| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Moderately Active Ulcerative Colitis, defined as:
•Total Mayo Clinic score of 4 to 9 (range: 0 to 12, with higher scores indicating more disease activity);
•Endoscopy subscore (mMES determined by a central reader) of at least 2; and
•Disease that extends ≥ 15 cm from the anal verge.
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Ulcerative colitis is a form of inflammatory bowel disease that causes inflammation and ulcers in the colon which is characterized by rectal bleeding, diarrhea, urgency, and abdominal pain. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• Induction Therapy - Part A: 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) to recommend for use in Part B;
• Induction Therapy - Part B: To determine if the recommended dose of KHK4083 identified in Part A improves the mucosa in subjects with moderately active UC at Week 12 as measured by the modified Mayo endoscopy subscore (mMES). |
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| E.2.2 | Secondary objectives of the trial |
• Determine if KHK4083 at dose levels different than the recommended dose improve the mucosa based on the mMES;
• Determine if any dose level of KHK4083 administered as Induction Therapy will meet the following objectives at Week 12 (or as noted):
–Improve the mucosa (modified Baron endoscopic; Ulcerative Colitis Endoscopic Index of Severity (UCEIS);
–Induce mucosal healing (mMES)
–Improve clinical signs and symptoms (total Mayo Clinic score; partial Mayo Clinic scores (Week 2 through Week 12, excludes endoscopy subscores));
–Induce a clinical response (reduction in the total Mayo Clinic score and rectal bleeding subscale (or a defined absolute rectal bleeding score of 0 or 1 at Week 12));
–Induce clinical remission based on a total Mayo Clinic score and subscores
• Characterize the pharmacokinetics (PK) of KHK4083 in subjects with moderately active UC following multiple dose administration;
• Evaluate the development of antibodies against KHK4083
(immunogenicity).
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Subject is able and willing to comply with study procedures, dosing and visit schedules and follow-up procedures as described in the protocol and ICF;
2) Subject voluntarily signs/dates an 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, defined as:
•Total Mayo Clinic score of 4 to 9 (range: 0 to 12, with higher scores indicating more disease activity);
•Endoscopy subscore (mMES determined by a central reader) of at least 2; and •Disease that extends ≥ 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 tumor necrosis factor (TNF)
antagonist therapy that was unsuccessful because of a lack of efficacy response or AEs, as defined below:
a)corticosteroids for induction therapy of at least prednisolone equivalent of 20 mg (or oral budesonide 9 mg) oral daily for 2 weeks or injectable for 1 week, or for maintenance therapy at least two failed attempts to reduce to less than prednisolone-equivalent 10 mg (or oral budesonide 3 mg) oral daily, or a history of intolerance to corticosteroids (including but not limited to hypertension, insomnia, osteopenia, osteoporosis, hyperglycemia, infection or Cushing's syndrome);
b)Azathioprine or 6-mercaptopurine of at least 1.5 mg/kg/day or 0.75 mg/kg/day, respectively, for 8 weeks, or a history of intolerance to either agent (including but not limited to nausea, vomiting, abdominal pain, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevations, thiopurine methyltransferase genetic mutation, or infection);
c)TNFα antagonists for induction therapy with approved anti-TNF products including, but not limited to, infliximab 5 mg/kg IV for 2 doses at least 2 weeks apart, adalimumab 160 mg SC followed by at least 80 mg SC at least 2 weeks apart, and golimumab 200 mg SC followed by at least 100 mg at least 2 weeks apart and anti-TNF biosimilar products with approved dosages for 2 doses at least 2 weeks apart; or as maintenance therapy for recurrence of symptoms despite continued
dosing, or history of intolerance (including but not limited to infusion or injection reactions, demyelination or infection).
7) Female subjects who are considered to be women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening and Baseline. WOCBP must agree to use effective contraception, defined as oral contraceptives with one barrier method, or tubal ligation with one barrier method or double barrier method (condom plus spermicide
or diaphragm plus spermicide) during the study and for at least 6 months after the last dose of investigational product. Subjects are considered to not be of childbearing potential if they are ≥ 50 years of age and without menses for 24 consecutive months and have a follicle stimulating hormone level > 25 mIU/mL (or in postmenopausal range per local laboratory standards); or have undergone a hysterectomy and/or a bilateral salpingo-oophorectomy.
Egg donation is not permitted while on study medication and for at least 6 months after the last dose of study medication.
8) Male subjects (including those who have had a vasectomy) must use adequate contraception (e.g., latex condom, non-latex condom not made of natural animal membrane such as polyurethane condom) during the study and for at least 6 months after the last dose of investigational product.
Sperm donation is not permitted while on study medication and for at least 6 months after the last dose of study medication.
