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

Trial Summary

What is the purpose of this trial?

Background: Crohn s disease (CD) is an inflammatory bowel disease. It causes inflammation of the gut. Symptoms may include diarrhea, abdominal pain, fatigue, weight loss and malnutrition. CD has no cure, but symptoms can sometimes be controlled with medicine. Researchers want to see if it is safe to treat CD with the medicine vorinostat. It is thought that vorinostat may reduce the inflammation process of CD. This may then help to relieve symptoms of CD. Participants who respond to Vorinostat will be invited to an extension phase of treatment with Vorinostat and possibly a maintenance treatment using Ustekinumab. Objectives: To see if vorinostat is safe for people with moderate-to-severe CD. To see if it is safe for people with moderate-to-sever CD to receive maintenance therapy using Ustekinumab after successful treatment of Vorinostat. Eligibility: Adults 18-65 with moderate-to-severe CD that medicine is not controlling. Design: Phase I is screening. It may last 120 days. Participants will have: Physical exam Medical history Tests of blood, urine, and stool samples Heart test Questionnaires Tuberculosis skin test They may have a colonoscopy and lymphapheresis collection. These will be explained in a separate consent. They will keep a diary of symptoms. Phase II is treatment using Vorinostat. It will take 12-13 weeks. Participants will take the study drug by mouth twice daily for 12 weeks. They will get a weekly phone call to talk about how the drug makes them feel. They will have blood taken regularly. Every 4 weeks, they will have a check-up that will repeat some screening tests. Phase III extension treatment of Vorinostat for an additional 6 months for those who respond to vorinostat and it is safe for them to continue treatment. Participants will continue to receive weekly calls to talk about how the drug makes them feel. They will have blood taken regularly. Every 3 months, they will have a check-up that will repeat some screening tests. Phase IV: is maintenance therapy for 2 years with Ustekinumab. Participants will receive a one time loading dose of ustekinumab, and then will receive the approved maintenance dose once every 8 weeks, at which time they will return to the NIH Clinical Center for evaluation. The participant will get a phone call 3 days after each dose and again 2 weeks later to see how the drug makes them feel. After two years of receiving treatment with ustekinumab the participant will have an end of study visit, where some of the screening tests, including a colonoscopy, will be repeated.

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.

What data supports the effectiveness of the drug Ustekinumab for treating Crohn's Disease?

Research shows that Ustekinumab is effective and relatively safe for treating moderate to severe Crohn's Disease, as demonstrated in clinical trials and real-life studies. It is approved for patients who have not responded to other biologic treatments. ^{1 2 3 4 5}

How is the drug Vorinostat + Ustekinumab unique for treating Crohn's disease?

Vorinostat + Ustekinumab is unique because it combines Vorinostat, a drug that modifies gene expression, with Ustekinumab, a monoclonal antibody targeting specific proteins involved in inflammation, offering a novel approach by potentially addressing Crohn's disease through different mechanisms than standard treatments. ^{1 6 7 8 9}

Research Team

Ivan J Fuss, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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, 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]

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 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]

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 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 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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Ustekinumab in Crohn's Disease: New Data for Positioning in Treatment Algorithm. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Ustekinumab in Crohn's disease: evidence to date and place in therapy. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Ustekinumab for Crohn's Disease: Results of the ICC Registry, a Nationwide Prospective Observational Cohort Study. [2020]

4. United States 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. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Evolution of Symptoms After Ustekinumab Induction Therapy in Patients With Crohn's Disease. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Ustekinumab Exposure-outcome Analysis in Crohn's Disease Only in Part Explains Limited Endoscopic Remission Rates. [2020]

7. Australia pubmed.ncbi.nlm.nih.gov

Real-world effectiveness and safety of ustekinumab for the treatment of Crohn's disease: the Scottish ustekinumab cohort. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Real World Experience With Ustekinumab in Children and Young Adults at a Tertiary Care Pediatric Inflammatory Bowel Disease Center. [2023]

9. United States 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. [2023]