Achieve Combined Fistula Remission at Week 24 | Percentage of participants who achieve combined fistula remission at Week 24 will be reported. Combined fistula remission is defined as 100 percentage (%) closure of all treated external openings without development of new fistulas or abscesses and without any drainage by the external openings [occurring spontaneously or after gentle finger compression] and absence of collections greater than (>) 2 centimeters (cm) of the perianal fistulas in at least two of three dimensions, confirmed by a blinded central review of the magnetic resonance imaging [MRI] results. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who Achieve Combined Fistula Remission at Week 48 | Percentage of participants who achieve combined fistula remission at Week 48 will be reported. | Week 48 | 
| Percentage of Participants who Achieve Clinically Assessed Fistula Remission | Percentage of participants who achieve clinically assessed fistula remission will be reported. Clinically assessed fistula remission is defined as 100% closure of all treated external openings, without development of new fistulas or abscesses and without any drainage by the external openings, occurring spontaneously or after gentle finger compression. | Week 24 | 
| Percentage of Participants who Achieve Radiological Fistula Remission Based on Radiological Findings Assessed by MRI | Percentage of participants who achieve radiological fistula remission based on radiological findings assessed by MRI will be reported. Radiological remission is defined as absence of collections >2 cm of the perianal fistulas in at least two of three dimensions, confirmed by a blinded central review of the MRI results. | Week 24 | 
| Percentage of Participants who Achieve Clinically Assessed Fistula Response at Week 24 | Percentage of participants who achieve clinically assessed fistula response at Week 24 will be reported. Clinically assessed fistula response is defined as closure of at least 50 percent (%) of all external openings that were draining at baseline. | Week 24 | 
| Percentage of Participants who Achieve Clinically Assessed Fistula Response at Week 12 | Percentage of participants who achieve clinically assessed fistula response at Week 12 will be reported. Clinically assessed fistula response is defined as closure of at least 50% of all external openings that were draining at baseline. | Week 12 | 
| Change from Baseline in Crohn's Disease Activity Index (CDAI) by Visit Over Time Through Week 48 | Change from baseline in CDAI by visit over time will be reported. CDAI will be assessed by collecting information on 8 different Crohn's disease-related variables: extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid or very soft stools, abdominal pain (AP)/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being with scores ranging from 0 to approximately 600. The last 4 variables are scored over 7 days by the participant on a diary card that participants are to complete on a daily basis. | Baseline up to Week 48 | 
| Percentage of Participants who Achieve Clinical Remission (CDAI less than [<] 150) by Visit Over Time Through Week 48 Among Participants with CDAI Greater than (>) 150 at Baseline | Percentage of participants who achieve clinical remission (CDAI <150) by visit over time through Week 48 among participants with CDAI >150 at baseline will be reported. CDAI will be assessed by collecting information on 8 different Crohn's disease-related variables: extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid or very soft stools, abdominal pain [AP]/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being with scores ranging from 0 to approximately 600. The last 4 variables are scored over 7 days by the participant on a diary card that participants are to complete on a daily basis. | Through Week 48 | 
| Percentage of Participants who Achieve a Clinical Response by Visit Over Time Through Week 48 Among Participants with CDAI >150 at Baseline | Percentage of participants who achieve a clinical response by visit over time through Week 48 among participants with CDAI >150 at baseline will be reported. Clinical response is defined greater than or equal to (>=) 100-point reduction from baseline in CDAI, or CDAI <150. | Through Week 48 | 
| Percentage of Participants who Achieve Steroid-free Clinical Remission by Visit Over Time Through Week 48 Among Participants with CDAI >150 at Baseline | Percentage of participants who achieve steroid-free clinical remission by visit over time through Week 48 among participants with CDAI >150 at baseline will be reported. Steroid-free clinical remission is defined as CDAI <150 and not receiving corticosteroids by visit over time through Week 48 among participants with CDAI >150 at baseline. | Through Week 48 | 
| Percentage of Participants who Achieve Combined Clinical Response and Clinically Assessed Fistula Response Among Participants With CDAI >220 at Baseline | Percentage of participants who achieve combined clinical response and clinically assessed fistula response among participants with CDAI >220 at baseline at baseline will be reported. Clinical response is defined >=100-point reduction from baseline in CDAI, or CDAI <150. Clinically assessed fistula response is defined as closure of at least 50% of all external openings that were draining at baseline. | Week 24 and Week 48 | 
