Abdominal Pain, Autoimmune Disease, Colitis, Colitis, Ulcerative, Colonic Diseases, Digestive System Diseases, Gastrointestinal Diseases, Inflammatory Bowel Diseases, Intestinal Diseases, Ulcerative Colitis
Conditions
Keywords
4083-002, Intestinal Diseases, Ulcerative Colitis, UC, Mayo Clinic Scoring, Gastrointestinal Tract
Brief summary
The purpose of this study is to determine the safety and tolerability of administration of multiple ascending doses of KHK4083 and to select the highest dose tolerated by subjects with moderately active Ulcerative Colitis (UC) followed by a Long-term Extension Therapy (LTE) phase for eligible subjects with a clinical response.
Detailed description
A Phase 2, double-blind clinical study of multiple ascending doses of KHK4083 (or placebo) with an Long-term Extension Therapy (LTE) phase will be conducted in approximately 60 randomized adult subjects with moderately active UC who have a documented unsuccessful previous treatment. The Treatment Period includes double-blind Induction Therapy (12 weeks) and Open-label Therapy (OLE) phase (40 weeks) for eligible subjects at Week 12. Subjects already enrolled in the double-blind, long-term extension (LTE) under preceding versions of the protocol who worsen may be eligible to transition to the OLE up to Week 28. The Follow Up Period after the last administration will be for up to 16 weeks.
Interventions
DRUGKHK4083
IV Infusion
DRUGPlacebo
IV Infusion
Sponsors
Kyowa Kirin, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Double-blind Induction Therapy was separated into Part A for administration of multiple ascending IV doses of KHK4083 (or placebo) to subjects in Cohorts 1-3 and Part B for administration of the maximally tolerated dose (as determined in cohorts 1-3) in expansion cohort 4. Subjects in Part A were prohibited from participating in Part B. Subjects in each cohort were randomly assigned in a 3:1 ratio to receive KHK4083 or placebo by IV infusion over 60 minutes (± 10 min.). Each subject received a total of 6 treatments (1 IV infusion per treatment) every 2 weeks from Week 0 (Day 1) to Week 10. Subjects who completed double-blind Induction Therapy (i.e., at least 5 of 6 treatments) and had a clinical response or mucosal healing, as defined above, were eligible to continue in double-blind Long Term Extension Therapy (Weeks 12-52) & after protocol amendment all subjects who received at least 5 of 6 treatments were eligible for Open Label Extension Therapy (Weeks 12-52).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subject is able and willing to comply with study procedures, and to adhere to dosing, visit schedules and follow-up procedures as described in the protocol and ICF; 2. Subject voluntarily signs/dates an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF in accordance with regulatory and Institutional Guidelines; 3. Male and female subjects ≥ 18 years of age at the time of enrollment; 4. Subject has UC that was diagnosed at least 6 months prior to the Screening visit; 5. Subject has moderately active UC with a total Mayo score of 4-9 and an endoscopic sub-score of at least 2, with disease that extends at least 15 cm from the anal verge; 6. Subject has had previous treatment (within 5 years prior to Screening) with one or more of the following: corticosteroids, immunosuppressive medications or TNF antagonist therapy that was unsuccessful because of a lack of efficacy response. 7. Female subjects (WOCBP) must have a negative pregnancy test at Screening and Baseline. WOCBP must agree to use effective contraception; 8. Male subjects (including those who have had a vasectomy) must use adequate contraception during the study and for at least 6 months after the last dose of investigational product.
