E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Ulcerative colitis - which is a disease of the large intenstine (colon) that causes open sores (ulcers) in the colon. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
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 |
The primary objective is to characterize the change in the Pharmacodynamic (PD) biomarker, fecal calprotectin, during treatment with anrukinzumab. |
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E.2.2 | Secondary objectives of the trial |
• Characterization of the PK profile and total IL 13 of three multiple escalating IV doses of anrukinzumab versus placebo.
• Determination of the safety, tolerability and immunogenicity of anrukinzumab in patients with active UC.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
2. Patients are willing and able to participate in the study, complete patient assessments, attend scheduled clinic visits, and comply with all protocol requirements as evidenced by written informed consent.
3. Male and/or female patients between the ages of ≥18 and ≤65 years at the time of informed consent.
4. Positive histological diagnosis of UC. A biopsy report must be available in the patient’s source documentation. In addition, a report documenting disease duration and extent of disease (eg, proctosigmoiditis, left sided colitis and pancolitis) based upon prior colonoscopy must also be available in source documentation. A colonoscopy with biopsy will need to be performed if this documentation is not available.
5. Diagnosis of active UC determined within the screening period as defined by a Mayo score ≥4 and <10 points and with an endoscopic sub score (based upon flexible sigmoidoscopy) of ≥2 points.
6. Fecal calprotectin ≥100 mg/kg within the screening period. The screening fecal calprotectin may be repeated once during the screening period with results available and reviewed prior to the baseline visit.
7. Subjects that are taking 5 ASA prior to screening must be on a stable dose for at least two (2) weeks prior to their first screening visit.
8. All women of childbearing potential (WOCBP) must have a negative serum pregnancy test result at screening and a negative urine pregnancy test result at baseline.
• WOCBP are defined as women who are biologically capable of becoming pregnant, including women who are using contraceptives or whose sexual partners are either sterile or using contraceptives.
• Women of non childbearing potential (WONCBP) are defined as either postmenopausal (history of amenorrhea for ≥52 weeks and confirmation by FSH level) or who are surgically sterile, such as after hysterectomy, bilateral oophorectomy, or tubal ligation (procedure performed ≥52 weeks before screening). This information must be documented in the patient's source documents.
• WONCBP do not require a serum and urine pregnancy test.
9. WOCBP who have sexual intercourse with a non surgically sterilized male must agree and commit to the use of the following highly effective methods of contraception for the duration of the study (defined as the time of the signing of the informed consent form through the conclusion of patient participation). Contraceptive methods considered acceptable for use in this study include:
• Established use of oral, injected, transdermal or implanted hormonal methods of contraception.
• Double barrier contraception: use of condom and occlusive diaphragm (cap or cervical/vault caps) with spermicidal foam/gel/ film/cream/suppository. A female condom and a male condom should not be used together as friction between the two can result in either, or both, product(s) failing.
• An intrauterine device or system.
10. All men (unless surgically sterile, as defined below) who have sexual intercourse with a WOCBP must agree and commit to use a highly effective method of contraception for the duration of the study (defined as the time of the signing of the informed consent form through the conclusion of patient participation). Highly effective methods of contraception include properly used spermicidal condom.
• To be considered surgically sterilized, a male partner must have had a vasectomy at least 24 weeks before study Day 1. |
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E.4 | Principal exclusion criteria |
Patients presenting with any of the following will not be included in the study:
1. Indeterminate colitis, ischemic colitis, fulminant colitis and Crohn’s disease.
2. UC confined to proctitis or disease confined to the rectum only.
3. Any previous colonic or likely to require colonic surgery within the duration of the study. Any other abdominal surgery within 12 weeks or likely to require abdominal surgery within the duration of the study.
4. Abnormal findings on the chest x ray film performed routinely before initiating a new biologic therapy, such as presence of tuberculosis (TB), general infections, heart failure, or malignancy. (Chest x ray examination may be performed up to 12 weeks prior to study entry. Documentation of the official reading must be located and available in the source documentation.).
