Study of a Monoclonal Antibody KHK4083 in Moderate Ulcerative Colitis

A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Multiple Ascending Dose Study (Induction Therapy) & Long-term Extension Therapy of an Anti-OX40 Monoclonal Antibody (KHK4083) in Subjects With Moderately Active UC

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.

Study Overview

• Status: Completed
• Conditions: Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Abdominal Pain; Inflammatory Bowel Diseases; Ulcerative Colitis; Colitis; Colitis, Ulcerative; Autoimmune Disease
• Intervention / Treatment: Drug: KHK4083; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Hradec Kralove, Czechia, 500 12
  • Znojmo, Czechia, 669 02
• Hungary
  • Budapest, Hungary, 1125
  • Budapest, Hungary, H-1032
  • Budapest, Hungary, H-1083
• Poland
  • Bydgoszcz, Poland, 85-168
  • Rzeszow, Poland, 35-302
  • Sopot, Poland, 81-756
  • Tychy, Poland, 43-100
  • Warsaw, Poland, 00-632
  • Warsaw, Poland, 03-580
  • Warsaw, Poland, 54-239
• Romania
  • Sector 2
    • Bucharest, Sector 2, Romania, 020125
• Russian Federation
  • Krasnoyarsk, Russian Federation, 660022
  • Moscow, Russian Federation, 129110
  • Novosibirsk, Russian Federation, 630091
  • Penza, Russian Federation, 440026
  • St. Petersburg, Russian Federation, 194354
  • St. Petersburg, Russian Federation, 196247
• Serbia
  • Belgrade, Serbia, 11080
    • Bežanija Kosa
  • Kragujevac, Serbia, 34 000
  • Belgrade
    • Zemun, Belgrade, Serbia, 11080
• United States
  • South Carolina
    • Greenville, South Carolina, United States, 29615

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: KHK4083; IV Infusion
Experimental: 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.	Drug: KHK4083; IV Infusion
Experimental: 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.	Drug: KHK4083; IV Infusion
Experimental: 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.	Drug: KHK4083; IV Infusion
Placebo Comparator: 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.	Drug: Placebo; IV Infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Treatment-related Adverse Events	To determine the safety and tolerability of KHK4083	Up to 52 weeks
Number of Subjects With Treatment-related Serious Adverse Events	To determine the safety and tolerability of KHK4083	Up to 52 weeks
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.	12 weeks
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.	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	52 weeks
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.	12 weeks
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.	52 weeks
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.	12 weeks
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.	52 weeks
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.	12 weeks
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.	52 weeks
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.	12 weeks
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.	52 weeks

Collaborators and Investigators

• Sponsor: Kyowa Kirin, Inc.
• Investigators: Study Director: Vincent Strout, MBA, Kyowa Kirin, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2016
• Primary Completion (Actual): September 1, 2018
• Study Completion (Actual): October 1, 2018

Study Registration Dates

• First Submitted: December 8, 2015
• First Submitted That Met QC Criteria: January 5, 2016
• First Posted (Estimate): January 6, 2016

Study Record Updates

• Last Update Posted (Actual): March 5, 2020
• Last Update Submitted That Met QC Criteria: February 21, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Ulcerative Colitis; Intestinal Diseases; UC; Gastrointestinal Tract; 4083-002; Mayo Clinic Scoring
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Pain; Neurologic Manifestations; Signs and Symptoms, Digestive; Gastroenteritis; Ulcer; Inflammatory Bowel Diseases; Abdominal Pain; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Colitis; Colitis, Ulcerative; Autoimmune Diseases; Colonic Diseases; Dermatologic Agents; KHK4083
• Other Study ID Numbers: 4083-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No