Biologic Therapies for Crohn's Disease

(PATHFINDER Trial)

Recruiting at 19 trial locations

Overseen By Christopher Ma, MD MPH

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Calgary

Must not be taking: TNF antagonists, Anti-integrins

Disqualifiers: Colonic dysplasia, Active infections, Recent surgery, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 12 months

297 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine which of the three approved biologic treatments for Crohn's disease most effectively heals small bowel ulcers without steroids after one year. It tests drugs targeting specific proteins involved in the disease, such as TNF alpha, integrins, and interleukins. Individuals with moderate-to-severe Crohn's disease affecting the small bowel, who have not previously taken biologics and are considering starting biologic treatment, may qualify for this study. As a Phase 4 trial, the treatment has already received FDA approval and proven effective, allowing researchers to understand how it benefits more patients.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that participants must not use any medications that are prohibited by the study. It's best to discuss your current medications with the trial team to see if they are allowed.

What is the safety track record for these treatments?

Research has shown that the treatments in this trial are generally safe for people with Crohn's disease. Health Canada has approved these treatments, indicating they have been tested for safety.

For TNFα blockers like adalimumab and infliximab, studies indicate similar safety profiles, meaning patients usually tolerate them well. Most side effects are mild, and serious issues are rare.

Drugs like ustekinumab and risankizumab, which target IL12/23 or IL23, also demonstrate positive safety results. One study found that serious side effects occurred in 10% of people taking risankizumab and 17% of those on ustekinumab, suggesting they are mostly safe, though monitoring for serious issues remains important.

Vedolizumab, whether administered by IV or as an injection under the skin, also maintains a good safety record. A small number of people developed antibodies against the drug, but serious issues are uncommon. Most side effects are not severe, and people usually continue treatment without problems.

Overall, these treatments tend to be well-tolerated. Serious side effects are uncommon, but discussing any concerns with a doctor is advisable. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for Crohn's disease because they offer targeted approaches that differ from the standard care options. Traditional treatments usually involve anti-inflammatory medications and immunosuppressants, but these biologics target specific pathways involved in the disease. For instance, Adalimumab and Infliximab are TNFα antagonists, Ustekinumab and Risankizumab inhibit interleukin pathways, and Vedolizumab acts as an anti-integrin. This specificity not only improves effectiveness but also may reduce side effects associated with broader immunosuppression. These targeted therapies can provide new hope for patients who haven't responded well to existing treatments.

What evidence suggests that this trial's treatments could be effective for Crohn's disease?

Research has shown that all treatments in this trial, which are already approved, effectively manage Crohn's disease. Participants in the TNFα antagonist arm will receive either Infliximab or Adalimumab. These medications block a specific protein that causes inflammation and have helped many patients achieve and maintain remission. In the Anti-IL12/23 or anti-IL23 arm, participants will receive either Ustekinumab or Risankizumab, which target other proteins involved in inflammation. Studies show these can greatly improve Crohn's symptoms, with many patients experiencing remission. The Anti-integrin arm involves Vedolizumab, which works differently by blocking certain cells from causing inflammation. It has also been effective, with many patients reaching remission after one year. All these treatments aim to reduce inflammation and heal ulcers in the intestines, which is crucial for managing Crohn's disease. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with moderate-to-severe ileal Crohn's Disease who haven't been treated with biologics before. They should have a documented large ileal ulcer and be experiencing active symptoms. Pregnant or breastfeeding women, those with recent surgeries, infections like TB or COVID-19, or a history of certain complications are excluded.

Inclusion Criteria

I had a colonoscopy showing a large ulcer in my ileum within the last 3 months.

Established CD diagnosis by conventional criteria

Written informed consent must be obtained and documented

Exclusion Criteria

I am not currently on treatment for any serious infections.

