A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 3 Subcutaneous and 1 Intravenous Dose of E6011 in Subjects With Active Crohn's Disease

Study Overview
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Brief Summary
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This is a multicenter, Phase 1b, randomized, double-blind, placebo-controlled, sequential-cohort, multiple ascending dose (MAD) study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of 3 subcutaneous and 1 intravenous dose of E6011 in subjects with active Crohn's disease (CD). Thirty-two subjects will be randomized to one of 4 dose cohorts (8 per cohort) and will receive E6011 or placebo for 10 weeks. The first 3 cohorts will receive E6011 or placebo via subcutaneous injection and the last cohort will receive E6011 or placebo by intravenous injection. The ratio of E6011 to placebo within each cohort will be 3:1. The study has 2 phases: Prerandomization and Randomization.

Official Title
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A Multicenter, Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Sequential-Cohort, Multiple-Ascending-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 3 Subcutaneous and 1 Intravenous Dose of E6011 in Subjects With Active Crohn's Disease

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: E6011
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Subjects must meet all of the following criteria to be included in this study: Male or female subjects age greater than or equal to 18 years old at the time of informed consent Confirmed diagnosis of CD, with at least one documented lesion within the reach of a colonoscope (terminal ileal or ileo-colonic or colonic) from a previous colonoscopy, for a minimum duration of 6 months at the time of screening Active CD with a CD activity index (CDAI) score greater than or equal to 220 and less than or equal to 450 Colonoscopic evidence of CD involvement with active inflammation of terminal ileum and/or colon at Screening (performed only in subjects who have otherwise met all of the inclusion and none of the exclusion criteria) Inadequate response to, loss of response to, or intolerance of at least one of the following agents as defined below: Immunomodulators: Signs and symptoms of persistently active disease despite a history of at least one 8-week regimen of oral azathioprine (AZA) (greater than or equal to 1.5 mg/kg) or 6-mercaptopurine (6-MP) mg/kg (greater than or equal to 0.75 mg/kg) OR Signs and symptoms of persistently active disease despite a history of at least one 8-week regimen of methotrexate (MTX) (greater than or equal to 12.5 mg/week) History of intolerance to at least 1 immunomodulator (including, but not limited to) nausea/vomiting, abdominal pain, pancreatitis, liver function test (LFT) abnormalities, lymphopenia, thiopurine methyltransferase (TPMT) genetic mutation, infection Tumor Necrosis Factor (TNF)-alpha antagonists: Signs and symptoms of persistently active disease despite a history of at least one 4-week induction regimen of one of the following agents: Infliximab: 5 mg/kg IV, 2 doses at least 2 weeks apart Adalimumab: one 80 mg SC dose followed by one 40-mg dose at least 2 weeks apart Certolizumab pegol: 400 mg SC dose, 2 doses at least 2 weeks apart OR Recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify) History of intolerance to at least 1 TNF antagonist (including, but not limited to infusion-related reaction, demyelination, congestive heart failure, infection) C-reactive protein greater than or equal to 5 mg/L at screening or fecal calprotectin greater than or equal to 250 ug/g Females must not be breastfeeding or pregnant at Screening (as documented by a negative beta-human chorionic gonadotropin [B-hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 70 days after study drug discontinuation. If currently abstinent, the subject must agree to use a double-barrier method as described above if she becomes sexually active during the study period or for 70 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 70 days after study drug discontinuation. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing). Provide written informed consent Willing and able to comply with all aspects of the protocol Exclusion Criteria Subjects who meet any of the following criteria will be excluded from this study: Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal [other than CD], renal disease, active infection, vasculitides) that in the opinion of the investigator(s) could affect the patient's safety or interfere with the study assessments Any neurologic abnormality at screening A prolonged QT/QTc interval (QTc greater than 450 ms) as demonstrated by a repeated ECG at Screening History of any severe allergy Scheduled for surgery during planned participation in the study Previous ileo-colonic resections or presence of an ostomy Presence of active fistulizing CD Total parenteral nutrition (TPN) or enema for treating CD within 2 weeks before Screening Treatment with adalimumab or certolizumab within 2 weeks before Screening Treatment with infliximab within 4 weeks (or 8 weeks if subjects received 10 mg/kg) before Screening Treatment with vedolizumab (in case of approval or off-label use) or any other monoclonal antibody within 8 weeks before starting the study treatment History of treatment with natalizumab Changes in dose of 5-aminosalicylic acid, 6-MP, MTX, and AZA therapy within 4 weeks of Screening Doses of greater than 30 mg/day of prednisone or equivalent at Screening Parenteral corticosteroids use within 4 weeks of Screening Treatment with cyclosporine (oral or IV), tacrolimus hydrate (excluding eyedrops or skin cream), sirolimus, or mycophenolate mofetil within 8 weeks before Screening Positive Clostridium difficile toxin test at Screening Known to be human immunodeficiency virus (HIV) positive at Screening History of tuberculosis or known current active tuberculosis Positive results for Mycobacterium tuberculosis using an Interferon-Gamma Release Assay at Screening Active viral hepatitis (B or C) as demonstrated by positive serology at Screening Use of live vaccine and immunoglobulin preparations within 12 weeks of screening Cluster of differentiation-4 (CD4) positive cell count below 200/microliter (uL) or white blood cell count below 3,000/uL at screening Any of the following laboratory abnormalities in tests conducted during Screening Hemoglobin: less than 8.0 g/dL Neutrophil count: less than 1,500/uL Platelet count: less than 100,000/uL Aspartate aminotransferase (AST) or alanine aminotransferase (ALT): greater than 2.5 times the upper limit of standard reference values Serum creatinine: greater than 1.5 mg/dL Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics or prior suicide attempt(s) within approximately the last 2 years History of drug or alcohol dependency or abuse within the 2 years prior to Screening Current use of illegal recreational drugs Currently enrolled in another clinical study or used any investigational drug or device within 28 days preceding informed consent

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>100 mg subcutaneous once every 2 weeks with initial double dose (200 mg total) | Drug: E6011<br>* E6011 solution for injection<br>|
| Experimental: Cohort 2<br>200 mg subcutaneous once every 2 weeks with initial double dose (400 mg total) | Drug: E6011<br>* E6011 solution for injection<br>|
| Experimental: Cohort 3<br>400 mg subcutaneous once every 2 weeks with initial double dose (800 mg total) | Drug: E6011<br>* E6011 solution for injection<br>|
| Experimental: Cohort 4<br>10 mg/kg IV at Day 1, Day 8, Day 15, and every 2 weeks thereafter | Drug: E6011<br>* E6011 solution for injection<br>|
| Placebo Comparator: Placebo<br>Placebo 2-mL vial solution for injection | Drug: Placebo<br>* Placebo 2-mL vial solution for injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of the short-term safety and tolerability of E6011 | The short-term safety and tolerability of subcutaneous (SC) and intravenous (IV) doses of E6011 compared to placebo in subjects with active CD. Safety assessments will consist of monitoring and recording all AEs and SAEs; regulatory monitoring of hematology, blood chemistry, and urine values; periodic measurement vital signs and ECGs; and performance of physical examinations. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of E6011 measured over time in blood samples. |  | Up to 3 years | 
| The number and percentage of participants with anti-E6011 antibodies detected in blood samples over time. |  | Up to 3 years | 
| The number of screen positives, confirm positives, and relative anti-E6011 levels measured in blood samples from participants. |  | Up to 3 years | 
| Change from baseline in the percentage of immunohistochemical staining for the CX3CR1+ protein in intestinal tissue over time. |  | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn's Disease