| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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| 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 |
| • To evaluate the efficacy of KRP203 in subjects with moderately active refractory ulcerative colitis by comparing the clinical remission rate of subjects on KRP203 versus placebo at Week 8 where clinical remission is defined as a Partial Mayo Index score of 0 or 1 together with the modified Baron score of 0 or 1 with no macroscopic bleeding, i.e. score 0 in the “Rectal bleeding” dimension of the Partial Mayo Index score |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety, tolerability and pharmacokinetics at steady-state of KRP203 given as an oral drug for 8 weeks once a day in ulcerative colitis subjects.
• To explore the relationship between KRP203 and KRP203-P pharmacokinetics and clinical efficacy outcomes
• To assess the pharmacodynamic effect of KRP203 on absolute lymphocyte count and leukocyte subsets in ulcerative colitis subjects
• To evaluate possible effect of KRP203 on markers of inflammation (ESR, CRP and fecal calprotectin/ lactoferrin) in ulcerative colitis subjects
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained before any assessment is performed.
2. Males and females 18-65 years of age with an established diagnosis of ulcerative colitis are eligible for the study.
3. Subjects must have active disease with a Partial Mayo Score between 5 and 9 (inclusive), with a score of at least 2 on either stool frequency or rectal bleeding and a Modified Baron Score of at least 2 upon endoscopic examination with the disease extending at least 25 cm from the anal verge.
4. Subjects must have responded inadequately to conventional therapy with oral 5-ASA prior to screening. Inadequate response is considered to be any of the following:
a. Active disease despite induction therapy with 5-ASA agents where adequate therapy is considered with an oral 5-ASA (mesalamine 2– 4.8 g/day, sulfasalazine 4–6 g/day, balsalazide 6-7.5 g/day or olsalazine 1.5–3 g/day) administered for at least 2 weeks.
b. Intolerance to oral 5-ASAs.
5. Female patients may be included in the study according to the following:
a. Female patients of child bearing potential must be using two highly effective methods of contraception (one primary and one secondary), from the time of screening and for the duration of the study, through Study Completion and for two (2) months after study completion. Period abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Primary contraception forms:
• Hormonal contraception (combination oral contraceptives, hormonal transdermal patch, combined injected hormones, injected single hormone, implanted hormones, or hormonal vaginal ring)
• Tubal sterilization
• Partner's vasectomy
• Intrauterine device (eg: synthetic progestin containing IUDs, IUD copper T380)
Secondary contraception forms:
• Male latex condom
• Diaphragm
• Cervical cap
b. Postmenopausal females must have had no regular menstrual bleeding for at least one (1) year prior to initial dosing. Menopause will be confirmed by a plasma FSH level of >40 IU/L at screening.
c. Female patients who report surgical sterilization must have had the procedure at least six (6) months prior to initial dosing. Surgical sterilization procedures should be supported with clinical documentation made available to the sponsor and noted in the Relevant Medical History / Current Medical Conditions section of the CRF.
d. All female patients must have negative pregnancy test results at Screening.
6. Male subjects must agree to comply with two highly effective contraceptive methods comprising a barrier method (condom or occlusive cap plus spermicidal) for up to the last drug administration, and refrain from fathering a child for at least two (2) months following the last study drug administration. Periodic abstinence and withdrawal are not acceptable methods of contraception.
7. Patients must be able to communicate well with the Investigator, to understand and comply with the requirements of the study and to understand and sign the written informed consent.
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|
| E.4 | Principal exclusion criteria |
1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment
2. Pregnant or nursing (lactating) women
3. Subjects who have been treated with
a. Anti-TNF α or biological therapy and cyclophosphamide with 3 months prior to randomization
b. Rituximab or other immunosuppressive treatments with effects potentially lasting over 6 months, within 12 months prior to randomization.
c. a dose of ≥ 1 mg prednisone or equivalent per body kg weight in the last 8 weeks prior to randomization.
4. Ongoing treatment with cyclosporine, methotrexate, azathioprine, 6-mercaptoprine, tacrolimus or rectally administered corticosteroid or 5-aminosalicylate containing medication. Eligible subjects must have stopped cyclosporine, methotrexate, azathioprine, 6-mercaptoprine and tacrolimus at least 4 weeks and antibiotics and rectal or topical therapy at least 1 week prior to randomization.
5. A history of macular edema, diabetic retinopathy, uveitis, central serious retinopathy, retinal vein occlusion, or any other eye disease that increases the risk of macular edema.
6. History or evidence abnormal cardiovascular conditions
7. Any of the following pulmonary conditions:
a. pulmonary fibrosis or any severe respiratory disease
b. tuberculosis, except for history of successfully treated tuberculosis or history of prophylactic treatment after positive PPD skin reaction
c. patients receiving chronic (daily) therapies for asthma
d. patients with any other types of clinically significant bronchoconstrictive disease
8. Uncontrolled diabetes mellitus
9. Repeated and confirmed laboratory findings showing:
a. known history of alcohol abuse, chronic liver or biliary disease
b. total bilirubin greater than the upper limit of the normal range (ULN) unless in context of Gilbert’s syndrome
c. conjugated bilirubin greater than the ULN
d. alkaline phosphatase (AP) greater than 1.5 x ULN
e. AST (SGOT), ALT (SGPT) greater than 1.5 x ULN
f. gamma-glutamyl-transferase (GGT) greater than 2 x ULN
g. serum creatinine greater than 1.5 times the upper limit of normal range
h. total white blood cell count (WBC) outside the range of 3,000 – 12,000 /µL. Subjects with mild leukocytosis (WBC not higher than 15,000 /µL) may be eligible, if the elevated WBC, according to the Investigator, is attributable to corticosteroid therapy and other causes such as hematological or infectious diseases can be excluded.
i. platelets <100,000/µL
j. Hemoglobin less 9 g/dL and/or other signs of severe anemia.
k. lymphocyte count <800/mm3 (<800 / µL)
10. Subjects who have been diagnosed with primary sclerosing cholangitis are excluded from the study.
11. History or presence of a significant renal disease
12. Clinical signs and symptoms of toxic megacolon
13. Positive alcohol or drug abuse test at screening.
14. Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing or longer if required by local regulation.
15. Have received any live or live attenuated vaccines (including for varicella-zoster virus or measles) within 2 months prior to randomization.
16. Significant illness within the two weeks prior to dosing or any active systemic infection or medical condition that may require treatment or therapeutic intervention during the study.
17. Current history of active systemic bacterial, viral or fungal infections
18. Diagnosis of AIDS, Hepatitis B, Hepatitis C infection defined as a positive HIV antibody, Hepatitis B surface antigen or Hepatitis C antibody tests, respectively,
19. Negative for varicella-zoster virus IgG antibodies
20. History of malignancy (other than basal cell carcinoma or adequately treated carcinoma-in-situ of the cervix).
21. History of hypersensitivity to KRP203 compound and/ or its class.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| clinical remission defined by both the partial Mayo and the modified Baron scores at visit 6 (week 8) where clinical remission is defined as a Partial Mayo Index score of 0 or 1 together with the modified Baron score of 0 or 1 with no macroscopic bleeding, i.e. score 0 in the “Rectal bleeding” dimension of the Partial Mayo Index score |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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 | Yes |
| 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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Last patient last visit or study terminated by sponsor |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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