Exclusion criteria
1. Subject, who, for any reason, is judged by the Investigator to be inappropriate for this study; 2. Subject has a medical history of other clinically significant diseases/disorders; 3. Two or more biologic treatments with different mechanisms of action (e.g., infliximab, vedolizumab and golimumab) or Three or more anti-TNF biologics e.g. infliximab, adalimumab 4. Subject requires prescription treatment for UC, except for the stable, oral treatment of UC for 4 weeks prior to screening. 5. Subject has received any of the following prior treatments or treatments within the specified time prior to the Baseline visit: * Natalizumab, efalizumab, rituximab or other lymphocyte-depleting treatments, including but not limited, to alkylating agents (such as cyclophosphamide or chlorambucil) and total lymphoid irradiation at any time; * TNF antagonists within 8 weeks, or 5 half-lives (up to 12 weeks); * Vedolizumab within 16 weeks; * Methotrexate, cyclosporine, mycophenolate, tacrolimus, thalidomide, or other immune altering drugs within 4 weeks (ophthalmologic preparations are permitted); * 5-ASA enema, steroid enema or suppository use within 2 weeks ; and/or Investigational agents within 8 weeks or 5 half-lives (whichever is longer). 6. Subject with recent, suspected or confirmed symptomatic stenosis of the colon, abdominal abscess, or ischemic colitis based on clinical or radiographic data; a history of toxic megacolon; or who had any previous surgery for UC; 7. Subject with known colonic dysplasia, adenomas or polyposis; 8. Subject had major surgery within 4 weeks prior to Screening or an anticipated requirement for major surgery; 9. Subject with enteric pathogens (including Clostridium difficile); 10. Subject with any of the following hematological and chemistry laboratory values: * Platelet count \< 100,000/mm3; * Neutrophils \< 1500/mm3; * Serum creatinine ≥ 1.6 mg/dL (≥ 144.4 μmol/L); * Alkaline phosphatase \> 3 times the upper limit of normal (ULN); * AST or ALT \> 2 times ULN; * Total bilirubin \> 2 mg/dL, unless due to Gilbert's Syndrome; * Serum albumin \< 3 g/dL; * Hemoglobin \< 9 g/dL; * Glycated serum hemoglobin A1c ≥ 9%. 11. Subject has clinically significant cardiac disease; 12. Subject is pregnant or breastfeeding; 13. Subject has had major immunologic reaction; 14. Subject is Hepatitis B core antibody or surface antigen positive and/or Hepatitis C antibody positive with detectable RNA; 15. Subject has a history of human immunodeficiency virus (HIV) positivity, tests positive for HIV, or has congenital or acquired immunodeficiency; 16. Subject has or has had active TB, suspected extra-pulmonary TB, a history of incompletely treated TB, or latent TB or other latent infection. Subjects with latent TB (clinical findings, purified protein derivative \[PPD\] or interferon gamma release assay \[IGRA\]) may be included in the study if prophylactic therapy for latent TB is started at least 4 weeks prior to Screening. Subjects with a potentially untreated other infection (clinical findings) are to be excluded. 17. Subject has bacterial infections requiring treatment with oral or parenteral antibiotics, within 2 and 4 weeks, respectively. 18. Subject has a history of systemic opportunistic infection or recurrent infections 19. Subject has malignancy or history of malignancy, except for adequately treated basal cell skin cancer or adequately treated carcinoma in-situ of the cervix without recurrence at least 5 years. 20. Subject who received a bacille Calmette-Guérin (BCG) vaccine within 6 months of randomization or live vaccination (e.g., measles, mumps, rubella \[MMR\]; herpes zoster; varicella, intranasal influenza; and oral poliomyelitis) within 4 weeks of randomization. 21. Subject with a history of or active substance abuse. 22. Subject has other severe acute or chronic medical or psychiatric condition or laboratory abnormality.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Treatment-related Adverse Events | Up to 52 weeks | To determine the safety and tolerability of KHK4083 |
| Number of Subjects With Treatment-related Serious Adverse Events | Up to 52 weeks | To determine the safety and tolerability of KHK4083 |
| Number of Subjects Who Show Improvement in the Mucosa at Week 12 | 12 weeks | Measured by the modified Mayo endoscopy sub-score (mMES), which ranges from 0-3 with higher scores = more severe disease. |
| Proportion of Subjects Who Show Improvement in the Mucosa at Week 52 | 52 weeks | Measured by the modified Mayo endoscopy sub-score (mMES), which ranges from 0-3 with higher scores = more severe disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Mayo Scale Score at Week 52 | 52 weeks | The Mayo Clinic Score is comprised of 4 parts: stool frequency, rectal bleeding, endoscopic findings and physician's global assessment, each scored from 0-3. The total score ranges from 0-12 with higher scores indicating increased severity of disease. Improvement was based on a reduction (mean change from Baseline \[Week 0\] to Week 52) in the total Mayo Clinic score. |
| Number of Subjects Who Achieve a Clinical Response at Week 12 | 12 weeks | The Mayo Clinic Score is comprised of 4 parts: stool frequency, rectal bleeding, endoscopic findings and physician's global assessment, each scored from 0-3. The total score ranges from 0-12 with higher scores indicating increased severity of disease. Clinical Response is a reduction in the total Mayo Clinic score of at least 3 points. |
| Number of Subjects With Confirmed Anti-KHK4083 Antibodies (Immunogenicity) | 52 weeks | The immunogenicity was assessed by determination of the development of anti-drug antibodies (ADA) against KHK4083. |
| Number of Subjects Who Achieve Clinical Remission at Week 12 | 12 weeks | The Mayo Clinic Score is comprised of 4 parts: stool frequency, rectal bleeding, endoscopic findings and physician's global assessment, each scored from 0-3. The total score ranges from 0-12 with higher scores indicating increased severity of disease. Clinical remission is defined as a total Mayo Clinic score of ≤ 2 and no subscores \> 1. |
