Vorinostat + Ustekinumab for Crohn's Disease

Overseen By Ivan J Fuss, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Anticoagulants, Anti-seizure, NSAIDs

Disqualifiers: Infections, Cancer, Diabetes, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

Duration: 12 weeks

35 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether vorinostat, a histone deacetylase inhibitor, can safely reduce inflammation in people with Crohn's disease, which causes gut inflammation and symptoms like diarrhea and abdominal pain. Participants who respond well to vorinostat may continue treatment and later receive maintenance therapy with ustekinumab to control symptoms long-term. The trial seeks adults whose moderate-to-severe Crohn's disease is not well-managed by current medications. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial protocol allows some medications to be continued if they meet specific conditions. For example, certain medications like 5-aminosalicylic acid compounds, corticosteroids, and CD-specific antibiotics can be continued if they have been stable for a specified period before the trial. However, some medications, like anti-TNF and anti-integrin therapies, require a washout period (time without taking the medication) before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that vorinostat, an HDAC inhibitor, is under study for its safety in treating various conditions, including intestinal inflammation. Some studies suggest that vorinostat might aid in gut healing, potentially benefiting those with inflammatory bowel diseases like Crohn's disease. However, as research for this use remains in early stages, detailed safety information for Crohn's patients is not yet fully available.

In contrast, ustekinumab is already approved for treating Crohn's disease and has a well-established safety record. Long-term studies have demonstrated its safety for people with Crohn's disease. Compared to placebo treatments, it consistently shows positive safety results over several years.

Overall, while vorinostat is still under investigation for safety in Crohn's disease, ustekinumab is already recognized as a safe option for many patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Crohn's Disease because they offer unique mechanisms of action compared to existing options like anti-inflammatory drugs, immunosuppressants, and biologics. Vorinostat, primarily known for its cancer treatment capabilities, operates as a histone deacetylase inhibitor, which could modulate immune responses differently and potentially reduce inflammation more effectively in Crohn's patients. Ustekinumab, already used in Crohn's treatment, targets specific proteins involved in inflammation, but in this trial, it's being tested in combination with Vorinostat to explore enhanced effects. This dual approach could offer more robust relief by simultaneously addressing multiple pathways involved in the disease.

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

Research suggests that vorinostat, one of the treatments in this trial, might help reduce inflammation in people with Crohn's disease by blocking certain proteins involved in causing inflammation. Studies have shown that these medications can have strong anti-inflammatory effects in various conditions, including experimental colitis, a model for bowel inflammation.

Ustekinumab, another treatment option in this trial, is already approved for Crohn's disease. It has proven effective, with more than half of patients continuing treatment after two years. Many patients experience symptom relief within a year of starting ustekinumab, and it remains effective over time. ^{6 7 8 9 10}

Who Is on the Research Team?

Ivan J Fuss, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Are You a Good Fit for This Trial?

Adults aged 18-65 with moderate-to-severe Crohn's Disease not well-controlled by standard treatments, including corticosteroids or immunomodulators. Participants must have a confirmed diagnosis of CD and active symptoms. Women of childbearing age must use birth control and not be pregnant or breastfeeding; men are also required to use contraception post-treatment.

Inclusion Criteria

I have Crohn's disease confirmed by tests and need a colonoscopy to show my current condition.

I have Crohn's disease with moderate symptoms not managed by standard treatments.

I have tried treatments like steroids or biologics without success.

Exclusion Criteria

I have a history of getting infections often.

I have a history of tuberculosis, hepatitis B or C, HIV, or serious infections.

Positive for tuberculosis via QuantiFERON-Gold (QFT-G)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

17 weeks

Multiple visits for exams and tests

Treatment

Participants receive Vorinostat 100mg PO BID for 12 weeks

12 weeks

Weekly phone calls, blood tests, and check-ups every 4 weeks

Extension Treatment

Participants who respond to Vorinostat continue treatment for an additional 6 months

24 weeks

Weekly phone calls, blood tests, and check-ups every 3 months

Maintenance Therapy

Participants receive Ustekinumab for 2 years with a loading dose followed by maintenance doses every 8 weeks

24 months

Phone calls 3 days and 2 weeks after each dose, end of study visit

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ustekinumab
• Vorinostat

Trial Overview The trial is testing Vorinostat for treating Crohn's Disease over a period of up to six months for responders, followed by maintenance therapy with Ustekinumab for two years. The study includes initial screening, treatment phases where participants take Vorinostat orally and receive Ustekinumab injections at intervals, along with regular check-ups and tests.

