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Oral OKT3 for the Treatment of Active Ulcerative Colitis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Scott B. Snapper, M.D., Ph.D., Brigham and Women's Hospital
ClinicalTrials.gov Identifier:
NCT01287195
First received: January 28, 2011
Last updated: June 12, 2017
Last verified: April 2017
  Purpose
This study will assess the safety and efficacy of orally delivered short-term OKT3 in participants with active ulcerative colitis.

Condition Intervention Phase
Ulcerative Colitis Drug: Oral OKT3 Drug: Omeprazole Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Oral Anti-CD3 for the Treatment of Active Ulcerative Colitis

Resource links provided by NLM:


Further study details as provided by Scott B. Snapper, M.D., Ph.D., Brigham and Women's Hospital:

Primary Outcome Measures:
  • Number of Participants With Adverse Events [ Time Frame: From baseline to Week 10 ]
    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.

  • Number of Participants With Anti-Drug Antibodies [ Time Frame: From baseline to Week 10 ]
    Serum samples were obtained to measure anti-drug antibodies during the study.

  • Percentage of Biomarker-positive Immune Cells [ Time Frame: Baseline, Week 5 ]
    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.

  • T Cell Proliferation of PBMCs in Cell Culture [ Time Frame: Baseline, Weeks 1, 3 and 5 ]
    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.

  • Cytokine Production by PBMCs in Cell Culture [ Time Frame: Baseline, Weeks 1, 3 and 5 ]
    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.


Secondary Outcome Measures:
  • Mayo Score [ Time Frame: Baseline, Week 5 ]
    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.

  • Simple Clinical Colitis Activity Index (SCCAI) Score [ Time Frame: Baseline, Week 5 ]
    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.

  • Score in Histologic Evaluation of Flexible Sigmoidoscopy [ Time Frame: Baseline, Week 5 ]
    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.


Enrollment: 6
Actual Study Start Date: April 7, 2009
Study Completion Date: May 2, 2013
Primary Completion Date: May 2, 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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:
  • Muromonab CD3
  • OKT3
  • anti-CD3
Drug: Omeprazole
20 mg Omeprazole will be given orally to participants once daily for 30 days
Other Name: Prilosec

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01287195

Locations
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Brigham and Women's Hospital
Investigators
Principal Investigator: Scott Snapper, MD, PhD Brigham and Women's Hospital
  More Information

Publications:

Responsible Party: Scott B. Snapper, M.D., Ph.D., Director, Inflammatory Bowel Disease Research, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT01287195     History of Changes
Other Study ID Numbers: 2009P001448
Study First Received: January 28, 2011
Results First Received: April 11, 2017
Last Updated: June 12, 2017

Keywords provided by Scott B. Snapper, M.D., Ph.D., Brigham and Women's Hospital:
Ulcerative Colitis
Inflammatory Bowel Disease

Additional relevant MeSH terms:
Ulcer
Colitis, Ulcerative
Colitis
Pathologic Processes
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Inflammatory Bowel Diseases
Colonic Diseases
Intestinal Diseases
Muromonab-CD3
Omeprazole
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents
Anti-Ulcer Agents
Gastrointestinal Agents
Proton Pump Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on June 28, 2017