Ulcerative Colitis
Conditions
Keywords
Ulcerative Colitis, Inflammatory Bowel Disease
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.
Interventions
DRUGOral OKT3
1 mg or 2 mg Oral OKT3 will be given orally to participants once daily for 30 days
DRUGOmeprazole
20 mg Omeprazole will be given orally to participants once daily for 30 days
Sponsors
Brigham and Women's Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cytokine Production by PBMCs in Cell Culture | 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. |
| Number of Participants With Anti-Drug Antibodies | From baseline to Week 10 | Serum samples were obtained to measure anti-drug antibodies during the study. |
| Percentage of Biomarker-positive Immune Cells | 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 | 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. |
| Number of Participants With Adverse Events | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Simple Clinical Colitis Activity Index (SCCAI) Score | 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 | 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. |
| Mayo Score | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Oral OKT3 Participants with ulcerative colitis received 1 mg Oral OKT3 given with 20 mg oral Omeprazole once daily for 30 days. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Oral OKT3 |
|---|---|
| Age, Continuous | 39.5 years STANDARD_DEVIATION 13.5 |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 1 / 6 |
| serious Total, serious adverse events | 2 / 6 |
Outcome results
Primary
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.
Time frame: Baseline, Weeks 1, 3 and 5
Population: All participants enrolled in the study for whom data were available at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IFN gamma, Baseline | 4935 picograms/milliliter (pg/mL) | Standard Deviation 5520 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IFN gamma, Week 1 | 11521 picograms/milliliter (pg/mL) | Standard Deviation 6659 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IFN gamma, Week 3 | 10178 picograms/milliliter (pg/mL) | Standard Deviation 11671 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IFN gamma, Week 5 | 2832 picograms/milliliter (pg/mL) | Standard Deviation 2569 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-17A, Baseline | 69 picograms/milliliter (pg/mL) | Standard Deviation 93 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-17A, Week 1 | 114 picograms/milliliter (pg/mL) | Standard Deviation 117 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-17A, Week 3 | 181 picograms/milliliter (pg/mL) | Standard Deviation 368 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-17A, Week 5 | 74 picograms/milliliter (pg/mL) | Standard Deviation 95 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-6, Baseline | 1470 picograms/milliliter (pg/mL) | Standard Deviation 21010 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-6, Week 1 | 2678 picograms/milliliter (pg/mL) | Standard Deviation 3270 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-6, Week 3 | 1978 picograms/milliliter (pg/mL) | Standard Deviation 3491 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-6, Week 5 | 567 picograms/milliliter (pg/mL) | Standard Deviation 57980 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-1 beta, Baseline | 110 picograms/milliliter (pg/mL) | Standard Deviation 133 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-1 beta, Week 1 | 155 picograms/milliliter (pg/mL) | Standard Deviation 197 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-1 beta, Week 3 | 185 picograms/milliliter (pg/mL) | Standard Deviation 209 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-1 beta, Week 5 | 38 picograms/milliliter (pg/mL) | Standard Deviation 30 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | TNF, Baseline | 361 picograms/milliliter (pg/mL) | Standard Deviation 282 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | TNF, Week 1 | 585 picograms/milliliter (pg/mL) | Standard Deviation 324 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | TNF, Week 3 | 715 picograms/milliliter (pg/mL) | Standard Deviation 724 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | TNF, Week 5 | 195 picograms/milliliter (pg/mL) | Standard Deviation 157 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-10, Baseline | 63 picograms/milliliter (pg/mL) | Standard Deviation 79 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-10, Week 1 | 115 picograms/milliliter (pg/mL) | Standard Deviation 124 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-10, Week 3 | 120 picograms/milliliter (pg/mL) | Standard Deviation 97 |
| Oral OKT3 | Cytokine Production by PBMCs in Cell Culture | IL-10, Week 5 | 15 picograms/milliliter (pg/mL) | Standard Deviation 17 |
Primary
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.
Time frame: From baseline to Week 10
Population: All participants enrolled in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral OKT3 | Number of Participants With Adverse Events | 3 Participants |
Primary
Number of Participants With Anti-Drug Antibodies
Serum samples were obtained to measure anti-drug antibodies during the study.