| Number of Subjects Who Achieve Clinical Remission at Week 52 | 52 weeks | The Mayo Clinic Score is comprised of 4 parts: stool frequency, rectal bleeding, endoscopic findings and physician's global assessment, each scored from 0-3. The total score ranges from 0-12 with higher scores indicating increased severity of disease. Clinical remission is defined as a total Mayo Clinic score of ≤ 2 and no subscores \> 1. |
| Number of Subjects Who Achieve a Clinical Response at Week 52 | 52 weeks | The Mayo Clinic Score is comprised of 4 parts: stool frequency, rectal bleeding, endoscopic findings and physician's global assessment, each scored from 0-3. The total score ranges from 0-12 with higher scores indicating increased severity of disease. Clinical Response indicates the change from Baseline in the Total Mayo Clinic score \<= -3 and the percentage change from Baseline in the Total Mayo Clinic score \<= -30% to Week 12, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of \<= 1. |
| Number of Subjects Who Achieve Mucosal Healing at Week 12 | 12 weeks | The endoscopic Mayo Score (Mayo endoscopic subscore) evaluates ulcerative colitis stage, based only on endoscopic exploration. The scale ranges from 0 to 3, with higher scores = more severe activity. Mucosal healing is defined as modified Mayo endoscopy sub-score (mMES) of 0 or 1 at Week 12. |
| Number of Subjects Who Achieve Mucosal Healing at Week 52 | 52 weeks | The endoscopic Mayo Score (Mayo endoscopic subscore) evaluates ulcerative colitis stage, based only on endoscopic exploration. The scale ranges from 0 to 3, with higher scores = more severe activity. Mucosal healing is defined as modified Mayo endoscopy sub-score (mMES) of 0 or 1. |
| Number of Subjects Who Achieve Clinical Improvement at Week 12 | 12 weeks | The Mayo Clinic Score is comprised of 4 parts: stool frequency, rectal bleeding, endoscopic findings and physician's global assessment, each scored from 0-3. The total score ranges from 0-12 with higher scores indicating increased severity of disease. Improvement will be based on a reduction in the total Mayo Clinic score. |
Countries
Czechia, Hungary, Poland, Romania, Russia, Serbia, United States
Participant flow
Recruitment details
Investigative sites in the US, Poland, Czech Republic, Russia, Romania, Serbia, and Hungary screened patients from January 2016 until June 2017, with the first patient enrolled in June 2016.
Pre-assignment details
A total of 109 patients were screened during the recruiting period. Subjects were enrolled into the study only if all inclusion criteria and none of the exclusion criteria were fulfilled.
Participants by arm
| Arm | Count |
|---|---|
| KHK4083 Cohort 1 Subjects received one 1.0 mg/kg IV infusion treatment of KHK4083 every two weeks from Week 0 to Week 10 of Induction Therapy. Subjects who chose to continue into extension therapy and were eligible received one IV infusion every 4 weeks (at the same dose as Induction Therapy) from Week 12 to Week 48. | 9 |
| KHK4083 Cohort 2 Subjects received one 3.0 mg/kg IV infusion treatment of KHK4083 every two weeks from Week 0 to Week 10 of Induction Therapy. Subjects who chose to continue into extension therapy and were eligible received one IV infusion every 4 weeks (at the same dose as Induction Therapy) from Week 12 to Week 48. | 10 |
| KHK4083 Cohort 3 Subjects received one 10.0 mg/kg IV infusion treatment of KHK4083 every two weeks from Week 0 to Week 10 of Induction Therapy. Subjects who chose to continue into extension therapy and were eligible received one IV infusion every 4 weeks (at the same dose as Induction Therapy) from Week 12 to Week 48. | 9 |
| KHK4083 Cohort 4 Subjects received one maximum tolerated dose (10.0 mg/kg) IV infusion treatment of KHK4083 every two weeks from Week 0 to Week 10 of Induction Therapy. Subjects who chose to continue into extension therapy and were eligible received one IV infusion every 4 weeks (at the same dose as Induction Therapy) from Week 12 to Week 48. | 21 |
| Placebo Subjects received one IV infusion treatment of Placebo every two weeks from Week 0 to Week 10 of Induction Therapy. Subjects who chose to continue into extension therapy and were eligible received one IV infusion every 4 weeks (at the same dose as Induction Therapy) from Week 12 to Week 48. Subjects who participated in Open-Label Therapy received KHK4083 instead of placebo. | 17 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 | 2 | 1 |
| Overall Study | Death | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Disease Worsening | 3 | 1 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 1 | 0 | 2 |
| Overall Study | Subject moved to different country | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 2 | 4 | 4 |
Baseline characteristics
| Characteristic | KHK4083 Cohort 1 | KHK4083 Cohort 2 | KHK4083 Cohort 3 | KHK4083 Cohort 4 | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 8 Participants | 9 Participants | 19 Participants | 17 Participants | 60 Participants |
| Age, Continuous | 47.3 years | 46.1 years | 41.2 years | 41.1 years | 33.8 years | 40.8 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 10 Participants | 9 Participants | 21 Participants | 17 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 10 Participants | 9 Participants | 21 Participants | 16 Participants | 65 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 5 Participants | 6 Participants | 8 Participants | 25 Participants |
| Sex: Female, Male Male | 5 Participants | 8 Participants | 4 Participants | 15 Participants | 9 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 1 / 10 | 0 / 9 | 0 / 21 | 1 / 49 | 0 / 17 |
| other Total, other adverse events | 5 / 9 | 7 / 10 | 7 / 9 | 13 / 21 | 32 / 49 | 13 / 17 |
| serious Total, serious adverse events | 1 / 9 | 1 / 10 | 1 / 9 | 3 / 21 | 6 / 49 | 3 / 17 |
Outcome results
Primary
Number of Subjects Who Show Improvement in the Mucosa at Week 12
Measured by the modified Mayo endoscopy sub-score (mMES), which ranges from 0-3 with higher scores = more severe disease.
