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Oral OKT3 for the Treatment of Active Ulcerative Colitis

Primary Purpose

Ulcerative Colitis

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Oral OKT3
Omeprazole
Sponsored by
Brigham and Women's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ulcerative Colitis focused on measuring Ulcerative Colitis, Inflammatory Bowel Disease

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Brigham and Women's Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Oral OKT3

Arm Description

Participants with ulcerative colitis will receive Oral OKT3 given with Omeprazole once daily for 30 days.

Outcomes

Primary Outcome Measures

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.
Number of Participants With Anti-Drug Antibodies
Serum samples were obtained to measure anti-drug antibodies during the study.
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.
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.
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.

Secondary Outcome Measures

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.
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.
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.

Full Information

First Posted
January 28, 2011
Last Updated
January 28, 2019
Sponsor
Brigham and Women's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT01287195
Brief Title
Oral OKT3 for the Treatment of Active Ulcerative Colitis
Official Title
Oral Anti-CD3 for the Treatment of Active Ulcerative Colitis
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
April 7, 2011 (Actual)
Primary Completion Date
May 2, 2013 (Actual)
Study Completion Date
May 2, 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Brigham and Women's Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ulcerative Colitis
Keywords
Ulcerative Colitis, Inflammatory Bowel Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Oral OKT3
Arm Type
Experimental
Arm Description
Participants with ulcerative colitis will receive Oral OKT3 given with Omeprazole once daily for 30 days.
Intervention Type
Drug
Intervention Name(s)
Oral OKT3
Other Intervention Name(s)
Muromonab CD3, OKT3, anti-CD3
Intervention Description
1 mg or 2 mg Oral OKT3 will be given orally to participants once daily for 30 days
Intervention Type
Drug
Intervention Name(s)
Omeprazole
Other Intervention Name(s)
Prilosec
Intervention Description
20 mg Omeprazole will be given orally to participants once daily for 30 days
Primary Outcome Measure Information:
Title
Number of Participants With Adverse Events
Description
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.
Time Frame
From baseline to Week 10
Title
Number of Participants With Anti-Drug Antibodies
Description
Serum samples were obtained to measure anti-drug antibodies during the study.
Time Frame
From baseline to Week 10
Title
Percentage of Biomarker-positive Immune Cells
Description
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.
Time Frame
Baseline, Week 5
Title
T Cell Proliferation of PBMCs in Cell Culture
Description
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.
Time Frame
Baseline, Weeks 1, 3 and 5
Title
Cytokine Production by PBMCs in Cell Culture
Description
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.
Time Frame
Baseline, Weeks 1, 3 and 5
Secondary Outcome Measure Information:
Title
Mayo Score
Description
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.
Time Frame
Baseline, Week 5
Title
Simple Clinical Colitis Activity Index (SCCAI) Score
Description
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.
Time Frame
Baseline, Week 5
Title
Score in Histologic Evaluation of Flexible Sigmoidoscopy
Description
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.
Time Frame
Baseline, Week 5

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Scott Snapper, MD, PhD
Organizational Affiliation
Brigham and Women's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
19756989
Citation
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.
Results Reference
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PubMed Identifier
20720210
Citation
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.
Results Reference
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PubMed Identifier
19433458
Citation
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.
Results Reference
background
PubMed Identifier
17456848
Citation
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.
Results Reference
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PubMed Identifier
16715091
Citation
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.
Results Reference
background

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Oral OKT3 for the Treatment of Active Ulcerative Colitis

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