A Phase 1/2 Study of Repeated Intravenous E6011 Administration in Japanese Subjects With Crohn's Disease

Study Overview
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Brief Summary
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This study is a multicenter, open-label, uncontrolled, multiple ascending dose (MAD) study to evaluate mainly the safety and tolerability of 12-week repeated intravenous administration of E6011. A total of 24 subjects will enroll into four cohorts. Six subjects per cohort will receive repeated intravenous administration of E6011.

Detailed Description
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This study consists of Screening Phase, Observation Phase, Treatment Phase, Extension Phase, and Follow-up Phase. Screening assessments will be performed between 42 to 2 days before study drug administration. Observation Phase assessments will be performed a day before or on a day of the initial administration to confirm the eligibility of subjects. The eligible subjects will receive the repeated intravenous administration of E6011. E6011 will be dissolved in physiological saline (nearly 100 mL) for approximately 30-minute infusion. During the Treatment Phase, for the first and second cohorts, E6011 will be administered every 2 weeks up to Week 10, a total of 6 times (with a double dose at Week 0). For the third and fourth cohorts, E6011 will be administered at Weeks 0, 1 and 2, then every 2 weeks up to Week 10, a total of 7 times. Under no safety concerns, Crohn's Disease Activity (CDAI) is less than 150 or a decrease in CDAI from the Observation Phase is greater than 70 and a subject intends to continue administrations, the subject will receive a total of 20 subsequent biweekly administrations (40 weeks) at stable dose (Extension Phase). Subjects will be hospitalized for 24 hours after the initial and second administrations for postdose monitoring and will have out-patient monitoring until 12 weeks after the initial administration. If hospitalization is difficult after the second administration, the subjects can be held at the hospital for 6 hours and then allowed to go home after confirmation of the safety. Subjects who roll over onto the Extension Phase will have continued monitoring until 52 weeks after the initial administration. When the subjects complete (Week 12 or Week 52) or discontinue the study, they will undergo an on-site follow-up 28 days after the study completion or discontinuation and an off-site follow-up or telephone interview 70 days after the final administration. The investigator will conduct full assessments of subjects safety next day of the second administration (24 hours after the second administration) to confirm presence of absence of study-related manifestations which may affect the study drug administration of next cohort. When the sponsor is informed of investigator's judgment on the sixth subject in each cohort, the appropriateness of next cohort will be judged based on the safety data available including the judgment of individual investigator on the next day of the second administration.

Official Title
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A Phase 1/2 Study of Repeated Intravenous E6011 Administration in Japanese Subjects With Crohn's Disease

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: E6011 2 mg/kg
* Drug: E6011 5 mg/kg
* Drug: E6011 10 mg/kg
* Drug: E6011 15 mg/kg