Time frame: 12 weeks
Population: Full analysis set - All randomized subjects who received at least one full dose of investigational product and had a Baseline and at least one post-treatment primary efficacy variable.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| KHK4083 Cohort 1 | Number of Subjects Who Show Improvement in the Mucosa at Week 12 | mMES Improvement | 2 Participants |
| KHK4083 Cohort 1 | Number of Subjects Who Show Improvement in the Mucosa at Week 12 | Modified Baron Endoscopic Score Improvement | 3 Participants |
| KHK4083 Cohort 2 | Number of Subjects Who Show Improvement in the Mucosa at Week 12 | mMES Improvement | 4 Participants |
| KHK4083 Cohort 2 | Number of Subjects Who Show Improvement in the Mucosa at Week 12 | Modified Baron Endoscopic Score Improvement | 5 Participants |
| KHK4083 Cohort 3 | Number of Subjects Who Show Improvement in the Mucosa at Week 12 | mMES Improvement | 9 Participants |
| KHK4083 Cohort 3 | Number of Subjects Who Show Improvement in the Mucosa at Week 12 | Modified Baron Endoscopic Score Improvement | 8 Participants |
| KHK4083 Cohort 4 | Number of Subjects Who Show Improvement in the Mucosa at Week 12 | Modified Baron Endoscopic Score Improvement | 16 Participants |
| KHK4083 Cohort 4 | Number of Subjects Who Show Improvement in the Mucosa at Week 12 | mMES Improvement | 15 Participants |
| KHK4083 Combined | Number of Subjects Who Show Improvement in the Mucosa at Week 12 | mMES Improvement | 5 Participants |
| KHK4083 Combined | Number of Subjects Who Show Improvement in the Mucosa at Week 12 | Modified Baron Endoscopic Score Improvement | 6 Participants |
Primary
Number of Subjects With Treatment-related Adverse Events
To determine the safety and tolerability of KHK4083
Time frame: Up to 52 weeks
Population: Safety Analysis Set - All randomized subjects who received any (even partial dose) investigational product (KHK4083 or placebo).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| KHK4083 Cohort 1 | Number of Subjects With Treatment-related Adverse Events | With Any Drug-related TEAE | 3 Participants |
| KHK4083 Cohort 1 | Number of Subjects With Treatment-related Adverse Events | With Any TEAE | 5 Participants |
| KHK4083 Cohort 1 | Number of Subjects With Treatment-related Adverse Events | With Any TEAE with an Outcome of Death | 0 Participants |
| KHK4083 Cohort 2 | Number of Subjects With Treatment-related Adverse Events | With Any Drug-related TEAE | 2 Participants |
| KHK4083 Cohort 2 | Number of Subjects With Treatment-related Adverse Events | With Any TEAE | 7 Participants |
| KHK4083 Cohort 2 | Number of Subjects With Treatment-related Adverse Events | With Any TEAE with an Outcome of Death | 1 Participants |
| KHK4083 Cohort 3 | Number of Subjects With Treatment-related Adverse Events | With Any Drug-related TEAE | 3 Participants |
| KHK4083 Cohort 3 | Number of Subjects With Treatment-related Adverse Events | With Any TEAE | 7 Participants |
| KHK4083 Cohort 3 | Number of Subjects With Treatment-related Adverse Events | With Any TEAE with an Outcome of Death | 0 Participants |
| KHK4083 Cohort 4 | Number of Subjects With Treatment-related Adverse Events | With Any Drug-related TEAE | 3 Participants |
| KHK4083 Cohort 4 | Number of Subjects With Treatment-related Adverse Events | With Any TEAE | 14 Participants |
| KHK4083 Cohort 4 | Number of Subjects With Treatment-related Adverse Events | With Any TEAE with an Outcome of Death | 0 Participants |
| KHK4083 Combined | Number of Subjects With Treatment-related Adverse Events | With Any Drug-related TEAE | 11 Participants |
| KHK4083 Combined | Number of Subjects With Treatment-related Adverse Events | With Any TEAE | 33 Participants |
| KHK4083 Combined | Number of Subjects With Treatment-related Adverse Events | With Any TEAE with an Outcome of Death | 1 Participants |
| Placebo | Number of Subjects With Treatment-related Adverse Events | With Any TEAE | 13 Participants |
| Placebo | Number of Subjects With Treatment-related Adverse Events | With Any TEAE with an Outcome of Death | 0 Participants |
