Ensayos clínicos

Inclusion Criteria - Induction Study (Cohorts A and B):

• Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
• Males or non-pregnant, non-lactating females, ages 18 to 75 years, inclusive based on the date of the screening visit.
• Females of childbearing potential must have a negative pregnancy test at screening and baseline.
• Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception.
• Documented diagnosis of UC of at least 6 months AND with a minimum disease extent of 15 cm from the anal verge. Documentation should include endoscopic and histopathologic evidence of UC as follows:
  • The criteria for documentation of UC based on endoscopy will be medical record documentation of, or an ileocolonoscopy (full colonoscopy with the intubation of the terminal ileum) report dated ≥ 6 months before enrollment, which shows  features consistent with UC, determined by the procedure performing physician;
  • The criteria for documentation of UC based on histopathology will be medical record documentation of or a histopathology report indicating features consistent with UC as determined by the pathologist.
• A surveillance colonoscopy is required at screening in individuals with a history of UC for 8 or more years, if one was not performed in the prior 24 months.
• Moderately to severely active UC as determined by a centrally read endoscopy score ≥ 2, a rectal bleeding score ≥ 1, a stool frequency score ≥ 1 and PGA of ≥ 2 as determined by the Mayo clinic scoring system with endoscopy occurring during screening; total score must be between 6 and 12, inclusive.
• Meets one of the following TB screening criteria:
  • No evidence of active or latent TB:
    • A negative QuantiFERON® TB-Gold In-Tube test (or centrally reported equivalent assay) at screening; AND
    • A chest radiograph (views as per local guidelines) taken at screening or within the 3 months prior to screening (with the report or films available for investigator review) without evidence of active or latent TB infection; AND
    • No history of either untreated or inadequately treated latent or active TB infection.
• Previously treated for TB; i.e., if a subject has previously received an adequate course of therapy as per local standard of care for either latent TB (e.g., 9 months of isoniazid in a location where rates of primary multi-drug resistant TB infections are < 5% or an acceptable alternative regimen) or active TB (acceptable multi-drug regimen). In these cases, no QuantiFERON® TB-Gold In-Tube test (or centrally reported equivalent assay) need be obtained, but a chest radiograph must be obtained if not done so within 3 months prior to screening (with the report or films available for investigator review). It is the responsibility of the investigator to verify the adequacy of previous anti- TB treatment and provide appropriate documentation.
• Newly identified latent TB during screening: i.e., a subject who has a newly identified positive diagnostic TB test result (defined as a positive QuantiFERON® TB Gold in Tube test [or centrally reported equivalent assay]) in which active TB has been ruled out and for which appropriate, ongoing, prophylactic treatment for latent TB has been initiated for a minimum of 4 weeks prior to the first administration of study medication. Adequate treatment for latent TB is defined according to local country guidelines for immunocompromised subjects. Quantiferon testing may not be repeated except in the case of a single repeat for indeterminate results.
• Cases falling under category “b” and “c” need to be approved by the Sponsor prior to enrollment in the study. No subject with currently ACTIVE TB may be enrolled in the study, regardless of past or present anti-TB medication use.
• Laboratory parameters (subjects who fail to meet the below reference laboratory tests may be re-tested once at discretion of investigator prior to being considered a screen failure):
  • Hepatic panel (AST, ALT, total bilirubin) ≤ 2 times the ULN;
  • Estimated CrCl ≥ 40 ml/min as calculated by the CC&G equation;
  • Hemoglobin ≥ 8 g/dL;
  • Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (1,500/mm3);
  • Platelets ≥ 100 × 109/L;
  • White blood cells (WBC) ≥ 3.0 x 109/L;
  • Absolute Lymphocyte count > 750/mm3.
• May be receiving the following drugs (subjects on these therapies must be willing to remain on stable doses for the noted times):
  • Oral 5-aminosalicylate (5-ASA) compounds provided the dose prescribed has been stable for at least 4 weeks prior to randomization; dose must be stable for first 10 weeks after randomization;
  • Azathioprine, 6-MP or MTX provided the dose prescribed has been stable for 4 weeks prior to randomization; dose must be stable for first 10 weeks after randomization;
  • Oral corticosteroid therapy (prednisone prescribed at a stable dose ≤ 30 mg/day or budesonide prescribed at a stable dose of ≤ 9 mg/day) provided the dose prescribed has been stable for 2 weeks prior to randomization; dose must be stable for first 14 weeks after randomization.
• Willingness to refrain from live or attenuated vaccines during the study and for 12 weeks after last dose.