Additional Criteria to Enroll in OLE Therapy:
Prior to receiving one infusion every 4 weeks of KHK4083 in the OLE, subjects must meet the following criteria:
1) Subjects must have completed double-blind Induction Therapy, i.e., at least five of six double-blind treatments, or the subject is already in the double-blind LTE and not beyond Week 28 with a clinical worsening or a flare of disease as defined by the Investigator);
2) Subjects must have evaluable total Mayo Clinic scores at baseline and Week 12;
3) Subjects must have been compliant with the protocol (including concomitant medication restrictions); and
4) Subjects may have no clinically significant additional risks, as determined by the Investigator or the Sponsor, of treatment with KHK4083.
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|
| E.4 | Principal exclusion criteria |
1) Subject, who is judged by the Inv to be inappropriate for this study;
2) Medical history of clinically significant (as determined by Inv or Sponsor) cardiac, renal, hepatic/biliary, pulmonary or other medical condition or is not generally in good health; Subjects with history of immunologic, autoimmune or chronic inflammatory disorders (e.g., uveitis, rheumatoid arthritis, ankylosing spondylitis or spondyloarthritis, psoriasis) other than UC or autoimmune connective tissue diseases (e.g., systemic lupus erythematosus, systemic sclerosis) and are well controlled may be included into the trial after consultancy with medical monitor.
Subjects with thyroid disorders, vitiligo, or alopecia are eligible for inclusion.
3) Subject's UC had failed to respond to: a) 2 or more biologic treatments with different mechanisms of action (e.g infliximab and vedolizumab), or b) 3 or more anti-TNF biologics (e.g. infliximab, adalimumab and golimumab)
4) Requires prescription treatment for UC, except for stable, oral treatment of UC:
•Aminosalicylates for at least 14d prior to Screening visit; and/or
•Glucocorticoids for at least 14d prior to Screening visit and/or
•Azathioprine up to 3 mg/kg/d or 6-mercaptopurine up to 1.5 mg/kg/d for total period of at least 12 wk, including 4 wk of stable treatment, prior to Screening visit.
5) Received any of the following treatments within the specified time prior to Baseline visit:
•Natalizumab, efalizumab or rituximab or other lymphocyte-depleting treatments, including but not limited, to alkylating agents and total lymphoid irradiation at any time •TNF antagonists within 8 wk, or 5 half-lives (not exceeding 12 wk) •Vedolizumab within 16 wk •Methotrexate, cyclosporine, mycophenolate, tacrolimus, thalidomide, or other immune altering drugs within 4 wk •5-ASA enema, or steroid enema or suppository use within 2 wk and/or
•Investigational agents within 8 wk or 5 half-lives, whichever is longer.
6) Recent, suspected or confirmed symptomatic stenosis of the colon, abdominal abscess,ischemic colitis based on clinical or radiographic data; or suspected, confirmed or history of toxic megacolon; or any colonic resection, subtotal or total colectomy, ileostomy, or colostomy; or any previous surgery for UC or an anticipated requirement for surgery for UC;
7) Known colonic dysplasia, adenomas or polyposis;
8) Major surgery within 4 weeks prior to Screening or anticipated requirement for major surgery;
9) Enteric pathogens detected on stool analysis; or C difficile infection within 8 wk prior to Screening; or intestinal pathogen infection detected within 4 wk prior to Screening;
10) Any of the following laboratory values •Platelet count < 100,000/mm3•Neutrophils < 1500/mm3 •Serum creatinine ≥ 1.6 mg/dL (≥ 144.4 μmol/L) •Alkaline phosphatase > 3 times ULN
•Aspartate aminotransferase 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) Clinically significant cardiac disease; unstable angina pectoris; myocardial infarction within 6m or post angioplasty or stenting within 6m; uncontrolled hypertension; or clinically significant abnormality, eg cardiac arrhythmia, on 12-lead ECG at Screening;
12) Pregnant or breastfeeding;
13) Has had a major immunologic reaction
14) Hep B core antibody or surface antigen +ve at Screening and/or Hep C antibody +ve with detectable RNA at Screening;
15) History of HIV positivity, tests +ve for HIV at Screening, or has congenital or acquired immunodeficiency;
16) Has or had active TB, suspected extra-pulmonary TB, a history of incompletely treated TB, or latent TB or other latent infection. Subjects with latent TB may be included if prophylactic therapy for latent TB is started at least 4 wk prior to Screening. Subjects with potentially untreated other infection are excluded.
17) Bacterial infections requiring treatment with oral or parenteral antibiotics within 2 and 4 wk, respectively, of the Screening period;
18) History of systemic opportunistic infection or recurrent infections;
19) Malignancy or history of malignancy, except for adequately treated basal cell skin cancer or adequately treated carcinoma in-situ of the cervix without recurrence, treatment must have been completed at least 5yr before Screening;
20) Received a BCG vaccine within 6m of randomization or live vaccination within 4 wk of randomization . Subject is allowed vaccinations of inactivated vaccines
21) History of substance abuse within 1 yr of Screening; or active marijuana use or active substance abuse;
22) Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results, as determined by the Investigator;
23) Previously participated in a study of KHK4083. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy - mean change in the mMES from Baseline (Week 0) to Week 12 for all subjects who receive the recommended dose in Parts A and B.