How Is the Trial Designed?

Group I: 2 Experimental Treatment 1 Intervention

participants will receive Vorinostat 100mg PO BID for 6months

Group II: 1 Experimental Treatment 1 Intervention

participants will receive Vorinostat 100mg PO BID for 12 weeks

Group III: 3 Active Control 1 Intervention

participants will receive ustekinumab (weight base induction dose followed by 90mg SC every 8 weeks for 24 months)

Vorinostat is already approved in United States, European Union for the following indications:

Approved in United States as Zolinza for:

• Cutaneous T-cell lymphoma

Approved in European Union as Zolinza for:

• Cutaneous T-cell lymphoma

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

Ustekinumab, a monoclonal antibody that targets IL-12 and IL-23, has been shown to be both effective and safe for treating moderate to severe Crohn's disease in various clinical trials and real-life studies.

Currently, ustekinumab is approved for use in both treatment-naive patients and those who have previously received biologic therapies, although a comprehensive therapeutic algorithm for its use is still lacking.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ustekinumab in Crohn's Disease: New Data for Positioning in Treatment Algorithm. D'Amico, F., Peyrin-Biroulet, L., Danese, S.[2022]

Ustekinumab treatment for Crohn's disease showed significant symptom improvement, such as reduced stool frequency, as early as day 1 post-infusion, compared to placebo.

By week 16, cumulative clinical remission rates increased notably, reaching 55.5% in patients without prior biologic failure, indicating that ustekinumab is effective for long-term management of Crohn's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolution of Symptoms After Ustekinumab Induction Therapy in Patients With Crohn's Disease. Colombel, JF., Sands, BE., Gasink, C., et al.[2023]

In a study of 216 patients with moderate to severe Crohn's disease treated with ustekinumab, the 12-month cumulative rates of clinical remission and mucosal healing were 32.0% and 32.7%, respectively, indicating its effectiveness in managing the disease.

The treatment was found to be safe, with a serious adverse event rate of 13.6 per 100 patient-years, suggesting that ustekinumab can be a reliable option for patients with complex Crohn's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world effectiveness and safety of ustekinumab for the treatment of Crohn's disease: the Scottish ustekinumab cohort. Plevris, N., Fulforth, J., Siakavellas, S., et al.[2021]

In a comparison of risankizumab (RZB) and ustekinumab (UST) for treating Crohn's disease, RZB showed significantly higher rates of clinical and endoscopic improvement during the induction phase, with 15% more patients achieving CDAI remission and 26% more showing endoscopic response.

After the maintenance phase, the rates of CDAI remission were similar between RZB and UST, but RZB still demonstrated better endoscopic response and remission rates, indicating that while both treatments are effective, RZB may offer advantages during initial treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-Adjusted Indirect Comparison Between Risankizumab and Ustekinumab for Induction and Maintenance Treatment of Moderately to Severely Active Crohn's Disease. Dubinsky, M., Ma, C., Griffith, J., et al.[2023]

In a study of 34 Crohn's disease patients who previously failed anti-TNF therapies, ustekinumab (UST) achieved a clinical remission rate of 70.5%, indicating its efficacy as a treatment option for these patients.

UST was particularly effective in patients with fistulizing disease, with a 70% remission rate, suggesting it may be a preferred treatment for this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

P066 Real-World Experience of Ustekinumab in Crohn's Disease Patients With Prior Anti-TNF Therapy at a Tertiary Care Hospital. Tripathi, K., Groudan, K., Chalhoub, J., et al.[2023]

In a study of 221 Crohn's disease patients treated with ustekinumab over a median follow-up of 52 weeks, 38.2% achieved corticosteroid-free clinical remission by week 24, and 37.1% by week 52, indicating its effectiveness in managing the disease.

Ustekinumab was found to be relatively safe, with a low incidence of severe infections (3.5 per 100 patient-years), and treatment discontinuation primarily occurred due to lack of response, affecting 33.9% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ustekinumab for Crohn's Disease: Results of the ICC Registry, a Nationwide Prospective Observational Cohort Study. Biemans, VBC., van der Meulen-de Jong, AE., van der Woude, CJ., et al.[2020]

In a study of 86 Crohn's disease patients who were mostly resistant to other treatments, ustekinumab showed a clinical remission rate of 39.5% after 24 weeks, indicating its effectiveness in managing symptoms.