Exclusion Criteria - Induction Study (Cohorts A and B): 

• Pregnant or lactating females.
• Males and females of reproductive potential who are unwilling to abide by protocol-specified contraceptive methods.
• Females who may wish to become pregnant and/or plan to undergo egg donation or egg harvesting for the purpose of current or future fertilization during the course of the study and up to 35 days after last dose of the study drug.
• Male subjects unwilling to refrain from sperm donation for at least 90 days after last dose of the study drug.
• Known hypersensitivity to filgotinib, its metabolites, or formulation excipients.
• Exhibit acute severe UC as defined by the following criteria:
  • ≥ 6 bloody stools daily AND 1 or more of the following:
    • Body temperature ≥ 100.4°F (or 38°C);
    • Pulse > 90 beats per minute.
• Use of rectal formulations of 5-ASA compounds or rectal corticosteroids 2 weeks prior to screening.
• History of major surgery or trauma within 30 days prior to screening.
• Presence of CD, indeterminate colitis, ischemic colitis, fulminant colitis, isolated ulcerative proctitis, or toxic mega-colon.
• Prior surgical intervention for UC (eg, total colectomy, subtotal colectomy, partial or hemicolectomy, ileostomy, or colostomy) or likely requirement for surgery during the study.
• Dependence on parenteral nutrition.
• History or evidence of incompletely resected colonic mucosal dysplasia.
• Stool sample positive for Clostridium difficile (C. diff) toxin, pathogenic Escherichia coli (E. coli), Salmonella species (spp), Shigella spp, Campylobacter spp or Yersinia spp.
• Stool sample positive for ova and parasites test (O&P) unless approved by the medical monitor.
• Active clinically significant infection, or any infection requiring hospitalization or treatment with intravenous anti-infectives within 30 days of screening (or 8 weeks of Day 1); or any infection requiring oral anti-infective therapy within 2 weeks of screening (or 6 weeks of day 1).
• Infection with HIV, hepatitis B or hepatitis C.
• Presence of Child-Pugh Class C hepatic impairment.
• Active TB or history of latent TB that has not been treated (See inclusion criterion 8 for further information).
• History of malignancy in the last 5 years except for subjects who have been successfully treated for non-melanoma skin cancer or cervical carcinoma in situ.
• History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma.
• History of treatment with lymphocyte-depleting therapies, including but not limited to alemtuzumab, cyclophosphamide, total lymphoid irradiation, and rituximab.
• History of cytapheresis ≤ 2 months prior to screening.
• Use of prohibited concomitant medications.
• Any chronic medical condition (including, but not limited to, cardiac or pulmonary disease, or substance abuse) or psychiatric problem that, in the opinion of the Investigator or Sponsor, would make the subject unsuitable for the study or would prevent compliance with the study protocol procedures.
• Administration of a live or attenuated vaccine within 30 days of randomization.
• History of opportunistic infection or immunodeficiency syndrome.
• Currently on any chronic systemic (oral or intravenous) anti-infective therapy for chronic infection (such as pneumocystis (PCP), cytomegalovirus (CMV), herpes zoster, atypical mycobacteria).
• History of disseminated Staphylococcus aureus.
• History of symptomatic herpes zoster or herpes simplex within 12 weeks of screening, or any history of disseminated herpes simplex, disseminated herpes zoster, ophthalmic zoster, or central nervous system zoster.

Inclusion Criteria - (Biologic-naïve) Induction Study (Cohort A only):

Subjects must meet all of the additional following inclusion criteria to be eligible for participation in Cohort A Induction Study:

• Previously demonstrated an inadequate clinical response, loss of response to, or intolerance of at least 1 of the following agents (depending on current country treatment recommendations/guidelines):
  • Corticosteroids
    • Active disease despite a history of at least an induction regimen of a dose equivalent to oral prednisone 30 mg daily for 2 weeks or intravenously (IV) for 1 week; OR
    • Two failed attempts to taper steroids below a dose equivalent of 10 mg daily prednisone; OR
    • History of steroid intolerance including, but not limited to, Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, serious infections, depression, allergic reactions, mood disturbances, or any other condition that contributed to discontinuation of the agent.
  • Immunomodulators
    • Active disease despite a history of at least a 12-week regimen of oral azathioprine (≥2 mg/kg/day) or 6-MP (≥1 mg/kg/day), or MTX (25 mg subcutaneously [SC] or intramuscularly [IM] per week for induction and ≥15mg IM per week for maintenance); OR
    • History of intolerance to at least 1 immunomodulator including, but not limited to, serious infections, hepatotoxicity, cytopenia, pancreatitis, thiopurine methyltransferase (TPMT) genetic mutation, allergic reactions, or any other condition that contributed to discontinuation of the agent.

