Oral OKT3 for the Treatment of Active Ulcerative Colitis

Study Overview
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Brief Summary
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This study will assess the safety and efficacy of orally delivered short-term OKT3 in participants with active ulcerative colitis.

Detailed Description
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Ulcerative colitis (UC) is a chronic disease of unknown etiology characterized by infiltration of inflammatory cells into the intestinal tract. OKT3 is an approved drug for intravenous use in the treatment of solid-organ transplantation. However, intravenous dosing has been limited by significant toxicities. Data from animal models suggest that antibody recognizing the T3 antigen complex Cluster of Differentiation 3 (anti-CD3) administered via the oral route is effective at treating a variety of autoimmune diseases. No side effects were observed in a recent phase I study of healthy participants receiving oral anti-CD3 monoclonal antibody (mAb). The objectives of the current study are to assess the safety, immunologic effects and efficacy of short-term oral administration of OKT3 in participants with active ulcerative colitis. OKT3 will be delivered orally as a 1 milligram (mg) or 2 mg dose with Omeprazole 20 mg daily for 30 consecutive days in an open-label pilot trial. Thirty two participants will be screened for a targeted completion of 16 enrolled participants. The participants will be evaluated at baseline, day 1, day 2, week 1, week 3, as well as after completion of therapy at week 5 and 10 after the initiation of treatment. Lab tests will be performed at screening, baseline, day 2, week 1, week 3, week 5 and week 10. Clinical data will be collected at all study visits and via diary entries throughout the study period. A flexible sigmoidoscopy will be done at baseline and at week 5. Stool studies will be performed at screening to rule out infection. To be eligible for this study, participants must be between the ages of 18 and 65 years and have a history of moderately to severely active UC as defined by a Mayo score of 6 to 12. They may not be taking concurrent biologic or immunomodulator therapy for UC.

Official Title
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Oral Anti-CD3 for the Treatment of Active Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Oral OKT3
* Drug: Omeprazole