| Placebo | Number of Subjects With Treatment-related Adverse Events | With Any Drug-related TEAE | 2 Participants |
Primary
Number of Subjects With Treatment-related Serious Adverse Events
To determine the safety and tolerability of KHK4083
Time frame: Up to 52 weeks
Population: Safety Analysis Set - All randomized subjects who received any (even partial dose) investigational product (KHK4083 or placebo).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| KHK4083 Cohort 1 | Number of Subjects With Treatment-related Serious Adverse Events | With Any Drug-related Serious TEAE | 0 Participants |
| KHK4083 Cohort 1 | Number of Subjects With Treatment-related Serious Adverse Events | With Any Serious TEAE | 1 Participants |
| KHK4083 Cohort 1 | Number of Subjects With Treatment-related Serious Adverse Events | Who Died | 0 Participants |
| KHK4083 Cohort 2 | Number of Subjects With Treatment-related Serious Adverse Events | With Any Drug-related Serious TEAE | 0 Participants |
| KHK4083 Cohort 2 | Number of Subjects With Treatment-related Serious Adverse Events | With Any Serious TEAE | 1 Participants |
| KHK4083 Cohort 2 | Number of Subjects With Treatment-related Serious Adverse Events | Who Died | 1 Participants |
| KHK4083 Cohort 3 | Number of Subjects With Treatment-related Serious Adverse Events | With Any Drug-related Serious TEAE | 0 Participants |
| KHK4083 Cohort 3 | Number of Subjects With Treatment-related Serious Adverse Events | With Any Serious TEAE | 1 Participants |
| KHK4083 Cohort 3 | Number of Subjects With Treatment-related Serious Adverse Events | Who Died | 0 Participants |
| KHK4083 Cohort 4 | Number of Subjects With Treatment-related Serious Adverse Events | With Any Drug-related Serious TEAE | 0 Participants |
| KHK4083 Cohort 4 | Number of Subjects With Treatment-related Serious Adverse Events | With Any Serious TEAE | 3 Participants |
| KHK4083 Cohort 4 | Number of Subjects With Treatment-related Serious Adverse Events | Who Died | 0 Participants |
| KHK4083 Combined | Number of Subjects With Treatment-related Serious Adverse Events | With Any Drug-related Serious TEAE | 0 Participants |
| KHK4083 Combined | Number of Subjects With Treatment-related Serious Adverse Events | With Any Serious TEAE | 6 Participants |
| KHK4083 Combined | Number of Subjects With Treatment-related Serious Adverse Events | Who Died | 1 Participants |
| Placebo | Number of Subjects With Treatment-related Serious Adverse Events | With Any Serious TEAE | 3 Participants |
| Placebo | Number of Subjects With Treatment-related Serious Adverse Events | Who Died | 0 Participants |
| Placebo | Number of Subjects With Treatment-related Serious Adverse Events | With Any Drug-related Serious TEAE | 0 Participants |
Primary
Proportion of Subjects Who Show Improvement in the Mucosa at Week 52
Measured by the modified Mayo endoscopy sub-score (mMES), which ranges from 0-3 with higher scores = more severe disease.
Time frame: 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KHK4083 Cohort 1 | Proportion of Subjects Who Show Improvement in the Mucosa at Week 52 | 1 Participants |
| KHK4083 Cohort 2 | Proportion of Subjects Who Show Improvement in the Mucosa at Week 52 | 3 Participants |
| KHK4083 Cohort 3 | Proportion of Subjects Who Show Improvement in the Mucosa at Week 52 | 9 Participants |
| KHK4083 Cohort 4 | Proportion of Subjects Who Show Improvement in the Mucosa at Week 52 | 13 Participants |
| KHK4083 Combined | Proportion of Subjects Who Show Improvement in the Mucosa at Week 52 | 4 Participants |
Secondary
Change From Baseline in Total Mayo Scale Score at Week 52
The Mayo Clinic Score is comprised of 4 parts: stool frequency, rectal bleeding, endoscopic findings and physician's global assessment, each scored from 0-3. The total score ranges from 0-12 with higher scores indicating increased severity of disease. Improvement was based on a reduction (mean change from Baseline \[Week 0\] to Week 52) in the total Mayo Clinic score.