Exclusion Criteria - (Biologic-naïve) Induction Study (Cohort A only):

Subjects who meet any of the following exclusion criteria are not to be enrolled in Cohort A Induction Study:

• Prior use of any TNFα antagonist including (but not limited to) infliximab, adalimumab, golimumab, certolizumab, or biosimilar agents at any time.
• Prior or current use of vedolizumab at any time.

Inclusion Criteria - (Biologic-experienced) Induction Study (Cohort B only):

Subjects must meet all the additional following inclusion criteria to be eligible for participation in Cohort B Induction Study:

• Previously demonstrated an inadequate clinical response, loss of response to, or intolerance of at least one of the following agents (depending on current country treatment recommendations/guidelines):
  • TNFα Antagonists;
    • Active disease despite a history of at least one induction regimen of a TNFα Antagonist:
    • Infliximab: Minimum induction regimen of 5 mg/kg at 0, 2, and 6 weeks (in the EU, duration of treatment of 14 weeks)
    • Adalimumab: An 8-week induction regimen consisting of 160 mg (four 40-mg injections in 1 day or two 40-mg injections per day for 2 consecutive days) on Day 1, followed by a second dose 2 weeks later (Day 15) of 80 mg and a 40 mg dose 2 weeks later (Day 29), followed by a 40 mg dose every other week until Week 8 (Day 57).
  • Golimumab: Minimum induction duration of 6 weeks (12 weeks in EU) is required for golimumab, which includes 200 mg SC injection at Week 0, followed by 100 mg at Week 2 and then 100 mg every 4 weeks. OR
    • Recurrence of symptoms during maintenance therapy with the above agents; OR
    • History of intolerance to any TNFα antagonists including, but not limited to, serious infections, hepatotoxicity, heart failure, allergic reactions, or any other condition that contributed to discontinuation of the agent
  • Vedolizumab
    • Active disease despite a history of at least a 14 week (10 weeks in EU) induction regimen of vedolizumab consisting of 300 mg IV at weeks 0, two, and six; OR
    • History of intolerance to vedolizumab including, but not limited to, serious infections hepatotoxicity, cytopenia, allergic reactions, or any other condition that contributed to discontinuation of the agent.
• Must not have used any TNFα antagonist or vedolizumab ≤ 8 weeks prior to screening or any other biologic agent ≤ 8 weeks prior to screening or within 5 times the half-life of the biologic agent prior to screening, whichever is longer.

Exclusion Criteria - (Biologic-experienced) Induction Study (Cohort B only):

Subjects who meet the following exclusion criterion are not eligible to be enrolled in Cohort B Induction Study.

• Have used any TNFα antagonist or vedolizumab within ≤ 8 weeks prior to screening, or any other biologic agent ≤ 8 weeks prior to screening or within 5 times the half-life of the biologic agent prior to screening, whichever is longer.

Inclusion Criteria - Maintenance Study:

Subjects must meet all of the following inclusion criteria to be eligible for participation in the Maintenance Study.

• Completion of Cohort A or B induction study with MCS response or EBS remission based on Week 10 assessments.
• Willingness to refrain from live or attenuated vaccines during the study and for 12 weeks after last dose.
• May be on oral corticosteroid therapy (prednisone prescribed at a stable dose ≤ 30 mg/day or budesonide at a dose of ≤ 9 mg/day); dose must remain stable to Week 14.

Exclusion Criteria - Maintenance Study:

Subjects who meet any of the following exclusion criteria are not to be enrolled in the Maintenance Study:

• Males and Females of reproductive potential who are unwilling to abide by protocol-specified contraceptive methods.
• Females who may wish to become pregnant and/or plan to undergo egg donation or egg harvesting for the purpose of current or future fertilization during the course of the study and up to 35 days after last dose of the study drug.
• Male subjects unwilling to refrain from sperm donation during the study and for at least 90 days after last dose of the study drug.
• Use of prohibited concomitant medications.