An Open-Label, Proof of Consent Study of Vorinostat for the Treatment of Mdoerate-to-Severe Crohn s Disease and Maintenance Therapy With Ustekinumab

NCT03167437 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 17010117-I-0101
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Crohn's Disease

Keywords

Reduce Symptoms of Crohn's Disease; HDAC Inhibitors

Outcome Measures

Primary Outcomes (1)

• 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

  Days 28, 56 and 12 and 24 weeks after start of treatment

Secondary Outcomes (7)

• 170 or greater score on IBDQ

  end of Phase III

• Determine safety and tolerability of ustekinumab maintenance

  end of study

• Mucosal healing from use of Vorinostat

  end of Phase III

• Changes in CDAI score equal to or greater than 70

  weeks 12 and 24

• Acheive clinical remission

  weeks 12 and 24

Study Arms (3)

1

EXPERIMENTAL

participants will receive Vorinostat 100mg PO BID for 12 weeks

Drug: Vorinostat

2

EXPERIMENTAL

participants will receive Vorinostat 100mg PO BID for 6months

Drug: Vorinostat

3

ACTIVE COMPARATOR

participants will receive ustekinumab (weight base induction dose followed by 90mg SC every 8 weeks for 24 months)

Drug: Ustekinumab

Interventions

Ustekinumab DRUG

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.

3

Vorinostat DRUG

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

1; 2

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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 \>=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
• 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) (\>= 2.5 mg/kg/Day) or 6-MP (\>= 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 (\>= 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 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 or UC 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
• d. Anti-integrin antibodies:

You may not qualify if:

• Individuals who meet ANY of the following criteria will be excluded from participation in this
• study:
• 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.
• A conduction abnormality on baseline electrocardiogram (ECG) that in the opinion of a cardiologist, is deemed significant.
• 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 last 30-days of the screening window.
• Presence of abnormal hematological and biochemical parameters, including:
• Neutrophil count \< 1500 cells/mm3
• Hemoglobin \< 9 g/dL
• Platelet count \<= 150,000 cells/mm3
• Creatinine \>= 1.2 times the upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \>= 1.5 times
• ULN

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (4)

• Choi SW, Gatza E, Hou G, Sun Y, Whitfield J, Song Y, Oravecz-Wilson K, Tawara I, Dinarello CA, Reddy P. Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans. Blood. 2015 Jan 29;125(5):815-9. doi: 10.1182/blood-2014-10-605238. Epub 2014 Nov 26.

  PMID: 25428224 BACKGROUND

• Dinarello CA, Fossati G, Mascagni P. Histone deacetylase inhibitors for treating a spectrum of diseases not related to cancer. Mol Med. 2011 May-Jun;17(5-6):333-52. doi: 10.2119/molmed.2011.00116. Epub 2011 May 5.

  PMID: 21556484 BACKGROUND

• Choi SW, Braun T, Chang L, Ferrara JL, Pawarode A, Magenau JM, Hou G, Beumer JH, Levine JE, Goldstein S, Couriel DR, Stockerl-Goldstein K, Krijanovski OI, Kitko C, Yanik GA, Lehmann MH, Tawara I, Sun Y, Paczesny S, Mapara MY, Dinarello CA, DiPersio JF, Reddy P. Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol. 2014 Jan;15(1):87-95. doi: 10.1016/S1470-2045(13)70512-6. Epub 2013 Nov 30.

  PMID: 24295572 BACKGROUND

• Garcia AA, Koperniku A, Ferreira JCB, Mochly-Rosen D. Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives. Trends Pharmacol Sci. 2021 Oct;42(10):829-844. doi: 10.1016/j.tips.2021.07.002. Epub 2021 Aug 10.

  PMID: 34389161 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Crohn Disease

Interventions

Vorinostat; Ustekinumab

Condition Hierarchy (Ancestors)

Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Ivan J Fuss, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ivan J Fuss, M.D.

CONTACT

(301) 761-7091; ifuss@niaid.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2017
• First Posted: May 30, 2017
• Study Start: October 30, 2017
• Primary Completion (Estimated): June 30, 2035
• Study Completion (Estimated): June 30, 2035
• Last Updated: May 4, 2026

Record last verified: 2026-04-30

Locations

US (1)