Arthritis, Rheumatoid
Conditions
Keywords
Rheumatoid Arthritis, Japanese subjects
Brief summary
This study consist of treatment phase (12 weeks) and extension phase (40 weeks). This study is a multicenter, open-label, uncontrolled, multiple ascending dose (MAD) study to evaluate mainly the safety and tolerability of 12-week repeated subcutaneous administration of E6011 in Japanese subjects with Rheumatoid Arthritis. First 12 subjects will enroll as 100 mg group, next 12 subjects will enroll as 200 mg group, and last 9 subjects will enroll as 400 mg group. A total of 33 subjects will receive repeated subcutaneous administration of E6011. Subjects who roll over onto the Extension phase will have continued monitoring until 52 weeks after the initial administration.
Interventions
DRUGE6011
Sponsors
Eisai Co., Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
Subjects must meet all of the following criteria to be included in this study: 1. Japanese patients aged 20 to 64 years old at the time of informed consent. 2. Diagnosed with rheumatoid arthritis (RA) who meet the 1987 ACR or 2010 ACR/EULAR criteria. 3. Presenting tenderness in more than 4 joints (out of 68) and swelling in more than 4 joints (out of 66) at Screening and Observation phase. 4. Never been treated with non-anti-TNF biologics or never been treated with 2 or more anti-TNF agents. 5. Subjects with greater than or equal to 0.6 mg/dL of high-sensitivity CRP (hs-CRP) level or greater than or equal to 28 mm/hr of erythrocyte sedimentation rate (ESR) at Screening. 6. Weighs greater than or equal to 30 kg and less than or equal to 100 kg at Screening. 7. Consent to use contraception (both the subject and the subject's partner), for at least 70 days after the last dose of study medication starting on the day of informed consent, if the subject is a man capable of reproduction or a woman of childbearing potential. 8. Has voluntarily consented, in writing, to participate in this study 9. Has been thoroughly briefed on the conditions for participation in the study, and is 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: 1. Any history or complication of inflammatory arthritic disorder other than rheumatoid arthritis or Sjogren's syndrome. 2. Meet Class 4 with the Steinbrocker functional classification. 3. History or current clinical condition, or associated complications of malignant tumor, lymphoma, leukemia, or lymphoproliferative disease. 4. Immunodeficiency or history of HIV infection 5. Infection requiring hospitalization or intravenous administration of antibiotics within 4 weeks before the first dose of study treatment, or an infection requiring oral antibiotics within 2 weeks before the first dose of study treatment. 6. History of tuberculosis or current complication of active tuberculosis. 7. History of severe allergy (shock, or anaphylactoid symptoms). 8. History of clinically important vascular edema, hematemesis, hemorrhagic stool, or hemoptysis. 9. History of acute myocardial infarction, cerebral infarction, cerebral hemorrhage, or arteriosclerosis obliterans. 10. History of clinically important vasculitis (such as mononeuritis multiplex). 11. Tested positive for any of the following at Screening: 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. 12. Any result other than negative in tuberculosis test (T-SPOT.TB Test or QuantiFERON TB Gold Test) at Screening. 13. Findings indicating a history of tuberculosis on chest X-ray at Screening. 14. Ineligible to participate in the study in the opinion of the investigator or sub investigator.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Up to 52 Weeks |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants With Positive Anti-E6011 Antibodies Results | Up to 52 weeks |
| Serum Concentrations of E6011 | At Week 0 (predose), Week 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 (postdose) |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 13 investigative sites in Japan from 26 May 2014 to 13 July 2017. As planned separate pharmacokinetics (PK) parameters are not reported and PK analyses was performed for serum E6011 concentrations. Also as planned, combined data for Treatment Phase and Expansion Phase is reported.
Pre-assignment details
Total 53 participants were enrolled and screened, of which 16 were screen failures, 37 participants received study drug in 12-week Treatment Phase. Out of them, 32 participants completed 12-week Treatment Phase. Of 32 participants, 28 participants entered Extension Phase, 22 completed 40-week Extension Phase. '\>='signifies greater than or equal to.