| Percentage of Participants who Achieve Combined Clinical Remission and Clinically Assessed Fistula Remission Among Participants with CDAI >220 at Baseline | Percentage of participants who achieve combined clinical remission and clinically assessed fistula remission among participants with CDAI >220 at baseline at will be reported. Clinical remission is defined as CDAI <150. Clinically assessed fistula remission is defined as 100% closure of all treated external openings, without development of new fistulas or abscesses and without any drainage by the external openings, occurring spontaneously or after gentle finger compression. | Week 24 and Week 48 | 
| Percentage of Participants who Achieve Combined Clinical Response and Clinically Assessed Fistula Remission Among Participants with CDAI >220 at Baseline | Percentage of participants who achieve combined clinical response and clinically assessed fistula remission among participants with CDAI >220 at baseline will be reported. Clinical response is defined >=100-point reduction from baseline in CDAI, or CDAI <150. Clinically assessed fistula remission is defined as 100% closure of all treated external openings, without development of new fistulas or abscesses and without any drainage by the external openings, occurring spontaneously or after gentle finger compression. | Week 24 and Week 48 | 
| Percentage of Participants who Achieve Combined Clinical Remission and Clinically Assessed Fistula Response among Participants with CDAI >220 at Baseline | Percentage of participants who achieve combined clinical remission and clinically assessed fistula response among participants with CDAI >220 at baseline will be reported. Clinically assessed fistula response is defined as closure of at least 50% of all external openings that were draining at baseline. | Week 24 and Week 48 | 
| Percentage of Participants who Achieve Combined Clinical Response and Clinically Assessed Fistula Response at Week 24 and Week 48 | Percentage of participants who achieve combined clinical response and clinically assessed fistula response at Week 24 and Week 48 will be reported. Clinical response is defined >=100-point reduction from baseline in CDAI, or CDAI <150. Clinically assessed fistula response is defined as closure of at least 50% of all external openings that were draining at baseline. | Week 24 and Week 48 | 
| Percentage of Participants who Achieve Combined Clinical Response and Clinically Assessed Fistula Remission at Week 24 and Week 48 | Percentage of participants who achieve combined clinical response and clinically assessed fistula remission at Week 24 and Week 48 will be reported. Clinical response is defined >=100-point reduction from baseline in CDAI, or CDAI <150. Clinically assessed fistula remission is defined as 100% closure of all treated external openings, without development of new fistulas or abscesses and without any drainage by the external openings, occurring spontaneously or after gentle finger compression. | Week 24 and Week 48 | 
| Percentage of Participants who Achieve Combined Clinical Remission and Clinically Assessed Fistula Response at Week 24 and Week 48 | Percentage of participants who achieve combined clinical remission and clinically assessed fistula response at Week 24 and Week 48 will be reported. Clinically assessed fistula response is defined as closure of at least 50% of all external openings that were draining at baseline. | Week 24 and Week 48 | 
| Percentage of Participants who Achieve Combined Clinical Remission and Clinically Assessed Fistula Remission at Week 24 and Week 48 | Percentage of participants who achieve combined clinical remission and clinically assessed fistula remission will be reported. Clinically assessed fistula remission is defined as 100% closure of all treated external openings, without development of new fistulas or abscesses and without any drainage by the external openings, occurring spontaneously or after gentle finger compression. | Week 24 and Week 48 | 
| Change from Baseline in Perianal Disease Activity Index (PDAI) Overall Score, Discharge Score, and Pain Score by Visit Over Time Through Week 48 | Change from baseline in PDAI overall score, discharge score, and pain score by visit over time through Week 48 will be reported. The PDAI is a scoring system to evaluate the severity of perianal lesion associated with Crohn's disease. It includes the following 5 items: (a) Discharge; (0=no discharge to 4= Gross fecal soiling) (b) Pain; (0=no activity to 4= severe pain, severe limitation) (c) Restriction of sexual activity;(0=no perianal disease/skin tags to 4= unable to engage in sexual activity) (d) Type of perianal disease; (0=no perianal disease/skin tags to 4=Anal sphincter ulceration or fistulae with significant undermining ok skin) and (e) Degree of induration; (0=no induration to 4=gross fluctuance/abscess. Higher scores indicate more severe or active disease. | Baseline up to Week 48 | 