Safety - safety and tolerability will be determined by physical
examination, vital signs, body weight,12-lead ECGs, and clinical
laboratory findings; and the number and percentage of subjects
reporting AEs (frequency, severity, and relationship to investigational product), SAEs, and treatment discontinuation due to AEs. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints for all subjects who receive the recommended dose during double-blind Induction Therapy are as follows:
•Improvement in the mucosa at Week 12;
–Changes in the mucosa will be based on the percentage of subjects with at least a 1 point improvement in their mMES (0 to 3) from Baseline (Week 0) to Week 12; and/or
–Changes in the mucosa will be based the percentage of subjects with at least a 1 point improvement in their modified Baron endoscopic score (5- point scale) from Baseline (Week 0) to Week 12; and/or
–Changes in the mucosa will be based on the mean change in UCEIS (0 to 8) and subscores from Baseline (Week 0) to Week 12.
•Mucosal healing at Week 12;
Mucosal healing is defined as a mMES of 0 or 1.
•Clinical improvement at Week 12;
Improvement will be based on a reduction (mean change from Baseline [Week 0] at Week 12) in the total Mayo Clinic score (0 to 12).
•Clinical improvement at Weeks 2, 4, 6, 8, 10, and 12; Improvement will be based on mean changes from Baseline (Week 0) in the partial (excludes endoscopy subscores) Mayo Clinic score (0 to 10).
•Clinical response at Week 12;
A clinical response is defined as a reduction in the total Mayo Clinic score of at least 3 points and a decrease of at least 30% from Baseline (Week 0) to Week 12, and a reduction in the rectal bleeding subscale of at least 1 point from Baseline (Week 0) to Week 12 or an absolute rectal bleeding score of 0 or 1 at Week 12.
•Clinical remission at Week 12;
Clinical remission is defined as a total Mayo Clinic score of ≤ 2 and no subscores > 1.
For all subjects who receive KHK4083 at dose levels different than the recommended dose during double-blind Induction Therapy, improvement in the mucosa at Week 12 based on the mean change in the mMES from Baseline (Week 0) to Week 12 is the main secondary endpoint. The other secondary efficacy endpoints at Week 12 for all subjects who receive KHK4083 at other than the recommended dose are the same as those
listed and defined above, i.e., improvement in the mucosa based on the modified Baron endoscopic score and the UCEIS; mucosal healing; clinical improvement based on total, as well as partial (excludes endoscopy subscore at Weeks 2, 4, 6, 8, 10, and 12) Mayo Clinic scores; clinical response; and clinical remission. The PK for KHK4083 will be characterized in the UC subject population following multiple ascending doses.
The exploratory endpoints for all subjects who receive both Induction
Therapy and LTE /OLE Maintenance Therapy are as follows:
•Clinical improvement at Week 52;
Improvement will be based on a reduction (mean change from Baseline [Week 0] to Week 52) in the total Mayo Clinic score (0 to 12).
•Clinical improvement at Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 and at LTE/OLE Maintenance Therapy Follow-up Period visits (Weeks 56, 60, and 64); Improvement will be based on mean changes from Baseline (Week 0) in the partial (excludes endoscopy subscores) Mayo Clinic score (0 to 10).
•Clinical response at Week 52;
A clinical response is defined as a reduction in the total Mayo Clinic score of at least 3 points and a decrease of at least 30% from Baseline (Week 0) to Week 52, and a reduction in the rectal bleeding subscale of at least 1 point from Baseline (Week 0) to Week 52 or an absolute rectal bleeding score of 0 or 1 at Week 52.
•Clinical remission (i.e., a total Mayo Clinic score of ≤ 2 and no
subscores > 1) at Week 52;
•Durable clinical responses and durable clinical remissions at Week 52 (i.e., present at both Week 12 and Week 52), and glucocorticoid-free clinical remission at Week 52;
•Mucosal healing (i.e., an mMES of 0 or 1) at Week 52;
•Improvement in the mucosa according to the following assessments:
–At least a 1-point improvement in the mMES from Baseline (Week 0) to Week 52;
–A mean change in the UCEIS score from Baseline (Week 0) to Week 52; and/or
–At least a 1-point improvement in the modified Baron endoscopic score from Baseline (Week 0) to Week 52.
•Remission (i.e., mMES of 0 or 1, stool frequency subscore of 0 or 1, and rectal bleeding subscore of 0) rates at Week 12 and Week 52;
•Improvement in the HRQL, which will be based on the subject's completed IBDQs;
•Lowered corticosteroid (glucocorticoid) dosages;
•Glucocorticoid-free treatment duration from Week 16 through Week 52, and through the LTE/OLE Maintenance Therapy Follow-up Period (Week 56 through Week 64);
•PD profile of KHK4083; |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary - Week 12
Exploratory - Weeks 16, 20,24,28,32,36,40,44,48 and 52 ; follow up period visits at Weeks 56,60 and 64 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Russian Federation |
| Serbia |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The date of the subject’s last post-treatment study visit will be considered the End of Study date. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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