Safety and Tolerability of Vorinostat for the Treatment of Moderate-to-Severe Crohn s Disease
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|ClinicalTrials.gov Identifier: NCT03167437|
Recruitment Status : Recruiting
First Posted : May 30, 2017
Last Update Posted : March 29, 2019
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.
To see if vorinostat is safe for people with moderate-to-severe CD.
Adults 18 65 with moderate-to-severe CD that medicine is not controlling.
Phase I is screening. It may last 120 days. Participants will have:
Tests of blood, urine, and stool samples
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. 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 is post-treatment. It starts with a check-up that lasts up to 2 days. Participants will repeat some screening tests. They will have a follow-up phone call 30 days after treatment ends. They will have check-ups 6 and 9 months after starting the study drug. They will repeat some screening tests.
The study ends after the 9-month follow-up.
|Condition or disease||Intervention/treatment||Phase|
|Crohn's Disease||Drug: Vorinostat||Phase 1 Phase 2|
Crohn's Disease (CD), a major sub-type of inflammatory bowel disease (IBD), is a chronic, life-long condition characterized by relapsing inflammation of the gastrointestinal (GI) tract. Despite recent advances in IBD therapeutics, a significant number of patients with CD continue to have significant symptoms.
In prior studies, it has been demonstrated that epigenetic modifications of the genome are associated with and may contribute to the pathogenesis of various disease entities. One type of epigenetic modification involves acetylation and deacetlyation of histones, mediated by histone acetyl transferases (HATs) and histone deacetylases (HDACs). Acetylation and deacetylation of histones regulates the affinity of histones for DNA, thus modulating the accessibility of transcription factors to gene promoters and enhancer sites. Of interest in this context is evidence that epigenetic modifications brought about by HDAC inhibitors (HDACi), i.e., agents that cause hyperacetylation of histones, can limit the course of gastrointestinal inflammation1-3. One naturally occurring HDAC inhibitor, the bacterial product butyrate, has been shown to have effects on gene transcription 4,5 that regulate potentially deleterious pro-inflammatory responses to microbiota in the gut environment. It has been shown that treatment of dendritic cells and macrophages with butyrate leads to down-regulation of lipopolysaccharide induced pro-inflammatory mediators such as nitric oxide, IL-6 and IL-12.6 In addition, butyrate has been shown to enhance the differentiation of intestinal Foxp3-positive T cells (T regulatory T cell (Treg) development that then modulates GI inflammation and contributes to mucosal homeostasis7,8. Along the same lines, another HDAC inhibitor, vorinostat, has been shown to ameliorate graft-vs-host disease (GVHD) affecting the GI tract in patients undergoing allogeneic bone marrow transplantation9. This anti-inflammatory effect was also attributable to increased Treg activity, suggesting that vorinostat, like butyrate, decreases inflammation by enhancing the activity of cells with the capacity to down-regulate immune responses. The effect of vorinostat on Treg cell expansion in this study was particularly notable because it suggested that Treg cell numbers can be increased by agents that have an intrinsic effect on the transcription of key Treg cell transcription factors. On this basis, treatment of patients with inflammatory and autoimmune diseases by influencing Treg cell numbers may be more effective than alternative existing methods of inducing Treg cell expansion such as administration of purified Tregs.
We propose a Phase I/II clinical trial to study the safety and efficacy of vorinostat (100 mg PO BID for 12 weeks) in treating 20 individuals with moderate-to-severe CD who are not controlled by standard maintenance therapy. We will assess the effectiveness of vorinostat by evaluating changes in symptom scores, endoscopic/histologic findings, and immunologic/laboratory parameters. The participant will return to the NIH CC after starting treatment on Days 28, 56 and Week 12 for assessing safety and testing of clinical and immunologic response. They will return again 6 and 9 months post-treatment initiation for safety and efficacy evaluations.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||35 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||An Open-Label, Phase I/II Pilot Study to Assess the Safety and Tolerability of Vorinostat for the Treatment of Moderate-to-Severe Crohn s Disease|
|Actual Study Start Date :||October 30, 2017|
|Estimated Primary Completion Date :||June 30, 2021|
|Estimated Study Completion Date :||June 30, 2022|
Placebo Comparator: 1
participants will receive Vorinostat 100mg PO BID for 12 weeks
It is a histone deacetylase (HDAC) inhibitor indicated for the treatment of cutaneous manifestations in patient with cutaneous T-cell lymphoma (CTCL) who have progress, persistent or recurrent disease on or following two systemic therapies. We are using this drug off label for the purpose of this study
- To evaluate the safety and tolerability of vorinostat in patients with moderate to severe CD as measured by the rate, frequency, and severity of adverse events (AEs) after 12 weeks of treatment. [ Time Frame: Days 28, 56 and 12 and 24 weeks after start of treatment ]This is assessing safety issue
- 170 or greater score on IBDQ [ Time Frame: end of study ]4. Change in IBDQ score from baseline and proportion of participants with a total score of 170 or greater.
- Determine stability of remission/response [ Time Frame: week 24 and week 36 ]5. Stability of remission/response at Week 24 and Week 36 (6 and 9 months after start of treatment) as determined by CDAI score.
- Mucosal healing [ Time Frame: end of study ]3. To determine the number of participants with mucosal healing, as assessed by a decrease in endoscopic scores from baseline to zero (Simple Endoscopic Score Crohn's Disease [SES-CD] for CD) or the number of participants with mucosal response as assessed by a decrease from baseline in SES-CD by 50%.
- Changes in CDAI score equal to or greater than 70 [ Time Frame: weeks 12 and 24 ]1. To determine the number of participants that achieve a clinical response at Week 12 and Week 24, as defined by a decrease in CDAI from baseline by greater than or equal to 70 points for CD patients.
- Acheive clinical remission [ Time Frame: weeks 12 and 24 ]2. To determine the number of participants that achieve clinical remission at Week 12 and Week 24 as defined by a CDAI score of 150 points or less.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03167437
|Contact: Ivan J Fuss, M.D.||(301) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 email@example.com|
|Principal Investigator:||Ivan J Fuss, M.D.||National Institute of Allergy and Infectious Diseases (NIAID)|