| Percentage of Participants who Achieve Clinically Assessed Fistula Response by Visit Over Time Through Week 48 | Percentage of participants with clinically assessed fistula response by visit over time through Week 48 will be reported. Clinically assessed fistula response is defined as closure of at least 50% of all external openings that were draining at baseline. | Through Week 48 | 
| Percentage of Participants who Achieve Clinically Assessed Fistula Remission by Visit over Time Through Week 48 | Percentage of participants with clinically assessed fistula remission by visit over through Week 48 time will be reported. Clinically assessed fistula remission is defined as 100% closure of all treated external openings, without development of new fistulas or abscesses and without any drainage by the external openings, occurring spontaneously or after gentle finger compression. | Through Week 48 | 
| Percentage of Participants who Achieve Clinically Assessed Fistula Remission at Week 48 Among the Participants who Achieve Clinical Fistula Remission at Week 24 | Percentage of participants who achieve clinically assessed fistula remission at Week 48 among the participants who achieve clinical fistula remission at Week 24 will be reported. Clinically assessed fistula remission is defined as 100% closure of all treated external openings, without development of new fistulas or abscesses and without any drainage by the external openings, occurring spontaneously or after gentle finger compression. | Week 48 | 
| Percentage of Participants who Achieve Clinically Assessed Fistula Remission at Week 48 Among Those who Achieve Fistula Remission or Response at Week 24 | Percentage of participants achieving clinically assessed fistula remission at Week 48 among those who achieve fistula remission or response (defined either by clinical or radiological assessment) at Week 24 will be reported. Clinically assessed fistula remission is defined as 100% closure of all treated external openings, without development of new fistulas or abscesses and without any drainage by the external openings, occurring spontaneously or after gentle finger compression. | Week 48 | 
| Time to Clinical Fistula Remission | Time to clinical fistula remission will be reported. Clinical fistula remission is defined as 100% closure of all treated external openings without development of new fistulas or abscesses and without any drainage by the external openings (occurring spontaneously or after gentle finger compression). | Up to Week 96 | 
| Percentage of Participants who Achieve Radiological Fistula Predominantly Fibrotic Status for all Existent Fistulas Assessed by MRI at Week 24 and Week 48 | Percentage of participants who achieve radiological fistula predominantly fibrotic status for all existent fistulas assessed by MRI at Week 24 and Week 48 will be reported. | Week 24 and Week 48 | 
| Percentage of participants who Achieve Radiological Remission Based on Radiological Findings Assessed by MRI at Week 48 | Percentage of participants with radiological remission based on radiological findings assessed by MRI at Week 48 will be reported. Radiological remission is defined as absence of collections >2 cm of the perianal fistulas, confirmed by a blinded central review of the MRI results. | Week 48 | 
| Percentage of Participants who Achieve Radiological Remission Assessed by MRI at Week 48 Among the Participants who Achieve Radiological Remission at Week 24 | Percentage of participants who achieve radiological remission assessed by MRI at Week 48 among the participants who achieve radiological remission at Week 24 will be reported. Radiological remission is defined as absence of collections >2 cm of the perianal fistulas, confirmed by a blinded central review of the MRI results. | Week 48 | 
| Percentage of Participants who Achieve Combined Clinically Assessed and Radiological Fistula Remission at Week 48 Among the Participants who Achieve Combined Clinical and Radiological Fistula Remission at Week 24 | Percentage of participants who achieve combined clinically assessed and radiological (assessed by MRI) fistula remission at Week 48 among the participants who achieve combined clinical and radiological fistula remission at Week 24. | Week 48 | 
| Percentage of Participants who Achieve Combined Clinically Assessed and Radiological Fistula Remission as Week 48 Among the Participants with Clinical Fistula Response at Week 24 | Percentage of participants who achieve combined clinically assessed and radiological (assessed by MRI) fistula remission at Week 48 among the participants who achieve clinical fistula response at Week 24 will be reported. | Week 48 | 
| Percentage of Participants with Proctitis at Week 48 Among Participants with MRI-confirmed Proctitis at Baseline | Percentage of participants with proctitis at Week 48 among participants with MRI-confirmed proctitis at baseline will be reported. Proctitis is defined as the inflammation of the lining of the rectum. | Week 48 | 
