Resumen

Este estudio de fase III, doble ciego, controlado con placebo y con comparador activo, multicéntrico, investigará la eficacia y seguridad de etrolizumab en la inducción de la remisión en participantes con colitis ulcerosa (CU) de actividad moderada a grave que no han recibido tratamiento previo con inhibidores del factor de necrosis tumoral (TNF) y que son refractarios o intolerantes al tratamiento previo con inmunosupresores y/o corticosteroides. Además de este estudio, se llevó a cabo de forma independiente un segundo ensayo clínico de fase III con diseño idéntico (GA28948; NCT02163759).

Elegibilidad

Edad mínima: 18 YearsEdad máxima: 80 YearsSexo: ALL

Criterios de inclusión

Diagnosis of ulcerative colitis (UC) established at least 3 months prior to randomization (Day 1)
Moderately to severely active UC as determined by the MCS
Naive to treatment with TNF inhibitor therapy
An inadequate response, loss of response, or intolerance to prior corticosteroid and/or immunosuppressant treatment
Background UC therapy may include oral 5-aminosalisylate (5-ASA), budesonide, oral corticosteroids, probiotics, azathioprine (AZA), 6-mercaptopurine (6MP), or methotrexate (MTX) if doses have been stable for:
AZA, 6-MP, MTX: 8 weeks immediately prior to randomization
ASA: 4 weeks immediately prior to randomization
Corticosteroids: 4 weeks immediately prior to randomization; if corticosteroids are being tapered, dose has to be stable for at least 2 weeks prior to randomization
Use of highly effective contraception method as defined by the protocol
Have received a colonoscopy within the past year or be willing to undergo a colonoscopy in lieu of a flexible sigmoidoscopy at screening

Criterios de exclusión

Prior extensive colonic resection, subtotal or total colectomy, or planned surgery for UC
Past or present ileostomy or colostomy
Diagnosis of indeterminate colitis
Suspicion of ischemic colitis, radiation colitis, or microscopic colitis
Diagnosis of toxic megacolon within 12 months of initial screening visit
Any diagnosis of Crohn's disease
Past or present fistula or abdominal abscess
A history or current evidence of colonic mucosal dysplasia
Patients with any stricture (stenosis) of the colon
Patients with history or evidence of adenomatous colonic polyps that have not been removed
Prior treatment with TNF-alpha antagonists
Any prior treatment with etrolizumab or other anti-integrin agents
Any prior treatment with rituximab
Any treatment with tofacitinib during screening
Any prior treatment with anti-adhesion molecules
Use of intravenous (IV) steroids within 30 days prior to screening with the exception of a single administration of IV steroid
Use of agents that deplete B or T cells
Use of anakinra, abatacept, cyclosporine, sirolimus, or mycophenolate mofetil (MMF) within 4 weeks prior to randomization
Chronic nonsteroidal anti-inflammatory drug (NSAID) use
Patients who are currently using anticoagulants including, but not limited to, warfarin, heparin, enoxaparin, dabigatran, apixaban, rivaroxaban
Patients who have received treatment with corticosteroid enemas/suppositories and/or topical (rectal) 5-ASA preparations within 2 weeks prior to randomization
Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to randomization
Received any investigational treatment including investigational vaccines within 5 half lives of the investigational product or 28 days after the last dose, whichever is greater, prior to randomization
History of moderate or severe allergic or anaphylactic/anaphylactoid reactions to chimeric, human, or humanized antibodies, fusion proteins, or murine proteins or hypersensitivity to etrolizumab (active drug substance) or any of the excipients (L histidine, L-arginine, succinic acid, polysorbate 20)
Patients administered tube feeding, defined formula diets, or parenteral alimentation/nutrition who have not discontinued these treatments within 3 weeks prior to randomization
Pregnant or lactating
Lack of peripheral venous access
Hospitalization (other than for elective reasons) during the screening period
Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart failure New York Heart Association Class III/IV), pulmonary, renal, hepatic, endocrine, or gastrointestinal disorders
Neurological conditions or diseases that may interfere with monitoring for PML
History of demyelinating disease
Clinically significant abnormalities on screening neurologic examination (PML Objective Checklist)
Clinically significant abnormalities on the screening PML Subjective Checklist
History of alcohol, drug, or chemical abuse less than 6 months prior to screening
Conditions other than UC that could require treatment with \>10 mg/day of prednisone (or equivalent) during the course of the study
History of cancer, including hematologic malignancy, solid tumors, and carcinoma in situ, within 5 years before screening
Congenital or acquired immune deficiency
Patients must undergo screening for HIV and test positive for preliminary and confirmatory tests
Positive hepatitis C virus (HCV) antibody test result
Positive hepatitis B virus (HBV) antibody test result
Evidence of or treatment for Clostridium difficile (as assessed by C. difficile toxin testing) within 60 days prior to randomization or other intestinal pathogens (as assessed by stool culture and ova and parasite evaluation) within 30 days prior to randomization
Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis (based on the investigator's judgment) within 60 days prior to randomization
History of active or latent TB
History of recurrent opportunistic infections and/or history of severe disseminated viral infections
Any serious opportunistic infection within the last 6 months prior to screening
Any current or recent signs or symptoms (within 4 weeks before screening and during screening) of infection
Any major episode of infection requiring treatment with IV antibiotics within 8 weeks prior to screening or oral antibiotics within 4 weeks prior to screening
Received a live attenuated vaccine within 4 weeks prior to randomization
History of organ transplant
Serum creatinine \>2 x upper limit of normal (ULN)
ALT or AST \>3 x ULN or alkaline phosphatase \>3 x ULN or total bilirubin \>2.5 x ULN
Platelet count \<100,000/uL
Hemoglobin \<8 g/dL
Absolute neutrophil count \<1500/uL
Absolute lymphocyte count \<500/uL

Intervenciones

drug

Adalimumab

Adalimumab 160 milligrams (mg) will be administered subcutaneously (SC) at Week 0; 80 mg SC at Week 2; 40 mg SC at Weeks 4, 6 and 8.

other

Adalimumab Placebo

Placebo matching to adalimumab will be administered SC at Weeks 0, 2, 4, 6, and 8.

drug

Etrolizumab

Etrolizumab 105 mg will be administered SC every 4 weeks (Q4W) up to Week 12 (at Weeks 0 \[Day 1\], 4, 8, and 12 \[clinical remitters only\]).

other

Etrolizumab Placebo

Placebo matching to etrolizumab will be administered SC once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 \[Day 1\], 4, 8, and 12 \[clinical remitters only\]).