Study of a Monoclonal Antibody KHK4083 in Moderate Ulcerative Colitis
Condition: Ulcerative Colitis; Digestive System Diseases; Colitis, Ulcerative; Colitis; Gastrointestinal Diseases; Inflammatory Bowel Diseases; Intestinal Diseases; Colonic Diseases; Autoimmune Disease; Abdominal Pain
MeSH terms: Colitis; Colitis, Ulcerative; Intestinal Diseases; Inflammatory Bowel Diseases; Gastrointestinal Diseases; Digestive System Diseases; Colonic Diseases; Autoimmune Diseases; Ulcer; Abdominal Pain
Intervention: KHK4083; Placebo
Intervention description: IV Infusion; IV Infusion
Intervention MeSH terms: KHK4083
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
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).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 66.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: 4083-002; Intestinal Diseases; Ulcerative Colitis; UC; Mayo Clinic Scoring; Gastrointestinal Tract

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.
    

Eligibility criteria:

        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.