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: Japanese patients aged 20 to 64 years old at the time of informed consent. Diagnosed with Crohn's disease based on the diagnostic criteria for Crohn's disease of the Health and Labor Sciences Research Grants Research on Measures against Intractable Diseases (Inflammatory Bowel Disease) Group (2012). Mild to moderate severity at Observation Phase (CDAI between 150 and 450, based on the above diagnosis criteria for Crohn's disease). History of aminosalycylic acid (5-ASA), salazosulfapyridine, cortical steroid, immunomodulators, infliximab or adalimumab treatment with no apparent effect, or unable to continue the treatment due to AEs (except for infliximab and adalimumab). Consent to use contraception (both the subject and the subject's partner), if the subject is a a man capable of reproduction or a woman of childbearing potential. Has voluntarily consented, in writing, to participate in this study. Has been thoroughly briefed on the conditions for participation in the study, and is willing and able to comply with the conditions. Exclusion Criteria Subjects who meet any of the following criteria will be excluded from this study: Abscess or suspected abscess found at Screening or Observation Phase (not applicable to perianal abscess). Diagnosed with gastrointestinal epithelia dysplasia at Screening or Observation Phase. Suspected of colitis other than Crohn's disease at Screening or Observation Phase (such as pseudomembranous colitis). Symptomatic obstruction at Screening or Observation Phase. Underwent intestinal resection within 24 weeks before the start of the study treatment, or planning to undergo intestinal resection in the next 52 weeks. Newly started with Seaton drainage within 12 weeks before Observation Phase. Diagnosed with short bowel syndrome at Screening or Observation Phase. Positive C.Difficile toxin test at Screening. Prior history or current complication of malignant tumor, lymphoma, leukemia, or lymphoproliferative disease. Immunodeficiency or history of HIV infection. Infection requiring hospitalization or intravenous administration of antibiotics within 4 weeks before the start of the study treatment; or an infection requiring oral antibiotics within 2 weeks before the start of the study treatment. History of tuberculosis or current complication of active tuberculosis. History of serious allergy (shock, or anaphylactoid symptoms). History of clinically important vascular edema, hematemesis, or hemoptysis. History of acute myocardial infarction, cerebral infarction, cerebral hemorrhage, or arteriosclerosis obliterans. History of clinically important vasculitis (such as mononeuritis multiplex). In tests conducted at Screening, a positive finding for any of the following: human immunodeficiency virus (HIV), hepatitis B virus surface antigen (HBs antigen), hepatitis B virus surface antibody (HBs antibody), hepatitis B virus core antibody (HBc antibody), hepatitis B virus DNA (HBV DNA), hepatitis C virus antibody (HCV antibody), human T-lymphotrophic virus Type I antibody (HTLV-1 antibody), or syphilis screening. Except for the subject, if HBs antibody is only positive and is clear due to vaccination of Hepatitis B. Any result other than negative in tuberculosis test (T-SPOT TB Test or QuantiFERON TB Gold Test) at Screening. Findings indicating a history of tuberculosis on chest x-ray during screening. Received a live vaccine within 12 weeks before starting the study treatment, or planning to receive a live vaccine before Week 52. Planning to have surgery before Week 52. Currently participating in another clinical trial, or used an investigational drug or investigational device, or participated in another clinical study, within 24 weeks of the start of the study treatment. Judged to be ineligible to participate in this study by the investigator or sub-investigator

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 64 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: Non-Randomized
Intervention Model: Parallel Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>E6011 2 mg/kg | Drug: E6011 2 mg/kg<br> <br> |
| Experimental: 2<br>E6011 5 mg/kg | Drug: E6011 5 mg/kg<br> <br> |
| Experimental: 3<br>E6011 10 mg/kg | Drug: E6011 10 mg/kg<br> <br> |
| Experimental: 4<br>E6011 15 mg/kg | Drug: E6011 15 mg/kg<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs was defined as adverse event (AEs) that emerged during the treatment, having been absent at pretreatment (Baseline) or re-emerged during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. An AE was defined as any untoward medical occurrence in a participants or clinical study participant temporally associated with the use of study treatment, whether or not considered related to the study treatment. A SAE was defined as any untoward medical occurrence at any dose if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect. | Baseline up to Week 62 (70 days after last dose of study drug) | 
| Number of Participants With Clinically Significant Change in Laboratory Parameters | Clinical laboratory parameters included biochemistry, hematology, urinalysis and other screening test. Number of participants with clinically significant abnormalities in laboratory parameters which were deemed clinically significant by the investigator were reported. | Baseline up to Week 52 | 
| Number of Participants With Clinically Significant Change in Vital Sign Measurements | Vital sign measurements included blood pressure (systolic and diastolic blood pressure) and pulse rate. Number of participants with clinically significant change in vital signs measurements which were deemed clinically significant by the investigator were reported. | Baseline up to Week 52 | 
| Number of Participants With Treatment-emergent Clinically Significant Abnormal Electrocardiogram (ECG) Findings | Number of participants with treatment-emergent clinically significant abnormal ECG findings which were deemed clinically significant by the investigator were reported. | Baseline up to Week 52 | 
| Number of Participants With Abnormal Chest X-ray Findings | Number of participants with abnormal chest X-ray findings were reported. | Baseline up to Week 52 | 
| Number of Participants With Neurological Findings | Number of participants with neurological findings were reported. | Baseline up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Trough Serum Concentration of E6011 at Week 12 and 52 |  | Week 12: Pre-dose; Week 52: Pre-dose | 
| Number of Participants With Serum Anti-E6011 Antibody at Week 12 and 52 | Number of participants with serum anti-E6011 antibody were reported. | At Week 12 and Week 52 | 

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