I have an active hepatitis B, hepatitis C, or HIV infection.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive biologic treatments (TNF antagonist, anti-integrin, or anti-IL23) according to standard of care

12 months

Visits at weeks 0, 2, 4, 6, 8, and every 8 weeks thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments for endoscopic remission and biomarker levels

4 weeks

Evaluations at months 4, 8, and 12

Extension

Participants may continue treatment based on standard care and clinical outcomes

Ongoing

What Are the Treatments Tested in This Trial?

Interventions

• Adalimumab
• Infliximab
• Risankizumab
• Ustekinumab
• Vedolizumab IV
• Vedolizumab IV and SC

Trial Overview The PATHFINDER trial is testing which class of approved biologic treatments (anti-TNF alpha, anti-integrin, anti-IL-23) best induces endoscopic remission in small bowel Crohn's disease at one year without steroids. Patients will receive Vedolizumab IV/SC, Risankizumab, Ustekinumab, Infliximab or Adalimumab.

How Is the Trial Designed?

Group I: TNFα antagonist Active Control 2 Interventions

Participants will receive either: * Infliximab 5 mg/kg intravenously \[IV\] at weeks 0, 2, 6, then 5 mg/kg every 8 weeks; OR * Adalimumab subcutaneously \[SC\] 160 mg at week 0, 80 mg at week 2, then 40 mg every 2 weeks

Group II: Anti-IL12/23 or anti-IL23 Active Control 2 Interventions

Participants will receive either: * Ustekinumab \~6 mg/kg IV x1, then 90 mg SC every 8 weeks; OR * Risankizumab 600 mg IV at weeks 0, 4, and 8, then 360 mg SC every 8 weeks

Group III: Anti-integrin Active Control 2 Interventions

Participants will receive either: * Vedolizumab 300 mg IV at weeks 0, 2, and 6, then every 8 weeks; OR * Vedolizumab 300 mg IV at weeks 0 and 2, then 108 mg SC every 2 weeks

Adalimumab is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Humira for:

• Rheumatoid arthritis
• Psoriatic arthritis
• Ankylosing spondylitis
• Crohn's disease
• Ulcerative colitis
• Plaque psoriasis
• Juvenile idiopathic arthritis

Approved in United States as Humira for:

• Rheumatoid arthritis
• Psoriatic arthritis
• Ankylosing spondylitis
• Crohn's disease
• Ulcerative colitis
• Plaque psoriasis
• Juvenile idiopathic arthritis
• Hidradenitis suppurativa

Approved in Canada as Humira for:

• Rheumatoid arthritis
• Psoriatic arthritis
• Ankylosing spondylitis
• Crohn's disease
• Ulcerative colitis
• Plaque psoriasis
• Juvenile idiopathic arthritis

Approved in Japan as Humira for:

• Rheumatoid arthritis
• Psoriatic arthritis
• Ankylosing spondylitis
• Crohn's disease
• Ulcerative colitis
• Plaque psoriasis
• Juvenile idiopathic arthritis

Who Is Running the Clinical Trial?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

Alimentiv Inc.

Collaborator

Trials

15

Recruited

3,300+

Published Research Related to This Trial

Antibodies targeting tumor necrosis factor, such as adalimumab, have been shown to effectively induce and maintain remission in patients with ulcerative colitis and Crohn's disease.

A recent randomized controlled trial specifically demonstrated the efficacy of adalimumab in inducing remission in patients with moderately to severely active ulcerative colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IBD: Adalimumab for ulcerative colitis— is the glass half empty or half full? Armuzzi, A., Pugliese, D.[2021]

Biologic treatments, particularly the anti-TNF monoclonal antibody infliximab, have significantly advanced the management of inflammatory bowel disease (IBD), especially for moderate-to-severe cases of Crohn's disease (CD) and ulcerative colitis (UC).

The review highlights various biologics under evaluation or approved for IBD, indicating a growing range of treatment options, although infliximab remains the only widely available biologic globally.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in biologic therapy for ulcerative colitis and Crohn's disease. D'Haens, G., Daperno, M.[2019]

In a 52-week study involving 24 patients with Crohn's disease who previously lost response to infliximab, adalimumab demonstrated significant efficacy, with clinical remission rates increasing from 35% at baseline to 58% at week 52.

