A clinical study to test the safety and possible benefits of an investigational study drug, KHK4083, in patients with ulcerative colitis.

• Register: EUCTR
• Last refreshed on: 26 November 2018
• Main ID: EUCTR2015-001555-69-HU
• Date of registration: 17/11/2015
• Prospective Registration: Yes
• Primary sponsor: Kyowa Kirin Pharmaceutical Development, Inc.
• Public title: A clinical study to test the safety and possible benefits of an investigational study drug, KHK4083, in patients with ulcerative colitis.
• Scientific title: A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Multiple Ascending Dose Study (Induction Therapy) and Long-term Extension Therapy of an Anti-OX40 Monoclonal Antibody (KHK4083) in Subjects with Moderately Active Ulcerative Colitis
• Date of first enrolment: 15/01/2016
• Target sample size: 60
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-001555-69
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Czech Republic, Hungary, Poland, Russian Federation, Serbia, United States

Contacts

• Name: Clinical Trial Information
• Affiliation: Kyowa Kirin Pharmaceutical Development, Inc.

• Name: Clinical Trial Information
• Affiliation: Kyowa Kirin Pharmaceutical Development, Inc.

Key inclusion & exclusion criteria

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)Tumor necrosis factor-alpha 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,
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 halflives (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 bscess, 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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

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.
MedDRA version: 20.1 Level: LLT Classification code 10045365 Term: Ulcerative colitis System Organ Class: 100000004856

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Intervention(s)

Product Name: KHK4083
Product Code: KHK4083
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Not available
Current Sponsor code: KHK4083
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

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.

Secondary Objective: • 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).

Main Objective: • 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).

Timepoint(s) of evaluation of this end point: Week 12

Secondary Outcome(s)

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 9).
•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 OLE/LTE 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 OLE/LTE 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 9).
•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 OLE/LTE Therapy Follow-up Period (Week 56 through Week 64);
•PD profile of KHK4083;
•PK-PD relationships.

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

Secondary ID(s)

NCT02647866

4083-002

Source(s) of Monetary Support

Kyowa Kirin Pharmaceutical Development, Inc.