5. Any history or current evidence of latent or active tuberculosis infection, evidence of prior or currently active tuberculosis by chest radiography, residing with or frequent close contact with individual(s) with active tuberculosis. Patients who have a positive Mantoux (PPD) tuberculin skin test or a positive Interferon Gamma Release Assay (IGRA to be tested at the site’s local lab) during screening or within 12 weeks prior to randomization. The following are acceptable assays; QuantiFERON® TB Gold test (QFT G), QuantiFERON® TB Gold In Tube test (GFT GIT) and T SPOT® TB test.
• A positive Mantoux tuberculin skin test is defined as ≥5 mm of induration (or as defined by country specific or local standards) at 48 72 hours without consideration of prior Bacillus Calmette Guérin (BCG) vaccination. Documentation of the dose and product used for the Mantoux tuberculin test as well as the official test reading must be obtained and available in the patient's study file.
• An IGRA is preferred for patients with a prior Bacillus Calmette Guérin (BCG) vaccination (to be tested by a site’s local lab). Documentation of the IGRA product used and the test result must be in the patient’s source documentation.
6. Active enteric infections, pseudomembranous colitis, salmonella, shigella campylobacter or other GI bacterial, fungal or parasitic infection or known active invasive fungal infections such as histoplasmosis (stool culture and sensitivity, ova & parasites as well as Clostridium difficile toxins A and B may be tested by the site’s local lab). Any underlying disease that could predispose the patient to infections or history of serious infection (requiring parenteral antibiotic and/or hospitalization) within 4 weeks before the baseline visit. Pyoderma gangrenosum is allowed.
7. Preexisting demyelinating disorder including multiple sclerosis or new onset seizures, unexplained sensory, motor, or cognitive/behavioral or neurological deficits.
8. Significant concurrent medical conditions at the time of screening or baseline visit, including, but not limited to, the following:
• Any major illness/condition or evidence of an acute or unstable clinical condition (eg, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, immunologic [eg, Felty syndrome], or infectious illness) that, in the investigator’s judgment, will substantially increase the risk to the patient if he or she participates in the study.
• Cancer or history of cancer or lymphoproliferative disease within the previous 5 years (other than resected cutaneous basal cell or squamous cell carcinoma that has been treated with no evidence of recurrence).
• Class III or IV congestive heart failure as defined by the New York Heart Association.
• Acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris) and any history of significant cerebrovascular disease within 24 weeks before screening.
9. Known history of human immunodeficiency virus (HIV) based on documented history with positive serological test or positive HIV screen test performed locally at the time of screening. A negative HIV test result within 12 months of the screening period will be accepted. Documentation of the negative test result must be located and available in the source documentation.
10. Presence of a transplanted organ.
For the full list of Exclusion Criteria please refer to the protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
• Fold change from baseline in fecal calprotectin at Week 14.
Note: Fold change is defined as (post-treatment measurement)/(baseline measurement), which is related to percent change from baseline by the following equation: Percent change from baseline = 100% x (fold change-1).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Pharmacokinetic Endpoints
• The PK of anrukinzumab will be characterized from data obtained at pre specified time points up to 32 weeks. The pharmacokinetic parameters including AUC and half life will be estimated using noncompartmental analysis and additional parameters may be estimated using population PK analysis.
Pharmacodynamic Endpoints
• Fold change from baseline in fecal calprotectin at Weeks 2, 4, 8, and 12.
• Total IL 13 (free IL 13 and IL 13 complexed with anrukinzumab) measured at pre specified time points up to 32 weeks.
Safety Endpoints
• The frequency of on treatment adverse events, serious adverse events and withdrawals due to adverse events will be summarized.
• Frequency of ADAs and Nabs, if observed, at pre specified timepoints up to 32 weeks.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints are defined within the secondary end points |
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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 | No |
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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | 43 |
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 |
Austria |
Belgium |
Bulgaria |
Canada |
France |
Hungary |
Netherlands |
Poland |
Romania |
Spain |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 11 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 4 |