Participants by arm
| Arm | Count |
|---|---|
| E6011: 100 mg Participants received E6011 100 mg, subcutaneously, injection, at Week 0, 1, 2, followed by every 2 weeks up to Week 10 in Treatment Phase and continued to receive E6011 100 mg, subcutaneously, injection, at every two weeks in Extension Phase (for a total of 52 weeks \[Treatment Phase of 12 Weeks and Extension Phase of 40 Weeks\]). | 12 |
| E6011: 200 mg Participants received E6011 200 mg, subcutaneously, injection, at Week 0, 1, 2, followed by every 2 weeks up to 10 weeks in Treatment Phase and continued to receive E6011 200 mg, subcutaneously, injection, at every two weeks in Extension Phase (for a total of 52 weeks \[Treatment Phase of 12 Weeks and Extension Phase of 40 Weeks\]). | 15 |
| E6011: 400 mg Participants received E6011 400 mg, subcutaneously, injection, at Week 0, 1, 2, followed by every 2 weeks up to 10 weeks in Treatment Phase and continued to receive E6011 400 mg, subcutaneously, injection, at every two weeks in Extension Phase (for a total of 52 weeks \[Treatment Phase of 12 Weeks and Extension Phase of 40 Weeks\]). | 10 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Extension Phase (40 Weeks) | Adverse Event | 1 | 2 | 0 |
| Extension Phase (40 Weeks) | Inadequate therapeutic effect | 1 | 1 | 1 |
| Treatment Phase (12 Weeks) | Adverse Event | 0 | 2 | 0 |
| Treatment Phase (12 Weeks) | Participant Choice | 0 | 1 | 1 |
| Treatment Phase (12 Weeks) | Progression of Disease | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | E6011: 100 mg | E6011: 200 mg | E6011: 400 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 47.8 years STANDARD_DEVIATION 8.95 | 51.5 years STANDARD_DEVIATION 12.02 | 48.6 years STANDARD_DEVIATION 8.28 | 49.5 years STANDARD_DEVIATION 10.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 15 Participants | 10 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 12 Participants | 15 Participants | 10 Participants | 37 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 11 Participants | 11 Participants | 7 Participants | 29 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 3 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 15 | 0 / 10 |
| other Total, other adverse events | 10 / 12 | 13 / 15 | 7 / 10 |
| serious Total, serious adverse events | 1 / 12 | 3 / 15 | 1 / 10 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: Up to 52 Weeks
Population: The safety analysis set included group of participants who received at least 1 dose of study drug and had at least 1 postdose safety assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| E6011: 100 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 10 Participants |
| E6011: 100 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| E6011: 200 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 14 Participants |
| E6011: 200 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 3 Participants |
| E6011: 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 7 Participants |
| E6011: 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
Secondary
Number of Participants With Positive Anti-E6011 Antibodies Results
Time frame: Up to 52 weeks
Population: The safety analysis set included group of participants who received at least 1 dose of study drug and had at least 1 postdose safety assessment. Here, number analyzed signifies the participants who were evaluable for this outcome measure for given time points.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| E6011: 100 mg | Number of Participants With Positive Anti-E6011 Antibodies Results | Treatment Phase (12 Weeks) | 9 Participants |
| E6011: 100 mg | Number of Participants With Positive Anti-E6011 Antibodies Results | Extension Phase (40 Weeks) | 9 Participants |
| E6011: 200 mg | Number of Participants With Positive Anti-E6011 Antibodies Results | Treatment Phase (12 Weeks) | 6 Participants |
| E6011: 200 mg | Number of Participants With Positive Anti-E6011 Antibodies Results | Extension Phase (40 Weeks) | 5 Participants |
| E6011: 400 mg | Number of Participants With Positive Anti-E6011 Antibodies Results | Treatment Phase (12 Weeks) | 1 Participants |
| E6011: 400 mg | Number of Participants With Positive Anti-E6011 Antibodies Results | Extension Phase (40 Weeks) | 2 Participants |
Secondary
Serum Concentrations of E6011
Time frame: At Week 0 (predose), Week 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 (postdose)
Population: The pharmacokinetics (PK) analysis set included group of participants who received at least 1 dose of study drug and had at least 1 serum E6011 concentration data. Here, number analyzed signifies the participants who were evaluable for this outcome measure for given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| E6011: 100 mg | Serum Concentrations of E6011 | Week 4 | 15.6 mcg/ml (microgram per milliliter) | Standard Deviation 6.75 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 0 (predose) | 0.00 mcg/ml (microgram per milliliter) | Standard Deviation 0 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 1 | 8.12 mcg/ml (microgram per milliliter) | Standard Deviation 3.06 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 2 | 15.7 mcg/ml (microgram per milliliter) | Standard Deviation 6.3 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 6 | 12.5 mcg/ml (microgram per milliliter) | Standard Deviation 6.04 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 8 | 12.4 mcg/ml (microgram per milliliter) | Standard Deviation 7.17 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 10 | 12.9 mcg/ml (microgram per milliliter) | Standard Deviation 8.2 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 12 | 11.6 mcg/ml (microgram per