Time frame: 52 weeks
Population: The overall number of participants is the number in the full analysis set. The number of patients analyzed is the number of patients who had values at the noted visits.~There were no subjects in the 10.0 mg/kg KHK4083 group in the LTE Therapy Period. There were no subjects in the 1.0 mg/kg KHK4083 group in the OLE Therapy Period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| KHK4083 Cohort 1 | Change From Baseline in Total Mayo Scale Score at Week 52 | LTE Period - Week 52 Change from Baseline | -5.5 score on a scale | Standard Deviation 2.1 |
| KHK4083 Cohort 1 | Change From Baseline in Total Mayo Scale Score at Week 52 | LTE Period - Week 52 Score | 2.5 score on a scale | Standard Deviation 2.1 |
| KHK4083 Cohort 1 | Change From Baseline in Total Mayo Scale Score at Week 52 | LTE Period - Baseline Score | 8.0 score on a scale | Standard Deviation 0 |
| KHK4083 Cohort 2 | Change From Baseline in Total Mayo Scale Score at Week 52 | OLE Period - Week 52 Score | 3.7 score on a scale | Standard Deviation 3.1 |
| KHK4083 Cohort 2 | Change From Baseline in Total Mayo Scale Score at Week 52 | LTE Period - Baseline Score | 7.8 score on a scale | Standard Deviation 0.8 |
| KHK4083 Cohort 2 | Change From Baseline in Total Mayo Scale Score at Week 52 | OLE Period - Week 52 Change from Baseline | -4.0 score on a scale | Standard Deviation 2.4 |
| KHK4083 Cohort 2 | Change From Baseline in Total Mayo Scale Score at Week 52 | OLE Period - Baseline Score | 7.6 score on a scale | Standard Deviation 1.1 |
| KHK4083 Cohort 3 | Change From Baseline in Total Mayo Scale Score at Week 52 | OLE Period - Week 52 Change from Baseline | -4.4 score on a scale | Standard Deviation 2.7 |
| KHK4083 Cohort 3 | Change From Baseline in Total Mayo Scale Score at Week 52 | OLE Period - Week 52 Score | 3.6 score on a scale | Standard Deviation 2.4 |
| KHK4083 Cohort 3 | Change From Baseline in Total Mayo Scale Score at Week 52 | OLE Period - Baseline Score | 7.8 score on a scale | Standard Deviation 1.5 |
| KHK4083 Cohort 4 | Change From Baseline in Total Mayo Scale Score at Week 52 | LTE Period - Week 52 Change from Baseline | -5.5 score on a scale | Standard Deviation 2.1 |
| KHK4083 Cohort 4 | Change From Baseline in Total Mayo Scale Score at Week 52 | OLE Period - Baseline Score | 7.8 score on a scale | Standard Deviation 1.4 |
| KHK4083 Cohort 4 | Change From Baseline in Total Mayo Scale Score at Week 52 | OLE Period - Week 52 Score | 3.6 score on a scale | Standard Deviation 2.5 |
| KHK4083 Cohort 4 | Change From Baseline in Total Mayo Scale Score at Week 52 | OLE Period - Week 52 Change from Baseline | -4.3 score on a scale | Standard Deviation 2.5 |
| KHK4083 Cohort 4 | Change From Baseline in Total Mayo Scale Score at Week 52 | LTE Period - Baseline Score | 7.9 score on a scale | Standard Deviation 0.6 |
| KHK4083 Cohort 4 | Change From Baseline in Total Mayo Scale Score at Week 52 | LTE Period - Week 52 Score | 2.5 score on a scale | Standard Deviation 2.1 |
| KHK4083 Combined | Change From Baseline in Total Mayo Scale Score at Week 52 | OLE Period - Week 52 Change from Baseline | -3.5 score on a scale | Standard Deviation 2.8 |
| KHK4083 Combined | Change From Baseline in Total Mayo Scale Score at Week 52 | OLE Period - Baseline Score | 7.6 score on a scale | Standard Deviation 0.9 |
| KHK4083 Combined | Change From Baseline in Total Mayo Scale Score at Week 52 | OLE Period - Week 52 Score | 4.3 score on a scale | Standard Deviation 3.4 |
| KHK4083 Combined | Change From Baseline in Total Mayo Scale Score at Week 52 | LTE Period - Baseline Score | 7.5 score on a scale | Standard Deviation 2.1 |
Secondary
Number of Subjects Who Achieve a Clinical Response at Week 12
The Mayo Clinic Score is comprised of 4 parts: stool frequency, rectal bleeding, endoscopic findings and physician's global assessment, each scored from 0-3. The total score ranges from 0-12 with higher scores indicating increased severity of disease. Clinical Response is a reduction in the total Mayo Clinic score of at least 3 points.
