Accepts Healthy Volunteers
Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms
An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.
An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.
Searching Both is inclusive of interventional and observational studies.
|Eligible Ages||18 Years - 65 Years|
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 (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV)], bacterial infection, systemic fungal infection, or syphilis). 3. 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 can not have received tuberculosis vaccine within 12 months prior to start of study and can not receive tuberculosis vaccine while on study or within 12 months from the time of conclusion of study participation. 4. 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. 5. A conduction abnormality on baseline electrocardiogram (ECG) that in the opinion of a cardiologist, is deemed significant. 6. At the discretion of the principal 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. 7. 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. 8. Individuals on chronic anticoagulation medications. 9. Stool sample positive for GI pathogens potentially causing disease (as assessed by FilmArray GI panel for 22 viral, bacterial, and parasitic organisms that can cause infectious diarrhea [GI pathogen panel]). The principal investigator will consult with an infectious disease specialist to review results and decide whether treatment is warranted. 10. Presence of cytomegalovirus (CMV) infection as defined by positive immunohistochemical staining on tissue intestine biopsy. 11. History of low-grade or high-grade colonic mucosal dysplasia. 12. 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. 13. 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. 14. Known or suspected short bowel syndrome. 15. Requirement of parenteral, total parenteral, elemental oral, or nasogastric nutrition. 16. History or current evidence of cancer, other than non-melanomatous cancer of the skin, or participants that have undergone excision of basal cell carcinoma, squamous cell carcinoma of the skin. All patients receiving ustekinumab will be monitored for the appearance of non-melanoma skin cancer. Patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment will be followed closely. 17. Unwillingness or inability to comply with study requirements. 18. 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. 19. Refusal to abstain from using COX-2 inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) throughout the study agent administration period. 20. Has uncontrolled diabetes. 21. Is taking anti-seizure medication, such as valproic acid or its derivative (i.e., Depakote) 22. Presence of any condition that, in the opinion of the principal investigator, contraindicates participation in this study. 23. 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.
This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.
Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.
Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.
Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.
Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
|Phase 1/Phase 2|
The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.
|National Institute of Allergy and Infectious Diseases (NIAID)|
The person who is responsible for the scientific and technical direction of the entire clinical study.
|Ivan J Fuss, M.D.|
|Principal Investigator Affiliation||National Institute of Allergy and Infectious Diseases (NIAID)|
Category of organization(s) involved as sponsor (and collaborator) supporting the trial.
The disease, disorder, syndrome, illness, or injury that is being studied.
|Study Website:||View Trial Website|
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 deacetylation 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 inflammation. One naturally occurring HDAC inhibitor, the bacterial product butyrate, has been shown to have effects on gene transcription 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. 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 homeostasis. 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 transplantation. 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 a more effective than alternative existing methods of inducing Treg cell expansion such as administration of purified Tregs. In this protocol we propose a proof of concept clinical trial to study the safety and efficacy of vorinostat (100 mg PO BID for 36 weeks) in treating 20 individuals with moderate-to- severe CD who have not been controlled by standard maintenance therapy. This will be accomplished in Phase II (12 weeks of treatment) and Phase III (36 weeks of treatment). 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 week 4, week 8, and week 24 for assessment of safety labs and testing of clinical response. On Week 12 and week 36 participants will return to the NIH CC for assessment of safety labs and testing of clinical and immunologic response. In Crohn s disease most patients have alternating periods of relapse and remission with half of patients requiring surgery within 10 years of diagnosis on present maintenance therapy. Therefore, the approach to treatment must also evolve from induction control of symptoms to preventing progression of the disease with maintenance therapy. Thus, treatments that safely maintain long-term remission are essential. Treatment guidelines for Crohn s disease recommend maintenance therapy after remission is achieved, particularly for moderate- to-high risk patients. Potential benefits include reduction in hospitalization and surgery and improved quality of life. Long-term efficacy has been studied with azathioprine/mercaptopurine, methotrexate, tumor necrosis factor (TNF) antagonists, and vedolizumab. Although TNF antagonists have significantly advanced the care of Crohn s disease, their efficacy is limited and the development of anti-drug antibodies is associated with loss of response in maintenance therapy. In addition, potential significant side effects of maintenance treatments include bone marrow suppression malignancy and serious infections. Therefore, a need exists for safer agents that have demonstrated improved long-term maintenance efficacy. The gut inflammation complicating Crohn s disease has been characterized as a T helper type 1 (Th1)/T helper type 17 (Th17) inflammatory response, with excess IL-12, IL-23 cytokine production leading to the generation of excessive IFN-g and IL-17. Ustekinumab, a monoclonal antibody to the p40 subunit of IL-12 and IL-23, is currently FDA approved for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, and moderately to severely active CD. Prior clinical trials have demonstrated long-term efficacy and safety profile of ustekinumab in psoriasis. Similarly, the long-term efficacy and safety of ustekinumab in Crohn s disease dosing had been established in the UNITI trial studies (up to 44 week treatment) in patients who have failed TNF antagonists or other conventional therapies. These studies demonstrated significant response rates and induction of remission rates with a positive safety profile. Studies addressing long term maintenance efficacy of ustekinumab in patients that are in remission have not been performed. In the present protocol (Phase IV), Crohn s disease patients that have achieved either a defined clinical response or are in remission with vorinostat will then be enrolled to receive long term maintenance treatment with ustekinumab. Participants will receive a weight- based IV loading dose of ustekinumab followed by administration of maintenance doses of 90 mg subcutaneously (SC) every 8 weeks with participants followed over a 2-year period.
participants will receive Vorinostat 100mg PO BID for 12 weeks
participants will receive Vorinostat 100mg PO BID for 6months
Active Comparator: 3
participants will receive ustekinumab (weight base induction dose followed by 90mg SC every 8 weeks for 24 months)
Drug: - Vorinostat
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
Drug: - Ustekinumab
Ustekinumab 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.
Contact a Trial Team
If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.