Time frame: From baseline to Week 10
Population: All participants enrolled in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral OKT3 | Number of Participants With Anti-Drug Antibodies | 0 Participants |
Primary
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.
Time frame: Baseline, Week 5
Population: All participants enrolled in the study for whom data were available at both time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral OKT3 | Percentage of Biomarker-positive Immune Cells | CD3, Week 5 | 30 percentage of biomarker-positive T cells | Standard Deviation 22 |
| Oral OKT3 | Percentage of Biomarker-positive Immune Cells | CD4, Baseline | 59 percentage of biomarker-positive T cells | Standard Deviation 30 |
| Oral OKT3 | Percentage of Biomarker-positive Immune Cells | CD3, Baseline | 38 percentage of biomarker-positive T cells | Standard Deviation 19 |
| Oral OKT3 | Percentage of Biomarker-positive Immune Cells | LAP, Baseline | 0.9 percentage of biomarker-positive T cells | Standard Deviation 0.5 |
| Oral OKT3 | Percentage of Biomarker-positive Immune Cells | CD4, Week 5 | 75 percentage of biomarker-positive T cells | Standard Deviation 11 |
| Oral OKT3 | Percentage of Biomarker-positive Immune Cells | CD8, Baseline | 31 percentage of biomarker-positive T cells | Standard Deviation 16 |
| Oral OKT3 | Percentage of Biomarker-positive Immune Cells | CD8, Week 5 | 24 percentage of biomarker-positive T cells | Standard Deviation 11 |
| Oral OKT3 | Percentage of Biomarker-positive Immune Cells | FOXP3, Baseline | 5 percentage of biomarker-positive T cells | Standard Deviation 2.5 |
| Oral OKT3 | Percentage of Biomarker-positive Immune Cells | FOXP3, Week 5 | 4 percentage of biomarker-positive T cells | Standard Deviation 2 |
| Oral OKT3 | Percentage of Biomarker-positive Immune Cells | LAP, Week 5 | 0.5 percentage of biomarker-positive T cells | Standard Deviation 0.4 |
Primary
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.
Time frame: Baseline, Weeks 1, 3 and 5
Population: All participants enrolled in the study for whom data were available at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral OKT3 | T Cell Proliferation of PBMCs in Cell Culture | Baseline | 27470 radioactive counts of cells per minute | Standard Error 12340 |
| Oral OKT3 | T Cell Proliferation of PBMCs in Cell Culture | Week 1 | 49617 radioactive counts of cells per minute | Standard Error 17168 |
| Oral OKT3 | T Cell Proliferation of PBMCs in Cell Culture | Week 3 | 46575 radioactive counts of cells per minute | Standard Error 26762 |
| Oral OKT3 | T Cell Proliferation of PBMCs in Cell Culture | Week 5 | 20993 radioactive counts of cells per minute | Standard Error 15805 |
Secondary
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.
Time frame: Baseline, Week 5
Population: All participants enrolled in the study for whom data were available at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral OKT3 | Mayo Score | Baseline | 8.8 score on a scale | Standard Error 1.6 |
| Oral OKT3 | Mayo Score | Week 5 | 7.5 score on a scale | Standard Error 1.7 |
Secondary
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.
Time frame: Baseline, Week 5
Population: All participants enrolled in the study for whom data were available at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral OKT3 | Score in Histologic Evaluation of Flexible Sigmoidoscopy | Baseline | 2.2 score on a scale | Standard Error 0.7 |
| Oral OKT3 | Score in Histologic Evaluation of Flexible Sigmoidoscopy | Week 5 | 1.75 score on a scale | Standard Error 0.9 |
Secondary
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.
Time frame: Baseline, Week 5
Population: All participants enrolled in the study for whom data were available at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral OKT3 | Simple Clinical Colitis Activity Index (SCCAI) Score | Baseline | 7.7 score on a scale | Standard Error 1.6 |
| Oral OKT3 | Simple Clinical Colitis Activity Index (SCCAI) Score | Week 5 | 6 score on a scale | Standard Error 2.5 |