Time frame: 12 weeks
Population: Full analysis set - All randomized subjects who received at least one full dose of investigational product and had a Baseline and at least one post-treatment primary efficacy variable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KHK4083 Cohort 1 | Number of Subjects Who Achieve a Clinical Response at Week 12 | 3 Participants |
| KHK4083 Cohort 2 | Number of Subjects Who Achieve a Clinical Response at Week 12 | 8 Participants |
| KHK4083 Cohort 3 | Number of Subjects Who Achieve a Clinical Response at Week 12 | 11 Participants |
| KHK4083 Cohort 4 | Number of Subjects Who Achieve a Clinical Response at Week 12 | 22 Participants |
| KHK4083 Combined | Number of Subjects Who Achieve a Clinical Response at Week 12 | 9 Participants |
Secondary
Number of Subjects Who Achieve a Clinical Response at Week 52
The Mayo Clinic Score is comprised of 4 parts: stool frequency, rectal bleeding, endoscopic findings and physician's global assessment, each scored from 0-3. The total score ranges from 0-12 with higher scores indicating increased severity of disease. Clinical Response indicates the change from Baseline in the Total Mayo Clinic score \<= -3 and the percentage change from Baseline in the Total Mayo Clinic score \<= -30% to Week 12, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of \<= 1.
Time frame: 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KHK4083 Cohort 1 | Number of Subjects Who Achieve a Clinical Response at Week 52 | 2 Participants |
| KHK4083 Cohort 2 | Number of Subjects Who Achieve a Clinical Response at Week 52 | 4 Participants |
| KHK4083 Cohort 3 | Number of Subjects Who Achieve a Clinical Response at Week 52 | 14 Participants |
| KHK4083 Cohort 4 | Number of Subjects Who Achieve a Clinical Response at Week 52 | 20 Participants |
| KHK4083 Combined | Number of Subjects Who Achieve a Clinical Response at Week 52 | 5 Participants |
Secondary
Number of Subjects Who Achieve Clinical Improvement at Week 12
The Mayo Clinic Score is comprised of 4 parts: stool frequency, rectal bleeding, endoscopic findings and physician's global assessment, each scored from 0-3. The total score ranges from 0-12 with higher scores indicating increased severity of disease. Improvement will be based on a reduction in the total Mayo Clinic score.
Time frame: 12 weeks
Population: Full analysis set - All randomized subjects who received at least one full dose of investigational product and had a Baseline and at least one post-treatment primary efficacy variable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KHK4083 Cohort 1 | Number of Subjects Who Achieve Clinical Improvement at Week 12 | 2 Participants |
| KHK4083 Cohort 2 | Number of Subjects Who Achieve Clinical Improvement at Week 12 | 4 Participants |
| KHK4083 Cohort 3 | Number of Subjects Who Achieve Clinical Improvement at Week 12 | 9 Participants |
| KHK4083 Cohort 4 | Number of Subjects Who Achieve Clinical Improvement at Week 12 | 15 Participants |
| KHK4083 Combined | Number of Subjects Who Achieve Clinical Improvement at Week 12 | 5 Participants |
Secondary
Number of Subjects Who Achieve Clinical Remission at Week 12
The Mayo Clinic Score is comprised of 4 parts: stool frequency, rectal bleeding, endoscopic findings and physician's global assessment, each scored from 0-3. The total score ranges from 0-12 with higher scores indicating increased severity of disease. Clinical remission is defined as a total Mayo Clinic score of ≤ 2 and no subscores \> 1.
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KHK4083 Cohort 1 | Number of Subjects Who Achieve Clinical Remission at Week 12 | 1 Participants |
| KHK4083 Cohort 2 | Number of Subjects Who Achieve Clinical Remission at Week 12 | 3 Participants |
| KHK4083 Cohort 3 | Number of Subjects Who Achieve Clinical Remission at Week 12 | 6 Participants |
| KHK4083 Cohort 4 | Number of Subjects Who Achieve Clinical Remission at Week 12 | 10 Participants |
| KHK4083 Combined | Number of Subjects Who Achieve Clinical Remission at Week 12 | 3 Participants |
Secondary
Number of Subjects Who Achieve Clinical Remission at Week 52
The Mayo Clinic Score is comprised of 4 parts: stool frequency, rectal bleeding, endoscopic findings and physician's global assessment, each scored from 0-3. The total score ranges from 0-12 with higher scores indicating increased severity of disease. Clinical remission is defined as a total Mayo Clinic score of ≤ 2 and no subscores \> 1.