Adalimumab was well tolerated, with no patients experiencing intolerance and no serious toxicities reported, indicating it is a safe option for maintaining remission in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adalimumab maintenance therapy for Crohn's disease with intolerance or lost response to infliximab: an open-label study. Peyrin-Biroulet, L., Laclotte, C., Bigard, MA.[2015]

In a study of 53 patients with Crohn's disease who did not respond to infliximab, adalimumab showed a long-term clinical response maintenance rate of 50.8% at 130 weeks, indicating its effectiveness as a second-line therapy.

The treatment also helped 80% of patients avoid major abdominal surgery and allowed for steroid tapering in 80% of those who had fistulas, although 58.5% experienced adverse events, leading to withdrawal in 17% of cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adalimumab for Crohn's disease with intolerance or lost response to infliximab: a 3-year single-centre experience. Oussalah, A., Babouri, A., Chevaux, JB., et al.[2022]

Monoclonal anti-TNF antibodies like infliximab and adalimumab are effective in inducing sustained remission in Crohn's disease and are also beneficial for ulcerative colitis, showcasing their efficacy in managing these chronic inflammatory bowel diseases.

New therapies targeting specific inflammatory pathways, such as ustekinumab, which inhibits IL12 and IL23, are showing promising clinical responses in Crohn's disease, indicating a shift towards more targeted and effective treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Biologic therapies in chronic inflammatory bowel diseases]. Reenaers, C., Louis, E., Belaiche, J.[2016]

Vedolizumab is an effective and safe treatment for Crohn's disease, specifically targeting α4β7-integrin to prevent lymphocyte trafficking to the gut, as shown in pivotal GEMINI studies involving patients with moderately to severely active disease.

The drug has a favorable safety profile, with no reported cases of progressive multifocal leukoencephalopathy (PML) or reactivation of latent infections like tuberculosis or hepatitis B, making it a suitable option for both first-line therapy and after previous treatment failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vedolizumab in the treatment of Crohn's disease. Tarabar, D., Hirsch, A., Rubin, DT.[2016]

Vedolizumab is a humanized monoclonal antibody that targets the α4β7 integrin receptor, specifically designed for treating moderate-to-severe ulcerative colitis and Crohn's disease in adults who have not responded well to standard therapies.

It has received global approval, including in the US and EU, for patients who have had inadequate responses to other treatments, highlighting its role as an important option for those with difficult-to-treat inflammatory bowel diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vedolizumab: first global approval. Poole, RM.[2021]

In a study of 336 patients with Crohn's disease and ulcerative colitis, vedolizumab was found to induce endoscopic improvement in 56.1% of ulcerative colitis patients and remission in 39.1% of Crohn's disease patients, indicating its efficacy as a treatment.

Anti-TNF naïve patients experienced significantly better endoscopic outcomes compared to those previously exposed to anti-TNF therapies, suggesting that prior treatment may affect the effectiveness of vedolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of Drug Exposure on Vedolizumab-Induced Endoscopic Remission in Anti-Tumour Necrosis Factor [TNF] Naïve and Anti-TNF Exposed IBD Patients. Verstockt, B., Mertens, E., Dreesen, E., et al.[2021]

In a systematic review of five randomized controlled trials involving patients with moderate-to-severe Crohn's disease who were nonresponsive or intolerant to TNF-antagonist therapy, ustekinumab and vedolizumab showed no significant differences in clinical response or remission during both induction and maintenance phases.

The safety profiles of ustekinumab and vedolizumab were also comparable, with no significant differences in the risk of adverse events, indicating that both treatments are similarly safe for patients with Crohn's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An indirect comparison of ustekinumab and vedolizumab in the therapy of TNF-failure Crohn's disease patients. Kawalec, P., Moćko, P.[2019]

Vedolizumab is a monoclonal antibody that effectively targets the α4β7 integrin to inhibit gut lymphocyte trafficking, providing a safe treatment option for patients with moderate to severe Crohn's disease and ulcerative colitis.

