The Use of Oral Budesonide and Rectal Hydrocortisone for the Treatment of Active Ulcerative Colitis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate if the combination of oral budesonide and rectal hydrocortisone improves symptoms in patients with active ulcerative colitis. Also, we would like to determine if oral budesonide and rectal hydrocortisone has fewer and less severe side effects compared to standard steroids (prednisone).

Detailed Description
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Ulcerative colitis (UC) is a common chronic inflammatory condition of the intestines that results in bloody diarrhea, abdominal pain, and extraintestinal manifestations of disease. The disease course is typically chronic, characterized by periodic exacerbations followed by symptom- free intervals; less commonly symptoms are continuous and unrelenting. The symptoms and disease course have a profound, detrimental impact on the quality of life in patients with UC. The initial therapeutic approach depends upon both the extent of colonic involvement and the severity of the disease process at presentation. Typically, patients are treated based on a pyramid or Step up approach. If patients have mild symptoms, they receive less powerful therapies lower in the pyramid with fewer side effects. Patients with disease confined to distal colon are typically treated with topical therapies including either 5-ASA or steroid enemas. However, as symptoms worsen or if severe at the time of diagnosis, patients receive more aggressive therapies higher in the pyramid including steroids. Despite medical therapy, 50% will have colectomy or become steroid dependent one year after receiving steroids. Steroids are associated with significant side effects. Adverse consequences of steroids are related to dose and duration of exposure, and include but are not limited to cosmetic side effects, ocular disease (glaucoma, cataracts), diabetes, hypertension, vascular disease, osteoporosis, neuropsychiatric complications, and increased risk of infection. Newer designer corticosteroids including budesonide have reduced systemic bioavailability and high local anti-inflammatory activity; as a result it is associated with fewer and less severe side effects. Studies have proven the efficacy of budesonide in inducing remission in active Crohn's disease. However, the data for the use of oral budesonide in patients with UC is less extensive. However, the data regarding the efficacy of topical therapy for left-sided UC is extensive. Randomized controlled trials of budesonide enemas have demonstrated similar efficacy and safety profile to hydrocortisone enemas in the induction of remission of left sided UC. We have chosen to utilize hydrocortisone enemas in our study as it is widely available in the United States. A 52-week open-label pilot study will be performed at the University of Maryland Medical Center. Subjects will include patients with previously or newly diagnosed extensive ulcerative colitis. Patients will be treated with oral budesonide and rectal hydrocortisone for 8 weeks followed by a predetermined taper. All patients will undergo research clinic visits at enrollment and week 8. During these visits, patients will complete a series of questionnaires that measure the patient's disease activity, quality of life, side effects, medical compliance, and other parameters. Blood draws and stool studies are required at each study visit to monitor blood counts, electrolytes, liver function, inflammatory markers, and adrenal function. Additionally, at week 16, an ACTH (cosyntropin) stimulation test will be performed. After obtaining a basal cortisol level, 250 ug of cosyntropin is given intravenously. Plasma samples of cortisol will then be drawn at 30 minutes to assess for adrenal insufficiency. Close follow-up with eight 30-min telephone sessions (every 2-3 weeks) will also be conducted to assess disease activity and adverse events. The goal of this study is to determine whether combination therapy using oral budesonide and topical hydrocortisone will result in the induction of remission in patients with active extensive ulcerative colitis. Further, we aim to show that combination therapy is better tolerated and has less severe side effects compared to conventional therapy with prednisone.

Official Title
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Oral Budesonide and Rectal Hydrocortisone for the Treatment of Extensive Ulcerative Colitis: A Pilot Study

Conditions
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Inflammatory Bowel Disease, Ulcerative Colitis

Intervention / Treatment
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* Drug: Combination Oral Budesonide and Rectal Hydrocortisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written, voluntary, informed consent given 18 years or older Speak and read English Extensive ulcerative colitis based upon endoscopy, histopathology, and clinical symptoms SCCAI Score > 3 Presence of diarrhea (3 or more bowel movements per 24 hours) AND grossly visible blood in stool Exclusion Criteria: Serum creatinine > 2.0 mg/dL Pregnant or breastfeeding Prior history of total or subtotal colectomy, or currently has an ostomy History or suspicion of Crohn's disease or Indeterminate colitis Diagnosis of any condition deemed by the investigator inhibiting completion of the trial Initiated therapy with or change in mesalamine dose within the last 4 weeks Change in azathioprine, 6-mercaptopurine, or cyclosporine within the last 8 weeks Currently taking or have used corticosteroids within the last 8 weeks Rectally administered mesalamine or steroids within the last 2 weeks Current or prior use of anti-TNF alpha agents within the last 8 weeks Experimental ulcerative colitis agents within the last 8 weeks Concomitant use of CYP3A4 activity inhibitor (e.g. ketoconazole, itraconazole, ritonavir, indinavir, erythromycin) Uncontrolled diabetes (HgA1c > 8.0) within 1 year Unstable Coronary artery disease/Class III/IV CHF Decompensated cirrhosis (e.g. encephalopathy, renal failure, ascites, GIB) Any known infection requiring antibiotics Active Clostridium difficile infection COPD requiring home oxygen HIV/AIDS with CD4 < 200 or AIDs-defining illnesses/infections

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination Oral Budesonide and Rectal Hydrocortisone<br>See intervention | Drug: Combination Oral Budesonide and Rectal Hydrocortisone<br>* Budesonide 9 mg PO (oral) daily and hydrocortisone 100 mL PR (enema) for an 8-week period. The doses of each drug to be used in the pilot study are standard doses used in clinical practice. After 8-weeks, the budesonide will be tapered in the following manner: 1) budesonide 6 mg PO daily and hydrocortisone 100 ml PR every other day (EOD) for 3 weeks then 2) budesonide 3 mg PO daily and hydrocortisone 100 ml PR 2 x per week for 3 weeks then 3) discontinue budesonide.<br>* Other names: Entocort;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Simple Clinical Colitis Disease Activity (SCCAI) | Scores range from 0-19. Higher scores indicated increased disease severity. A score less than 3 is consistent with clinical remission. | 0, 2, 4, 6, and 8 weeks | 
| Short Inflammatory Bowel Disease Questionnaire (SIBDQ) | Scores range from 10-70 where higher scores indicated better quality of life. | Week 0 and 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ACTH Stimulation Test | An increase in cortisol after stimulation by ACTH is normal. Blood cortisol after ACTH stimulation should be greater than 18 - 20 mcg/dL, depending on the dose of cosyntropin used. | Week 16 | 
| Adverse Events |  | 0, 2, 4, 6, 8, 11, 14, 20, 26, and 52 weeks | 
| C Reactive Protein | Higher values indicated increased disease activity | Week 0 and 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inflammatory Bowel Disease, Ulcerative Colitis, Budesonide, Corticosteroids