Safety and Tolerability of Vorinostat for the Treatment of Moderate-to-Severe Crohn s Disease

Clinical Trial ID: NCT03167437


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. Objectives: To see if vorinostat is safe for people with moderate-to-severe CD. 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. 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.

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.


  • INCLUSION CRITERIA: 1. Are 18 to 65 years of age, inclusive, at enrollment date. 2. Have a diagnosis of CD that has been endoscopically or radiographically confirmed. A colonoscopy will be required at baseline to document mucosal disease activity. SES-CD will be obtained with minimum score of 7. 3. Have active CD symptoms as defined by a CDAI score between 220 and 350 and demonstrate active symptoms as defined by continued weight loss, abdominal pain and/or diarrhea not controlled by standard therapy. 4. The participant must have active CD symptoms 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 sign antagonists or Anti-integrin antibodies) a. Corticosteroids i. Signs and symptoms of persistently active disease despite a history of at least one 4-week induction regimen that included a dose equivalent to prednisone greater than or equal to 30 mg PO once daily (QD) for 2 weeks or intravenously (IV) for 1 week OR ii. One failed attempt to taper corticosteroids to below a dose equivalent to prednisone 10 mg PO QD or to taper to below a dose of 9 mg of budesonide OR iii. History of intolerance of corticosteroids at the discretion of the principal investigator (PI) (including but not limited to Cushing s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, or infection) b. Immunomodulators i. Signs and symptoms of persistently active disease despite a history of at least one 12-week regimen of oral azathioprine (AZA) (greater than or wqual to 2.5 mg/kg/Day) or 6-MP (greater than or equal to 1.5 mg/kg/Day) OR ii. Signs and symptoms of persistently active disease despite a history of at least one 12-week regimen of MTX (greater than or equal to 25 mg/week) OR iii. History of intolerance of at least one immunomodulator (including but not limited to nausea/vomiting leading to discontinuation, abdominal pain, pancreatitis, liver function test abnormalities, lymphopenia, thiopurine methyltransferase genetic mutation, or serious infection) c. TNF-alpha sign antagonists with signs and symptoms of persistently active disease despite a history of receiving infliximab, adalimumab, or certolizumab at a dose approved for the treatment of CD and: i. Patient had an inadequate response after completing the full induction regimen, per approved product labeling ii. Responded initially but then lost response with continued therapy iii. Patient had a significant adverse event response which precluded further use including but not exclusion of infusion reaction, serum sickness and/or lupus-like rash. d. Anti-integrin antibodies: with signs and symptoms of persistently active disease despite a history of receiving an anti-integrin antibody agent (natalizumab or vedolizumab) at a dose approved for the treatment of CD and: i. Patient had an inadequate response after completing the full induction regimen, per approved product labeling ii. Responded initially but then lost response with continued therapy iii. Patient had a significant adverse event response which precluded further use including but not exclusion of infusion reaction, serum sickness and/or lupus-like reaction. 5. At the discretion of the PI, concomitant medications will be permitted if the following conditions are met prior to baseline assessment (Day-1): a. 5-aminosalicylic acid (ASA)-based compounds are permissible if: i. Oral 5-ASA-based compounds must be at a stable dose for at least 3 weeks prior to baseline or ii. Recently discontinued oral 5-ASA-based compounds must have been discontinued at least 3 weeks prior to baseline or iii. Rectal 5-ASA-based compounds are not permissible during the study and must have been discontinued at least 3 weeks prior to baseline. b. Corticosteroids (e.g., prednisone, budesonide) are permissible if: i. Oral corticosteroids must be at a prednisone-equivalent dose of less than or equal to 40 mg/day, or 9 mg/day of budesonide, and have been at a stable dose for at least 3 weeks prior to baseline or ii. Discontinuation of oral corticosteroids must have been completed at least 3 weeks prior to baseline or iii. Parenteral (subcutaneous, intramuscular, or IV) or rectal corticosteroids are not permitted during the study and must not have been used within a 3-week period prior to baseline c. CD-specific antibiotics are permissible if using an antibiotic for treatment of CD ( a CD-specific antibiotic i.e., metronidazole, ciprofloxacin, rifaximin, ampicillin, sulfonamide and tetracycline) i. Participants must have been using the antibiotic for at least 3 weeks before baseline at a stable dose or ii. If not currently using a CD-specific antibiotic, the stop date must have been at least 3 weeks prior to baseline. d. Immunomodulators are permissible if: i. Participants receiving chronic (i.e., greater than or equal to 12 weeks) treatment with AZA, 6-MP, or MTX prior to baseline must be on a stable dose for at least 6- 8 weeks prior to baseline and must continue on this same dose during the study. OR ii. Participants who have discontinued therapy with AZA, 6-MP, or MTX must have stopped the medication at least 4 weeks prior to baseline. OR iii. Participants must not have received therapy with other known immunomodulators (e.g., cyclosporine, tacrolimus, sirolimus, pentoxifylline, or mycophenolate mofetil) or experimental agents (e.g., granulocyte- or macrophage colony stimulating factor) for at least 8 weeks or 5 half-lives of agent from baseline, whichever is longer. e. The use of Anti-TNF and Anti-integrin therapy or other biological therapy listed below will not be permitted and the following washout period will be required in order for participant to be eligible: i. Three months washout prior to baseline for certolizumab or natalizumab. ii. Two months washout prior to baseline for adalimumab, infliximab, and vedolizumab. iii. 8 week washout prior to baseline for cyclosporine, pimecrolimus, tacrolimus, and any other systemic immunosuppressant. 