Unlike anti-TNF agents, which some patients may become intolerant to or lose response over time, vedolizumab offers a promising alternative for those who are primary nonresponders or have developed antidrug antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vedolizumab as a Treatment for Crohn's Disease and Ulcerative Colitis. Ha, C., Kornbluth, A.[2022]

Vedolizumab, a gut-selective integrin blocker for Crohn's disease and ulcerative colitis, showed a similar rate of serious adverse events (35.9%) compared to anti-TNF drugs (32.1%) in a study analyzing 499 reports for vedolizumab and 119,620 for anti-TNFs.

The study identified 22 groups of adverse events associated with vedolizumab, including 9 with serious outcomes, suggesting potential cardiovascular risks; however, these findings are preliminary and require further investigation through long-term studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of the real-world safety profile of vedolizumab using the United States Food and Drug Administration adverse event reporting system. Cross, RK., Chiorean, M., Vekeman, F., et al.[2023]

Citations

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Efficacy and Safety of Adalimumab in Crohn's Disease - PMC Pooled data from the two adalimumab doses showed that 70 patients met the study criteria. Fistula healing rates from the start of CHARM were 50% (6 and 12 ...

2. eurjmedres.biomedcentral.com eurjmedres.biomedcentral.com/articles/10.1186/s40001-022-00817-6

Adalimumab for induction of remission in patients with Crohn's ... Seventy-three percent (406/553) of ADA participants failed to achieve clinical remission at 4 weeks compared with 92% (336/366) of placebo ...

3. humirapro.com humirapro.com/crohns-disease

HUMIRA® (adalimumab) for Crohn's Disease in adults Learn about the efficacy of HUMIRA in maintaining remission and response in adults with moderate to severe Crohn's disease (CD).

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6701510/

Adalimumab Effectiveness Up to Six Years in ... Adalimumab improved disease activity, work productivity, and activity impairment in adalimumabnaïve patients enrolled in PYRAMID registry. No ...

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Study Details | NCT02871635 | BI 695501 Versus Humira ... The primary objective of this trial is to compare the clinical efficacy of BI 695501 with EU-approved Humira® in patients with active Crohn's disease (CD).

6. skyrizihcp.com skyrizihcp.com/gastroenterology/crohns-disease/efficacy/skyrizi-vs-stelara

SKYRIZI vs STELARA ® (ustekinumab) RESULTS ... Head-to-head data of SKYRIZI vs STELARA (ustekinumab) for the treatment of moderately to severely active Crohn's disease (CD) in adults. See Important Safety

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Risankizumab versus Ustekinumab for Moderate-to-Severe ... Background: The efficacy and safety of risankizumab as compared with ustekinumab in patients with Crohn's disease are unknown. Methods: In ...

8. news.abbvie.com news.abbvie.com/2023-10-15-AbbVies-SKYRIZI-R-risankizumab-Versus-STELARA-R-ustekinumab-Head-to-Head-Study-in-Crohns-Disease-Meets-All-Primary-and-Secondary-Endpoints

AbbVie's SKYRIZI® (risankizumab) Versus STELARA® ... Serious adverse events occurred in 10% of risankizumab-treated patients and 17% of ustekinumab-treated patients, respectively.1. Risankizumab is ...

9. mayoclinic.org mayoclinic.org/medical-professionals/digestive-diseases/news/examining-the-real-world-effectiveness-and-safety-of-risankizumab-in-patients-with-crohns-disease/mac-20589059

Examining the real-world effectiveness and safety of ... 85.8% of patients were previously exposed to advanced therapy and 54.7% had prior UST exposure. · Rates of clinical remission achieved at 12 ...

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P0722 Efficacy and Safety of Risankizumab in Patients With ... Among the intent-to-treat pts, clinical remission rates (per AO data) remained stable from wk52 to wk100 (CDAI: 75.3% [168/223] to 84.4% [141/ ...