However, the study found low rates of endoscopic response (20.5%) and remission (7.1%), suggesting that higher doses of ustekinumab may be necessary to improve these endoscopic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ustekinumab Exposure-outcome Analysis in Crohn's Disease Only in Part Explains Limited Endoscopic Remission Rates. Verstockt, B., Dreesen, E., Noman, M., et al.[2020]

In a study of 52 pediatric patients with inflammatory bowel disease (IBD) treated with ustekinumab, 50% of those previously exposed to biologics and 90% of biologic-naïve patients achieved steroid-free remission after 52 weeks, indicating its effectiveness in this age group.

The treatment was found to be safe, with only two infusion reactions reported and no serious adverse events or infections, suggesting a favorable safety profile for ustekinumab in children and young adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real World Experience With Ustekinumab in Children and Young Adults at a Tertiary Care Pediatric Inflammatory Bowel Disease Center. Dayan, JR., Dolinger, M., Benkov, K., et al.[2023]

Ustekinumab, an interleukin 12/23p40 inhibitor, has been found to be an effective and relatively safe treatment option for moderate to severe Crohn's disease, addressing a significant need for nonresponders to other therapies.

The review highlights the promise of ustekinumab in managing Crohn's disease, although further data from randomized controlled trials and real-life studies are still needed to fully establish its efficacy and safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ustekinumab in Crohn's disease: evidence to date and place in therapy. Engel, T., Kopylov, U.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9935642/

Long-term effectiveness and safety of ustekinumab in Crohn's ... Ustekinumab is an effective and well-tolerated treatment for Crohn's disease. More than half of all patients continued ustekinumab treatment after 104 weeks.

2. stelarahcp.com stelarahcp.com/crohns-disease/efficacy

Crohn's Disease (CD): Efficacy | STELARA® (ustekinumab) HCP A Majority of Patients in the Maintenance Study Were in Clinical Remission at1 Year After Induction Dose · More Than Two-thirds of Patients in Clinical Remission ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1590865822007344

Rates, predictive factors and effectiveness of ustekinumab ... We reported a corticosteroid-free clinical remission rate of 29.6% at last follow-up (median follow-up time after dose intensification: 16.9 months), which is ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6032827/

Long‐term efficacy and safety of ustekinumab for Crohn's ... Using observed data, clinical remission rates were also maintained from Week 44 through Week 92 in the ustekinumab 90 mg every 12 weeks group (77.4%‐79.2%), as ...

5. nature.com nature.com/articles/s41598-024-65987-1

Efficacy, drug sustainability, and safety of ustekinumab ... At year 3, the clinical remission rate of the Q8 dosage patients was 69.5% whereas it was 61.9% for the Q12 regimen subjects. These results are ...

6. stelarahcp.com stelarahcp.com/crohns-disease/safety-profile

Crohn's Disease (CD): Safety Profile View STELARA® (ustekinumab) safety profile data, including common adverse reactions and additional safety information. See full Prescribing & Safety ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38310565/

Safety of Ustekinumab in Inflammatory Bowel Disease The final cumulative ustekinumab safety data through 5 years in CD and 4 years in UC demonstrated favourable safety compared to placebo.

8. academic.oup.com academic.oup.com/ecco-jcc/article/18/7/1091/7600484

Safety of Ustekinumab in Inflammatory Bowel Disease: Pooled ... The final cumulative ustekinumab safety data through 5 years in CD and 4 years in UC demonstrated favourable safety compared to placebo and continue to support ...

9. jnj.com jnj.com/media-center/press-releases/new-stelara-ustekinumab-long-term-data-support-its-established-safety-profile-in-inflammatory-bowel-disease-and-durable-efficacy-in-ulcerative-colitis

New STELARA® (ustekinumab) Long-Term Data Support ... Final cumulative pooled IBD safety data support the longstanding safety profile of STELARA across all IBD approved indications

10. sciencedirect.com sciencedirect.com/science/article/pii/S1590865825011284

Long-term safety of ustekinumab in Crohn's disease Here we summarise the long-term safety data for adult patients with Crohn's disease who were treated with ustekinumab, were followed in I ...