Time frame: 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KHK4083 Cohort 1 | Number of Subjects Who Achieve Clinical Remission at Week 52 | 1 Participants |
| KHK4083 Cohort 2 | Number of Subjects Who Achieve Clinical Remission at Week 52 | 3 Participants |
| KHK4083 Cohort 3 | Number of Subjects Who Achieve Clinical Remission at Week 52 | 6 Participants |
| KHK4083 Cohort 4 | Number of Subjects Who Achieve Clinical Remission at Week 52 | 10 Participants |
| KHK4083 Combined | Number of Subjects Who Achieve Clinical Remission at Week 52 | 5 Participants |
Secondary
Number of Subjects Who Achieve Mucosal Healing at Week 12
The endoscopic Mayo Score (Mayo endoscopic subscore) evaluates ulcerative colitis stage, based only on endoscopic exploration. The scale ranges from 0 to 3, with higher scores = more severe activity. Mucosal healing is defined as modified Mayo endoscopy sub-score (mMES) of 0 or 1 at Week 12.
Time frame: 12 weeks
Population: Full analysis set - All randomized subjects who received at least one full dose of investigational product and had a Baseline and at least one post-treatment primary efficacy variable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KHK4083 Cohort 1 | Number of Subjects Who Achieve Mucosal Healing at Week 12 | 1 Participants |
| KHK4083 Cohort 2 | Number of Subjects Who Achieve Mucosal Healing at Week 12 | 3 Participants |
| KHK4083 Cohort 3 | Number of Subjects Who Achieve Mucosal Healing at Week 12 | 8 Participants |
| KHK4083 Cohort 4 | Number of Subjects Who Achieve Mucosal Healing at Week 12 | 12 Participants |
| KHK4083 Combined | Number of Subjects Who Achieve Mucosal Healing at Week 12 | 4 Participants |
Secondary
Number of Subjects Who Achieve Mucosal Healing at Week 52
The endoscopic Mayo Score (Mayo endoscopic subscore) evaluates ulcerative colitis stage, based only on endoscopic exploration. The scale ranges from 0 to 3, with higher scores = more severe activity. Mucosal healing is defined as modified Mayo endoscopy sub-score (mMES) of 0 or 1.
Time frame: 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KHK4083 Cohort 1 | Number of Subjects Who Achieve Mucosal Healing at Week 52 | 1 Participants |
| KHK4083 Cohort 2 | Number of Subjects Who Achieve Mucosal Healing at Week 52 | 3 Participants |
| KHK4083 Cohort 3 | Number of Subjects Who Achieve Mucosal Healing at Week 52 | 7 Participants |
| KHK4083 Cohort 4 | Number of Subjects Who Achieve Mucosal Healing at Week 52 | 11 Participants |
| KHK4083 Combined | Number of Subjects Who Achieve Mucosal Healing at Week 52 | 3 Participants |
Secondary
Number of Subjects With Confirmed Anti-KHK4083 Antibodies (Immunogenicity)
The immunogenicity was assessed by determination of the development of anti-drug antibodies (ADA) against KHK4083.
Time frame: 52 weeks
Population: All subjects who received at least one dose of KHK4083, including 14 subjects initially randomized to placebo and who then continued into Open-Label Extension therapy, where they received the maximum tolerated dose of KHK4083.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| KHK4083 Cohort 1 | Number of Subjects With Confirmed Anti-KHK4083 Antibodies (Immunogenicity) | Subjects with Pre-Existing ADA at Baseline | 1 Participants |
| KHK4083 Cohort 1 | Number of Subjects With Confirmed Anti-KHK4083 Antibodies (Immunogenicity) | Subjects with Production of Treatment-Induced ADA | 3 Participants |
| KHK4083 Cohort 2 | Number of Subjects With Confirmed Anti-KHK4083 Antibodies (Immunogenicity) | Subjects with Pre-Existing ADA at Baseline | 2 Participants |
| KHK4083 Cohort 2 | Number of Subjects With Confirmed Anti-KHK4083 Antibodies (Immunogenicity) | Subjects with Production of Treatment-Induced ADA | 0 Participants |
| KHK4083 Cohort 3 | Number of Subjects With Confirmed Anti-KHK4083 Antibodies (Immunogenicity) | Subjects with Pre-Existing ADA at Baseline | 1 Participants |
| KHK4083 Cohort 3 | Number of Subjects With Confirmed Anti-KHK4083 Antibodies (Immunogenicity) | Subjects with Production of Treatment-Induced ADA | 1 Participants |
| KHK4083 Cohort 4 | Number of Subjects With Confirmed Anti-KHK4083 Antibodies (Immunogenicity) | Subjects with Production of Treatment-Induced ADA | 5 Participants |
| KHK4083 Cohort 4 | Number of Subjects With Confirmed Anti-KHK4083 Antibodies (Immunogenicity) | Subjects with Pre-Existing ADA at Baseline | 0 Participants |
| KHK4083 Combined | Number of Subjects With Confirmed Anti-KHK4083 Antibodies (Immunogenicity) | Subjects with Pre-Existing ADA at Baseline | 1 Participants |
| KHK4083 Combined | Number of Subjects With Confirmed Anti-KHK4083 Antibodies (Immunogenicity) | Subjects with Production of Treatment-Induced ADA | 4 Participants |