Participation Criteria
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Eligibility Criteria
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1.1 Inclusion Criteria Ability to provide informed consent Age between 18 and 65 years Confirmed diagnosis of UC for at least 3 months with the extent defined within the previous year Moderate to severe UC as defined by a Mayo score of 6-12 Concomitant medications: Can be on 5-amino salicylate (5-ASA) medications and stable doses (same dose > 4 weeks) of oral steroids Concomitant medications cannot include Infliximab, Adalimumab, Certolizumab or Natalizumab for 4 weeks; rectal steroids, 6-mercaptopurine (6-MP), Azathioprine, Tacrolimus, Methotrexate, Thalidomide, Cellcept for 4 weeks; Theophylline, sulfonylureas, non-steroidal anti-inflammatory drug (NSAIDs) or aspirin for 10 days Negative serum pregnancy test within 2 weeks prior to receiving the first dose of study drug in female participants of child-bearing potential Female participants of child-bearing potential must be willing to use birth control during the study and for 4 weeks following the last dose of study drug. 1.2 Exclusion Criteria Crohn's disease or indeterminate colitis Mayo score of <6 (mild UC) Hospitalized or exhibiting signs of toxicity (abdominal distension, severe abdominal tenderness, fever, nausea, vomiting, or tachycardia) A history of colorectal cancer or colorectal dysplasia Pregnant or breastfeeding females or females wishing to become pregnant within the next 6 months or unwilling to use birth control Serum creatinine ≥ 2.0 milligrams per deciliter (mg/dL) Alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), or direct bilirubin >1.5x normal: elevated indirect bilirubin related to likely Gilbert's disease permissible Use of any of the following medications: Azathioprine, 6-MP, Methotrexate, Mycophenolate Mofetil, Tacrolimus, Cyclosporine, Thalidomide, Adalimumab, Infliximab, Certolizumab, Natalizumab, rectal steroids. Theophylline, sulfonylureas, NSAIDs or aspirin within 10 days of study enrollment Psychiatric illness or substance abuse that would interfere with ability to comply with protocol requirements or give informed consent Surgery within the last 3 months Prior gastrointestinal surgery Clinically significant infectious, immune mediated or malignant disease Receiving an elemental diet or parenteral nutrition History of coagulopathy Human immunodeficiency virus (HIV) positive Hepatitis B surface antigen (HBsAg) positive Active cytomegalovirus (CMV) Anemia: hemoglobin (Hb) < 8 grams/deciliter (g/dL). If the subject has known significant cardiac disease, subjects with Hb < 10.5 g/dL will be excluded. Thrombocytopenia (platelets < 100,000 per microliter [100K/mcL]) Lymphopenia (absolute lymphocyte count <0.7) Immunoglobulin G (IgG) anti-cardiolipin antibody positive >16 International Units (IU) Prior exposure to OKT3 Positive quantiferon gold, tuberculosis (TB) spot test, or purified protein derivative (PPD) test Known sensitivity to any ingredients in the study drug Anti-mouse antibody titer >1:1000 Any known autoimmune disease except for ulcerative colitis Allergy or hypersensitivity to Omeprazole Participated in another clinical trial within 30 days of screening for this trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Oral OKT3<br>Participants with ulcerative colitis will receive Oral OKT3 given with Omeprazole once daily for 30 days. | Drug: Oral OKT3<br>* 1 mg or 2 mg Oral OKT3 will be given orally to participants once daily for 30 days<br>* Other names: anti-CD3;Drug: Omeprazole<br>* 20 mg Omeprazole will be given orally to participants once daily for 30 days<br>* Other names: Prilosec;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. | From baseline to Week 10 | 
| Number of Participants With Anti-Drug Antibodies | Serum samples were obtained to measure anti-drug antibodies during the study. | From baseline to Week 10 | 
| Percentage of Biomarker-positive Immune Cells | Peripheral blood mononuclear cells were (PBMCs) were isolated from blood samples taken from each participant at baseline and Week 5. PBMCs were stained with a panel of fluorochrome-conjugated antibodies against multiple surface and intracellular biomarkers, including Cluster of Differentiation (CD) 3, CD4, CD8, Forkhead box P3 protein (FOXP3) and latency-associated peptide (LAP). The percentage of T cells positive for each of these biomarkers was determined by fluorescence activated cell sorting (FACS) and the mean percentage of positive T cells for each biomarker for all analyzed participants is reported. | Baseline, Week 5 | 
| T Cell Proliferation of PBMCs in Cell Culture | PBMCs isolated from whole blood obtained from participants at baseline, Weeks 1, 3, and 5 were assessed for proliferation in cell culture using a radioactive thymidine incorporation assay. A higher number indicates a higher level of proliferation. | Baseline, Weeks 1, 3 and 5 | 
| Cytokine Production by PBMCs in Cell Culture | Cytokine production was assessed in cell cultures of PBMCs obtained from participants at baseline, Weeks 1, 3 and 5. The following cytokines were detected and are reported here: interferon gamma (IFN-gamma), interleukin (IL)-17A, IL-6, IL-1 beta, tumor necrosis factor (TNF) and IL-10. | Baseline, Weeks 1, 3 and 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mayo Score | The Mayo Score is determined by the investigator by assigning a score to the following four assessments: stool frequency, rectal bleeding, physician's global assessment and endoscopy. Total range for Mayo score is 0-12 with a higher score indicating a worse outcome. | Baseline, Week 5 | 
| Simple Clinical Colitis Activity Index (SCCAI) Score | SCCAI is a symptom based questionnaire addressing five assessments, including bowel frequency day, bowel frequency night, urgency of defecation, blood in stool and general well-being. Score ranges from 0-15 with one additional point added for each manifestation of extracolonic features. A higher score indicates a worse outcome. | Baseline, Week 5 | 
| Score in Histologic Evaluation of Flexible Sigmoidoscopy | Mucosal biopsies were obtained from the most inflamed area seen during flexible sigmoidoscopy and blindly scored by a single pathologist with scores ranging 0-3 with a higher score indicating a worse outcome. | Baseline, Week 5 | 

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