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....
Are 18 to 65 years of age, inclusive, at enrollment date.
Have a diagnosis of CD, UC, or CGD colitis that has been endoscopically or radiographically confirmed. A colonoscopy will be required at baseline to document mucosal disease activity. SES-CD for CD and CGD colitis will be obtained with minimum score of 7 and MES for UC patients will be obtained with minimum score of 2.
Have active CD symptoms as defined by a CDAI score between 220 and 350, UC symptoms defined by a Mayo score of 6 to 10 (moderate) or 10 to 12 (severe), or CGD colitis symptoms defined as an HBI score of 8-16 (moderate) or > 16 (severe), and demonstrate active symptoms as defined by continued weight loss, abdominal pain and/or diarrhea not controlled by standard therapy.
The participant must have active CD and UC symptoms (as noted above) and therefore have had an inadequate response to, loss of response to, or intolerance to at least 1 of the following agent groups in control of their disease (as defined below for each individual agent group: Corticosteroids or Immunomodulators or TNF-alpha antagonists or Anti-integrin antibodies or JAK inhibitors or IL-12p19 (IL-23) antagonists). No specific induction therapy or long-term treatment for CGD colitis patients has been defined; therefore all symptomatic patients will be evaluated for inclusion on individual basis.
Presence of clinically significant systemic infection (e.g., chronic or acute infection, urinary tract infection, or upper respiratory tract infection) within three months of screening.
History or presence of recurrent or chronic infection (e.g., viral infection [including hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV)], bacterial infection, systemic fungal infection, or syphilis).
Positive for tuberculosis (TB) via QuantiFERON-Gold (QFT-G). Individuals who are known to have received the tuberculosis vaccine will be administered the QFT-G. Patients cannot have received tuberculosis vaccine within 12 months prior to start of study and cannot receive tuberculosis vaccine while on study or within 12 months from the time of conclusion of study participation.
Has a history of active tuberculosis (TB) or a chest x-ray (CXR) with findings suggestive of old TB infection including calcified nodular lesions, apical fibrosis, or pleural scarring), acute or chronic HBV, HCV, HIV, or opportunistic infections.
Single group
Vorinostat
DrugIt 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
Ustekinumab
DrugUstekinumab inhibits the bioactivity of human IL-12 and IL- 23 by preventing these cytokines from binding to the IL- 12Rbeta1 receptor protein expressed on the surface of immune cells. It is FDA approved for the treatment of adult patients with active psoriatic arthritis and more recently, in September 2016, ustekinumab has been approved for the treatment of patients with Crohn s disease.
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.
This is assessing safety issue
170 or greater score on IBDQ
Change in Inflammatory Bowel Disease Questionnaire (IBDQ) score from baseline and proportion of participants with a total score of 170 or greater in response to vorinostat.
Determine safety and tolerability of ustekinumab maintenance
To determine if ustekinumab is safe and tolerated in CD patients that have received treatment with vorinostat as measured by the rate, frequency, and severity of adverse events (AEs).
Mucosal healing from use of Vorinostat
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% in response to vorinostat
Changes in CDAI score equal to or greater than 70
To determine the number of participants participants that achievea clinical response at week 12 and week 36, as defined by a decrease in CDAI from baseline by greater than or equal to 70 points for CD patients, upon completion of study Phase II and Phase III
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