6. Participants must agree to have samples of their blood and tissue stored for potential future research use. 7. Participants must have a primary medical care provider. 8. Male participants must agree to employ birth control measures to prevent pregnancy in female partners from start of treatment, and continuing through 8 weeks post treatment. 9. Females of childbearing potential must not be breast-feeding, possibly or actually pregnant, must not have had unprotected intercourse for one month prior to dosing, and must agree not to become pregnant beginning from enrollment in the study to at least 8 weeks after the end of treatment. Participants must remain completely abstinent of potentially reproductive sexual intercourse (e.g. due to a committed lifestyle) or to consistently use BOTH a barrier method with a spermicide (male or female condom) AND ALSO one of the below listed methods of birth control: 1. Continuous/daily hormonal methods including oral contraceptive pills, patch, implant/injection, etc. 2. Surgical sterilization of either partner, of sufficient duration to be effective, and NOT known to have failed. 3. Intrauterine device. EXCLUSION CRITERIA: 1. 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. 2. History or presence of recurrent or chronic infection (e.g., viral infection including hepatitis B or C, human immunodeficiency virus (HIV), bacterial infection, systemic fungal infection, or syphilis). 3. Positive for tuberculosis via PPD or QFT-G. Individuals who are known to have received the tuberculosis vaccine will be administered the QFT-G (QuantiFERON-TB Gold), all others will undergo PPD skin test to rule out TB. 4. A conduction abnormality on baseline electrocardiogram (ECG) that in the opinion of a cardiologist, is deemed significant. 5. At the discretion of the investigator, off-label use of any small molecule therapeutics that are immune modulators (e.g., naltrexone) within 90 days of beginning screening or at any time during the 30 days of the screening window. 6. Presence of abnormal hematological and biochemical parameters, including: 1. Neutrophil count < 1500 cells/mm3. 2. Hemoglobin < 9 g/dL. 3. Platelet count less than or equal to 150,000 cells/mm3. 4. Creatinine greater than or equal to 1.2 times the upper limit of normal (ULN). 5. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater than or equal to 1.5 times ULN. 6. Prothrombin time-international normalized ratio (PT-INR) > 1.0 ULN 7. Serum bilirubin level > 1.0 times ULN. 7. Individuals on chronic anticoagulation medications. 8. Stool sample for GI pathogens (FilmArray GI Panel testing for 22 viral, bacterial and parasitic GI pathogens that cause infectious diarrhea) If a stool sample determined positive for acute gastrointestinal infection with impact of occurrence on gastrointestinal inflammation as determined by principal investigator during screening. In addition, stool samples positive for GI pathogens will be discussed with an infectious disease physician to determine impact of occurrence on gastrointestinal inflammation. If the organism is thought to be pathogenic the patient will receive appropriate treatment. This will be documented in the participant s medical record. 9. Presence of cytomegalovirus (CMV) infection as defined by positive immunohistochemical staining on tissue intestine biopsy. 10. History of low-grade or high-grade colonic mucosal dysplasia. 11. History of bowel surgery other than perianal (e.g., fistulotomy, seton placement, or abscess drainage) within 6 months prior to beginning the CDAI screening diary or drawing screening blood samples. 12. Presence of surgical changes to gut anatomy that preclude administration of clinical activity indices; this includes but is not limited to ileostomy, colostomy, or subtotal colectomy with ileorectal anastomosis. 13. Known or suspected short bowel syndrome. 14. Requirement of parenteral, total parenteral, elemental oral, or nasogastric nutrition. 15. History of cancer, other than non-melanomatous cancer of the skin, within the past 5 years. 16. Unwillingness or inability to comply with study requirements. 17. Presence of only small bowel CD that is inaccessible by standard colonoscopy for harvest of research biopsies. Individuals with only upper gastrointestinal CD or only perianal fistulizing CD are also excluded for this reason. 18. Refusal to abstain from using COX-2 inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) throughout the study agent administration period. 19. Has uncontrolled diabetes 20. Is taking anti-seizure medication, such as valproic acid or its derivative (i.e., Depakote) 21. Presence of any condition that, in the opinion of the investigator, contraindicates participation in this study. 22. Has participated in another investigational trial within 8 weeks (or 5 half-lives of any investigational study agent), whichever is greater, prior to the pre-trial (screening) visit. The window will be derived from the last date of treatment on the previous trial.
  • Start Date


  • Last Updated


  • Sponsor

    National Institute of Allergy and Infectious Diseases (NIAID)

  • Condition Name

    Crohn's Disease

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