| Change from Baseline in Magnetic Resonance Novel Index for Fistula imaging in Crohn's disease (MAGNIFI-CD) by Visit Over Time Through Week 48 | Change from baseline in MAGNIFI-CD by visit over time through Week 48 will be reported. The MAGNIFI-CD is based on MRI assessment of 6 items including number of fistula tracts, fistula length, hyperintensity of primary tract on post-contrast T1-weighted images, dominant feature, extension, and inflammatory mass. The total MAGNIFI-CD score ranges from 0 (no disease activity) to 25 (severe disease activity). It assesses the MRI data and determines perianal fistulizing CD activity with improved operating characteristics compared to the Van Assche Index (VAI) and the modified VAI (mVAI). | Baseline up to Week 48 | 
| Change from Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) by Visit Over Time Through Week 48 | Change from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) by visit over time through Week 48 will be reported. The IBDQ is a validated, 32-item, self-reported questionnaire for participants with IBD to evaluate patient reported outcomes (PROs) across 4 dimensions: bowel symptoms (loose stools, AP), systemic symptoms (fatigue, altered sleep pattern), social function (work attendance, need to cancel social events), and emotional function (anger, depression, irritability). Scores range from 32 to 224, with higher scores indicating better outcomes. | Baseline up to Week 48 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-F) Score by Visit Over Time Through Week 48 | Change From baseline in FACIT-F Score at Week 48 will be reported. The FACIT-F is a questionnaire that assesses self-reported tiredness, weakness, and difficulty conducting usual activities due to fatigue. The subscale consists of 13-item instrument to measure fatigue. Each of the 13 items has a set of five response categories: Not at all (=0), A little bit (=1), Somewhat (=2), Quite a bit (=3) and Very much (=4). A total FACIT-Fatigue subscale score is calculated as the sum of the 13 item scores (reserved scores [4 - score]) and ranges from 0 to 52, with a higher score indicating less fatigue. Positive changes from baseline indicate improvement of fatigue. Items are reverse scored when appropriate to provide a scale in which higher scores represent better functioning or less fatigue. | Baseline; Up to Week 48 | 
| Change From Baseline in Work Productivity and Activity Impairment Questionnaire: Crohn's Disease (WPAI:CD) by Visit Over Time Through Week 48 | Change from baseline in WPAI:CD by visit over time through Week 48 will be reported. The WPAI:CD assesses the impact of CD on work and activity during the past 7 days. The specificity of WPAI:CD is achieved by replacing health problems in the general health version of the WPAI with CD. It consists of 6 questions, which elicit the following information: employment status; hours missed due to CD; hours missed due to other reasons; hours actually worked; the degree to which CD affected productivity while working from 0 (no effect) to 10 (maximum impairment); and the degree to which CD affected regular activities (from 0-10). The sum of worktime missed and impairment at work yields the overall work impairment (productivity loss) score; scores are expressed as percent of impairment/productivity loss, with higher scores indicating greater impairment. | Baseline; Up to Week 48 | 
| Change from Baseline in Quality-of-life as Assessed by European Quality-of-Life Five Dimension Five Level Scale (EQ5D-5L) Score by Visit Over Time Through Week 48 | Change from baseline in quality-of-life (EQ5D-5L) score by visit over time through Week 48 will be reported. The EQ-5D-5L is a generic measure of health status. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). | Baseline up to Week 48 | 
| Change from Baseline in the Jorge-Wexner Score by Visit Over Time Through Week 48 | Change from baseline in the Jorge-Wexner score by visit over time through Week 48 will be reported. The Jorge-Wexner scoring system cross-tabulates frequencies and different anal incontinence presentations. | Baseline; Through Week 48 | 
| Change from Baseline in the Inflammatory Bowel Disease-Disability Index (IBD-DI) by Visit Over Time Through Week 48 | Change from baseline in the Inflammatory Bowel Disease-Disability Index (IBD-DI) by visit over time through Week 48 will be reported. The IBD-DI consists of 28 items that evaluate the 5 domains of overall health, body function, body structures, activity participation and environmental factors. Each item response is graded from 0 to 4 for each area evaluated (0 = very good; 1 = Good; 2 = medium; 3 = Bad; 4 = Very bad). The final composite score representative of the overall degree of disability ranging from -80 (maximum degree of disability) to 22 (no disability). | Baseline; Through Week 48 | 
| Number of Participants with Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs are defined as AEs with onset or worsening on or after date of first dose of study treatment. | Up to Week 48 | 
| Number of Participants with Treatment-emergent Serious Adverse Events (TESAEs) | An serious adverse event (SAE) is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product. TESAEs are defined as serious events between administration of study drug and after the last dose that were absent before treatment or that worsen relative to pretreatment state. | Up to Week 48 |