milliliter) | Standard Deviation 7.02 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 16 | 14.4 mcg/ml (microgram per milliliter) | Standard Deviation 6.33 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 20 | 14.6 mcg/ml (microgram per milliliter) | Standard Deviation 6.97 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 24 | 13.7 mcg/ml (microgram per milliliter) | Standard Deviation 7.76 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 28 | 13.8 mcg/ml (microgram per milliliter) | Standard Deviation 8.33 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 32 | 15.1 mcg/ml (microgram per milliliter) | Standard Deviation 6.25 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 36 | 14.0 mcg/ml (microgram per milliliter) | Standard Deviation 7.23 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 40 | 14.6 mcg/ml (microgram per milliliter) | Standard Deviation 8.9 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 44 | 13.2 mcg/ml (microgram per milliliter) | Standard Deviation 7.56 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 48 | 14.6 mcg/ml (microgram per milliliter) | Standard Deviation 8.43 |
| E6011: 100 mg | Serum Concentrations of E6011 | Week 52 | 16.2 mcg/ml (microgram per milliliter) | Standard Deviation 11.2 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 52 | 37.0 mcg/ml (microgram per milliliter) | Standard Deviation 12.7 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 4 | 38.8 mcg/ml (microgram per milliliter) | Standard Deviation 16.6 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 32 | 31.4 mcg/ml (microgram per milliliter) | Standard Deviation 12.4 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 0 (predose) | 0.00 mcg/ml (microgram per milliliter) | Standard Deviation 0 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 20 | 30.6 mcg/ml (microgram per milliliter) | Standard Deviation 10.9 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 10 | 29.2 mcg/ml (microgram per milliliter) | Standard Deviation 11.1 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 1 | 20.0 mcg/ml (microgram per milliliter) | Standard Deviation 9.11 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 44 | 40.4 mcg/ml (microgram per milliliter) | Standard Deviation 15.5 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 48 | 37.5 mcg/ml (microgram per milliliter) | Standard Deviation 19 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 2 | 37.1 mcg/ml (microgram per milliliter) | Standard Deviation 11.9 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 24 | 30.5 mcg/ml (microgram per milliliter) | Standard Deviation 12.6 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 40 | 39.2 mcg/ml (microgram per milliliter) | Standard Deviation 11.5 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 36 | 31.6 mcg/ml (microgram per milliliter) | Standard Deviation 13.4 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 6 | 34.8 mcg/ml (microgram per milliliter) | Standard Deviation 16.6 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 16 | 28.2 mcg/ml (microgram per milliliter) | Standard Deviation 11.2 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 28 | 33.6 mcg/ml (microgram per milliliter) | Standard Deviation 11.6 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 8 | 35.1 mcg/ml (microgram per milliliter) | Standard Deviation 20.4 |
| E6011: 200 mg | Serum Concentrations of E6011 | Week 12 | 31.2 mcg/ml (microgram per milliliter) | Standard Deviation 11.9 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 8 | 84.1 mcg/ml (microgram per milliliter) | Standard Deviation 31.3 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 10 | 90.7 mcg/ml (microgram per milliliter) | Standard Deviation 38 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 12 | 90.7 mcg/ml (microgram per milliliter) | Standard Deviation 39.7 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 40 | 113 mcg/ml (microgram per milliliter) | Standard Deviation 30.2 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 16 | 111 mcg/ml (microgram per milliliter) | Standard Deviation 28.1 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 20 | 103 mcg/ml (microgram per milliliter) | Standard Deviation 37.6 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 24 | 116 mcg/ml (microgram per milliliter) | Standard Deviation 26 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 44 | 112 mcg/ml (microgram per milliliter) | Standard Deviation 37.9 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 28 | 98.3 mcg/ml (microgram per milliliter) | Standard Deviation 31.1 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 52 | 111 mcg/ml (microgram per milliliter) | Standard Deviation 41.1 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 0 (predose) | 0.00 mcg/ml (microgram per milliliter) | Standard Deviation 0 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 32 | 106 mcg/ml (microgram per milliliter) | Standard Deviation 30.7 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 1 | 39.9 mcg/ml (microgram per milliliter) | Standard Deviation 13.6 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 2 | 73.9 mcg/ml (microgram per milliliter) | Standard Deviation 20.7 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 4 | 80.9 mcg/ml (microgram per milliliter) | Standard Deviation 28.7 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 6 | 82.1 mcg/ml (microgram per milliliter) | Standard Deviation 27.9 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 36 | 108 mcg/ml (microgram per milliliter) | Standard Deviation 32.4 |
| E6011: 400 mg | Serum Concentrations of E6011 | Week 48 | 111 mcg/ml (microgram per milliliter) | Standard Deviation 32.9 |