Oral OKT3 for the Treatment of Active Ulcerative Colitis

Oral Anti-CD3 for the Treatment of Active Ulcerative Colitis

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

Study Overview

• Status: Completed
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Drug: Oral OKT3; Drug: Omeprazole

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral OKT3; Participants with ulcerative colitis will receive Oral OKT3 given with Omeprazole once daily for 30 days.	Drug: Oral OKT3; 1 mg or 2 mg Oral OKT3 will be given orally to participants once daily for 30 days; Other Names: OKT3; Muromonab CD3; anti-CD3; Drug: Omeprazole; 20 mg Omeprazole will be given orally to participants once daily for 30 days; Other Names: Prilosec

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Scott Snapper, MD, PhD, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Ilan Y, Zigmond E, Lalazar G, Dembinsky A, Ben Ya'acov A, Hemed N, Kasis I, Axelrod E, Zolotarov L, Klein A, El Haj M, Gandhi R, Baecher-Allan C, Wu H, Murugaiyan G, Kivisakk P, Farez MF, Quintana FJ, Khoury SJ, Weiner HL. Oral administration of OKT3 monoclonal antibody to human subjects induces a dose-dependent immunologic effect in T cells and dendritic cells. J Clin Immunol. 2010 Jan;30(1):167-77. doi: 10.1007/s10875-009-9323-7. Epub 2009 Sep 16.
• Wu HY, Maron R, Tukpah AM, Weiner HL. Mucosal anti-CD3 monoclonal antibody attenuates collagen-induced arthritis that is associated with induction of LAP+ regulatory T cells and is enhanced by administration of an emulsome-based Th2-skewing adjuvant. J Immunol. 2010 Sep 15;185(6):3401-7. doi: 10.4049/jimmunol.1000836. Epub 2010 Aug 18.
• Wu HY, Center EM, Tsokos GC, Weiner HL. Suppression of murine SLE by oral anti-CD3: inducible CD4+CD25-LAP+ regulatory T cells control the expansion of IL-17+ follicular helper T cells. Lupus. 2009 Jun;18(7):586-96. doi: 10.1177/0961203308100511.
• Ishikawa H, Ochi H, Chen ML, Frenkel D, Maron R, Weiner HL. Inhibition of autoimmune diabetes by oral administration of anti-CD3 monoclonal antibody. Diabetes. 2007 Aug;56(8):2103-9. doi: 10.2337/db06-1632. Epub 2007 Apr 24.
• Ochi H, Abraham M, Ishikawa H, Frenkel D, Yang K, Basso AS, Wu H, Chen ML, Gandhi R, Miller A, Maron R, Weiner HL. Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+ CD25- LAP+ T cells. Nat Med. 2006 Jun;12(6):627-35. doi: 10.1038/nm1408. Epub 2006 May 21.

Study record dates

Study Major Dates

• Study Start (Actual): April 7, 2011
• Primary Completion (Actual): May 2, 2013
• Study Completion (Actual): May 2, 2013

Study Registration Dates

• First Submitted: January 28, 2011
• First Submitted That Met QC Criteria: January 28, 2011
• First Posted (Estimate): February 1, 2011

Study Record Updates

• Last Update Posted (Actual): February 11, 2019
• Last Update Submitted That Met QC Criteria: January 28, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Ulcerative Colitis; Inflammatory Bowel Disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Omeprazole; Muromonab-CD3
• Other Study ID Numbers: 2009P001448